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|PGQEHPNARK YKGANKKGLS KGCFGLKLDR IGSMSGLGC|
(Disulfide bridge: 23-39)
1480724-61-5[RN]BMN 111L-Cysteine, L-prolylglycyl-L-glutaminyl-L-α-glutamyl-L-histidyl-L-prolyl-L-asparaginyl-L-alanyl-L-arginyl-L-lysyl-L-tyrosyl-L-lysylglycyl-L-alanyl-L-asparaginyl-L-lysyl-L-lysylglycyl-L-leucyl-L-seryl-L-lysylglycyl-L-cysteinyl-L-phenylalanylglycyl-L-leucyl-L-lysyl-L-leucyl-L-α-aspartyl-L-arginyl-L-isoleucylglycyl-L-seryl-L-methionyl-L-serylglycyl-L-leucylglycyl-, cyclic (23→39)-disulfideL-prolylglycyl-(human C-type natriuretic peptide-(17-53)-peptide (CNP-37)), cyclic-(23-39)-disulfideUNII:7SE5582Q2Pвосоритид [Russian] [INN]فوسوريتيد [Arabic] [INN]伏索利肽 [Chinese] [INN]
Voxzogo, 2021/8/26 EU APPROVED
|Agency product number||EMEA/H/C/005475|
|International non-proprietary name (INN) or common name||vosoritide|
|Therapeutic area (MeSH)||Achondroplasia|
|Anatomical therapeutic chemical (ATC) code||M05BX|
|Orphan||This medicine was designated an orphan medicine. This means that it was developed for use against a rare, life-threatening or chronically debilitating condition or, for economic reasons, it would be unlikely to have been developed without incentives. For more information, see Orphan designation.|
|Marketing-authorisation holder||BioMarin International Limited|
|Date of issue of marketing authorisation valid throughout the European Union||26/08/2021|
On 24 January 2013, orphan designation (EU/3/12/1094) was granted by the European Commission to BioMarin Europe Ltd, United Kingdom, for modified recombinant human C-type natriuretic peptide for the treatment of achondroplasia.
The sponsorship was transferred to BioMarin International Limited, Ireland, in February 2019.
This medicine is now known as Vosoritide.
The medicinal product has been authorised in the EU as Voxzogo since 26 August 2021.
|Treatment of Achondroplasia|
modified recombinant human C-type natriuretic peptide (CNP)
The most common side effects include injection site reactions (such as swelling, redness, itching or pain), vomiting and decreased blood pressure.
Voxzogo is a medicine for treating achondroplasia in patients aged 2 years and older whose bones are still growing.
Achondroplasia is an inherited disease caused by a mutation (change) in a gene called fibroblast growth-factor receptor 3 (FGFR3). The mutation affects growth of almost all bones in the body including the skull, spine, arms and legs resulting in very short stature with a characteristic appearance.
Achondroplasia is rare, and Voxzogo was designated an ‘orphan medicine’ (a medicine used in rare diseases) on 24 January 2013. Further information on the orphan designation can be found here: ema.europa.eu/medicines/human/orphan-designations/EU3121094.
Voxzogo contains the active substance vosoritide.
Vosoritide is indicated for the treatment of achondroplasia in people two years of age and older whose epiphyses are not closed.
Mechanism of action
A: Chondrocyte with constitutionally active FGFR3 that down-regulates its development via the MAPK/ERK pathway
B: Vosoritide (BMN 111) blocks this mechanism by binding to the atrial natriuretic peptide receptor B (NPR-B), which subsequently inhibits the MAPK/ERK pathway at the RAF-1 protein.
Vosoritide works by binding to a receptor (target) called natriuretic peptide receptor type B (NPR-B), which reduces the activity of fibroblast growth factor receptor 3 (FGFR3). FGFR3 is a receptor that normally down-regulates cartilage and bone growth when activated by one of the proteins known as acidic and basic fibroblast growth factor. It does so by inhibiting the development (cell proliferation and differentiation) of chondrocytes, the cells that produce and maintain the cartilaginous matrix which is also necessary for bone growth. Children with achondroplasia have one of several possible FGFR3 mutations resulting in constitutive (permanent) activity of this receptor, resulting in overall reduced chondrocyte activity and thus bone growth.
The protein C-type natriuretic peptide (CNP), naturally found in humans, reduces the effects of over-active FGFR3. Vosoritide is a CNP analogue with the same effect but prolonged half-life, allowing for once-daily administration.
Vosoritide is an analogue of CNP. It is a peptide consisting of the amino acids proline and glycine plus the 37 C-terminal amino acids from natural human CNP. The complete peptide sequence isPGQEHPNARKYKGANKKGLS KGCFGLKLDR IGSMSGLGC
Vosoritide is being developed by BioMarin Pharmaceutical and, being the only available causal treatment for this condition, has orphan drug status in the US as well as the European Union. As of September 2015, it is in Phase II clinical trials.
Society and culture
Some people with achondroplasia, as well as parents of children with this condition, have reacted to vosoritide’s study results by saying that dwarfism is not a disease and consequently does not need treatment.
Vosoritide has resulted in increased growth in a clinical trial with 26 children. The ten children receiving the highest dose grew 6.1 centimetres (2.4 in) in six months, compared to 4.0 centimetres (1.6 in) in the six months before the treatment (p=0.01). The body proportions, more specifically the ratio of leg length to upper body length – which is lower in achondroplasia patients than in the average population – was not improved by vosoritide, but not worsened either.
As of September 2015, it is not known whether the effect of the drug will last long enough to result in normal body heights, or whether it will reduce the occurrence of achondroplasia associated problems such as ear infections, sleep apnea or hydrocephalus. This, together with the safety of higher doses, is to be determined in further studies.
- ^ Jump up to:a b c d e f g “Voxzogo EPAR”. European Medicines Agency. 23 June 2021. Retrieved 9 September 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
- ^ Jump up to:a b “European Commission Approves BioMarin’s Voxzogo (vosoritide) for the Treatment of Children with Achondroplasia from Age 2 Until Growth Plates Close”. BioMarin Pharmaceutical Inc. (Press release). 27 August 2021. Retrieved 9 September 2021.
- ^ Jump up to:a b c Lorget F, Kaci N, Peng J, Benoist-Lasselin C, Mugniery E, Oppeneer T, et al. (December 2012). “Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia”. American Journal of Human Genetics. 91 (6): 1108–14. doi:10.1016/j.ajhg.2012.10.014. PMC 3516592. PMID 23200862.
- ^ Jump up to:a b c Clinical trial number NCT02055157 for “A Phase 2 Study of BMN 111 to Evaluate Safety, Tolerability, and Efficacy in Children With Achondroplasia (ACH)” at ClinicalTrials.gov
- ^ “International Nonproprietary Names for Pharmaceutical Substances (INN): List 112” (PDF). WHO Drug Information. 28 (4): 539. 2014.
- ^ “Food and Drug Administration Accepts BioMarin’s New Drug Application for Vosoritide to Treat Children with Achondroplasia” (Press release). BioMarin Pharmaceutical. 2 November 2020. Retrieved 9 September 2021 – via PR Newswire.
- ^ Jump up to:a b Spreitzer H (6 July 2015). “Neue Wirkstoffe – Vosoritid”. Österreichische Apothekerzeitung (in German) (14/2015): 28.
- ^ Pollack A (17 June 2015). “Drug Accelerated Growth in Children With Dwarfism, Pharmaceutical Firm Says”. The New York Times.
- ^ “BMN 111 (vosoritide) Improves Growth Velocity in Children With Achondroplasia in Phase 2 Study”. BioMarin. 17 June 2015.
- ^ Jump up to:a b “Vosoritid” (in German). Arznei-News.de. 20 June 2015.
- “Vosoritide”. Drug Information Portal. U.S. National Library of Medicine.
|Legal status||EU: Rx-only |
|Chemical and physical data|
|Molar mass||4102.78 g·mol−1|
|3D model (JSmol)||Interactive image|
NEW DRUG APPROVALS
ONE TIME TO MAINTAIN THIS BLOG
Ferric pyrophosphate citrate
tetrairon(3+) bis((phosphonooxy)phosphonic acid) tris(2-hydroxypropane-1,2,3-tricarboxylate) (hydrogen phosphonooxy)phosphonate
Iron(3+) diphosphate (4:3)
Proper name: ferric pyrophosphate citrate Chemical names: Iron (3+) cation; 2-oxidopropane-1,2,3-tricarboxylate; diphosphate 1,2,3-propanetricarboxylic acid, 2-hydroxy-, iron (3+), diphosphate Molecular formula: [Fe4 3+(C6H5O7)3(P2O7)3] Molecular mass: 1313
Physicochemical properties: TRIFERIC AVNU (ferric pyrophosphate citrate) contains no asymmetric centers. Ferric pyrophosphate citrate is a yellow to green amorphous powder. The drug substance does not melt, or change state, below 300 °C. Thermal decomposition was observed at 263 ± 3ºC. Ferric pyrophosphate citrate is freely soluble in water (>100 g/L). Ferric pyrophosphate citrate is completely insoluble in most organic solvents (MeOH, Acetone, THF, DMF, DMSO). A 5% solution in water exhibits a solution pH of about 6. … https://pdf.hres.ca/dpd_pm/00060816.PDF
- Ferric pyrophosphate citrate
- Tetraferric nonahydrogen citrate pyrophosphate
Summary Basis of Decision – Triferic AVNU – Health Canada
Date SBD issued:2021-07-29
The following information relates to the new drug submission for Triferic AVNU.
Iron (supplied as ferric pyrophosphate citrate)
Drug Identification Number (DIN):
DIN 02515334 – 1.5 mg/mL iron (supplied as ferric pyrophosphate citrate), solution, intravenous administration
Rockwell Medical Inc.
New Drug Submission Control Number: 239850
On April 22, 2021, Health Canada issued a Notice of Compliance to Rockwell Medical Inc. for the drug product Triferic AVNU.
The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit-harm-uncertainty profile of Triferic AVNU is favourable for the replacement of iron to maintain hemoglobin in adult patients with hemodialysis-dependent chronic kidney disease (CKD-HD). Triferic AVNU is not intended for use in patients receiving peritoneal dialysis and has not been studied in patients receiving home hemodialysis.
Triferic AVNU, an iron preparation, was authorized for the replacement of iron to maintain hemoglobin in adult patients with hemodialysis-dependent chronic kidney disease (CKD-HD). Triferic AVNU is not intended for use in patients receiving peritoneal dialysis and has not been studied in patients receiving home hemodialysis.
Triferic AVNU is not authorized for use in pediatric patients (<18 years of age), as its safety and effectiveness have not been established in this population. No overall differences in efficacy or safety were observed in geriatric patients (≥65 years of age) compared to younger patients in clinical trials.
Triferic AVNU is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation, or component of the container.
Triferic AVNU was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Triferic AVNU (1.5 mg/mL iron [supplied as ferric pyrophosphate citrate]) is presented as a solution. In addition to the medicinal ingredient, the solution contains water for injection.
Additional information may be found in the Triferic AVNU Product Monograph, approved by Health Canada and available through the Drug Product Database.
Health Canada considers that the benefit-harm-uncertainty profile of Triferic AVNU is favourable for the replacement of iron to maintain hemoglobin in adult patients with hemodialysis-dependent chronic kidney disease (CKD-HD). Triferic AVNU is not intended for use in patients receiving peritoneal dialysis and has not been studied in patients receiving home hemodialysis.
Chronic kidney disease (CKD) is a worldwide public health concern. One of the most common comorbidities of CKD-HD patients is anemia, which may be due to low body iron stores (as a result of blood loss during dialysis) and impaired utilization of iron. Consequently, there is an ongoing need to replenish body iron in CKD-HD patients.
Iron deficiency anemia in CKD-HD patients is generally treated using parenteral (intravenous) iron administration used in conjunction with erythropoiesis stimulating agents (ESAs). Intravenous administration is preferred, as oral iron is not well absorbed and gastrointestinal intolerance is common. At the time of authorization of Triferic AVNU, there were four other intravenous iron products marketed in Canada: Dexiron, an iron dextran (≥1,000 mg/dose); Ferrlecit (sodium ferric gluconate; 125 mg/dose); Venofer (iron sucrose; 200 mg/dose); and the more recently approved Monoferric (Iron Isomaltoside 1,000; up to 500 mg/bolus injection and up to 1,500 mg/infusion). Each of these intravenous iron products are indicated for the treatment of iron deficiency anemia and are associated with safety concerns for hypersensitivity reactions. Serious hypersensitivity reactions have been reported, including life threatening and fatal anaphylactic/anaphylactoid reactions.
Triferic AVNU is an iron replacement product delivered via intravenous infusion into the blood lines pre- and post-dialyzer in CKD-HD patients at each hemodialysis treatment. It is a preservative-free sterile solution containing 1.5 mg elemental iron/mL in water for injection.
Triferic AVNU has been shown to be efficacious in maintaining hemoglobin (Hb) during the treatment period in CKD-HD patients. The market authorization was primarily based on the results of two pivotal, randomized, placebo-controlled, single blind, Phase III clinical studies (Studies SFP-4 and SFP-5). Both studies were identical in design and enrolled a combined total of 599 adult patients with CKD-HD who were iron-replete. Patients were randomized to receive either Triferic AVNU added to bicarbonate concentrate with a final concentration of 110 μg of iron/L in dialysate or placebo (standard dialysate) administered 3 to 4 times per week during hemodialysis. All patients were to remain randomized in their treatment group until pre-specified Hb or ferritin criteria were met, indicating the need for a change in anemia management, or until they had completed 48 weeks of treatment. After randomization, patients’ ESA product, doses, or route of administration were not to be changed and oral or intravenous iron administration were not allowed.
The primary efficacy endpoint (mean change in Hb level from baseline to the end-of-treatment period) was met in both pivotal studies. In Study SFP-4, the mean Hb decreased 0.04 g/dL in the Triferic AVNU group compared to 0.39 g/dL in the placebo group. In Study SFP-5, the mean Hb decreased 0.09 g/dL in the Triferic AVNU group compared to 0.45 g/dL in the placebo group. In both studies, the treatment difference in mean hemoglobin change was 0.36 g/dL (p = 0.011) between the Triferic AVNU and the placebo groups. This value was statistically significant for both studies. The treatment difference of 0.35 g/dL was also statistically significant (p = 0.010) for both studies in the analysis using the intent-to-treat population. A high proportion of patients did not complete the planned 48 weeks of study treatment mainly due to protocol-mandated changes in anemia management (ESA dose changes). However, the proportion was similar for both arms and the analysis of Hb change in this subgroup was consistent with that of the primary efficacy analysis. Secondary endpoints which included changes in reticulocyte Hb content, serum ferritin, and pre-dialysis serum iron panel to the end of treatment, were consistent with the primary efficacy results.
The safety of Triferic AVNU was evaluated in seven controlled and uncontrolled Phase II/III studies, which included the two pivotal studies. In total, 1,411 CKD-HD patients were exposed to Triferic AVNU in the clinical program. In the pivotal studies, 78% of patients in the Triferic AVNU group and 75% of patients in the placebo group had at least one treatment-emergent adverse event (TEAE). The most common TEAEs in the Triferic AVNU group (which were higher than the placebo group) were procedural hypotension (21.6%), muscle spasms (9.6%), headache (9.2%), pain in extremity (6.8%), edema peripheral (6.8%) and dyspnoea (5.8%). Serious TEAEs were reported at similar rates for the two groups at 27.7% for the Triferic AVNU group and 27.4% for the placebo group. The most common serious TEAEs occurring in the Triferic AVNU group (which were higher than the placebo group) were cardiac arrest (1.7%), arteriovenous fistula thrombosis (1.7%), and pulmonary edema (1.4%). Few patients discontinued study treatment due to TEAEs (4.5% in the Triferic AVNU group and 2.4% in the placebo group).
In the overall clinical program, there were two cases (0.1%) of hypersensitivity reactions related to treatment out of the 1,411 patients treated with Triferic AVNU. There were no cases of serious hypersensitivity reaction and no cases of anaphylaxis related to Triferic AVNU treatment. A Serious Warnings and Precautions box describing a warning for hypersensitivity reaction has been included in the Product Monograph for Triferic AVNU.
A Risk Management Plan (RMP) for Triferic AVNU was submitted by Rockwell Medical Inc. to Health Canada. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product. In the RMP, the sponsor included ‘hypersensitivity reactions’ as an important identified risk; ‘systemic/serious infections’ as an important potential risk; and ‘use in pregnant and breastfeeding women’, ‘use in children’ and ‘concomitant use with other intravenous iron product’ as missing information. Labelling for these safety concerns has been included in the Product Monograph and the sponsor has committed to systemically review clinical and post-marketing safety data as part of routine pharmacovigilance activities. Upon review, the RMP was considered to be acceptable.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Triferic AVNU Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.
A review of the submitted brand name assessment, including testing for look-alike sound-alike attributes, was conducted and the proposed name Triferic AVNU was accepted.
Overall, the therapeutic benefits of Triferic AVNU therapy seen in the pivotal studies are positive and are considered to outweigh the potential risks. Triferic AVNU has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Triferic AVNU Product Monograph to address the identified safety concerns.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
The Chemistry and Manufacturing information submitted for Triferic AVNU has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 36 months is acceptable when the drug product is stored protected from light in the aluminum pouch at room temperature (15 ºC to 30 ºC).
Proposed limits of drug-related impurities are considered adequately qualified (i.e. within International Council for Harmonisation [ICH] limits and/or qualified from toxicological studies).
All sites involved in production are compliant with Good Manufacturing Practices.
None of the excipients used in the formulation of Triferic AVNU are of human or animal origin. All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.
Product Monograph/Veterinary Labelling:
Date: 2021-04-21 Product monograph/Veterinary Labelling (PDF version ~ 175K)
ROCKWELL MEDICAL INC
30142 S Wixom Rd
United States 48393
Route(s) of administration:
Number of active ingredient(s):
Biosimilar Biologic Drug:
American Hospital Formulary Service (AHFS):See footnote3
20:04.04 IRON PREPARATIONS
Anatomical Therapeutic Chemical (ATC):See footnote4
B03AC IRON, PARENTERAL PREPARATIONS
Active ingredient group (AIG) number:See footnote5
|IRON (FERRIC PYROPHOSPHATE CITRATE)||1.5 MG / ML|
(ferric pyrophosphate citrate) Solution, for Hemodialysis Use
(ferric pyrophosphate citrate) powder packet for hemodialysis use
Triferic (ferric pyrophosphate citrate) solution, an iron replacement product, is a mixed-ligand iron complex in which iron (III) is bound to pyrophosphate and citrate. It has a molecular formula of Fe4(C6H4O7)3(H2P2O7)2(P2O7) and a relative molecular weight of approximately 1313 daltons. Ferric pyrophosphate citrate has the following structure:
Triferic (ferric pyrophosphate citrate) solution–is a clear, slightly yellow-green color sterile solution containing 27.2 mg of elemental iron (III) per 5 mL (5.44 mg iron (III) per mL) filled in a 5 mL or 272 mg of elemental iron (III) per 50 mL (5.44 mg iron (III) per mL) filled in a 50 Ml low density polyethylene (LDPE) ampule. Each Triferic ampule contains iron (7.5-9.0% w/w), citrate (15-22% w/w), pyrophosphate (15-22% w/w), phosphate (< 2% w/w), sodium (18-25% w/w) and sulfate (20-35%). One Triferic 5 mL ampule is added to 2.5 gallons (9.46 L) of bicarbonate concentrate. One Triferic 50 mL ampule is added to 25 gallons (94.6 L) of master bicarbonate mix.
Triferic Powder Packets
Triferic (ferric pyrophosphate citrate) powder is a slightly yellow-green powder, packaged in single use paper, polyethylene and aluminum foil packets, each containing 272.0 mg of elemental iron (III). Each Triferic packet contains iron (7.5-9.0% w/w), citrate (15-22% w/w), pyrophosphate (15-22% w/w), phosphate (< 2% w/w), sodium (18-25% w/w) and sulfate (20- 35%). One Triferic powder packet is added to 25 (94.6 L) gallons of master bicarbonate mix.
Ferric pyrophosphate citrate (FPC), a novel iron-replacement agent, was approved by the US Food and Drug Administration in January 2015 for use in adult patients receiving chronic hemodialysis (HD). This iron product is administered to patients on HD via the dialysate.
Ferric pyrophosphate citrate is a soluble iron replacement product. Free iron presents several side effects as it can catalyze free radical formation and lipid peroxidation as well as the presence of interactions of iron in plasma. The ferric ion is strongly complexed by pyrophosphate and citrate.1 FPC is categorized in Japan as a second class OTC drug.6 This category is given to drugs with ingredients that in rare cases may cause health problems requiring hospitalization or worst.7 It is also FDA approved since 2015.Label
Iron(III) pyrophosphate is an inorganic chemical compound with the formula Fe4(P2O7)3.
Anhydrous iron(III) pyrophosphate can be prepared by heating the mixture of iron(III) metaphosphate and iron(III) phosphate under oxygen with the stoichiometric ratio 1:3. The reactants can be prepared by reacting iron(III) nitrate nonahydrate with phosphoric acid.
It can be also prepared via the following reaction:3 Na4P2O7(aq) + 4 FeCl3(aq) → Fe4(P2O7)3(s) + 12 NaCl(aq)
- ^ W.M.Haynes. CRC Handbook of Chemistry and Physics (97th edition). New York: CRC Press, 2016. pp 4-68
- ^ Elbouaanani, L.K; Malaman, B; Gérardin, R; Ijjaali, M (2002). “Crystal Structure Refinement and Magnetic Properties of Fe4(P2O7)3 Studied by Neutron Diffraction and Mössbauer Techniques”. Journal of Solid State Chemistry. Elsevier BV. 163 (2): 412–420. doi:10.1006/jssc.2001.9415. ISSN 0022-4596.
- ^ Rossi L, Velikov KP, Philipse AP (May 2014). “Colloidal iron(III) pyrophosphate particles”. Food Chem. 151: 243–7. doi:10.1016/j.foodchem.2013.11.050. PMID 24423528.
- Gupta A, Amin NB, Besarab A, Vogel SE, Divine GW, Yee J, Anandan JV: Dialysate iron therapy: infusion of soluble ferric pyrophosphate via the dialysate during hemodialysis. Kidney Int. 1999 May;55(5):1891-8. doi: 10.1046/j.1523-1755.1999.00436.x. [Article]
- Naigamwalla DZ, Webb JA, Giger U: Iron deficiency anemia. Can Vet J. 2012 Mar;53(3):250-6. [Article]
- Fidler MC, Walczyk T, Davidsson L, Zeder C, Sakaguchi N, Juneja LR, Hurrell RF: A micronised, dispersible ferric pyrophosphate with high relative bioavailability in man. Br J Nutr. 2004 Jan;91(1):107-12. [Article]
- Pratt RD, Swinkels DW, Ikizler TA, Gupta A: Pharmacokinetics of Ferric Pyrophosphate Citrate, a Novel Iron Salt, Administered Intravenously to Healthy Volunteers. J Clin Pharmacol. 2017 Mar;57(3):312-320. doi: 10.1002/jcph.819. Epub 2016 Oct 3. [Article]
- Underwood E. (1977). Trace elements in human and animal nutrition (4th ed.). Academic press.
- KEGG [Link]
- Nippon [Link]
- FDA Reports [Link]
|Other namesFerric pyrophosphate|
|CAS Number||10058-44-3 (anhydrous) 10049-18-0 (nonahydrate)|
|3D model (JSmol)||Interactive image|
|UNII||QK8899250F 1ZJR117WBQ (nonahydrate)|
|CompTox Dashboard (EPA)||DTXSID6047600|
|Molar mass||745.224 (anhydrate)|
|Appearance||yellow solid (nonahydrate)|
|Solubility in water||insoluble|
|Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).|
Iron deficiency is a significant health problem across the world. While many patients benefit from oral iron supplements, some, including those on hemodialysis require intravenous iron therapy to maintain adequate iron levels. Until recently, all iron compounds suitable for parenteral administration were colloidal iron–carbohydrate conjugates that require uptake and processing by macrophages. These compounds are associated with variable risk of anaphylaxis, oxidative stress, and inflammation, depending on their physicochemical characteristics. Ferric pyrophosphate citrate (FPC) is a novel iron compound that was approved for parenteral administration by US Food and Drug Administration in 2015. Here we report the physicochemical characteristics of FPC. FPC is a noncolloidal, highly water soluble, complex iron salt that does not contain a carbohydrate moiety. X-ray absorption spectroscopy data indicate that FPC consists of iron (III) complexed with one pyrophosphate and two citrate molecules in the solid state. This structure is preserved in solution and stable for several months, rendering it suitable for pharmaceutical applications in solid or solution state.
Iron deficiency with or without associated anemia represents a significant health problem worldwide. While many patients can restore iron levels with the use of oral iron supplements, oral supplementation is not suitable in some patients, including those undergoing chronic hemodialysis for chronic kidney disease (CKD) (Fudin et al. 1998; Macdougall et al. 1996; Markowitz et al. 1997). The limitations of oral iron replacement in patients undergoing hemodialysis likely arise from excessive ongoing losses and insufficient absorption, thus intravenous (IV) iron has become the primary route of administration in such patients (Shah et al. 2016). Multiple IV iron formulations are available, including iron dextran, iron sucrose, sodium ferric gluconate, iron carboxymaltose, ferrumoxytol, and iron isomaltoside (Macdougall et al. 1996). All such formulations are iron–carbohydrate macromolecular complexes, and the majority consist of an iron oxide core surrounded by a carbohydrate moiety (Macdougall et al. 1996; Markowitz et al. 1997).
Intravenous iron products have been used extensively for over 30 years for the treatment of iron-deficiency anemia and to maintain iron balance in hemodialysis patients since these patients have obligatory excessive losses. While these agents are generally well tolerated, they have been associated with risk of anaphylaxis (Wang et al. 2015). Compared to oral iron agents, there may be an increased risk of cardiovascular complications and infections in nondialysis patients with CKD (Macdougall et al. 1996). Additionally, higher mortality rates have been reported with use of high-dose IV iron in hemodialysis patients (Bailie et al. 2015).
Iron possesses oxidizing properties that may cause injury to cells and tissues (Koskenkorva-Frank et al. 2013; Vaziri 2013). Iron loading in general is associated with endocrinological, gastrointestinal, infectious, neoplastic, neurodegenerative, obstetric, ophthalmic, orthopedic, pulmonary, and vascular complications. In addition, excessive or misplaced tissue iron also can contribute to aging and mortality (Weinberg 2010). Normally, the body is able to protect tissues from the damaging effects of iron by regulating iron absorption in the intestine and sequestering iron with iron-binding proteins. However, the concentrations of iron introduced into the bloodstream with IV iron therapy can be as much as 100 times more than that absorbed normally through the intestine. Combined with the fact that IV iron is administered over a period of minutes compared to the slow, regulated absorption in the gut, it is possible that the increased iron load may damage cells and tissues.
A novel parenteral iron formulation, ferric pyrophosphate citrate (FPC), potentially offers a more physiologic delivery of iron. Unlike previous forms of IV iron, FPC contains no carbohydrate shell. Soluble ferric pyrophosphate-citrate complexes, generally referred to as soluble ferric pyrophosphate (SFP) were first described in the mid-1800s by Robiquet and Chapman (Chapman 1862; Robiquet 1857). This class of food-grade iron salts has been available for over 100 years as oral iron supplements and for fortification of food. In the late-1990s, Gupta et al. demonstrated that food-grade SFP could be administered to hemodialysis patients via the dialysate (Gupta et al. 1999). However, the commercially available compounds are poorly characterized and not suitable for further development as a parenteral iron supplement. Therefore, a pharmaceutical-grade SFP was developed. This product had a higher solubility than food-grade SFP and was granted a new USAN name—FPC. In 2015 FPC was approved by the US Food and Drug Administration (FDA) for parenteral delivery by hemodialysis to replace iron losses and thereby maintain hemoglobin levels in hemodialysis-dependent patients with CKD (Rockwell Medical Inc 2018). FPC is currently marketed under the trade name Triferic® (Rockwell Medical Inc., Wixom, Michigan, USA). FPC is the first carbohydrate-free, noncolloidal, water-soluble iron salt suitable for parenteral administration.
Infrared (IR) spectroscopy was used to determine the main functional groups present in FPC. Figure 1 shows a representative IR spectrum of FPC. Peak assignments and positions for FPC as well as for sodium citrate, sodium pyrophosphate, and ferric sulfate, which were used to confirm the peak assignments, are shown in Table 1.
X-ray spectra of solid and aqueous iron standards and FPC. a XANES spectra of iron (II) and iron (III) standards as well as FPC in the solid and solution phases show that FPC consists exclusively of iron (III) and that the solid-phase structure is maintained in solution. b EXFAS modeling of FPC in the solid phase (top) and in solution (bottom) at Day 1 and Month 4
Chemical composition of ferric pyrophosphate citrate
https://patents.google.com/patent/WO2017040937A1/enProperties of Conventional SFP
Another example of SFP is the composition is the chelate composition described in US Patent Nos. 7,816,404 and 8,178,709. The SFP may be a ferric pyrophosphate citrate (FPC) comprising a mixed-ligand iron compound comprising iron chelated with citrate andpyrophosphate, optionally FPC has the following formula: Fe4(C6H407)3(H2P207)2(P207) (relative MW 1313 daltons), e.g., structure (I):
 An exemplary SFP according to the present disclosure is known to have the properties described in Table 3.Table 3 – Properties of SFP according to the present disclosure
NEW DRUG APPROVALS
////////////ferric pyrophosphate citrate, Triferic AVNU, , Ferric pyrophosphate citrate, FPC, SFP, Tetraferric nonahydrogen citrate pyrophosphate, Triferic, FDA 2015, APPROVALS 2021, CANADA 2021, hemodialysis-dependent chronic kidney disease
- Molecular FormulaC15H30N2O5
- Average mass318.409 Da
AUSTRALIA APPROVAL 2021
Evaluation commenced: 30 Sep 2020
Registration decision: 6 Jul 2021
Date registered: 14 Jul 2021
Approval time: 166 (175 working days)
BioMarin Pharmaceutical Australia Pty Ltd
PALYNZIQ (solution for injection, pre-filled syringe) is indicated for the treatment of patients with phenylketonuria (PKU) aged 16 years and older who have inadequate blood phenylalanine control despite prior management with available treatment options.
Pegvaliase, sold under the brand name Palynziq, is a medication for the treatment of the genetic disease phenylketonuria. Chemically, it is a pegylated derivative of the enzyme phenylalanine ammonia-lyase that metabolizes phenylalanine to reduce its blood levels.
Pegvaliase is a recombinant phenylalanine ammonia lyase (PAL) enzyme derived from Anabaena variabilis that converts phenylalanine to ammonia and trans-cinnamic acid. Both the U.S. Food and Drug Administration and European Medicines Agency approved pegvaliase-pqpz in May 2018 for the treatment of adult patients with phenylketonuria (PKU). Phenylketonuria is a rare autosomal recessive disorder that is characterized by deficiency of the enzyme phenylalanine hydroxylase (PAH) and affects about 1 in 10,000 to 15,000 people in the United States. PAH deficiency and inability to break down an amino acid phenylalanine (Phe) leads to elevated blood phenylalanine concentrations and accumulation of neurotoxic Phe in the brain, causing chronic intellectual, neurodevelopmental and psychiatric disabilities if untreated. Individuals with PKU also need to be under a strictly restricted diet as Phe is present in foods and products with high-intensity sweeteners. The primary goal of lifelong treatment of PKU, as recommended by the American College of Medical Genetics and Genomics (ACMG) guidelines, is to maintain blood Phe concentration in the range of 120 µmol/L to 3690 µmol/L. Pegvaliase-pqpz, or PEGylated pegvaliase, is used as a novel enzyme substitution therapy and is marketed as Palynziq for subcutanoues injection. It is advantageous over currently available management therapies for PKU, such as [DB00360], that are ineffective to many patients due to long-term adherence issues or inadequate Phe-lowering effects. The presence of a PEG moiety in pegvaliase-pqpz allows a reduced immune response and improved pharmacodynamic stability.
- ^ Jump up to:a b “Palynziq”. Therapeutic Goods Administration (TGA). 23 July 2021. Retrieved 5 September 2021.
- ^ Jump up to:a b “FDA approves a new treatment for PKU, a rare and serious genetic disease” (Press release). Food and Drug Administration. May 24, 2018.
- ^ Mahan KC, Gandhi MA, Anand S (April 2019). “Pegvaliase: a novel treatment option for adults with phenylketonuria”. Current Medical Research and Opinion. 35 (4): 647–651. doi:10.1080/03007995.2018.1528215. PMID 30247930.
- ^ “Palynziq”. BioMarin Pharmaceutica.
- ^ New Drug Therapy Approvals 2018 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2019. Retrieved 16 September 2020.
- “Pegvaliase”. Drug Information Portal. U.S. National Library of Medicine.
|Pronunciation||peg val’ i ase|
|Other names||Pegvaliase-pqpz; PEG-PAL; RAvPAL-PEG|
|License data||US DailyMed: Pegvaliase|
|ATC code||A16AB19 (WHO)|
|Legal status||AU: S4 (Prescription only) US: ℞-onlyEU: Rx-only|
|Chemical and physical data|
|Molar mass||318.414 g·mol−1|
|3D model (JSmol)||Interactive image|
////////////pegvaliase, PALYNZIQ, AUSTRALIA 2021, APPROVALS 2021, BioMarin, BMN 165, Palynziq, pegvaliase, pegvaliase-pqpz
NEW DRUG APPROVALS
- Molecular FormulaC30H53NO11
- Average mass603.742 Da
104-31-4[RN]2,5,8,11,14,17,20,23,26-Nonaoxaoctacosan-28-yl 4-(butylamino)benzoateбензонататبنزوناتات苯佐那酯ベンゾナテート;KM 652,5,8,11,14,17,20,23,26-nonaoxaoctacosan-28-yl 4-(butylamino)benzoate2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-(butylamino)benzoate
Benzonatate bulk and Benzonatate capsules 100mg, cdsco india 2021, 15.07.2021
For the treatment of refractory coughCAS Registry Number: 104-31-4CAS Name: 4-(Butylamino)benzoic acid 3,6,9,12,15,18,21,24,27-nonaoxaoctacos-1-yl esterAdditional Names: nonaethyleneglycol monomethyl ether p-n-butylaminobenzoate; p-butylaminobenzoic acid w-O-methylnonaethyleneglycol ester; benzononatineTrademarks: Exangit; Tessalon (Forest)Molecular Formula: C30H53NO11Molecular Weight: 603.74Percent Composition: C 59.68%, H 8.85%, N 2.32%, O 29.15%Literature References: Prepn: Matter, US2714608 (1955 to Ciba).Properties: Colorless to faintly yellow oil. Soluble in most organic solvents except aliphatic hydrocarbons.Therap-Cat: Antitussive.Keywords: Antitussive.
Matter, M.; U.S. Patent 2,714,608; August 2, 1955; assigned to Ciba Pharmaceutical Products, Inc.
Substances Referenced in Synthesis Path
|CAS-RN||Formula||Chemical Name||CAS Index Name|
|94-32-6||C13H19NO2||ethyl 4-butylaminobenzoate||Benzoic acid, 4-(butylamino)-, ethyl ester|
|6048-68-6||C19H40O10||nonaethylene glycol monomethyl ether||2,5,8,11,14,17,20,23,26-Nonaoxaoctacosan-28-ol|
Benzonatate, sold under the brand name Tessalon among others, is a medication used to try to help with the symptoms of cough and hiccups. It is taken by mouth. Use is not recommended in those under the age of ten. Effects generally begin within 20 minutes and last up to eight hours.
Side effects include sleepiness, dizziness, headache, upset stomach, skin rash, hallucinations, and allergic reactions. Excessive doses may cause seizures, irregular heartbeat, and death. Chewing or sucking on the capsule can lead to laryngospasm, bronchospasm, and circulatory collapse. It is unclear if use in pregnancy or breastfeeding is safe. It works by numbing stretch receptors in the lungs and suppressing the cough reflex in the brain.
Benzonatate was approved for medical use in the United States in 1958. It is available as a generic medication. It is not available in many countries. In 2018, it was the 113th most commonly prescribed medication in the United States, with more than 6 million prescriptions.
100mg generic benzonatate capsules
Benzonatate is a prescription non-opioid alternative for the symptomatic relief of cough. It has been shown to improve cough associated with a variety of respiratory conditions including asthma, bronchitis, pneumonia, tuberculosis, pneumothorax, opiate-resistant cough in lung cancer, and emphysema.
Benzonatate does not treat the underlying cause of the cough.
Benzonatate has been shown to have use in the suppression of hiccups.
Benzonatate acts as a local anesthetic and the liquid inside the capsule can be applied in the mouth to numb the oropharynx for awake intubation. However, there can be life-threatening adverse effects when the medication is absorbed by the oral mucosa, including choking, hypersensitivity reactions, and circulatory collapse.
Hypersensitivity to benzonatate or any related compounds is a contraindication to its administration.
- Constipation, dizziness, fatigue, stuffy nose, nausea, headache are frequently reported.
- Sedation, a feeling of numbness in the chest, sensation of burning in the eyes, a vague “chilly” sensation, itchiness, and rashes are also possible.
- Ingestion of a small handful of capsules has caused seizures, cardiac arrhythmia, and death in adults.
Benzonatate is structurally related to anesthetic medications of the para-aminobenzoic acid (PABA) class which includes procaine and tetracaine. Procaine and tetracaine, previously used heavily in the fields of dentistry and anesthesiology, have fallen out of favor due to allergies associated with their metabolites. Similarly, severe hypersensitivity reactions to benzonatate have been reported and include symptoms of laryngospasm, bronchospasm, and cardiovascular collapse. These reactions are possibly associated with chewing, sucking, or crushing the capsule in the mouth.
Benzonatate should be swallowed whole. Crushing or sucking on the liquid-filled capsule, or “softgel,” will cause release of benzonatate from the capsule and can produce a temporary local anesthesia of the oral mucosa. Rapid development of numbness of the tongue and choking can occur. In severe cases, excessive absorption can lead to laryngospasm, bronchospasm, seizures, and circulatory collapse. This may be due to a hypersensitivity reaction to benzonatate or a systemic local anesthetic toxicity, both of which have similar symptoms. There is a potential for these adverse effects to occur at a therapeutic dose, that is, a single capsule, if chewed or sucked on in the mouth.
Isolated cases of bizarre behavior, mental confusion, and visual hallucinations have been reported during concurrent use with other prescribed medications. Central nervous system effects associated with other para-aminobenozic acid (PABA) derivative local anesthetics, for example procaine or tetracaine, could occur with benzonatate and should be considered.
Safety and efficacy in children below the age of 10 have not been established. Accidental ingestion resulting in death has been reported in children below the age of 10. Benzonatate may be attractive to children due to its appearance, a round-shaped liquid-filled gelatin capsule, which looks like candy. Chewing or sucking of a single capsule can cause death of a small child. Signs and symptoms can occur rapidly after ingestion (within 15–20 minutes) and include restlessness, tremors, convulsions, coma, and cardiac arrest. Death has been reported within one hour of ingestion.
Pregnancy and breast feeding
In the U.S., benzonatate is classified by the U.S. Food and Drug Administration (FDA) as pregnancy category C. It is not known if benzonatate can cause fetal harm to a pregnant woman or if it can affect reproduction capacity. Animal reproductive studies have not yet been conducted with benzonatate to evaluate its teratogenicity. Benzonatate should only be given to a pregnant woman if it is clearly needed.
Benzonatate overdose is characterized by symptoms of restlessness, tremors, seizures, abnormal heart rhythms (cardiac arrhythmia), cerebral edema, absent breathing (apnea), fast heart beat (tachycardia), and in severe cases, coma and death. Symptoms develop rapidly, typically within 1 hour of ingestion. Treatment focuses on removal of gastric contents and on managing symptoms of sedation, convulsions, apnea, and cardiac arrhythmia.
Despite a long history of safe and appropriate usage, the safety margin of benzonatate is reportedly narrow. Toxicity above the therapeutic dose is relatively low and ingestion of a small handful of pills can cause symptoms of overdose. Children are at an increased risk for toxicity, which have occurred with administration of only one or two capsules.
Due to increasing usage of benzonatate and rapid onset of symptoms, there are accumulating cases of benzonatate overdose deaths, especially in children.
Mechanism of action
Similar to other local anesthetics, benzonatate is a potent voltage-gated sodium channel inhibitor. After absorption and circulation to the respiratory tract, benzonatate acts as a local anesthetic, decreasing the sensitivity of vagal afferent fibers and stretch receptors in the bronchi, alveoli, and pleura in the lower airway and lung. This dampens their activity and reduces the cough reflex. Benzonatate also has central antitussive activity on the cough center in central nervous system at the level of the medulla. However, there is minimal inhibition of the respiratory center at a therapeutic dosage.
Benzonatate is hydrolyzed by plasma butyrylcholinesterase (BChE) to the metabolite 4-(butylamino)benzoic acid (BABA) as well as polyethylene glycol monomethyl esters. Like many other local anesthetic esters, the hydrolysis of the parent compound is rapid. There are concerns that those with pseudocholinesterase deficiencies may have an increased sensitivity to benzonatate as this hydrolysis is impaired, leading to increased levels of circulating medication.
Benzonatate is a butylamine, structurally related to other polyglycol ester local anesthetics such as procaine and tetracaine. The molecular weight of benzonatate is 603.7 g/mol. However, the reference standard for benzonatate is a mixture of n-ethoxy compounds, differing in the abundance of 7-9 repeating units, with an average molecular weight of 612.23 g/mol. There is also evidence that the compound is not uniform between manufacturers.
Society and culture
Benzonatate was first made available in the U.S. in 1958 as a prescription medication for the treatment of cough in individuals over the age of 10. There are a variety of prescription opioid-based cough relievers, such as hydrocodone and codeine, but have unwanted side effects and potential of abuse and diversion. However, benzonatate is currently the only prescription non-opioid antitussive and its usage has been rapidly increasing. The exact reasons of this increase are unclear.
In the United States between 2004 and 2009, prescriptions increased 50% from 3.1 million to 4.7 million, the market share of benzonatate among antitussives increased from 6.3% to 13%, and the estimated number of children under the age of 10 years receiving benzonatate increased from 10,000 to 19,000. Throughout this same period, greater than 90% of prescriptions were given to those 18 or older. The majority of prescriptions were given by general, family, internal, and osteopathic physicians with pediatricians account for about 3% of prescribed benzonatate.
Tessalon is a brand name version of benzonatate manufactured by Pfizer, Inc. It is available as perles or capsules. Zonatuss was a brand name manufactured by Atley Pharmaceuticals, Inc. and Vertical Pharmaceuticals, Inc.
- ^ Jump up to:a b c d e f g h i j k l m n o p q r s “Benzonatate Monograph for Professionals”. Drugs.com. American Society of Health-System Pharmacists. Retrieved 23 March 2019.
- ^ Jump up to:a b c Becker, DE (2010). “Nausea, vomiting, and hiccups: a review of mechanisms and treatment”. Anesthesia Progress. 57 (4): 150–6, quiz 157. doi:10.2344/0003-3006-57.4.150. PMC 3006663. PMID 21174569.
- ^ Jump up to:a b c d “Drugs for cough”. The Medical Letter on Drugs and Therapeutics. 60 (1562): 206–208. 17 December 2018. PMID 30625123.
- ^ Jump up to:a b c d e f g h i j k l m n o p q r s t u v w x y z “Tessalon – benzonatate capsule”. DailyMed. 20 November 2019. Retrieved 21 April 2020.
- ^ Jump up to:a b c d e f “Benzonatate Use During Pregnancy”. Drugs.com. 10 October 2019. Retrieved 20 February 2020.
- ^ Walsh, T. Declan; Caraceni, Augusto T.; Fainsinger, Robin; Foley, Kathleen M.; Glare, Paul; Goh, Cynthia; Lloyd-Williams, Mari; Olarte, Juan Nunez; Radbruch, Lukas (2008). Palliative Medicine E-Book. Elsevier Health Sciences. p. 751. ISBN 9781437721942.
- ^ Jump up to:a b “The Top 300 of 2021”. ClinCalc. Retrieved 18 February2021.
- ^ Jump up to:a b “Benzonatate – Drug Usage Statistics”. ClinCalc. Retrieved 18 February 2021.
- ^ Jump up to:a b c d Homsi, J.; Walsh, D.; Nelson, K. A. (November 2001). “Important drugs for cough in advanced cancer”. Supportive Care in Cancer. 9 (8): 565–574. doi:10.1007/s005200100252. ISSN 0941-4355. PMID 11762966. S2CID 25881426.
- ^ Estfan, Bassam; LeGrand, Susan (November 2004). “Management of cough in advanced cancer”. The Journal of Supportive Oncology. 2 (6): 523–527. ISSN 1544-6794. PMID 16302303.
- ^ Jump up to:a b c d e f g h i j k l McLawhorn, Melinda W.; Goulding, Margie R.; Gill, Rajdeep K.; Michele, Theresa M. (January 2013). “Analysis of benzonatate overdoses among adults and children from 1969-2010 by the United States Food and Drug Administration”. Pharmacotherapy. 33 (1): 38–43. doi:10.1002/phar.1153. ISSN 1875-9114. PMID 23307543. S2CID 35165660.
- ^ Jump up to:a b “Benzonatate (Professional Patient Advice)”. Drugs.com. 4 March 2020. Retrieved 21 April 2020.
- ^ Jump up to:a b c d e f g h i j k l m n o p q r s t u v w Bishop-Freeman SC, Shonsey EM, Friederich LW, Beuhler MC, Winecker RE (June 2017). “Benzonatate Toxicity: Nothing to Cough At”. J Anal Toxicol. 41 (5): 461–463. doi:10.1093/jat/bkx021. PMID 28334901.
- ^ Jump up to:a b “Drugs for Cough”. The Medical Letter on Drugs and Therapeutics. 60 (1562): 206–208. 17 December 2018. PMID 30625123.
- ^ Jump up to:a b c d e f “FDA Drug Safety Communication: Death resulting from overdose after accidental ingestion of Tessalon (benzonatate) by children under 10 years of age”. U.S. Food and Drug Administration (FDA). 28 June 2019. Retrieved 22 April 2020.
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- ^ “Tessalon- benzonatate capsule”. DailyMed. 20 November 2019. Retrieved 25 April 2020.
- ^ “Zonatuss (Benzonatate Capsules USP, 150 mg)”. DailyMed. 2 June 2010. Retrieved 20 August 2020.
- ^ “Zonatuss (Benzonatate Capsules USP, 150 mg)”. DailyMed. 31 October 2016. Retrieved 20 August 2020.
- “Benzonatate”. Drug Information Portal. U.S. National Library of Medicine.
|Trade names||Tessalon, Zonatuss, others|
|License data||US DailyMed: Benzonatate|
|ATC code||R05DB01 (WHO)|
|Legal status||US: ℞-only|
|Elimination half-life||3-8 hours|
|CompTox Dashboard (EPA)||DTXSID9022655|
|Chemical and physical data|
|Molar mass||603.750 g·mol−1|
|3D model (JSmol)||Interactive image|
|(what is this?) (verify)|
///////////Benzonatate, refractory cough , INDIA 2021, APPROVALS 2021, бензонатат , بنزوناتات , 苯佐那酯 , KM 65 , ベンゾナテート, ANTITUSSIVE, IND 2021
NEW DRUG APPROVALS
FDA APPROVED 2021, Ryplazim, 2021/6/4
RYPLAZIM (plasminogen, human-tvmh)
Enzyme replacement (plasminogen), Plasminogen deficiency type 1
Proper Name: plasminogen, human-tvmh
Manufacturer: Prometic Biotherapeutics Inc.
For the treatment of patients with plasminogen deficiency type 1 (hypoplasminogenemia)
On August 11, 2017 Prometic Biotherapeutics submitted a BLA (STN 125659) for a Drug Product (DP) RYPLAZIM, Plasminogen (Human). This drug product is indicated for replacement therapy in children and adults with plasminogen deficiency.
Plasmin is an important enzyme (EC 18.104.22.168) present in blood that degrades many blood plasma proteins, including fibrin clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein is encoded by the PLG gene.
Plasmin is a serine protease that acts to dissolve fibrin blood clots. Apart from fibrinolysis, plasmin proteolyses proteins in various other systems: It activates collagenases, some mediators of the complement system, and weakens the wall of the Graafian follicle, leading to ovulation. Plasmin is also integrally involved in inflammation. It cleaves fibrin, fibronectin, thrombospondin, laminin, and von Willebrand factor. Plasmin, like trypsin, belongs to the family of serine proteases.
Plasmin is released as a zymogen called plasminogen (PLG) from the liver into the systemic circulation. Two major glycoforms of plasminogen are present in humans – type I plasminogen contains two glycosylation moieties (N-linked to N289 and O-linked to T346), whereas type II plasminogen contains only a single O-linked sugar (O-linked to T346). Type II plasminogen is preferentially recruited to the cell surface over the type I glycoform. Conversely, type I plasminogen appears more readily recruited to blood clots.
In circulation, plasminogen adopts a closed, activation-resistant conformation. Upon binding to clots, or to the cell surface, plasminogen adopts an open form that can be converted into active plasmin by a variety of enzymes, including tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), kallikrein, and factor XII (Hageman factor). Fibrin is a cofactor for plasminogen activation by tissue plasminogen activator. Urokinase plasminogen activator receptor (uPAR) is a cofactor for plasminogen activation by urokinase plasminogen activator. The conversion of plasminogen to plasmin involves the cleavage of the peptide bond between Arg-561 and Val-562.
Plasmin cleavage produces angiostatin.
Mechanism of plasminogen activation
Full length plasminogen comprises seven domains. In addition to a C-terminal chymotrypsin-like serine protease domain, plasminogen contains an N-terminal Pan Apple domain (PAp) together with five Kringle domains (KR1-5). The Pan-Apple domain contains important determinants for maintaining plasminogen in the closed form, and the kringle domains are responsible for binding to lysine residues present in receptors and substrates.
The X-ray crystal structure of closed plasminogen reveals that the PAp and SP domains maintain the closed conformation through interactions made throughout the kringle array . Chloride ions further bridge the PAp / KR4 and SP / KR2 interfaces, explaining the physiological role of serum chloride in stabilizing the closed conformer. The structural studies also reveal that differences in glycosylation alter the position of KR3. These data help explain the functional differences between the type I and type II plasminogen glycoforms.
In closed plasminogen, access to the activation bond (R561/V562) targeted for cleavage by tPA and uPA is blocked through the position of the KR3/KR4 linker sequence and the O-linked sugar on T346. The position of KR3 may also hinder access to the activation loop. The Inter-domain interactions also block all kringle ligand-binding sites apart from that of KR-1, suggesting that the latter domain governs pro-enzyme recruitment to targets. Analysis of an intermediate plasminogen structure suggests that plasminogen conformational change to the open form is initiated through KR-5 transiently peeling away from the PAp domain. These movements expose the KR5 lysine-binding site to potential binding partners, and suggest a requirement for spatially distinct lysine residues in eliciting plasminogen recruitment and conformational change respectively.
Mechanism of plasmin inactivation
Plasmin is inactivated by proteins such as α2-macroglobulin and α2-antiplasmin. The mechanism of plasmin inactivation involves the cleavage of an α2-macroglobulin at the bait region (a segment of the aM that is particularly susceptible to proteolytic cleavage) by plasmin. This initiates a conformational change such that the α2-macroglobulin collapses about the plasmin. In the resulting α2-macroglobulin-plasmin complex, the active site of plasmin is sterically shielded, thus substantially decreasing the plasmin’s access to protein substrates. Two additional events occur as a consequence of bait region cleavage, namely (i) a h-cysteinyl-g-glutamyl thiol ester of the α2-macroglobulin becomes highly reactive and (ii) a major conformational change exposes a conserved COOH-terminal receptor binding domain. The exposure of this receptor binding domain allows the α2-macroglobulin protease complex to bind to clearance receptors and be removed from circulation.
Plasmin deficiency may lead to thrombosis, as the clots are not adequately degraded. Plasminogen deficiency in mice leads to defective liver repair, defective wound healing, reproductive abnormalities.
In humans, a rare disorder called plasminogen deficiency type I (Online Mendelian Inheritance in Man (OMIM): 217090) is caused by mutations of the PLG gene and is often manifested by ligneous conjunctivitis.
Plasmin has been shown to interact with Thrombospondin 1, Alpha 2-antiplasmin and IGFBP3. Moreover, plasmin induces the generation of bradykinin in mice and humans through high-molecular-weight kininogen cleavage.
- ^ Jump up to:a b c GRCh38: Ensembl release 89: ENSG00000122194 – Ensembl, May 2017
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- ^ “Mouse PubMed Reference:”. National Center for Biotechnology Information, U.S. National Library of Medicine.
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- ^ Miyata T, Iwanaga S, Sakata Y, Aoki N (October 1982). “Plasminogen Tochigi: inactive plasmin resulting from replacement of alanine-600 by threonine in the active site”. Proc. Natl. Acad. Sci. U.S.A. 79 (20): 6132–6. Bibcode:1982PNAS…79.6132M. doi:10.1073/pnas.79.20.6132. PMC 347073. PMID 6216475.
- ^ Forsgren M, Råden B, Israelsson M, Larsson K, Hedén LO (March 1987). “Molecular cloning and characterization of a full-length cDNA clone for human plasminogen”. FEBS Lett. 213 (2): 254–60. doi:10.1016/0014-5793(87)81501-6. PMID 3030813. S2CID 9075872.
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- ^ Wu, Guojie; Quek, Adam J.; Caradoc-Davies, Tom T.; Ekkel, Sue M.; Mazzitelli, Blake; Whisstock, James C.; Law, Ruby H.P. (2019-03-05). “Structural studies of plasmin inhibition”. Biochemical Society Transactions. 47 (2): 541–557. doi:10.1042/bst20180211. ISSN 0300-5127. PMID 30837322.
- ^ Bezerra JA, Bugge TH, Melin-Aldana H, Sabla G, Kombrinck KW, Witte DP, Degen JL (December 21, 1999). “Plasminogen deficiency leads to impaired remodeling after a toxic injury to the liver”. Proc. Natl. Acad. Sci. U.S.A. Proceedings of the National Academy of Sciences of the United States of America. 96 (26): 15143–8. Bibcode:1999PNAS…9615143B. doi:10.1073/pnas.96.26.15143. PMC 24787. PMID 10611352.
- ^ Silverstein RL, Leung LL, Harpel PC, Nachman RL (November 1984). “Complex formation of platelet thrombospondin with plasminogen. Modulation of activation by tissue activator”. J. Clin. Invest. 74 (5): 1625–33. doi:10.1172/JCI111578. PMC 425339. PMID 6438154.
- ^ DePoli P, Bacon-Baguley T, Kendra-Franczak S, Cederholm MT, Walz DA (March 1989). “Thrombospondin interaction with plasminogen. Evidence for binding to a specific region of the kringle structure of plasminogen”. Blood. 73 (4): 976–82. doi:10.1182/blood.V73.4.976.976. PMID 2522013.
- ^ Wiman B, Collen D (September 1979). “On the mechanism of the reaction between human alpha 2-antiplasmin and plasmin”. J. Biol. Chem. 254 (18): 9291–7. doi:10.1016/S0021-9258(19)86843-6. PMID 158022.
- ^ Shieh BH, Travis J (May 1987). “The reactive site of human alpha 2-antiplasmin”. J. Biol. Chem. 262 (13): 6055–9. doi:10.1016/S0021-9258(18)45536-6. PMID 2437112.
- ^ Campbell PG, Durham SK, Suwanichkul A, Hayes JD, Powell DR (August 1998). “Plasminogen binds the heparin-binding domain of insulin-like growth factor-binding protein-3”. Am. J. Physiol. 275 (2 Pt 1): E321-31. doi:10.1152/ajpendo.1998.275.2.E321. PMID 9688635.
- ^ Marcos-Contreras OA, Martinez de Lizarrondo S, Bardou I, Orset C, Pruvost M, Anfray A, Frigout Y, Hommet Y, Lebouvier L, Montaner J, Vivien D, Gauberti M (August 2016). “Hyperfibrinolysis increases blood brain barrier permeability by a plasmin and bradykinin-dependent mechanism”. Blood. 128 (20): 2423–2434. doi:10.1182/blood-2016-03-705384. PMID 27531677.
- Shanmukhappa K, Mourya R, Sabla GE, Degen JL, Bezerra JA (July 2005). “Hepatic to pancreatic switch defines a role for hemostatic factors in cellular plasticity in mice”. Proc. Natl. Acad. Sci. U.S.A. 102 (29): 10182–7. Bibcode:2005PNAS..10210182S. doi:10.1073/pnas.0501691102. PMC 1177369. PMID 16006527.
- Anglés-Cano E, Rojas G (2002). “Apolipoprotein(a): structure-function relationship at the lysine-binding site and plasminogen activator cleavage site”. Biol. Chem. 383 (1): 93–9. doi:10.1515/BC.2002.009. PMID 11928826. S2CID 29248198.
- Ranson M, Andronicos NM (2003). “Plasminogen binding and cancer: promises and pitfalls”. Front. Biosci. 8 (6): s294-304. doi:10.2741/1044. PMID 12700073.
- The MEROPS online database for peptidases and their inhibitors: S01.233
- Plasmin at the US National Library of Medicine Medical Subject Headings (MeSH)
|Available structuresPDBOrtholog search: PDBe RCSBshowList of PDB id codes|
|Aliases||PLG, plasminogen, plasmin, HAE4|
|External IDs||OMIM: 173350 MGI: 97620 HomoloGene: 55452 GeneCards: PLG|
|showGene location (Human)|
|showGene location (Mouse)|
|showRNA expression pattern|
|RefSeq (mRNA)|| NM_001168338|
|RefSeq (protein)|| NP_000292|
|Location (UCSC)||Chr 6: 160.7 – 160.75 Mb||Chr 17: 12.38 – 12.42 Mb|
|View/Edit HumanView/Edit Mouse|
///////////Plasminogen, FDA 2021, APPROVALS 2021, Ryplazim
NEW DRUG APPROVALS
EVQLVESGGG LVQPGGSLRL SCAASGFTFS DYNMAWVRQA PGKGLEWVAT ITYEGRNTYY
RDSVKGRFTI SRDNAKNSLY LQMNSLRAED TAVYYCASPP QYYEGSIYRL WFAHWGQGTL
VTVSSASTKG PSVFPLAPSS KSTSGGTAAL GCLVKDYFPE PVTVSWNSGA LTSGVHTFPA
VLQSSGLYSL SSVVTVPSSS LGTQTYICNV NHKPSNTKVD KKVEPKSCDK THTCPPCPAP
ELLGGPSVFL FPPKPKDTLM ISRTPEVTCV VVDVSHEDPE VKFNWYVDGV EVHNAKTKPR
EEQYNSTYRV VSVLTVLHQD WLNGKEYKCK VSNKALPAPI EKTISKAKGQ PREPQVYTLP
PSRDELTKNQ VSLTCLVKGF YPSDIAVEWE SNGQPENNYK TTPPVLDSDG SFFLYSKLTV
DKSRWQQGNV FSCSVMHEAL HNHYTQKSLS LSPGK
AIQLTQSPSS LSASVGDRVT ITCRADESVR TLMHWYQQKP GKAPKLLIYL VSNSEIGVPD
RFSGSGSGTD FRLTISSLQP EDFATYYCQQ TWSDPWTFGQ GTKVEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
(Disulfide bridge: H22-H96, H152-H208, H228-L214, H234-H’234, H237-H’237, H269-H329, H375-H433, H’22-H’96, H’152-H’208, H’228-L’214, H’269-H’329, H’375-H’433, L23-L88, L134-L194, L’23-L’88, L’134-L’194)
EU APPROVED, 2021/8/20, Bimzelx
Immunoglobulin G1, anti-(human interleukin 17A/interleukin 17F) (human-Rattus norvegicus monoclonal UCB4940 heavy chain), disulfide with human-Rattus norvegicus monoclonal UCB4940 light chain, dimer
Sequence Length: 1338, 455, 455, 214, 214multichain; modified (modifications unspecified)
|Agency product number||EMEA/H/C/005316|
|International non-proprietary name (INN) or common name||bimekizumab|
|Therapeutic area (MeSH)||Psoriasis|
|Anatomical therapeutic chemical (ATC) code||L04AC|
Bimzelx 160 mg solution for injection in pre-filled syringe Bimzelx 160 mg solution for injection in pre-filled pen
The active substance in Bimzelx, bimekizumab, is a monoclonal antibody, a protein designed to attach to interleukins IL-17A, IL-17F and IL-17AF, which are messenger molecules in the body’s immune system (the body’s natural defences). High levels of these interleukins have been shown to be involved in developing inflammatory diseases caused by the immune system, such as plaque psoriasis. By attaching to these interleukins, bimekizumab prevents them from interacting with their receptors (targets) on the surface of the epidermis (outer layer of the skin), which reduces inflammation and improves the symptoms related to plaque psoriasis.,,, https://www.ema.europa.eu/en/documents/overview/bimzelx-epar-medicine-overview_en.pdf
Antipsoriatic, Anti-IL-17A/IL-17F antibody, Monoclonal antibody
Treatment of moderate to severe plaque psoriasis
The most common side effects include upper respiratory tract infections (nose and throat infection) and oral candidiasis (thrush, a fungal infection in the mouth or throat).
Monoclonal antibody treatments for psoriasis are stacking up—but UCB hopes to muscle into the market with bimekizumab this year. The anti-IL-17A and IL-17F injection showed up both Johnson & Johnson’s Stelara and Novartis blockbuster Cosentyx in trials.
UCB’s Stelara head-to-head, the Be Vivid study presented in June at the American Academy of Dermatology and later published in The Lancet, found 85% of bimekizumab patients had a 90% or greater reduction in the area and severity of their psoriasis symptoms at 16 weeks. Complete skin clearance, indicated by a score of PASI 100, happened in 59% of patients.
Stelara, for its part, helped just half of patients reach PASI 90 and 21% achieve complete skin clearance over the same time period.
That Be Vivid readout raised expectations of a potentially favorable outcome in UCB’s head-to-head study with Novartis blockbuster Cosentyx (secukinumab), called Be Radiant.
In July, UCB announced that in that phase 3 study, its candidate had “demonstrate(d) superiority to secukinumab for complete skin clearance at both weeks 16 and 48.” The full study results will be presented “in due course,” UCB promised.
The data from the Cosentyx trial could be worth a lot to UCB, Evaluate wrote in June, adding that Jefferies analysts at the time expected annual sales of bimekizumab to top out around $1.5 billion. If bimekizumab beats Cosentyx, the sales forecast could rise to above $2 billion, it said at the time.
Without specific Cosentyx-topping data from the Be Radiant study in hand, Evaluate pegs consensus sales estimates at $1.63 billion in 2026.
One concern for UCB is whether the smaller pharma will be able to compete with the big marketing budgets in psoriasis. AbbVie’s Skyrizi and Humira, Novartis’ Cosentyx, Eli Lilly’s Taltz and Amgen’s Otezla are just a handful of the psoriasis drugs that have spent millions on mainstream TV ads to build brand names.
In September, the FDA and EMA accepted UCB’s biologics license application (BLA) for bimekizumab for adults with moderate to severe plaque psoriasis, the company reported. Ongoing phase 3 trials are evaluating the drug to treat a variety of other conditions, including psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis and hidradenitis suppurativa.
In the meantime, more competition is on the way. South San Francisco biotech DiCE Molecules, for its part, last month nabbed new funding to the tune of $80 million to roll its oral small molecule IL-17 program into a clinical trial in psoriasis and build out preclinical programs.
In addition to IL-17 rivals, others are also looking to get in on the action—particularly, several TYK2 inhibitors. Bristol Myers Squibb’s deucravacitinib recently bested Otezla in a study, while both Pfizer and Nimbus Therapeutics are in phase 2 studies with prospects of their own.
Psoriatic arthritis (PsA) is a complex and heterogeneous inflammatory disease that affects 20% to 30% of patients with psoriasis and is associated with substantial disability, impaired quality of life (QoL), and several comorbidities.1–3 It involves diverse clinical domains that extend beyond musculoskeletal manifestations (peripheral and axial arthritis, enthesitis and dactylitis): eg, nails, gut, and eyes, in addition to latent or manifest psoriasis.
Although there is still a huge gap in knowledge on the pathophysiology of PsA, what is known has fortunately turned into new treatment approaches that have improved symptoms and outcomes for PsA patients over the last two decades. Pro-inflammatory cytokines have been recognized as potential treatment targets in inflammatory diseases and have led to the creation of a number of anti-cytokine monoclonal antibodies that have revolutionized its treatment, such as TNFα and IL-12/23 inhibitors.4 More recently, the IL-17 pathway has been shown to play an important role in the pathophysiology of psoriatic disease and its blockage has shown to be clinically beneficial, as demonstrated with IL-17A inhibitors secukinumab and ixekizumab.4 Some patients, however, still do not respond, stop responding over time or suffer from side effects, leading to drug discontinuation, and other times combination strategies are required to control all PsA’s disease domains. Thus, there is still a great need for novel therapeutic options.5
Dual inhibitor antibodies target two different cytokines simultaneously potentially offering a better disease control. Interleukin (IL)-17A and IL-17F share structural homology and have a similar biologic function. IL-17A is classically considered to be the most biologically active, but recent studies have shown that IL-17F is also increased in psoriatic skin and synovial cell in psoriatic arthritis, supporting the rationale for targeting both IL-17A and IL-17F in psoriatic disease. Bimekizumab is the first-in-class monoclonal antibody designed to simultaneously target IL-17A and IL-17F.
Bimekizumab is indicated for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy.
This drug is being developed by Belgian pharmaceutical UCB. Phase III trials have demonstrated that bimekizumab is superior to not only adalimumab but also secukinumab for the treatment of plaque psoriasis.
The Role of Interleukin (IL)‑17A and IL‑17F in Psoriatic Arthritis
The IL-17 cytokine family comprises six different members (from A to F), of which IL-17A is the most studied. Known to be produced by a wide range of immune cells, IL-17A is involved in the pathophysiology of several inflammatory diseases including spondyloarthritis.6–8
Most non-hematopoietic cells possess IL-17 receptors, including fibroblasts, epithelial cells and synoviocytes,8 but despite this ubiquitous presence, IL-17 seems to have only moderate inflammatory capability per se, rather recruiting and amplifying other pathways, such as IL-6, IL-8, TNF and inflammatory-cell attracting chemokines.6,7,9,10
Still, evidence supporting the centrality of the IL-17 pathway in both PsO and PsA is available from a wide range of data.11 Th17 cells, IL-17 protein and related genes are elevated in both skin, blood and synovial fluid of PsO and PsA patients.11,12 In PsA, increased levels of IL-17+ CD4 and CD813,14, as well as IL-17A+Tγδ cells, have been found in the synovial fluid compared with peripheral blood. Specifically, the levels of IL-17+CD8+ cells in the synovial fluid distinguish PsA from rheumatoid arthritis (RA) and correlate with increased DAS28 scores, C-reactive protein levels, power-doppler findings of activity and prevalence of erosions.13 Inhibition of this pathway is capable of normalizing almost four times more disease-related genes than anti-TNFα treatments.11,15
Within the entire IL-17 family, IL-17F is the most structurally homologous (~50%) to IL-17A8 (Figure 1). They can both be secreted as homodimers (ie IL-17A/A or IL-17F/F) or as heterodimers of IL-17A/IL-17F,9 sharing signaling pathways through the same heterodimeric complex of IL-17 receptors A and C (IL-RA/RC) and biologic function.7–9
|Figure 1 Summarized schematic of inhibition of the IL-17 cytokine family. *Not approved for psoriatic arthritis. Notes: Reprinted by permission from Springer Nature Customer Service Centre GmbH: Springer Nature, BioDrugs, Reis J, Vender R, Torres T. Bimekizumab: the first dual inhibitor of interleukin (IL)-17A and IL-17F for the treatment of psoriatic disease and ankylosing spondylitis, COPYRIGHT 2019.6Abbreviations: IL, interleukin; IL-17RA, IL-17 receptor A; IL-17RB, IL-17 receptor B; IL-17RC, IL-17 receptor C; IL-17RE, IL-17 receptor E.|
In enthesitis, a central pathologic process in PsA, Tγδ cells have recently been described that are capable of producing both IL-17A and IL-17F even independently of IL-23 stimulation.17 IL-17A and F had already been shown to promote osteogenic differentiation in in vitro models of human periosteum activated through the use of Th17 and Tγδ cells or through culture with serum from patients with ankylosing spondylitis,18 a mechanism potentially implied in the development of enthesitis. Importantly, both cytokines seem to be equipotent in this role, unlike in inflammatory processes where IL-17F seems to be less potent.18
Both IL-17A and IL-17F, when synergized with TNF, lead to increased production of pro-inflammatory cytokines, such as IL-8 and IL-6 in synoviocytes of PsA patients.9 IL-17A seems to be the most pro-inflammatory of the two cytokines.9,19 However, despite some inconsistencies in the literature regarding IL-17F detection levels which might be attributable to differences in methodology,19 IL-17F levels have been reported to be 30–50 times higher in some cytokine microenvironments, such as in psoriatic skin lesions of PsA patients20 or the synovium,21 which might dilute differences in relative potency. Additionally, IL-17F seems to be significantly increased in the synovium of PsA compared to osteoarthritis (OA) patients, unlike IL-17A.21 Dual neutralization of both IL-17A and IL-17F (using bimekizumab) resulted in greater downregulation of pro-inflammatory cytokine production than a single blockade in synovial fibroblasts.9,19 Critically, in in vitro models, anti-TNF blockade alone did not reduce the production of IL-8 as much as both IL-17A and F neutralization or even just anti-IL17A alone.9,19 In in vitro models of human periosteum dual blockade of IL-17A and F was also more effective in suppressing osteogenic differentiation than the blockade of either cytokine individually.18
Interestingly, in Tγδ cells, the predominant IL-17 production seems to be the F subtype.18 Also of note is the recent description that the IL-17receptorC (IL-17RC) competes with IL-17RA for IL-17F, IL-17A and IL-17A/F heterodimers,22 suggesting the possibility of IL-17RA-independent signaling pathways (and thus not targeted by brodalumab, an anti-IL17RA monoclonal antibody).
Bimekizumab is a humanized monoclonal IgG1 antibody that selectively neutralizes both IL-17A and IL-17F. In in vitro models, bimekizumab appears to be as potent as ixekizumab at inhibiting IL-17A (also more potent than secukinumab)8 but, unlike those drugs, also possesses the unique ability to inhibit IL-17F as well, functioning as a dual inhibitor. Unlike brodalumab, an IL-17 receptor A blocker – which targets not only IL-17A and F signaling but also IL-17 C, D and E – bimekizumab spares IL-17E (also known as IL-25), for example, which is believed to have anti-inflammatory properties.6
Bimekizumab demonstrates dose-proportional linear pharmacokinetics, with a half-life ranging from 17 to 26 days, and its distribution is restricted to the extravascular compartment.23 Currently, bimekizumab is in advanced clinical development for psoriasis, but also for psoriatic arthritis, and ankylosing spondylitis (both currently in phase III).
Bimekizumab in PsA – Efficacy
The first bimekizumab clinical trial in PsA was a phase Ib randomized, double-blind, placebo-controlled clinical trial that included 53 patients (39 treated with bimekizumab, 14 with placebo) with active psoriatic arthritis who had failed conventional disease-modifying antirheumatic drugs (DMARDs) and/or one biologic DMARD. Patients in the active treatment arm were randomized to four different treatment regimens of varying loading doses (ranging from 80 to 560 mg) and maintenance doses (from 40 to 320 mg) at weeks 0, 3 and 6. Patients were followed for up to 20 weeks.9
Patients treated with bimekizumab had a faster response, compared to placebo. This was first detected at week two, with maximal or near-maximal responses maintained up to week 20, for both arthritis and skin psoriasis. ACR20, 50 and 70 responses were maximal at week 8 (80%), week 12 (57%) and week 16 (37%), respectively. For patients with skin involvement, PASI75 and PASI100 responses at week 8 were 100% and 87%, respectively (Table 1).
BE ACTIVE10 was a 48-week multicentric, international, phase 2b dose-ranging, randomized, double-blind placebo-controlled trial to assess the efficacy and safety of bimekizumab. Two hundred and six adult patients (out of 308 screened) with active (tender and swollen count >3) PsA (diagnosed according to CASPAR criteria) were enrolled in 5 treatment arms (placebo, 16 mg, 160 mg with single 320 mg loading dose, 160 mg, 320 mg bimekizumab dose, with SC injections every 4 weeks). Concurrent use of TNF inhibitors was not permitted but conventional DMARDs (if on a stable dose and kept throughout the study), corticosteroids (equal or less 10mg/day) and NSAIDs were allowed. Sixteen-milligram bimekizumab (a much lower dose than other treatment arms) was tested with a programmed re-randomization at week 12 to either 160 or 320 mg dosing (meaning no placebo arm after 12 weeks). All patients received treatment up to week 48.
The primary outcome was ACR50 response at 12 weeks, a much more stringent outcome than used for other IL-17 inhibitors. The prespecified analysis was not possible due to the absence of a statistically significant difference versus placebo for the 320 mg group at week 12. All other outcomes were thus considered exploratory, rendering this a failed primary endpoint with no active comparator group.
At 12 weeks, significant ACR50 responses were present for every bimekizumab group, although lower in both the 16 mg and 320 mg dose group (Table 1 reports average values for all bimekizumab treatment groups). The 160 mg dosing had the greatest ACR and PASI response rates. These were confirmed to be increasing response rates up to week 24 and stability thereafter up to week 48, where the results of both 160 and 320 mg were similar. There were also responses in PASI scores, enthesitis, HAQ-DI and SF-36 across all bimekizumab doses. There was no loss of efficacy by week 48.
At the recent American College of Rheumatology (ACR) congress, additional data on BE ACTIVE were reported. BASDAI scoring was improved on the 93 patients in the treatment arm (160–320 mg bimekizumab) who had a baseline score >4 (mean 6.2 ± 1.42). BASDAI50 response rates were 43% and 56% at week 12 and 48, respectively.24
Regarding patient-reported outcomes (PROs), the Health assessment questionnaire Disability Index (HAQ-DI) and the psoriatic arthritis impact of disease-9 (PsAID-9) questionnaire developed specifically to assess health-related quality of life (QoL) in PsA were used on 206 patients from the BE ACTIVE trial. Rapid improvement was registered by week 12 and this response was sustained up to 48 weeks. Better QoL was associated with the better clinical outcomes reported in that study.25,26
Open-Label Extension Study (OLE)
Results from the 108 weeks of follow-up in the open-label extension study of BE ACTIVE (BE ACTIVE2, NCT03347110) have been recently presented.27,28 All patients who completed all 48 weeks of the BE ACTIVE trial were enrolled and switched to the 160 mg dosing regardless of previous treatment dose regimen. Over 108 weeks (an additional 60 weeks of OLE study over the 48 of the original BE ACTIVE trial) there was a 66.7% and 75.4% ACR 50 and body surface area (BSA) 0% response, respectively. Dactylitis and enthesitis were also significantly improved completely resolving in 65.9% and 77.9% of patients, respectively.27 Regarding week 12 responders, ACR20/50/70 and BSA 0% responses were maintained until week 108 in 80/78/81% and 72%, respectively.27 MDA/VLDA responses and DAPSA remission were maintained by 81/72/76% of Week 12 responders, respectively, to Week 120 (MDA/VLDA), and Week 108 (DAPSA remission).
Bimekizumab in PsA – Safety
Over 90% of reported adverse events, in both arms, were mild or moderate. In the treatment arm, two fungal infections (oropharyngeal and vulvovaginal candidiasis) were reported, both treated with oral medication. There was no increased incidence of other infections. There were no deaths or severe adverse events resulting from treatment, and no patient discontinued bimekizumab.9
No difference was found in the frequency of adverse events between placebo and treatment arms by week 12 in the BE ACTIVE trial. After reallocation (after week 12) and up to the 48 weeks of the trial 151 (74%) of the total 204 patients who ever received bimekizumab reported some AE (exposure adjusted incidence rate 166.8/100 patient-years). Most AE were mild or moderate (the most frequently reported were nasopharyngitis and upper respiratory tract infections) and there was no direct association with bimekizumab dose.
Nine patients (8 of which received bimekizumab) had serious adverse effects. These included one patient with drug-induced liver injury. Another patient also had severe liver enzyme elevation. Both had been given the 320 mg dosing. From the hepatic point of view, the other 11 patients were noted to have increased liver enzymes (>3x ULN). There was no relation with bimekizumab dose, and most were on DMARDs and one was on TB prophylaxis. At least two serious adverse events were related to infections across the entire study period (28 weeks) – 1 hepatitis E infection, 1 cellulitis (both with the 160 mg dosing). Non-severe Candida infection was reported in 7% of the patients, none led to treatment discontinuation. Other serious AEs reported were melanoma in situ (160 mg), suicidal ideation (160 mg loading dose), and neutropenia (320 mg dosing) (only in one patient each).10 In summary, this safety profile overlaps with those of other anti-IL17 therapies.29
In the OLE study, at week 108, serious adverse events occurred in 9.3% of patients (no deaths or major adverse cardiac events) and a total of 8.8% of patients withdrew from the study due to side effects. Full publication is still pending but the authors share that the safety profile observed in the OLE study reflected previous observations.27
Dual inhibitor antibodies represent a novel therapeutic strategy, and a logical extension of the success monoclonal antibodies has had over the last couple of decades.
Here we review the most recent information on IL-17A and F inhibition in psoriatic arthritis through the first-of-its-class bimekizumab, a dual inhibitor of both cytokines.
The importance of the IL-17 pathway in psoriatic arthritis, already suggested by preclinical data, was reinforced by the excellent results obtained by secukinumab30 or ixekizumab31 in the control of the disease in the last few years.
Indeed, IL-17 seems to be involved in all of the clinical domains of psoriatic arthritis. In preclinical trials, it has been shown that both IL-17A and F are capable of inducing pro-inflammatory cytokines, like IL-8 or IL-6, in synoviocytes, periosteum and the skin,23 and that this activation was greatly suppressed by blocking both these cytokines simultaneously. Research is expanding on the differential role of IL-17F in different environments,18,21 compared with the more studied IL-17A, as well as possible alternative signaling pathways.22 Taken together these findings could potentially explain different clinical phenotypes in PsA and treatment responses to anti-IL17A (secukinumab, ixekizumab) and IL-17RA (brodalumab) inhibitors furthering support for the use of dual cytokine blockade such as with bimekizumab (Figure 1).
Phase II trials, specifically BE ACTIVE results, have been encouraging. Bimekizumab has shown to be relatively fast-acting, with initial improvements detected by week 8 and well established by week 12. Additionally, at a dose of 160 mg every 4 weeks, bimekizumab has shown to be capable of retaining this level of response in a high percentage of patients for at least 2 years. These results are independent of prior exposure to anti-TNF therapy.10
As with all new drugs, there are still pending questions regarding its optimal use. In BE ACTIVE,10 in which patients received four different dosages through the first 12 weeks, the 160 mg seemed most effective. The initial lower response in the 320 mg group might have been produced by a higher proportion of refractory patients in which bimekizumab took longer to work. This impression is reinforced, in the author’s opinion, by the fact that response rates were different as early as week 4 in both 160 mg (loading dose) and 320 mg dose groups although by that time period both groups had received the same dose. Co-medication was balanced between both groups.
Whichever dose proves best, these results were achieved with mostly mild side-effects that did not lead to treatment discontinuation – most commonly nasopharyngitis, upper respiratory infections and candidiasis. Overall the available data have not revealed any unexpected adverse events. Nonetheless, the number of patients included in the trials is still small. Thirteen out of the 204 patients (6,4%) receiving any dose of bimekizumab in the BE ACTIVE trial had some hepatic adverse effect, raising the need for attentive monitoring by treating physicians. Co-medication needs to be well pondered in this setting as well, but if real-world outcomes of bimekizumab prove as beneficial as in the trials there might be a reduced need for concomitant use of other DMARDs. Although IL-17F has been shown to be associated with increased susceptibility in many forms of human cancer, it has shown a protective role in colon tumorigenesis in mice,32,33 mainly by regulating tumor angiogenesis.6 Longer and bigger trials will be needed to fully ascertain the safety of bimekizumab.
Overall the available results for this new therapeutic option in psoriatic arthritis are encouraging, although it is still early to completely understand the added value offered by bimekizumab. As of yet, however, there are no head-to-head trials directly comparing it to other treatment options in PsA. Anti-IL17A monoclonal antibodies have been evaluated against other therapies, such as anti-TNF inhibitors in the treatment of PsA with mixed results (using different endpoints).34,35
Right now we can only look to early reports from the more advanced Phase 3 trials in psoriasis, where bimekizumab was first studied, which already encompass hundreds of patients and compare bimekizumab with other biologics. A head-to-head comparison with ustekinumab was recently published36 involving 567 patients (321 randomized to bimekizumab, 163 to ustekinumab and 83 to a placebo arm that was switched to bimekizumab at week 16). Using a 320 mg dose of bimekizumab every 4 weeks (and not the 160 mg shown in BE ACTIVE to be the most efficacious in PsA) bimekizumab was superior to ustekinumab (85% vs 49.7% PASI 90 responses at week 16, p<0.001). This response was also sustained throughout the 52-week duration of the study (81.6% vs 55.8%, p<0.001). Similar responses (86.2% vs 47.2% PASI 90 at week 16, p<0.001) in the BE SURE trial comparing bimekizumab (320 mg every 4 weeks or 320 mg until week 16 and then every 8 weeks) and adalimumab (80 mg week 0, 40 mg week 1 and every 2 weeks) were recently presented.37 Switching adalimumab patients to bimekizumab resulted in increased response rates, comparable to rates in bimekizumab-randomized patients at week 56. UCB, the company developing bimekizumab, have also reported the superiority of bimekizumab against secukinumab.38
If nothing else, bimekizumab is a proof-of-concept for a novel avenue in treating inflammatory diseases. Up until now the clinical practice in inflammatory diseases has been to steer clear of the combination of monoclonal antibodies. The results of the trials reported here using bimekizumab to simultaneously inhibit two cytokines, even if related ones, are an important reminder of the redundant and overlapping nature of the immune system and of the multiple pathways through which one arrives at inflammatory disease.
As of yet, however, there are no head-to-head trials directly comparing bimekizumab to conventional DMARDS or other bDMARDs in PsA although the results reported here seem encouraging. Upcoming trials (see Table 2) will hopefully fill this gap in knowledge.
Psoriatic arthritis can be a severe and disabling disease. Although improvements in its treatment have been achieved in the past decade, its pathogenesis is not completely known, and its treatment is still difficult particularly throughout all disease domains.
The IL-17 pathway has been implicated in disease pathogenesis and targeting IL-17A with secukinumab and ixekizumab has shown good results, although there is still a large proportion of patients that respond only partially. The simultaneous blockade of both IL-17A and IL-17F seems to have a synergistic benefit, with IL-17F inhibition contributing with a differentiated role in both osteogenesis and skin inflammation, important domains of PsA.
Bimekizumab uses a novel approach to biologic treatment in psoriatic arthritis through dual cytokine blockade. Mounting evidence from early trials has shown a good safety and efficacy profile, with rapid onset and sustained response, with results now extending to 108 weeks of follow-up. Moreover, clinical trials in skin psoriasis have also shown that bimekizumab is highly effective, confirming the importance of inhibiting these two cytokines in psoriatic disease.
In the near future, phase III trials will help to better understand the potential of bimekizumab in the treatment of psoriatic arthritis.
- ^ Jump up to:a b c d e f “Bimzelx EPAR”. European Medicines Agency (EMA). 23 June 2021. Retrieved 24 August 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
- ^ Lim SY, Oon HH (2019-05-13). “Systematic review of immunomodulatory therapies for hidradenitis suppurativa”. Biologics. 13: 53–78. doi:10.2147/BTT.S199862. PMC 6526329. PMID 31190730.
- ^ “UCB Announces European Commission Approval of Bimzelx (bimekizumab) for the Treatment of Adults with Moderate to Severe Plaque Psoriasis”. UCB (Press release). 24 August 2021. Retrieved 24 August 2021.
- ^ Warren, Richard B.; Blauvelt, Andrew; Bagel, Jerry; Papp, Kim A.; Yamauchi, Paul; Armstrong, April; Langley, Richard G.; Vanvoorden, Veerle; De Cuyper, Dirk; Cioffi, Christopher; Peterson, Luke (2021-07-08). “Bimekizumab versus Adalimumab in Plaque Psoriasis”. New England Journal of Medicine. 385 (2): 130–141. doi:10.1056/NEJMoa2102388. ISSN 0028-4793. PMID 33891379.
- ^ Reich, Kristian; Warren, Richard B.; Lebwohl, Mark; Gooderham, Melinda; Strober, Bruce; Langley, Richard G.; Paul, Carle; De Cuyper, Dirk; Vanvoorden, Veerle; Madden, Cynthia; Cioffi, Christopher (2021-07-08). “Bimekizumab versus Secukinumab in Plaque Psoriasis”. New England Journal of Medicine. 385 (2): 142–152. doi:10.1056/NEJMoa2102383. ISSN 0028-4793. PMID 33891380.
- ^ World Health Organization (2014). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 72”. WHO Drug Information. 28 (3). hdl:10665/331112.
- Reis J, Vender R, Torres T (August 2019). “Bimekizumab: The First Dual Inhibitor of Interleukin (IL)-17A and IL-17F for the Treatment of Psoriatic Disease and Ankylosing Spondylitis”. BioDrugs. 33 (4): 391–9. doi:10.1007/s40259-019-00361-6. PMID 31172372. S2CID 174812750.
- “Bimekizumab”. Drug Information Portal. U.S. National Library of Medicine.
|Target||IL17A, IL17F, IL17AF|
|License data||EU EMA: by INN|
|Legal status||EU: Rx-only |
//////////Bimekizumab, Bimzelx, EU 2021, APPROVALS 2021, Monoclonal antibody
, plaque psoriasis,ビメキズマブ (遺伝子組換え) , UCB 4940
NEW DRUF APPROVALS
ONE TIME ANTHONY CRASTO +919321316780 email@example.com
D-Phe-D-Phe-D-Leu-D-Lys-[ω(4-aminopiperidine-4- carboxylic acid)]-OH
FDA APPROVED, 2021/8/23, FORSUVA
Analgesic, Antipruritic, Opioid receptor agonist
Treatment of moderate-to-severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis
Difelikefalin, CR-845; MR-13A-9; MR-13A9
4-amino-1- (D-phenylalanyl-D-phenylalanyl-D-leucyl-D-lysyl) piperidine-4-carboxylic acid
|CLASS||Analgesic drugs (peptides)|
|MECHANISM OF ACTION||Opioid kappa receptor agonists|
|WHO ATC CODES||D04A-X (Other antipruritics), N02A (Opioids)|
|EPHMRA CODES||D4A (Anti-Pruritics, Including Topical Antihistamines, Anaesthetics, etc), N2A (Narcotics)|
|INDICATION||Pain, Osteoarthritis, Pruritus|
Difelikefalin, sold under the brand name Korsuva , is an analgesic opioid peptide used for the treatment of moderate-to-severe pruritus. It acts as a peripherally specific, highly selective agonist of the κ-opioid receptor (KOR).
Difelikefalin acts as an analgesic by activating KORs on peripheral nerve terminals and KORs expressed by certain immune system cells. Activation of KORs on peripheral nerve terminals results in the inhibition of ion channels responsible for afferent nerve activity, causing reduced transmission of pain signals, while activation of KORs expressed by immune system cells results in reduced release of proinflammatory, nerve-sensitizing mediators (e.g., prostaglandins).
NEW DRUG APPROVALS
It is under development by Cara Therapeutics as an intravenous agent for the treatment of postoperative pain. An oral formulation has also been developed. Due to its peripheral selectivity, difelikefalin lacks the central side effects like sedation, dysphoria, and hallucinations of previous KOR-acting analgesics such as pentazocine and phenazocine. In addition to use as an analgesic, difelikefalin is also being investigated for the treatment of pruritus (itching). Difelikefalin has completed phase II clinical trials for postoperative pain and has demonstrated significant and “robust” clinical efficacy, along with being safe and well tolerated. It has also completed a phase III clinical trial for uremic pruritus in hemodialysis patients.Kappa opioid receptors have been suggested as targets for intervention for treatment or prevention of a wide array of diseases and conditions by administration of kappa opioid receptor agonists. See for example, Jolivalt et al., Diabetologia, 49(11):2775-85; Epub Aug. 19, 2006), describing efficacy of asimadoline, a kappa receptor agonist in rodent diabetic neuropathy; and Bileviciute-Ljungar et al., Eur. J. Pharm. 494:139-46 (2004) describing the efficacy of kappa agonist U-50,488 in the rat chronic constriction injury (CCI) model of neuropathic pain and the blocking of its effects by the opioid antagonist, naloxone. These observations support the use of kappa opioid receptor agonists for treatment of diabetic, viral and chemotherapy- induced neuropathic pain. The use of kappa receptor agonists for treatment or prevention of visceral pain including gynecological conditions such as dysmenorrheal cramps and endometriosis has also been reviewed. See for instance, Riviere, Br. J. Pharmacol. 141:1331-4 (2004). Kappa opioid receptor agonists have also been proposed for the treatment of pain, including hyperalgesia. Hyperalgesia is believed to be caused by changes in the milieu of the peripheral sensory terminal occur secondary to local tissue damage. Tissue damage (e.g., abrasions, burns) and inflammation can produce significant increases in the excitability of polymodal nociceptors (C fibers) and high threshold mechanoreceptors (Handwerker et al. (1991) Proceeding of the VIth World Congress on Pain, Bond et al., eds., Elsevier Science Publishers BV, pp. 59-70; Schaible et al. (1993) Pain 55:5-54). This increased excitability and exaggerated responses of sensory afferents is believed to underlie hyperalgesia, where the pain response is the result of an exaggerated response to a stimulus. The importance of the hyperalgesic state in the post-injury pain state has been repeatedly demonstrated and appears to account for a major proportion of the post-injury/inflammatory pain state. See for example, Woold et al. (1993) Anesthesia and Analgesia 77:362-79; Dubner et al.(1994) In, Textbook of Pain, Melzack et al., eds., Churchill-Livingstone, London, pp. 225-242. Kappa opioid receptors have been suggested as targets for the prevention and treatment of cardiovascular disease. See for example, Wu et al. “Cardioprotection of Preconditioning by Metabolic Inhibition in the Rat Ventricular Myocyte – Involvement of kappa Opioid Receptor” (1999) Circulation Res vol. 84: pp. 1388-1395. See also Yu et al. “Anti-Arrhythmic Effect of kappa Opioid Receptor Stimulation in the Perfused Rat Heart: Involvement of a cAMP-Dependent Pathway”(1999) JMoI Cell Cardiol, vol. 31(10): pp. 1809-1819. It has also been found that development or progression of these diseases and conditions involving neurodegeneration or neuronal cell death can be prevented, or at least slowed, by treatment with kappa opioid receptor agonists. This improved outcome is believed to be due to neuroprotection by the kappa opioid receptor agonists. See for instance, Kaushik et al. “Neuroprotection in Glaucoma” (2003) J. Postgraduate Medicine vol. 49 (1): pp. 90-95.  The presence of kappa opioid receptors on immune cells (Bidlak et al.,(2000) Clin. Diag. Lab. Immunol. 7(5):719-723) has been implicated in the inhibitory • action of a kappa opioid receptor agonist, which has been shown to suppress HIV-I expression. See Peterson PK et al, Biochem Pharmacol 2001, 61(19):1145-51.  Walker, Adv. Exp. Med. Biol. 521: 148-60 (2003) appraised the antiinflammatory properties of kappa agonists for treatment of osteoarthritis, rheumatoid arthritis, inflammatory bowel disease and eczema. Bileviciute-Ljungar et al., Rheumatology 45:295-302 (2006) describe the reduction of pain and degeneration in Freund’s adjuvant-induced arthritis by the kappa agonist U-50,488. Wikstrom et al, J. Am. Soc. Nephrol. 16:3742-7 (2005) describes the use of the kappa agonist, TRK-820 for treatment of uremic and opiate-induced pruritis, and Ko et al., J. Pharmacol. Exp. Ther. 305: 173-9 (2003) describe the efficacy of U- 50,488 in morphine-induced pruritis in the monkey.  Application of peripheral opioids including kappa agonists for treatment of gastrointestinal diseases has also been extensively reviewed. See for example, Lembo, Diges. Dis. 24:91-8 (2006) for a discussion of use of opioids in treatment of digestive disorders, including irritable bowel syndrome (IBS), ileus, and functional dyspepsia. Ophthalmic disorders, including ocular inflammation and glaucoma have also been shown to be addressable by kappa opioids. See Potter et ah, J. Pharmacol. Exp. Ther. 309:548-53 (2004), describing the role of the potent kappa opioid receptor agonist, bremazocine, in reduction of intraocular pressure and blocking of this effect by norbinaltorphimine (norBNI), the prototypical kappa opioid receptor antagonist; and Dortch-Carnes et al, CNS Drug Rev. 11(2): 195-212 (2005). U.S. Patent 6,191,126 to Gamache discloses the use of kappa opioid agonists to treat ocular pain. Otic pain has also been shown to be treatable by administration of kappa opioid agonists. See U.S. Patent 6,174,878 also to Gamache. Kappa opioid agonists increase the renal excretion of water and decrease urinary sodium excretion (i.e., produces a selective water diuresis, also referred to as aquaresis). Many, but not all, investigators attribute this effect to a suppression of vasopressin secretion from the pituitary. Studies comparing centrally acting and purportedly peripherally selective kappa opioids have led to the conclusion that kappa opioid receptors within the blood-brain barrier are responsible for mediating this effect. Other investigators have proposed to treat hyponatremia with nociceptin peptides or charged peptide conjugates that act peripherally at the nociceptin receptor, which is related to but distinct from the kappa opioid receptor (D. R. Kapusta, Life ScL, 60: 15-21, 1997) (U.S. Pat. No. 5,840,696). U.S. Pat Appl. 20060052284.
PATENTJpn. Tokkyo Koho, 5807140US 20090156508WO 2008057608
Example 2Synthesis of Compound (2): D-Phe-D-Phe-D-Leu-D-Lys-[ω(4-aminopiperidine-4-carboxylic acid)]-OHSee the scheme of FIG. 3 and Biron et al., Optimized selective N-methylation of peptides on solid support. J. Peptide Science 12: 213-219 (2006). The amino acid derivatives used were Boc-D-Phe-OH, Fmoc-D-Phe-OH, Fmoc-D-Leu-OH, Fmoc-D-Lys(Dde)-OH, and N-Boc-amino-(4-N-Fmoc-piperidinyl)carboxylic acid. HPLC and MS analyses were performed as described in the synthesis of compound (1) described above.The fully protected resin-bound peptide was synthesized manually starting from 2-Chlorotrityl chloride resin (1.8 g, 0.9 mmol; Peptide International). Attachment of N-Boc-amino-(4-N-Fmoc-piperidinyl)carboxylic acid followed by peptide chain elongation and deprotection of Dde in D-Lys(Dde) at Xaa4 was carried out according to the procedure described in the synthesis of compound (1). See above. The resulting peptide resin (0.9 mmol; Boc-D-Phe-D-Phe-D-Leu-D-Lys-(N-Boc-amino-4-piperidinylcarboxylic acid)-[2-Cl-Trt resin]) was split and a portion of 0.3 mmol was used for subsequent cleavage. The peptide resin (0.3 mmol) was then treated with a mixture of TFA/TIS/H2O (15 ml, v/v/v=95:2.5:2.5) at room temperature for 90 minutes. The resin was then filtered and washed with TFA. The filtrate was evaporated in vacuo and the crude synthetic peptide amide (0.3 mmol; D-Phe-D-Phe-D-Leu-D-Lys-[ω(4-aminopiperidine-4-carboxylic acid)]-OH) was precipitated from diethyl ether.For purification, the crude synthetic peptide amide (0.3 mmol) was dissolved in 2% acetic acid in H2O (50 ml) and the solution was loaded onto an HPLC column and purified using TEAP buffer system with a pH 5.2 (buffers A=TEAP 5.2 and B=20% TEAP 5.2 in 80% ACN). The compound was eluted with a linear gradient of buffer B, 7% B to 37% B over 60 minutes. Fractions with purity exceeding 95% were pooled and the resulting solution was diluted with two volumes of water. The diluted solution was then loaded onto an HPLC column for salt exchange and further purification with a TFA buffer system (buffers A=0.1% TFA in H2O and B=0.1% TFA in 80% ACN/20% H2O) and a linear gradient of buffer B, 2% B to 75% B over 25 minutes. Fractions with purity exceeding 97% were pooled, frozen, and dried on a lyophilizer to yield the purified synthetic peptide amide as white amorphous powder (93 mg). HPLC analysis: tR=16.43 min, purity 99.2%, gradient 5% B to 25% B over 20 min; MS (MH+): expected molecular ion mass 680.4, observed 680.3.Compound (2) was also prepared using a reaction scheme analogous to that shown in FIG. 3 with the following amino acid derivatives: Fmoc-D-Phe-OH, Fmoc-D-Leu-OH, Fmoc-D-Lys(Boc)-OH, and Boc-4-amino-1-Fmoc-(piperidine)-4-carboxylic acid.The fully protected resin-bound peptide was synthesized manually starting from 2-Chlorotrityl chloride resin (PS 1% DVB, 500 g, 1 meq/g). The resin was treated with Boc-4-amino-1-Fmoc-4-(piperidine)-4-carboxylic acid (280 g, 600 mmol) in a mixture of DMF, DCM and DIEA (260 mL of each) was added. The mixture was stirred for 4 hours and then the resin was capped for 1 h by the addition of MeOH (258 mL) and DIEA (258 mL).The resin was isolated and washed with DMF (3×3 L). The resin containing the first amino acid was treated with piperidine in DMF (3×3 L of 35%), washed with DMF (9×3 L) and Fmoc-D-Lys(Boc)-OH (472 g) was coupled using PyBOP (519 g) in the presence of HOBt (153 g) and DIEA (516 mL) and in DCM/DMF (500 mL/500 mL) with stiffing for 2.25 hours. The dipeptide containing resin was isolated and washed with DMF (3×3.6 L). The Fmoc group was removed by treatment with piperidine in DMF(3×3.6 L of 35%) and the resin was washed with DMF (9×3.6 L) and treated with Fmoc-D-Leu-OH (354 g), DIC (157 mL) and HOBt (154 g) in DCM/DMF (500 mL/500 mL) and stirred for 1 hour. Subsequent washing with DMF (3×4.1 L) followed by cleavage of the Fmoc group with piperidine in DMF (3×4.2 L of 35%) and then washing of the resin with DMF (9×4.2 L) provided the resin bound tripeptide. This material was treated with Fmoc-D-Phe-OH (387 g), DIC (157 mL) and HOBt (153 g) in DCM/DMF (500 mL/500 mL) and stirred overnight. The resin was isolated, washed with DMF (3×4.7 L) and then treated with piperidine in DMF (3×4.7 L of 35%) to cleave the Fmoc group and then washed again with DMF (9×4.7 L). The tetrapeptide loaded resin was treated with Fmoc-D-Phe-OH (389 g), DIC (157 mL) and HOBt (154 g) in DCM/DMF (500 mL/500 mL) and stirred for 2.25 hours. The resin was isolated, washed with DMF (3×5.2 L) and then treated piperidine (3×5.2 L of 35%) in DMF. The resin was isolated, and washed sequentially with DMF (9×5.2 L) then DCM (5×5.2 L). It was dried to provide a 90.4% yield of protected peptide bound to the resin. The peptide was cleaved from the resin using TFA/water (4.5 L, 95/5), which also served to remove the Boc protecting groups. The mixture was filtered, concentrated (⅓) and then precipitated by addition to MTBE (42 L). The solid was collected by filtration and dried under reduced pressure to give crude synthetic peptide amide.For purification, the crude synthetic peptide amide was dissolved in 0.1% TFA in H2O and purified by preparative reverse phase HPLC (C18) using 0.1% TFA/water—ACN gradient as the mobile phase. Fractions with purity exceeding 95% were pooled, concentrated and lyophilized to provide pure synthetic peptide amide (>95.5% pure). Ion exchange was conducted using a Dowex ion exchange resin, eluting with water. The aqueous phase was filtered (0.22 μm filter capsule) and freeze-dried to give the acetate salt of the synthetic peptide amide (2) with overall yield, 71.3%, >99% purity.Hydrochloride, hydrobromide and fumarate counterions were evaluated for their ability to form crystalline salts of synthetic peptide amide (2). Approximately 1 or 2 equivalents (depending on desired stoichiometry) of hydrochloric acid, hydrobromic acid or fumaric acid, as a dilute solution in methanol (0.2-0.3 g) was added to synthetic peptide amide (2) (50-70 mg) dissolved in methanol (0.2-0.3 g). Each individual salt solution was added to isopropyl acetate (3-5 mL) and the resulting amorphous precipitate was collected by filtration and dried at ambient temperature and pressure. Crystallization experiments were carried out by dissolving the 10-20 mg of the specific amorphous salt obtained above in 70:30 ethanol-water mixture (0.1-0.2 g) followed by the addition of ethanol to adjust the ratio to 90:10 (˜0.6-0.8 mL). Each solution was then seeded with solid particles of the respective precipitated salt. Each sample tube was equipped with a magnetic stir bar and the sample was gently stirred at ambient temperature. The samples were periodically examined by plane-polarized light microscopy. Under these conditions, the mono- and di-hydrochloride salts, the di-hydrobromide salt and the mono-fumarate salt crystallized as needles of 20 to 50 μm in length with a thickness of about 1 μm.PATENT
https://patents.google.com/patent/WO2008057608A2/en Compound (2): D-Phe-D-Phe-D-Leu-D-Lys-[ω(4-aminopiperidine-4- carboxylic acid)]-OH (SEQ ID NO: 2):
EXAMPLE 2: Synthesis of compound (2) D-Phe-D-Phe-D-Leu-D-Lys-[ω(4-aminopiperidine-4-carboxylic acid)]-OH (SEQ ID NO: 2): See the scheme of Figure 2 and B iron et al., Optimized selective N- methylation of peptides on solid support. J. Peptide Science 12: 213-219 (2006). The amino acid derivatives used were Boc-D-Phe-OH, Fmoc-D-Phe-OH, Fmoc-D-Leu- OH, Fmoc-D-Lys(Dde)-OH, and N-Boc-amino-(4-N-Fmoc-piperidinyl) carboxylic acid. HPLC and MS analyses were performed as described in the synthesis of compound (1) described above. The fully protected resin-bound peptide was synthesized manually starting from 2-Chlorotrityl chloride resin (1.8 g, 0.9 mmol; Peptide International). Attachment of N-Boc-amino-(4-N-Fmoc-piperidinyl) carboxylic acid followed by peptide chain elongation and deprotection of Dde in D-Lys(Dde) at Xa^ was carried out according to the procedure described in the synthesis of compound (1). See above. The resulting peptide resin (0.9 mmol; Boc-D-Phe-D-Phe-D-Leu-D-Lys-(N- Boc-amino-4-piperidinylcarboxylic acid)-[2-Cl-Trt resin]) was split and a portion of 0.3 mmol was used for subsequent cleavage. The peptide resin (0.3 mmol) was then treated with a mixture of TFA/TIS/H2O (15 ml, v/v/v = 95:2.5:2.5) at room temperature for 90 min. The resin was then filtered and washed with TFA. The filtrate was evaporated in vacuo and the crude peptide (0.3 mmol; D-Phe-D-Phe-D- Leu-D-Lys-[ω(4-aminopiperidine-4-carboxylic acid)]-OH) was precipitated from diethyl ether. For purification, the crude peptide (0.3 mmol) was dissolved in 2% acetic acid in H2O (50 ml) and the solution was loaded onto an HPLC column and purified using TEAP buffer system with a pH 5.2 (buffers A = TEAP 5.2 and B = 20% TEAP 5.2 in 80% ACN). The compound was eluted with a linear gradient of buffer B, 7%B to 37%B over 60 min. Fractions with purity exceeding 95% were pooled and the resulting solution was diluted with two volumes of water. The diluted solution was then loaded onto an HPLC column for salt exchange and further purification with a TFA buffer system (buffers A = 0.1% TFA in H2O and B = 0.1% TFA in 80% ACN/20% H2O) and a linear gradient of buffer B, 2%B to 75%B over 25 min. Fractions with purity exceeding 97% were pooled, frozen, and dried on a lyophilizer to yield the purified peptide as white amorphous powder (93 mg). HPLC analysis: tR = 16.43 min, purity 99.2%, gradient 5%B to 25%B over 20 min; MS (M+H+): expected molecular ion mass 680.4, observed 680.3. Compound (2) was also prepared using a reaction scheme analogous to that shown in figure 2 with the following amino acid derivatives: Fmoc-D-Phe-OH, Fmoc-D-Leu-OH, Fmoc-D-Lys(Boc)-OH, and Boc-4-amino-l-Fmoc-(piperidine)-4- carboxylic acid. The fully protected resin-bound peptide was synthesized manually starting from 2-Chlorotrityl chloride resin (PS 1%DVB, 500 g, 1 meq/g). The resin was treated with Boc-4-amino-l-Fmoc-4-(piperidine)-4-carboxylic acid (280 g, 600 mmol) in a mixture of DMF, DCM and DIEA (260 mL of each) was added. The mixture was stirred for 4 hours and then the resin was capped for Ih by the addition of MeOH (258 mL) and DIEA (258 mL). The resin was isolated and washed with DMF (3 x 3 L). The resin containing the first amino acid was treated with piperidine in DMF (3 x 3 L of 35%), washed with DMF (9 x 3 L) and Fmoc-D-Lys(Boc)-OH (472 g) was coupled using PyBOP (519 g) in the presence of HOBt (153 g) and DIEA (516 mL) and in DCM/DMF (500 mL/ 500 mL) with stirring for 2.25 hours. The dipeptide containing resin was isolated and washed with DMF (3 x 3.6 L). The Fmoc group was removed by treatment with piperidine in DMF  , (3 x 3.6 L of 35%) and the resin was washed with DMF (9 x 3.6 L) and treated with Fmoc-D-Leu-OH (354 g), DIC (157 mL) and HOBt (154 g) in DCM/DMF (500 mL / 500 mL) and stirred for 1 hour. Subsequent washing with DMF (3 x 4.1 L) followed by cleavage of the Fmoc group with piperidine in DMF (3 x 4.2 L of 35%) and then washing of the resin with DMF (9 x 4.2 L) provided the resin bound tripeptide. This material was treated with Fmoc-D-Phe-OH (387 g), DIC (157 mL) and HOBt (153 g) in DCM/DMF (500 mL / 500 mL) and stirred overnight. The resin was isolated, washed with DMF (3 x 4.7 L) and then treated with piperidine in DMF (3 x 4.7 L of 35%) to cleave the Fmoc group and then washed again with DMF (9 x 4.7 L). The tetrapeptide loaded resin was treated with Fmoc-D-Phe-OH (389 g), DIC (157 mL) and HOBt (154 g) in DCM/DMF (500 mL / 500 mL) and stirred for 2.25 hours. The resin was isolated, washed with DMF (3 x 5.2 L) and then treated piperidine (3 x 5.2 L of 35%) in DMF. The resin was isolated, and washed sequentially with DMF (9 x 5.2 L) then DCM (5 x 5.2 L). It was dried to provide a 90.4% yield of protected peptide bound to the resin. The peptide was cleaved from the resin using TFA/ water (4.5 L, 95/5), which also served to remove the Boc protecting groups. The mixture was filtered, concentrated (1/3) and then precipitated by addition to MTBE (42 L). The solid was collected by filtration and dried under reduced pressure to give crude peptide. For purification, the crude peptide was dissolved in 0.1% TFA in H2O and purified by preparative reverse phase HPLC (C 18) using 0.1% TF A/water – ACN gradient as the mobile phase. Fractions with purity exceeding 95% were pooled, concentrated and lyophilized to provide pure peptide (> 95.5% pure). Ion exchange was conducted using a Dowex ion exchange resin, eluting with water. The aqueous phase was filtered (0.22 μm filter capsule) and freeze-dried to give the acetate salt of the peptide (overall yield, 71.3%, >99% pure).
κ opioid receptor agonists are known to be useful as therapeutic agents for various pain. Among, kappa opioid receptor agonist with high selectivity for peripheral kappa opioid receptors, are expected as a medicament which does not cause the central side effects. Such as peripherally selective κ opioid receptor agonist, a synthetic pentapeptide has been reported (Patent Documents 1 and 2). The following formula among the synthetic pentapeptide (A)
[Formula 1] Being Represented By Compounds Are Useful As Pain Therapeutics. The Preparation Of This Compound, Solid Phase Peptide Synthesis Methods In Patent Documents 1 And 2 Have Been Described.Document 1 Patent: Kohyo 2010-510966 JP
Patent Document 2: Japanese Unexamined Patent Publication No. 2013-241447 Compound (1) or a salt thereof and compound (A), for example as shown in the following reaction formula, 4-aminopiperidine-4-carboxylic acid, D- lysine (D-Lys), D- leucine (D-Leu) , it can be prepared by D- phenylalanine (D-Phe) and D- phenylalanine (D-Phe) sequentially solution phase peptide synthesis methods condensation.[Of 4]The present invention will next to examples will be described in further detail.Example
1 (1) Synthesis of Cbz-D-Lys (Boc) -α-Boc-Pic-OMe (3)
to the four-necked flask of 2L, α-Boc-Pic- OMe · HCl [α-Boc-4 – aminopiperidine-4-carboxylic acid methyl hydrochloride] were charged (2) 43.7g (148mmol), was suspended in EtOAc 656mL (15v / w). To the suspension of 1-hydroxybenzotriazole (HOBt) 27.2g (178mmol), while cooling with Cbz-D-Lys (Boc) -OH 59.2g (156mmol) was added an ice-bath 1-ethyl -3 – (3-dimethylcarbamoyl amino propyl) was added to the carbodiimide · HCl (EDC · HCl) 34.1g (178mmol). After 20 minutes, stirring was heated 12 hours at room temperature. After completion of the reaction, it was added and the organic layer was 1 N HCl 218 mL of (5.0v / w). NaHCO to the resulting organic layer 3 Aq. 218ML (5.0V / W), Et 3 N 33.0 g of (326Mmol) was stirred for 30 minutes, and the mixture was separated. The organic layer HCl 218ML 1N (5.0V / W), NaHCO 3 Aq. 218mL (5.0v / w), NaClaq . Was washed successively with 218ML (5.0V / W), Na 2 SO 4 dried addition of 8.74g (0.2w / w). Subjected to vacuum filtration, was concentrated under reduced pressure resulting filtrate by an evaporator, and pump up in the vacuum pump, the Cbz-D-Lys (Boc) -α-Boc-Pic-OMe (3) 88.9g as a white solid obtained (96.5% yield, HPLC purity 96.5%).(2) D-Lys (Boc) Synthesis Of -Arufa-Boc-Pic-OMe (4)
In An Eggplant-Shaped Flask Of 2L, Cbz-D-Lys (Boc) -Arufa-Boc-Pic-OMe (3) 88.3g (142mmol) were charged, it was added and dissolved 441mL (5.0v / w) the EtOAc. The 5% Pd / C to the reaction solution 17.7g (0.2w / w) was added, After three nitrogen substitution reduced pressure Atmosphere, Was Performed Three Times A Hydrogen Substituent. The Reaction Solution Was 18 Hours With Vigorous Stirring At Room Temperature To Remove The Pd / C And After The Completion Of The Reaction Vacuum Filtration. NaHCO The Resulting Filtrate 3 Aq. 441ML And (5.0V / W) Were Added For Liquid Separation, And The Organic Layer Was Extracted By The Addition Of EtOAc 200ML (2.3V / W) In The Aqueous Layer. NaHCO The Combined Organic Layer 3 Aq. 441ML And (5.0V / W) Were Added for liquid separation, and the organic layer was extracted addition of EtOAc 200mL (2.3v / w) in the aqueous layer. NaClaq the combined organic layers. 441mL and (5.0v / w) is added to liquid separation, was extracted by the addition EtOAc 200ML Of (2.3V / W) In The Aqueous Layer. The Combined Organic Layer On The Na 2 SO 4 Dried Addition Of 17.7 g of (0.2W / W), Then The Filtrate Was Concentrated Under Reduced Pressure Obtained Subjected To Vacuum Filtration By an evaporator, and pump up in the vacuum pump, D-Lys (Boc) -α-Boc-Pic- OMe (4) to give 62.7g (90.5% yield, HPLC purity 93.6%).(3) Cbz-D-Leu -D-Lys (Boc) -α-Boc-Pic-OMe synthesis of (5)
in the four-necked flask of 2L, D-Lys (Boc) -α-Boc-Pic-OMe (4) was charged 57.7 g (120 mmol), was suspended in EtOAc 576mL (10v / w). HOBt 19.3g (126mmol) to this suspension, was added EDC · HCl 24.2g (126mmol) while cooling in an ice bath added Cbz-D-Leu-OH 33.4g (126mmol). After 20 minutes, after stirring the temperature was raised 5 hours at room temperature, further the EDC · HCl and stirred 1.15 g (6.00 mmol) was added 16 h. After completion of the reaction, it was added liquid separation 1N HCl 576mL (10v / w) . NaHCO to the resulting organic layer 3 Aq. 576ML (10V / W), Et 3 N 24.3 g of (240Mmol) was stirred for 30 minutes, and the mixture was separated. The organic layer HCl 576ML 1N (10V / W), NaHCO 3 Aq. 576mL (10v / w), NaClaq . Was washed successively with 576ML (10V / W), Na 2 SO 4 dried addition of 11.5g (0.2w / w). After the filtrate was concentrated under reduced pressure obtained subjected to vacuum filtration by an evaporator, and pump up in the vacuum pump, the Cbz-D-Leu-D- Lys (Boc) -α-Boc-Pic-OMe (5) 85.8g It was obtained as a white solid (98.7% yield, HPLC purity 96.9%).(4) D-Leu-D -Lys (Boc) -α-Boc-Pic-OMe synthesis of (6)
in an eggplant-shaped flask of 1L, Cbz-D-Leu- D-Lys (Boc) -α-Boc-Pic -OMe the (5) 91.9g (125mmol) were charged, was added and dissolved 459mL (5.0v / w) the EtOAc. The 5% Pd / C to the reaction solution 18.4g (0.2w / w) was added, After three nitrogen substitution reduced pressure atmosphere, was performed three times a hydrogen substituent. The reaction solution was subjected to 8 hours with vigorous stirring at room temperature to remove the Pd / C and after the completion of the reaction vacuum filtration. NaHCO the resulting filtrate 3 Aq. 200mL (2.2v / w) were added to separate liquid, NaHCO to the organic layer 3 Aq. 200mL (2.2v / w), NaClaq . It was sequentially added washed 200mL (2.2v / w). To the resulting organic layer Na 2 SO 4 dried added 18.4g (0.2w / w), to the filtrate concentrated under reduced pressure obtained subjected to vacuum filtration by an evaporator, and a pump-up with a vacuum pump. The resulting amorphous solid was dissolved adding EtOAc 200mL (2.2v / w), was crystallized by the addition of heptane 50mL (1.8v / w). Was filtered off precipitated crystals by vacuum filtration, the crystals were washed with a mixed solvent of EtOAc 120mL (1.3v / w), heptane 50mL (0.3v / w). The resulting crystal 46.1g to added to and dissolved EtOAc 480mL (5.2v / w), was crystallized added to the cyclohexane 660mL (7.2v / w). Was filtered off under reduced pressure filtered to precipitate crystals, cyclohexane 120mL (1.3v / w), and washed with a mixed solvent of EtOAc 20mL (0.2v / w), and 30 ° C. vacuum dried, D-Leu- as a white solid D-Lys (Boc) -α- Boc-Pic-OMe (6) to give 36.6 g (48.7% yield, HPLC purity 99.9%).(5) Synthesis of Cbz-D-Phe-D- Leu-D-Lys (Boc) -α-Boc-Pic-OMe (7)
to the four-necked flask of 1L, D-Leu-D- Lys (Boc) -α-Boc-Pic-OMe with (6) 35.8g (59.6mmol) was charged, it was suspended in EtOAc 358mL (10v / w). To this suspension HOBt 9.59g (62.6mmol), Cbz- D-Phe-OH 18.7g was cooled in an ice bath is added (62.6mmol) while EDC · HCl 12.0g (62.6mmol) It was added. After 20 minutes, a further EDC · HCl After stirring the temperature was raised 16 hours was added 3.09 g (16.1 mmol) to room temperature. After completion of the reaction, it was added and the organic layer was 1N HCl 358mL of (10v / w). NaHCO to the resulting organic layer 3 Aq. 358ML (10V / W), Et 3 N 12.1 g of (119Mmol) was stirred for 30 minutes, and the mixture was separated. The organic layer HCl 358ML 1N (10V / W), NaHCO 3 Aq. 358mL (10v / w), NaClaq . Was washed successively with 358ML (10V / W), Na 2 SO 4 dried addition of 7.16g (0.2w / w). After the filtrate was concentrated under reduced pressure obtained subjected to vacuum filtration by an evaporator, and pump up in the vacuum pump, Cbz-D-Phe-D -Leu-D-Lys (Boc) -α-Boc-Pic-OMe (7) was obtained 52.5g as a white solid (yield quant, HPLC purity 97.6%).(6) D-Phe-D -Leu-D-Lys (Boc) synthesis of -α-Boc-Pic-OMe ( 8)
in an eggplant-shaped flask of 2L, Cbz-D-Phe- D-Leu-D-Lys ( Boc) -α-Boc-Pic- OMe (7) the 46.9g (53.3mmol) were charged, the 840ML EtOAc (18V / W), H 2 added to and dissolved O 93.8mL (2.0v / w) It was. The 5% Pd / C to the reaction mixture 9.38g (0.2w / w) was added, After three nitrogen substitution reduced pressure atmosphere, was performed three times a hydrogen substituent. The reaction solution was subjected to 10 hours with vigorous stirring at room temperature to remove the Pd / C and after the completion of the reaction vacuum filtration. NaHCO the resulting filtrate 3 Aq. 235mL (5.0v / w) were added to separate liquid, NaHCO to the organic layer 3 Aq. 235mL (5.0v / w), NaClaq . It was added sequentially cleaning 235mL (5.0v / w). To the resulting organic layer Na 2 SO 4 dried addition of 9.38g (0.2w / w), then the filtrate was concentrated under reduced pressure obtained subjected to vacuum filtration by an evaporator, pump up with a vacuum pump to D-Phe -D-Leu-D-Lys ( Boc) -α-Boc-Pic-OMe (7) was obtained 39.7g (yield quant, HPLC purity 97.3%).351mL was suspended in (10v / w). To this suspension HOBt 7.92g (51.7mmol), Boc-D-Phe-OH HCl HCl(8) D-Phe-D -Phe-D-Leu-D-Lys-Pic-OMe Synthesis Of Hydrochloric Acid Salt (1)
In An Eggplant-Shaped Flask Of 20ML Boc-D-Phe-D -Phe-D- Leu-D- lys (Boc) -α -Boc- Pic-OMe (9) and 2.00gg, IPA 3.3mL (1.65v / w), was suspended by addition of PhMe 10mL (5v / w). It was stirred at room temperature for 19 hours by addition of 6N HCl / IPA 6.7mL (3.35v / w). The precipitated solid was filtered off by vacuum filtration and dried under reduced pressure to a white solid of D-Phe-D-Phe- D- Leu-D-Lys-Pic- OMe 1.59ghydrochloride (1) (yield: 99 .0%, HPLC purity 98.2%) was obtained.(9) D-Phe-D -Phe-D-Leu-D-Lys-Pic-OMe Purification Of The Hydrochloric Acid Salt (1)
In An Eggplant-Shaped Flask Of 20ML-D-Phe-D- Phe D-Leu -D-Lys- pic-OMe hydrochloride crude crystals (1) were charged 200mg, EtOH: MeCN = 1: after stirring for 1 hour then heated in a mixed solvent 4.0 mL (20v / w) was added 40 ° C. of 5 , further at room temperature for 2 was time stirring slurry. Was filtered off by vacuum filtration, the resulting solid was dried under reduced pressure a white solid ((1) Purification crystals) was obtained 161 mg (80% yield, HPLC purity 99.2% ).(10) D-Phe-D -Phe-D-Leu-D-Lys-Pic Synthesis (Using Purified
(1)) Of (A) To A Round-Bottomed Flask Of 10ML D-Phe-D-Phe-D- -D-Lys Leu-Pic-OMe Hydrochloride Salt (1) Was Charged With Purified Crystal 38.5Mg (0.0488Mmol), H 2 Was Added And Dissolved O 0.2ML (5.2V / W). 1.5H Was Stirred Dropwise 1N NaOH 197MyuL (0.197mmol) at room temperature. After completion of the reaction, concentrated under reduced pressure by an evaporator added 1N HCl 48.8μL (0.0488mmol), to obtain a D-Phe-D-Phe- D-Leu-D-Lys- Pic (A) (yield: quant , HPLC purity 99.7%).
D-Phe-D-Phe- D-Leu-D-Lys-Pic-OMe (1) physical properties 1 H NMR (400 MHz, 1M DCl) [delta] ppm by: 0.85-1.02 (yd,. 6 H), 1.34-1.63 ( m, 5 H), 1.65-2.12 ( m, 5 H), 2.23-2.45 (m, 2 H), 2.96-3.12 (m, 4 H), 3.19 (ddt, J = 5.0 & 5.0 & 10.0 Hz), 3.33-3.62 (m, 1 H), 3.68-3.82 (m, 1 H), 3.82-3.95 (m, 4 H), 3.95-4.18 (m, 1 H), 4.25-4.37 (m, 2 H), 4.61-4.77 (M, 2 H), 7.21-7.44 (M, 10 H) 13 C NMR (400MHz, 1M DCl) Deruta Ppm: 21.8, 22.5, 24.8, 27.0, 30.5, 30.8, 31.0, 31.2, 31.7, 37.2 , 37.8, 38.4, 39.0, 39.8, 40.4, 40.6, 41.8, 42.3, 49.8, 50.2, 52.2, 52.6, 54.6, 55.2, 57.7, 57.9, 127.6, 128.4, 129.2, 129.6, 129.7, 129.8 dp 209.5 ℃Example 2
(Trifluoroacetic Acid (TFA)
Use) (1) D-Phe-D-Phe-D-Leu-D-Lys-Pic-OMe TFA Synthesis Of Salt (1)
TFA 18ML Eggplant Flask Of 50ML (18V / W) , 1- Dodecanethiol 1.6ML (1.6V / W), Triisopropylsilane 0.2ML (0.2V / W), H 2 Sequentially Added Stirring The O 0.2ML (0.2V / W) Did. The Solution To The Boc-D-Phe- D- Phe-D-Leu-D -Lys (Boc) -α-Boc-Pic-OMe the (9) 1.00g (1.01mmol) was added in small portions with a spatula. After completion of the reaction, concentrated under reduced pressure by an evaporator, it was added dropwise the resulting residue in IPE 20mL (20v / w). The precipitated solid was filtered off, the resulting solid was obtained and dried under reduced pressure to D-Phe-D-Phe- D-Leu -D-Lys-Pic-OMe · TFA salt as a white solid (1) (Osamu rate 93.0%, HPLC purity 95.2%).(2) D-Phe-D -Phe-D-Leu-D-Lys-Pic synthesis of (A)
to a round-bottomed flask of 10mL D-Phe-D-Phe -D-Leu-D-Lys-Pic-OMe TFA were charged salt (1) 83mg (0.0843mmol), was added and dissolved H2O 431μL (5.2v / w). Was 12h stirring dropwise 1N NaOH 345μL (0.345mmol) at room temperature. After completion of the reaction, concentrated under reduced pressure by an evaporator added 1N HCl 84.3μL (0.0843mmol), to obtain a D-Phe-D-Phe- D-Leu-D-Lys-Pic (A) ( yield: quant, HPLC purity 95.4%).Example
3 (HCl / EtOAc
Use) (1) In An Eggplant-Shaped Flask Of 30ML Boc-D-Phe-D -Phe-D-Leu-D-Lys (Boc) -Arufa-Boc-Pic-OMe (9) 1. It was charged with 00g (1.01mmol ), was added and dissolved EtOAc7.0mL (7.0v / w). 4N HCl / EtOAc 5.0mL (5.0v / w) was added after 24h stirring at room temperature, the precipitated solid was filtered off by vacuum filtration, washed with EtOAc 2mL (2.0v / w). The resulting solid D-Phe-D-Phe- D-Leu-D-Lys-Pic-OMe hydrochloride (1) was obtained 781mg of a white solid was dried under reduced pressure (the 96.7% yield, HPLC purity 95.4%).(2) D-Phe-D -Phe-D-Leu-D-Lys-Pic (A) Synthesis of
eggplant flask of 10mL D-Phe-D-Phe -D-Leu-D-Lys-Pic-OMe hydrochloride were charged salt (1) 90 mg (0.112 mmol), H 2 was added and dissolved O 0.47mL (5.2v / w). Was 12h stirring dropwise 1N NaOH 459μL (0.459mmol) at room temperature. After completion of the reaction, concentrated under reduced pressure by an evaporator added 1N HCl 0.112μL (0.112mmol), was obtained D-Phe-D-Phe- D-Leu-D-Lys-Pic (A) ( yield: quant, HPLC purity 93.1%).4 Example
Compound (1) Of The Compound By Hydrolysis Synthesis Of (The A) (Compound (1) Without
Purification) Eggplant Flask 10ML D-Phe-D-Phe -D-Leu-D-Lys-Pic-OMe (1) Charged Hydrochloride Were (Without Pre-Step Purification) 114.5Mg (0.142Mmol), H 2 Was Added And Dissolved O 595MyuL (5.2V / W). Was 14H Stirring Dropwise 1N NaOH 586MyuL (0.586Mmol) At Room Temperature. After Completion Of the reaction, concentrated under reduced pressure by an evaporator added 1N HCl 0.15μL (0.150mmol), was obtained D-Phe-D-Phe- D-Leu-D-Lys-Pic (A) (yield: quant, HPLC purity 95.2 %).Example 1 Comparative
Path Not Via The Compound (1) (Using Whole Guard Boc-D-Phe-D-Phe-D-Leu-D-Lys (Boc) -Alpha-Boc-Pic-OMe
(A)) (1) D–Boc Phe- D-Phe-D-Leu-D-Lys (Boc) -Arufa-Boc-Pic-OH Synthesis Of
Eggplant Flask Of 30ML Boc-D-Phe-D -Phe-D-Leu-D- Lys (Boc) -α- Boc-Pic -OMe (9) were charged 1.00g (1.00mmol), was added and dissolved MeOH 5.0mL (5.0v / w). After stirring for four days by the addition of 1N NaOH 1.1 mL (1.10mmol) at room temperature, further MeOH 5.0mL (5.0v / w), 1N NaOH 2.0mL the (2.0mmol) at 35 ℃ in addition 3h and the mixture was stirred. After completion of the reaction, 1 N HCl 6.1 mL was added, After distilling off the solvent was concentrated under reduced pressure was separated and the organic layer was added EtOAc 5.0mL (5.0mL) .NaClaq. 5.0mL (5.0v / w) Wash the organic layer was added, the organic layer as a white solid was concentrated under reduced pressure to Boc-D-Phe-D- Phe-D-Leu-D-Lys (Boc) – α-Boc-Pic-OH 975.1mg (99.3% yield, HPLC purity 80.8% )(2) D-Phe-D -Phe-D-Leu-D-Lys-Pic synthesis of (A)
to a round-bottomed flask of 20mL Boc-D-Phe-D -Phe-D-Leu-D-Lys (Boc) It was charged -α-Boc-Pic-OH ( 10) 959mg (0.978mmol), was added and dissolved EtOAc 4.9mL (5.0v / w). And 4h stirring at room temperature was added dropwise 4N HCl / EtOAc 4.9mL (5.0mL) at room temperature. After completion of the reaction, it was filtered under reduced pressure, a white solid as to give D-Phe-D-Phe- D-Leu-D-Lys-Pic the (A) (96.4% yield, HPLC purity 79.2%) . If not via the compound of the present invention (1), the purity of the compound obtained (A) was less than 80%.
- ^ Janecka A, Perlikowska R, Gach K, Wyrebska A, Fichna J (2010). “Development of opioid peptide analogs for pain relief”. Curr. Pharm. Des. 16 (9): 1126–35. doi:10.2174/138161210790963869. PMID 20030621.
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- ^ Jump up to:a b c d e f g h i j Raymond S. Sinatra; Jonathan S. Jahr; J. Michael Watkins-Pitchford (14 October 2010). The Essence of Analgesia and Analgesics. Cambridge University Press. pp. 490–491. ISBN 978-1-139-49198-3.
- ^ Jump up to:a b c d e Jeffrey Apfelbaum (8 September 2014). Ambulatory Anesthesia, An Issue of Anesthesiology Clinics. Elsevier Health Sciences. pp. 190–. ISBN 978-0-323-29934-3.
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- ^ “Korsuva: FDA-Approved Drugs”. U.S. Food and Drug Administration. Retrieved 24 August 2021.
- ^ “Vifor Pharma and Cara Therapeutics announce U.S. FDA approval of Korsuva injection for the treatment of moderate-to-severe pruritus in hemodialysis patients” (Press release). Vifor Pharma. 24 August 2021. Retrieved 24 August 2021 – via Business Wire.
- ^ Fishbane S, Jamal A, Munera C, Wen W, Menzaghi F (2020). “A phase 3 trial of difelikefalin in hemodialysis patients with pruritus”. N Engl J Med. 382 (3): 222–232. doi:10.1056/NEJMoa1912770. PMID 31702883.
- “Difelikefalin”. Drug Information Portal. U.S. National Library of Medicine.
- Clinical trial number NCT03422653 for “A Study to Evaluate the Safety and Efficacy of CR845 in Hemodialysis Patients With Moderate-to-Severe Pruritus (KALM-1)” at ClinicalTrials.gov
- Clinical trial number NCT03636269 for “CR845-CLIN3103: A Global Study to Evaluate the Safety and Efficacy of CR845 in Hemodialysis Patients With Moderate-to-Severe Pruritus (KALM-2)” at ClinicalTrials.gov
|Other names||CR845, FE-202845, D-Phe-D-Phe-D-Leu-D-Lys-[γ-(4-N-piperidinyl)amino carboxylic acid]|
|License data||US DailyMed: Difelikefalin|
|Drug class||Kappa opioid receptor agonist|
|Legal status||US: ℞-only |
|Elimination half-life||2 hours|
|Excretion||Excreted as unchanged|
drug via bile and urine
|Chemical and physical data|
|Molar mass||679.863 g·mol−1|
|3D model (JSmol)||Interactive image|
//////////Difelikefalin acetate, FDA 2021, APPROVALS 2021, FORSUVA, ジフェリケファリン酢酸塩 , Difelikefalin, CR 845, MR 13A-9, MR-13A9, PEPTIDE
FPTIPLSRLF DNAMLRAHRL HQLAFDTYQE FEEAYIPKEQ KYSFLQNPQT SLCFSESIPT
PSNREETQQK SNLELLRISL LLIQSWLEPV QFLRSVFANS LVYGASDSNV YDLLKDLEEG
IQTLMGRLED GSPRTGQIFK QTYSKFDTNS HNDDALLKNY GLLYCFRKDM DKVETFLRIV
(Disulfide bridge: 53-165, 182-189)
FDA APPROVED, 25/8/21, Skytrofa, Treatment of growth hormone deficiency
To treat short stature due to inadequate secretion of endogenous growth hormone
1934255-39-6 CAS, UNII: OP35X9610Y
Molecular Formula, C1051-H1627-N269-O317-S9[-C2-H4-O]4n
ACP 001; ACP 011; lonapegsomatropin-tcgd; SKYTROFA; TransCon; TransCon growth hormone; TransCon hGH; TransCon PEG growth hormone; TransCon PEG hGH; TransCon PEG somatropin,
Biologic License Application (BLA): 761177
Company: ACENDIS PHARMA ENDOCRINOLOGY DIV A/S
SKYTROFA is a human growth hormone indicated for the treatment of pediatric patients 1 year and older who weigh at least 11.5 kg and have growth failure due to inadequate secretion of endogenous growth hormone (GH) (1).
- OriginatorAscendis Pharma
- DeveloperAscendis Pharma; VISEN Pharmaceuticals
- ClassGrowth hormones; Hormonal replacements; Polyethylene glycols
- Mechanism of ActionSomatotropin receptor agonists
- Orphan Drug StatusYes – Somatotropin deficiency
- RegisteredSomatotropin deficiency
- 25 Aug 2021Registered for Somatotropin deficiency (In children, In infants) in USA (SC)
- 27 May 2021Ascendis Pharma expects European Commission decision on the Marketing Authorisation Application (MAA) for Somatotropin deficiency (In children, In infants, In neonates) in fourth quarter of 2021
- 27 May 2021Phase-III clinical trials in Somatotropin deficiency (In children, Treatment-naive) in Japan (SC)
Ascendis Pharma A/S Announces U.S. Food and Drug Administration Approval of SKYTROFA® (lonapegsomatropin-tcgd), the First Once-weekly Treatment for Pediatric Growth Hormone Deficiency
SKYTROFA, the first FDA approved treatment utilizing TransCon™ technology, is a long-acting prodrug of somatropin that releases the same somatropin used in daily therapies –
– Once weekly SKYTROFA demonstrated higher annualized height velocity (AHV) at week 52 compared to a daily growth hormone with similar safety and tolerability –
– Availability in the U.S. expected shortly supported by a full suite of patient support programs –
– Ascendis Pharma to host investor conference call today, Wednesday, August 25 at 4:30 p.m. E.T. –
COPENHAGEN, Denmark, Aug. 25, 2021 (GLOBE NEWSWIRE) — Ascendis Pharma A/S (Nasdaq: ASND), a biopharmaceutical company that utilizes its innovative TransCon technologies to potentially create new treatments that make a meaningful difference in patients’ lives, today announced that the U.S. Food and Drug Administration (FDA) has approved SKYTROFA (lonapegsomatropin-tcgd) for the treatment of pediatric patients one year and older who weigh at least 11.5 kg (25.4 lb) and have growth failure due to inadequate secretion of endogenous growth hormone (GH).
As a once-weekly injection, SKYTROFA is the first FDA approved product that delivers somatropin (growth hormone) by sustained release over one week.
“Today’s approval represents an important new choice for children with GHD and their families, who will now have a once-weekly treatment option. In the pivotal head-to-head clinical trial, once-weekly SKYTROFA demonstrated higher annualized height velocity at week 52 compared to somatropini,” said Paul Thornton, M.B. B.Ch., MRCPI, a clinical investigator and pediatric endocrinologist in Fort Worth, Texas. “This once-weekly treatment could reduce treatment burden and potentially replace the daily somatropin therapies, which have been the standard of care for over 30 years.”
Growth hormone deficiency is a serious orphan disease characterized by short stature and metabolic complications. In GHD, the pituitary gland does not produce sufficient growth hormone, which is important not only for height but also for a child’s overall endocrine health and development.
The approval includes the new SKYTROFA® Auto-Injector and cartridges which, after first removed from a refrigerator, allow families to store the medicine at room temperature for up to six months. With a weekly injection, patients switching from injections every day can experience up to 86 percent fewer injection days per year.
“SKYTROFA is the first product using our innovative TransCon technology platform that we have developed from design phase through non-clinical and clinical development, manufacturing and device optimization, and out to the patients. It reflects our commitment and dedication to addressing unmet medical needs by developing a pipeline of highly differentiated proprietary products across multiple therapeutic areas,” said Jan Mikkelsen, Ascendis Pharma’s President and Chief Executive Officer. “We are grateful to the patients, caregivers, clinicians, clinical investigators, and our employees, who have all contributed to bringing this new treatment option to children in the U.S. with GHD.”
In connection with the commercialization of SKYTROFA, the company is committed to offering a full suite of patient support programs, including educating families on proper injection procedures for SKYTROFA as the first once-weekly treatment for children with GHD.
“It is wonderful that patients and their families now have the option of a once-weekly growth hormone therapy,” said Mary Andrews, Chief Executive Officer and co-founder of the MAGIC Foundation, a global leader in endocrine health, advocacy, education, and support. “GHD is often overlooked and undertreated in our children and managing it can be challenging for families. We are excited about this news as treating GHD is important, and children have a short time to grow.”
The FDA approval of SKYTROFA was based on results from the phase 3 heiGHt Trial, a 52-week, global, randomized, open-label, active-controlled, parallel-group trial that compared once-weekly SKYTROFA to daily somatropin (Genotropin®) in 161 treatment-naïve children with GHDii. The primary endpoint was, AHV at 52 weeks for weekly SKYTROFA and daily hGH treatment groups. Other endpoints included adverse events, injection-site reactions, incidence of anti-hGH antibodies, annualized height velocity, change in height SDS, proportion of subjects with IGF-1 SDS (0.0 to +2.0), PK/PD in subjects < 3 years, and preference for and satisfaction with SKYTROFA.
At week 52, the treatment difference in AHV was 0.9 cm/year (11.2 cm/year for SKYTROFA compared with 10.3 cm/year for daily somatropin) with a 95 percent confidence interval [0.2, 1.5] cm/year. The primary objective of non-inferiority in AHV was met for SKYTROFA in this trial and further demonstrated a higher AHV at week 52 for lonapegsomatropin compared to daily somatropin, with similar safety, in treatment-naïve children with GHD.
No serious adverse events or discontinuations related to SKYTROFA were reported. Most common adverse reactions (≥ 5%) in pediatric patients include: infection, viral (15%), pyrexia (15%), cough (11%), nausea and vomiting (11%), hemorrhage (7%), diarrhea (6%), abdominal pain (6%), and arthralgia and arthritis (6%)ii. In addition, both arms of the study reported low incidences of transient, non-neutralizing anti-hGH binding antibodies and no cases of persistent antibodies.
Conference Call and Webcast Information
|Date||Wednesday, August 25, 2021|
|Time||4:30 p.m. ET/1:30 p.m. Pacific Time|
|Dial In (U.S.)||844-290-3904|
|Dial In (International)||574-990-1036|
A live webcast of the conference call will be available on the Investors and News section of the Ascendis Pharma website at www.ascendispharma.com. A webcast replay will be available on this website shortly after conclusion of the event for 30 days.
The Following Information is Intended for the U.S. Audience Only
SKYTROFA® is a human growth hormone indicated for the treatment of pediatric patients 1 year and older who weigh at least 11.5 kg and have growth failure due to inadequate secretion of endogenous growth hormone (GH).
IMPORTANT SAFETY INFORMATION
- SKYTROFA is contraindicated in patients with:
- Acute critical illness after open heart surgery, abdominal surgery or multiple accidental trauma, or if you have acute respiratory failure due to the risk of increased mortality with use of pharmacologic doses of somatropin.
- Hypersensitivity to somatropin or any of the excipients in SKYTROFA. Systemic hypersensitivity reactions have been reported with post-marketing use of somatropin products.
- Closed epiphyses for growth promotion.
- Active malignancy.
- Active proliferative or severe non-proliferative diabetic retinopathy.
- Prader-Willi syndrome who are severely obese, have a history of upper airway obstruction or sleep apnea or have severe respiratory impairment due to the risk of sudden death.
- Increased mortality in patients with acute critical illness due to complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure has been reported after treatment with pharmacologic doses of somatropin. Safety of continuing SKYTROFA treatment in patients receiving replacement doses for the approved indication who concurrently develop these illnesses has not been established.
- Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with post-marketing use of somatropin products. Do not use SKYTROFA in patients with known hypersensitivity to somatropin or any of the excipients in SKYTROFA.
- There is an increased risk of malignancy progression with somatropin treatment in patients with active malignancy. Preexisting malignancy should be inactive with treatment completed prior to starting SKYTROFA. Discontinue SKYTROFA if there is evidence of recurrent activity.
- In childhood cancer survivors who were treated with radiation to the brain/head for their first neoplasm and who developed subsequent growth hormone deficiency (GHD) and were treated with somatropin, an increased risk of a second neoplasm has been reported. Intracranial tumors, in particular meningiomas, were the most common of these second neoplasms. Monitor all patients with a history of GHD secondary to an intracranial neoplasm routinely while on somatropin therapy for progression or recurrence of the tumor.
- Because children with certain rare genetic causes of short stature have an increased risk of developing malignancies, practitioners should thoroughly consider the risks and benefits of starting somatropin in these patients. If treatment with somatropin is initiated, carefully monitor these patients for development of neoplasms. Monitor patients on somatropin therapy carefully for increased growth, or potential malignant changes of preexisting nevi. Advise patients/caregivers to report marked changes in behavior, onset of headaches, vision disturbances and/or changes in skin pigmentation or changes in the appearance of preexisting nevi.
- Treatment with somatropin may decrease insulin sensitivity, particularly at higher doses. New onset type 2 diabetes mellitus has been reported in patients taking somatropin. Undiagnosed impaired glucose tolerance and overt diabetes mellitus may be unmasked. Monitor glucose levels periodically in all patients receiving SKYTROFA. Adjust the doses of antihyperglycemic drugs as needed when SKYTROFA is initiated in patients.
- Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea, and/or vomiting has been reported in a small number of patients treated with somatropin. Symptoms usually occurred within the first 8 weeks after the initiation of somatropin and resolved rapidly after cessation or reduction in dose in all reported cases. Fundoscopic exam should be performed before initiation of therapy and periodically thereafter. If somatropin-induced IH is diagnosed, restart treatment with SKYTROFA at a lower dose after IH-associated signs and symptoms have resolved.
- Fluid retention during somatropin therapy may occur and is usually transient and dose dependent.
- Patients receiving somatropin therapy who have or are at risk for pituitary hormone deficiency(s) may be at risk for reduced serum cortisol levels and/or unmasking of central (secondary) hypoadrenalism. Patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of SKYTROFA therapy. Monitor patients for reduced serum cortisol levels and/or need for glucocorticoid dose increases in those with known hypoadrenalism.
- Undiagnosed or untreated hypothyroidism may prevent response to SKYTROFA. In patients with GHD, central (secondary) hypothyroidism may first become evident or worsen during SKYTROFA treatment. Perform thyroid function tests periodically and consider thyroid hormone replacement.
- Slipped capital femoral epiphysis may occur more frequently in patients undergoing rapid growth. Evaluate pediatric patients with the onset of a limp or complaints of persistent hip or knee pain.
- Somatropin increases the growth rate and progression of existing scoliosis can occur in patients who experience rapid growth. Somatropin has not been shown to increase the occurrence of scoliosis. Monitor patients with a history of scoliosis for disease progression.
- Cases of pancreatitis have been reported in pediatric patients receiving somatropin. The risk may be greater in pediatric patients compared with adults. Consider pancreatitis in patients who develop persistent severe abdominal pain.
- When SKYTROFA is administered subcutaneously at the same site over a long period of time, lipoatrophy may result. Rotate injection sites when administering SKYTROFA to reduce this risk.
- There have been reports of fatalities after initiating therapy with somatropin in pediatric patients with Prader-Willi syndrome who had one or more of the following risk factors: severe obesity, history of upper airway obstruction or sleep apnea, or unidentified respiratory infection. Male patients with one or more of these factors may be at greater risk than females. SKYTROFA is not indicated for the treatment of pediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome.
- Serum levels of inorganic phosphorus, alkaline phosphatase, and parathyroid hormone may increase after somatropin treatment.
- The most common adverse reactions (≥5%) in patients treated with SKYTROFA were: viral infection (15%), pyrexia (15%), cough (11%), nausea and vomiting (11%), hemorrhage (7%), diarrhea (6%), abdominal pain (6%), and arthralgia and arthritis (6%).
- SKYTROFA can interact with the following drugs:
- Glucocorticoids: SKYTROFA may reduce serum cortisol concentrations which may require an increase in the dose of glucocorticoids.
- Oral Estrogen: Oral estrogens may reduce the response to SKYTROFA. Higher doses of SKYTROFA may be required.
- Insulin and/or Other Hypoglycemic Agents: SKYTROFA may decrease insulin sensitivity. Patients with diabetes mellitus may require adjustment of insulin or hypoglycemic agents.
- Cytochrome P450-Metabolized Drugs: Somatropin may increase cytochrome P450 (CYP450)-mediated antipyrine clearance. Carefully monitor patients using drugs metabolized by CYP450 liver enzymes in combination with SKYTROFA.
You are encouraged to report side effects to FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Ascendis Pharma at 1-844-442-7236.
Please click here for full Prescribing Information for SKYTROFA.
About SKYTROFA® (lonapegsomatropin-tcgd)
SKYTROFA® is a once-weekly prodrug designed to deliver somatropin over a one-week period. The released somatropin has the same 191 amino acid sequence as daily somatropin.
SKYTROFA single-use, prefilled cartridges are available in nine dosage strengths, allowing for convenient dosing flexibility. They are designed for use only with the SKYTROFA® Auto-Injector and may be stored at room temperature for up to six months. The recommended dose of SKYTROFA for treatment-naïve patients and patients switching from daily somatropin is 0.24 mg/kg body weight, administered once weekly. The dose may be adjusted based on the child’s weight and insulin-like growth factor-1 (IGF-1) SDS.
SKYTROFA has been studied in over 300 children with GHD across the Phase 3 program which consists of the heiGHt Trial (for treatment-naïve patients), the fliGHt Trial (for treatment-experienced patients), and the enliGHten Trial (an ongoing long-term extension trial). Patients who completed the heiGHt Trial or the fliGHt Trial were able to continue into the enliGHten Trial and some have been on SKYTROFA for over four years.
SKYTROFA is being evaluated for pediatric GHD in Phase 3 trials in Japan and Greater China, including the People’s Republic of China, Hong Kong, Macau and Taiwan. Ascendis Pharma is also conducting the global Phase 3 foresiGHt Trial in adults with GHD. SKYTROFA has been granted orphan designation for GHD in both the U.S. and Europe.
About TransCon™ Technologies
TransCon refers to “transient conjugation.” The proprietary TransCon platform is an innovative technology to create new therapies that are designed to potentially optimize therapeutic effect, including efficacy, safety and dosing frequency. TransCon molecules have three components: an unmodified parent drug, an inert carrier that protects it, and a linker that temporarily binds the two. When bound, the carrier inactivates and shields the parent drug from clearance. When injected into the body, physiologic conditions (e.g., pH and temperature) initiate the release of the active, unmodified parent drug in a predictable manner. Because the parent drug is unmodified, its original mode of action is expected to be maintained. TransCon technology can be applied broadly to a protein, peptide or small molecule in multiple therapeutic areas, and can be used systemically or locally.
About Ascendis Pharma A/S
Ascendis Pharma is applying its innovative platform technology to build a leading, fully integrated biopharma company focused on making a meaningful difference in patients’ lives. Guided by its core values of patients, science and passion, the company utilizes its TransCon technologies to create new and potentially best-in-class therapies.
Ascendis Pharma currently has a pipeline of multiple independent endocrinology rare disease and oncology product candidates in development. The company continues to expand into additional therapeutic areas to address unmet patient needs.
Ascendis is headquartered in Copenhagen, Denmark, with additional facilities in Heidelberg and Berlin, Germany, in Palo Alto and Redwood City, California, and in Princeton, New Jersey.
NEW DRUG APPROVALS
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MVC COVID-19 vaccine
MVC-COV1901 is a vaccine candidate developed and commercialized by Medigen Vaccine Biologics Corporation. The vaccine candidate contains a perfusion form of the SARS-Cov2 recombinant spike protein. Medigen has combined forces with Dynavax, which offers an advanced adjuvant, CpG 1018 (also known as ISS-1018), for use with its vaccine. As of September 2020, the vaccine candidate is in Phase 1 clinical trials to assess its safety and immunogenicity (NCT04487210).
The MVC COVID-19 vaccine, designated MVC-COV1901 and also known as the Medigen COVID-19 vaccine, is a protein subunit COVID-19 vaccine developed by Medigen Vaccine Biologics Corporation [zh] in Taiwan, American company Dynavax Technologies and the U.S. National Institute of Health.
This vaccine is made by the recombinant S-2P spike protein adjuvanted with CpG 1018 supplied by Dynavax. Preliminary results from Phase I trials on 77 participants were published in June 2021, indicating what the authors described as “robust” immune system response elicited by the vaccine.
The study authors have assessed the humoral immune response by measuring quantities of binding IgG to S protein, and also the cellular immune response by measuring the quantities of IFN-γ and IL-4 secreting T cells.
Taiwan-based Medigen Vaccine Biologics Corporation (MVC) and Dynavax Technologies Corporation, in the US, have announced the rollout of its COVID-19 vaccine, MVC-COV1901. Approximately 600,000 people are anticipated to receive the Medigen vaccine this week.
Ryan Spencer, Chief Executive Officer of Dynavax commented, “We are pleased that Medigen’s vaccine is now available for the people of Taiwan. We are very excited for this first, of hopefully multiple, EUAs and approvals for COVID-19 vaccines that include CpG 1018 adjuvant. Considering the limitations of current vaccines and the global vaccine shortage, we believe adjuvanted vaccines can contribute significantly to current vaccination efforts.”
In July, MVC received Taiwan Emergency Use Authorization and approval for inclusion in Taiwan’s COVID-19 vaccine immunization program, MVC-COV1901.
MVC COVID-19 vaccine is indicated for adults over 20 years old and is administered in two doses 28 days apart for prevention of COVID-19.
The Advisory Committee recommended that MVC should submit safety monitoring report monthly during the declared EUA period and should submit a vaccine effectiveness report within one year after obtaining EUA approval.
(CNN)Taiwan’s President Tsai Ing-wen received her first shot of the island’s homegrown Covid-19 vaccine on Monday, a public show of support for the new drug which is central to plans for inoculation self sufficiency amid low immunization rates and struggles to obtain vaccines from overseas.Monday’s island-wide rollout of the Medigen Covid-19 vaccine, developed by Taipei-based Medigen Vaccine Biologics Corporation, comes after the drug was approved for emergency use last month by Taiwanese authorities for anyone above 20 years old, with at least 28 days between the two doses.The vaccine has yet to complete phase 3 clinical trials and no efficacy data is available. Paul Torkehagen, Medigen’s director of overseas business development, told CNN in May that the company designed a “very large” phase 2 clinical trial to ensure the vaccine’s safety and effectiveness, with 3,800 participants. Normally, a stage 2 clinical trial only involves several hundred people. Data from the trials showed that 99.8% of participants were able to form antibodies against Covid-19 after taking two doses of the vaccine, Medigen’s CEO Charles Chen said.
Taiwanese President Tsai Ing-wen, center, receives her first shot of the island’s first domestically developed coronavirus vaccine at the Taiwan University Hospital in Taipei, Taiwan on Monday, August 23.
Taiwan’s Centers for Disease Control said in a July 19 statement that the vaccine posed no serious health effects. Taiwan has ordered 5 million doses of the vaccine from Medigen and more than 700,000 people have already signed up to receive it, according to Reuters.In a Facebook post after receiving the vaccine at a hospital in Taipei, Tsai said she hadn’t suffered from any post-vaccination pain and thanked the health care workers who had administered the shot.”Taking the vaccine can protect yourself, your family, as well as medical staff,” Tsai wrote. “Let’s do our part in boosting Taiwan’s collective defense against the virus!”With its borders sealed to most travelers and strict measures enacted to contain local outbreaks, Taiwan has so far been largely successful in containing Covid-19, reporting fewer than 16,000 total confirmed infections and 828 deaths. But the island has struggled to vaccinate its more than 23 million population, partly due to difficulties obtaining doses from international suppliers.Taiwan’s government has only managed to import around 10 million Covid-19 vaccines, according to Reuters. In July it ordered another 36 million doses of the Moderna shot.Fewer than 5% of Taiwan’s population has received both doses of their Covid-19 vaccine, according to Reuters, as the island delays second dose vaccinations so more people can receive a first shot.On Monday, Taiwan reported four new Covid-19 cases, according to the Central Epidemic Command Center (CECC). Authorities announced on the weekend they would ease virus prevention measures to allow for larger gatherings and the opening of study centers and indoor amusement parks.But Health and Welfare Minister Chen Shih-chung said current Covid-19 restrictions — which include the closure of bars and nightclubs — would remain in place until at least September 6, with the possibility of an extension if the global outbreak continued to grow.Taiwan could become increasingly isolated if it keeps pursuing its “Covid zero” strategy, with both Australia and New Zealand hinting they might abandon the approach once vaccinations reach a certain level.In an opinion piece published on Sunday, Australian Prime Minister Scott Morrison said that while lockdowns to prevent Covid-19 transmission were “sadly necessary for now,” they may not be once vaccination rates increased to the targets of 70% and 80%.”This is what living with Covid is all about. The case numbers will likely rise when we soon begin to open up. That is inevitable,” he said.In neighboring New Zealand, which has also attempted to eliminate the virus within its borders, Covid-19 response minister Chris Hipkins told local media the highly-contagious Delta variant raised “some pretty big questions about what the long-term future of our plans are.”“At some point we will have to start to be more open in the future,” he said.
On 16 February 2020, Medigen Vaccine Biologics Corp. (MVC) signed a collaboration agreement with National Institutes of Health (NIH) for COVID-19 vaccine development. The partnership will allow MVC to obtain NIH’s COVID-19 vaccine and related biological materials to conduct animal studies in Taiwan.
On 23 July 2020, Medigen Vaccine Biologics (MVC) announced collaboration with Dynavax Technologies to develop COVID-19 vaccine. The COVID-19 candidate vaccine will have the combination of SARS-CoV2 spike protein created by MVC and Dynavax’s vaccine adjuvant CpG 1018, which was used in a previously FDA-approved adult hepatitis B vaccine.
On 13 October 2020, Medigen Vaccine Biologics received Taiwan’s government subsidies for the initiation of Phase 1 Clinical Trial in Taiwan starting early October. The Phase 1 Clinical Trial was held at National Taiwan University Hospital with 45 participants ranging the age of 20-50.
On 25 January 2021, Medigen Vaccine Biologics initiated Phase 2 Clinical Trial for its COVID-19 vaccine candidate MVC-COV1901 with the first participant being dosed. The Phase 2 Clinical Trial for the MVC COVID-19 vaccine was a randomized, double-blinded, and multi-center clinical trial, planned to enroll 3,700 participants of any age 20 above.
On 10 June 2021, Medigen Vaccine Biologics released its COVID-19 vaccine Phase 2 interim analysis results, which demonstrates good safety profile in participants. The Phase 2 Clinical Trial in the end included 3,800 participants with all participants receiving second dose by 28 April 2021. Medigen Vaccine Biologics announced that it will request Emergency Use Authorization (EUA) with the concluding of the Phase 2 Clinical Trial.
On 20 July 2021, Medigen Vaccine Biologics filed a Phase 3 Clinical Trial IND application with Paraguay’s regulatory authority, which was later approved. The Phase 3 Clinical Trial, however, was different from regular Phase 3 Clinical Trial, which uses immune-bridging trial to compare the performance of MVC COVID-19 vaccine with the Oxford-AstraZeneca COVID-19 vaccine. The decision was a controversial announcement as immune-bridging trials were not fully approved or widely accepted by health authorities. In addition, the accuracy of immune-bridging trials were also been questioned for years.
In July 2021, Medigen commenced phase II trials for adolescents aged 12-18.
|Full authorization Emergency authorization|
On July 19, 2021, MVC COVID-19 vaccine obtained Emergency Use Authorization (EUA) approval from the Taiwanese government after fulfilling EUA requirements set by Taiwanese authority. The EUA, however, was met with controversy due to the lack of efficacy data and Phase 3 Clinical Trial. On August 23, 2021, President Tsai Ing-Wen was among the first Taiwanese to receive a dose of the vaccine. 
- ^ “Dynavax and Medigen Announce Collaboration to Develop a Novel Adjuvanted COVID-19 Vaccine Candidate”. GlobeNewswire. 23 July 2020. Retrieved 7 June 2021.
- ^ 黃驛淵 (10 June 2021). “【獨家】【國產疫苗解盲1】高端實體疫苗針劑首曝光 「每天9萬劑」生產基地直擊” (in Chinese). Mirror Media.
- ^ Jump up to:a b “Medigen Vaccine Biologics COVID-19 Vaccine Adjuvanted with Dynavax’s CpG 1018 Announces First Participant Dosed in Phase 2 Clinical Trial in Taiwan”. http://www.medigenvac.com. Retrieved 7 August 2021.
- ^ Jump up to:a b Hsieh SM, Liu WD, Huang YS, Lin YJ, Hsieh EF, Lian WC, Chen C, Janssen R, Shih SR, Huang CG, Tai IC, Chang SC (25 June 2021). “Safety and immunogenicity of a Recombinant Stabilized Prefusion SARS-CoV-2 Spike Protein Vaccine (MVCCOV1901) Adjuvanted with CpG 1018 and Aluminum Hydroxide in healthy adults: A Phase 1, dose-escalation study”. EClinicalMedicine: 100989. doi:10.1016/j.eclinm.2021.100989. ISSN 2589-5370. PMC 8233066. PMID 34222848.
- ^ “MVC and NIH Collaborate to Develop COVID-19 Vaccine”. http://www.medigenvac.com. Retrieved 7 August 2021.
- ^ “Medigen Collaborates with Dynavax to Develop Novel Adjuvanted COVID-19 Vaccine Candidate”. http://www.medigenvac.com. Retrieved 7 August 2021.
- ^ “MVC Signed an License Agreement with NIH on COVID-19 Vaccine”. Medigen. 5 May 2020. Retrieved 27 July 2021.
- ^ “Medigen’s COVID-19 Vaccine Combined with Dynavax’s CpG 1018 Adjuvant Receives Taiwan Government Subsidy with First Participant Dosed in Early October”. http://www.medigenvac.com. Retrieved 7 August 2021.
- ^ “A Study to Evaluate MVC-COV1901 Vaccine Against COVID-19 in Adult (COVID-19)”. clinicaltrials.gov. United States National Library of Medicine. Retrieved 11 March 2021.
- ^ “A Study to Evaluate the Safety and Immunogenicity of MVC-COV1901 Against COVID-19”. clinicaltrials.gov. United States National Library of Medicine. Retrieved 11 March 2021.
- ^ “A Study to Evaluate MVC-COV1901 Vaccine Against COVID-19 in Elderly Adults”. clinicaltrials.gov. United States National Library of Medicine. 28 March 2021. Retrieved 3 April 2021.
- ^ “MVC Released COVID-19 Vaccine Phase 2 Interim Analysis Result”. http://www.medigenvac.com. Retrieved 7 August 2021.
- ^ “MVC Announces Paraguay Approval of IND Application for Phase 3 Clinical Trial”. http://www.medigenvac.com. Retrieved 7 August 2021.
- ^ “A Study to Evaluate MVC-COV1901 Vaccine Against COVID-19 in Adolescents”. clinicaltrials.gov. United States National Library of Medicine. 6 July 2021. Retrieved 6 July 2021.
- ^ “MVC COVID-19 Vaccine Obtains Taiwan EUA Approval”. http://www.medigenvac.com. Retrieved 7 August 2021.
- ^ Taiwan begins contested rollout of new Medigen domestic vaccine, Nikkei Asia, Erin Hale, August 23, 2021
|Vaccine type||Protein subunit|
|Legal status||Full and Emergency Authorizations: List of MVC COVID-19 vaccine authorizations|
|Part of a series on the|
|COVID-19 (disease)SARS-CoV-2 (virus)CasesDeaths|
|showEconomic impact and recession|
////////Medigen vaccine, MVC COVID-19 vaccine, SARS-CoV-2, covid 19, corona virus, taiwan, approvals 2021, iss 1018, CpG 1018, MVC-COV1901
NEW DRUG APPROVALS