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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Lonapegsomatropin


FPTIPLSRLF DNAMLRAHRL HQLAFDTYQE FEEAYIPKEQ KYSFLQNPQT SLCFSESIPT
PSNREETQQK SNLELLRISL LLIQSWLEPV QFLRSVFANS LVYGASDSNV YDLLKDLEEG
IQTLMGRLED GSPRTGQIFK QTYSKFDTNS HNDDALLKNY GLLYCFRKDM DKVETFLRIV
QCRSVEGSCG F
(Disulfide bridge: 53-165, 182-189)

Ascendis Pharma: We've got making a difference for patients down to a  science

Lonapegsomatropin, ロナペグソマトロピン

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, 

WHO 10598

PEPTIDE

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

https://www.globenewswire.com/news-release/2021/08/25/2286624/0/en/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.html

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

DateWednesday, August 25, 2021
Time4:30 p.m. ET/1:30 p.m. Pacific Time
Dial In (U.S.)844-290-3904
Dial In (International)574-990-1036
Access Code8553236

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

INDICATION

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.

Please visit www.ascendispharma.com (for global information) or www.ascendispharma.us (for U.S. information).

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NEW DRUG APPROVALS

ONE TIME

$10.00

///////////Lonapegsomatropin, Skytrofa, APPROVALS 2021, FDA 2021, PEPTIDE, ロナペグソマトロピン , ACP 00, ACP 011,  lonapegsomatropin-tcgd, TransCon, TransCon growth hormone, TransCon hGH, TransCon PEG growth hormone, TransCon PEG hGH, TransCon PEG somatropin, ORPHAN DRUG

Pepinemab, VX 15


(Heavy chain)
QVQLVQSGAE VKKPGSSVKV SCKASGYSFS DYYMHWVRQA PGQGLEWMGQ INPTTGGASY
NQKFKGKATI TVDKSTSTAY MELSSLRSED TAVYYCARYY YGRHFDVWGQ GTTVTVSSAS
TKGPSVFPLA PCSRSTSEST AALGCLVKDY FPEPVTVSWN SGALTSGVHT FPAVLQSSGL
YSLSSVVTVP SSSLGTKTYT CNVDHKPSNT KVDKRVESKY GPPCPPCPAP EFLGGPSVFL
FPPKPKDTLM ISRTPEVTCV VVDVSQEDPE VQFNWYVDGV EVHNAKTKPR EEQFNSTYRV
VSVLTVLHQD WLNGKEYKCK VSNKGLPSSI EKTISKAKGQ PREPQVYTLP PSQEEMTKNQ
VSLTCLVKGF YPSDIAVEWE SNGQPENNYK TTPPVLDSDG SFFLYSRLTV DKSRWQEGNV
FSCSVMHEAL HNHYTQKSLS LSLGK
(Light chain)
DIVMTQSPDS LAVSLGERAT INCKASQSVD YDGDSYMNWY QQKPGQPPKL LIYAASNLES
GVPDRFSGSG SGTDFTLTIS SLQAEDVAVY YCQQSNEDPY TFGQGTKLEI KRTVAAPSVF
IFPPSDEQLK SGTASVVCLL NNFYPREAKV QWKVDNALQS GNSQESVTEQ DSKDSTYSLS
STLTLSKADY EKHKVYACEV THQGLSSPVT KSFNRGEC
(Disulfide bridge: H22-H96, H132-L218, H145-H201, H224-H’224, H227-H’227, H259-H319, H365-H423, H’22-H’96, H’132-L’218, H’145-H’201, H’259-H’319, H’365-H’423, L23-L92, L138-L198, L’23-L’92, L’138-L’198)

Pepinemab

VX15/2503

Antineoplastic, Anti-human semaphorin 4D antibody

Monoclonal antibody
Treatment of solid tumors, multiple sclerosis and Huntington’s disease

FormulaC6442H9910N1702O2052S48
MOL WGT145481.0022
  • Moab VX15/2503
  • Pepinemab
  • UNII-BPZ4A29SYE
  • VX-15
  • VX15
  • VX15/2503
Product namePepinemab Biosimilar – Anti-SEMA4D mAb – Research Grade
SourceCAS 2097151-87-4
SpeciesChimeric,Humanized
Expression systemMammalian cells
  • OriginatorVaccinex
  • DeveloperBristol-Myers Squibb; Children’s Oncology Group; Emory University; Merck KGaA; National Cancer Institute (USA); Teva Pharmaceutical Industries; UCLAs Jonsson Comprehensive Cancer Center; Vaccinex
  • ClassAntibodies; Antidementias; Antineoplastics; Immunotherapies; Monoclonal antibodies
  • Mechanism of ActionCD100 antigen inhibitors
  • Orphan Drug StatusYes – Huntington’s disease
  • New Molecular EntityYes
  • Phase IIHuntington’s disease
  • Phase I/IIAlzheimer’s disease; Non-small cell lung cancer; Osteosarcoma; Solid tumours; Squamous cell cancer
  • Phase IColorectal cancer; Malignant melanoma; Pancreatic cancer
  • No development reportedMultiple sclerosis
  • 22 May 2021Pepinemab is still in phase I trials for Colorectal cancer and Pancreatic cancer in USA (NCT03373188)
  • 17 May 2021Phase-I/II clinical trials in Squamous cell cancer (Combination therapy, Late-stage disease, Metastatic disease, Recurrent, Second-line therapy or greater) in USA (IV) (NCT04815720)
  • 17 May 2021Vaccinex plans a phase I/II trial for Alzheimer’s disease (In volunteers), in H2 2021

Semaphorin 4D (SEMA4D) plays a role in multiple cellular processes that contribute to the pathophysiology of neuroinflammatory/neurodegenerative diseases. SEMA4D is, therefore, a uniquely promising target for therapeutic development.

Pepinemab is a novel monoclonal antibody that blocks the activity of SEMA4D, and preclinical testing has demonstrated the beneficial effects of anti-SEMA4D treatment in a variety of neurodegenerative disease models. Vaccinex is committed to the development of this potentially important antibody that has the potential to help people with different neurodegenerative disorders that share common mechanisms of pathology.

Note: Pepinemab (VX15/2503) is an investigational drug currently in clinical studies. It has not been demonstrated to be safe and effective for any disease indication. There is no guarantee that pepinemab (VX15/2503) will be approved for the treatment of any disease by the U.S. Food and Drug Administration or by any other health authority worldwide.

////////////////////Pepinemab, VX15/2503, vx 15, Antineoplastic, Anti-human semaphorin 4D antibody, Monoclonal antibody, solid tumors, multiple sclerosis,  Huntington’s disease, PEPTIDES

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NEW DRUG APPROVALS

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Anifrolumab


(Heavy chain)
EVQLVQSGAE VKKPGESLKI SCKGSGYIFT NYWIAWVRQM PGKGLESMGI IYPGDSDIRY
SPSFQGQVTI SADKSITTAY LQWSSLKASD TAMYYCARHD IEGFDYWGRG TLVTVSSAST
KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF PEPVTVSWNS GALTSGVHTF PAVLQSSGLY
SLSSVVTVPS SSLGTQTYIC NVNHKPSNTK VDKRVEPKSC DKTHTCPPCP APEFEGGPSV
FLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYNSTY
RVVSVLTVLH QDWLNGKEYK CKVSNKALPA SIEKTISKAK GQPREPQVYT LPPSREEMTK
NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSKL TVDKSRWQQG
NVFSCSVMHE ALHNHYTQKS LSLSPGK
(Lihgt chain)
EIVLTQSPGT LSLSPGERAT LSCRASQSVS SSFFAWYQQK PGQAPRLLIY GASSRATGIP
DRLSGSGSGT DFTLTITRLE PEDFAVYYCQ QYDSSAITFG QGTRLEIKRT VAAPSVFIFP
PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS QESVTEQDSK DSTYSLSSTL
TLSKADYEKH KVYACEVTHQ GLSSPVTKSF NRGEC
(Disulfide bridge: H22-96, H144-H200, H220-L215, H226-H’226, H229-H’229, H261-H321, H367-H425, H’22-H’96, H’144-H’200, H’220-L’215, H’261-H’321, H’367-H’425, L23-L89, L135-L195, L’23-L’89, L’135-L’195)

Anifrolumab

アニフロルマブ (遺伝子組換え)

FDA APPROVED 2021/7/30, Saphnelo

  • MEDI 546
FormulaC6444H9964N1712O2018S44
Cas1326232-46-5
Mol weight145117.1846
Immunomodulator, Anti-IFN-type 1 receptor antibody
  DiseaseSystemic lupus erythematosus

Monoclonal antibody

Treatment of systemic lupus erythematosus (SLE)

  • OriginatorMedarex
  • DeveloperAstraZeneca; Medarex; MedImmune
  • ClassAntirheumatics; Monoclonal antibodies; Skin disorder therapies
  • Mechanism of ActionInterferon alpha beta receptor antagonists
  • RegisteredSystemic lupus erythematosus
  • Phase IILupus nephritis
  • DiscontinuedRheumatoid arthritis; Scleroderma
  • 02 Jul 2021Phase-III clinical trials in Systemic lupus erythematosus in USA (SC) (NCT04877691)
  • 25 Jun 2021AstraZeneca plans a phase III trial in Systemic lupus erythematosus (Adjunctive treatment) in the China, Hong Kong, South Korea, Philipines, Taiwan and Thailand (IV, Infusion), in July 2021 (NCT04931563)
  • 02 Jun 2021Pharmacokinetic, efficacy and adverse events data from a phase II TULIP-LN1 trial in Lupus nephritis presented at the 22nd Annual Congress of the European League Against Rheumatism (EULAR-2021)

Anifrolumab, sold under the brand name Saphnelo, is a monoclonal antibody used for the treatment of systemic lupus erythematosus (SLE).[1][2] It binds to the type I interferon receptor, blocking the activity of type I interferons such as interferon-α and interferon-β.[medical citation needed]

Anifrolumab was approved for medical use in the United States in August 2021.[1][3][4][5]

Anifrolumab is a monoclonal antibody that inhibits type 1 interferon receptors, indicated in the treatment of moderate to severe systemic lupus erythematosus.

Anifrolumab, or MEDI-546, is a type 1 interferon receptor (IFNAR) inhibiting IgG1κ monoclonal antibody indicated in the treatment of adults with moderate to severe systemic lupus erythematosus.7,11 The standard therapy for systemic lupus erythematosus consists of antimalarials like hydroxychloroquine, glucocorticoids like dexamethasone, and disease modifying antirheumatic drugs like methotrexate.8,11

Three monoclonal antibodies (anifrolumab, rontalizumab, and sifalimumab) that target the type 1 interferon pathway entered clinical trials as potential treatments for systemic lupus erythematosus, but so far only anifrolumab has been approved.3

The design of early clinical trials of anti-interferon treatments such as anifrolumab, rontalizumab, and sifalimumab have come under criticism.3 The design of the clinical trials use different definitions of autoantibody positivity, making comparison between trials difficult; all trials involve large portions of patients also using corticosteroids, which may alter patient responses in the experimental and placebo groups; and patient populations were largely homogenous, which may have increased the odds of success of the trial.3

Anifrolumab has also been investigated for the treatment of Scleroderma.1

Anifrolumab was granted FDA approval on 30 July 2021.11

Adverse effects

The most common adverse effect was shingles, which occurred in 5% of patients in the low-dose group, to 10% in the high-dose group, and to 2% in the placebo group. Overall adverse effect rates were comparable in all groups.[6]

History

The drug was developed by MedImmune, a unit of AstraZeneca, which chose to move anifrolumab instead of sifalimumab into phase III trials for lupus in 2015.[7][8][9]

Clinical trial results

Anifrolumab failed to meet its endpoint of significant reduction in disease as assessed by the SLE Responder Index 4 instrument in the TULIP 1 phase III trial.[10] This multi-center, double-blind, placebo-controlled study followed adults with moderate to severe SLE over the course of one year. Preliminary results were announced on 31 August 2018.

Names

Anifrolumab is the international nonproprietary name (INN).[11]

References

  1. Jump up to:a b chttps://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761123s000lbl.pdf
  2. ^ Statement On A Nonproprietary Name Adopted By The USAN Council – AnifrolumabAmerican Medical Association.
  3. ^https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/761123Orig1s000ltr.pdf
  4. ^ https://www.astrazeneca.com/media-centre/press-releases/2021/saphnelo-approved-in-the-us-for-sle.html
  5. ^ “Saphnelo (anifrolumab) Approved in the US for Moderate to Severe Systemic Lupus Erythematosus” (Press release). AstraZeneca. 2 August 2021. Retrieved 2 August 2021 – via Business Wire.
  6. ^ Spreitzer H (29 August 2016). “Neue Wirkstoffe – Anifrolumab”. Österreichische Apothekerzeitung (in German) (18/2016).
  7. ^ “Press release: New Hope for Lupus Patients”. MedImmune. 11 August 2015. Archived from the original on 31 July 2017.
  8. ^ “Anifrolumab”. NHS Specialist Pharmacy Service. Retrieved 31 July 2017.
  9. ^ “Anifrolumab”. AdisInsight. Retrieved 31 July 2017.
  10. ^ “Update on TULIP 1 Phase III trial for anifrolumab in systemic lupus erythematosus”http://www.astrazeneca.com. Retrieved 2019-02-05.
  11. ^ World Health Organization (2014). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 71”. WHO Drug Information28 (1). hdl:10665/331151.

Further reading

  • Anderson E, Furie R (April 2020). “Anifrolumab in systemic lupus erythematosus: current knowledge and future considerations”. Immunotherapy12 (5): 275–86. doi:10.2217/imt-2020-0017PMID 32237942.

External links

  • “Anifrolumab”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT01438489 for “A Study of the Efficacy and Safety of MEDI-546 in Systemic Lupus Erythematosus” at ClinicalTrials.gov
  • Clinical trial number NCT02446912 for “Efficacy and Safety of Two Doses of Anifrolumab Compared to Placebo in Adult Subjects With Active Systemic Lupus Erythematosus” at ClinicalTrials.gov
  • Clinical trial number NCT02446899 for “Efficacy and Safety of Anifrolumab Compared to Placebo in Adult Subjects With Active Systemic Lupus Erythematosus” at ClinicalTrials.gov
Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetInterferon α/β receptor
Clinical data
Trade namesSaphnelo
Other namesMEDI-546, anifrolumab-fnia
License dataUS DailyMedAnifrolumab
Routes of
administration
Intravenous
Drug classtype I interferon receptor antagonist (IFN)
ATC codeNone
Legal status
Legal statusUS: ℞-only [1]
Identifiers
CAS Number1326232-46-5
DrugBankDB11976
ChemSpidernone
UNII38RL9AE51Q
KEGGD11082
Chemical and physical data
FormulaC6444H9964N1712O2018S44
Molar mass145119.20 g·mol−1
  1. Goldberg A, Geppert T, Schiopu E, Frech T, Hsu V, Simms RW, Peng SL, Yao Y, Elgeioushi N, Chang L, Wang B, Yoo S: Dose-escalation of human anti-interferon-alpha receptor monoclonal antibody MEDI-546 in subjects with systemic sclerosis: a phase 1, multicenter, open label study. Arthritis Res Ther. 2014 Feb 24;16(1):R57. doi: 10.1186/ar4492. [Article]
  2. Peng L, Oganesyan V, Wu H, Dall’Acqua WF, Damschroder MM: Molecular basis for antagonistic activity of anifrolumab, an anti-interferon-alpha receptor 1 antibody. MAbs. 2015;7(2):428-39. doi: 10.1080/19420862.2015.1007810. [Article]
  3. Massarotti EM, Allore HG, Costenbader K: Editorial: Interferon-Targeted Therapy for Systemic Lupus Erythematosus: Are the Trials on Target? Arthritis Rheumatol. 2017 Feb;69(2):245-248. doi: 10.1002/art.39985. [Article]
  4. Furie R, Khamashta M, Merrill JT, Werth VP, Kalunian K, Brohawn P, Illei GG, Drappa J, Wang L, Yoo S: Anifrolumab, an Anti-Interferon-alpha Receptor Monoclonal Antibody, in Moderate-to-Severe Systemic Lupus Erythematosus. Arthritis Rheumatol. 2017 Feb;69(2):376-386. doi: 10.1002/art.39962. [Article]
  5. Tummala R, Rouse T, Berglind A, Santiago L: Safety, tolerability and pharmacokinetics of subcutaneous and intravenous anifrolumab in healthy volunteers. Lupus Sci Med. 2018 Mar 23;5(1):e000252. doi: 10.1136/lupus-2017-000252. eCollection 2018. [Article]
  6. Riggs JM, Hanna RN, Rajan B, Zerrouki K, Karnell JL, Sagar D, Vainshtein I, Farmer E, Rosenthal K, Morehouse C, de Los Reyes M, Schifferli K, Liang M, Sanjuan MA, Sims GP, Kolbeck R: Characterisation of anifrolumab, a fully human anti-interferon receptor antagonist antibody for the treatment of systemic lupus erythematosus. Lupus Sci Med. 2018 Apr 5;5(1):e000261. doi: 10.1136/lupus-2018-000261. eCollection 2018. [Article]
  7. Bui A, Sanghavi D: Anifrolumab . [Article]
  8. Trindade VC, Carneiro-Sampaio M, Bonfa E, Silva CA: An Update on the Management of Childhood-Onset Systemic Lupus Erythematosus. Paediatr Drugs. 2021 Jul;23(4):331-347. doi: 10.1007/s40272-021-00457-z. Epub 2021 Jul 10. [Article]
  9. Ryman JT, Meibohm B: Pharmacokinetics of Monoclonal Antibodies. CPT Pharmacometrics Syst Pharmacol. 2017 Sep;6(9):576-588. doi: 10.1002/psp4.12224. Epub 2017 Jul 29. [Article]
  10. Koh JWH, Ng CH, Tay SH: Biologics targeting type I interferons in SLE: A meta-analysis and systematic review of randomised controlled trials. Lupus. 2020 Dec;29(14):1845-1853. doi: 10.1177/0961203320959702. Epub 2020 Sep 22. [Article]
  11. FDA Approved Drug Products: Saphnelo (Anifrolumab-fnia) Intravenous Injection [Link]

SAPHNELO (anifrolumab) Approved in the US for Moderate to Severe Systemic  Lupus Erythematosus | Business Wire//////////Anifrolumab, Saphnelo, FDA 2021, APPROVALS 2021, peptide, Monoclonal antibody, アニフロルマブ (遺伝子組換え) , MEDI 546, AstraZeneca, Medarex, MedImmune

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Nangibotide


Nangibotide molecular structure.png
File:Nangibotide molecular structure.png - Wikipedia
ChemSpider 2D Image | nangibotide | C54H82N14O22S2

Nangibotide

LQEEDAGEYGCM-amide

CAS 2014384-91-7

  • Molecular FormulaC54H82N14O22S2
  • Average mass1343.439 Da
  • 2014384‐91‐7
  • L-Leucyl-L-glutaminyl-L-α-glutamyl-L-α-glutamyl-L-α-aspartyl-L-alanylglycyl-L-α-glutamyl-L-tyrosylglycyl-L-cysteinyl-L-methioninamide
  • LR 12 peptide
  • LQEEDAGEYG CM

L-Leucyl-L-glutaminyl-L-glutaminyl-L-α-glutamyl-L-α-aspartyl-L-alanylglycyl-L-α-glutamyl-L-tyrosylglycyl-L-cysteinyl-L-methionine
L-Methionine, L-leucyl-L-glutaminyl-L-glutaminyl-L-α-glutamyl-L-α-aspartyl-L-alanylglycyl-L-α-glutamyl-L-tyrosylglycyl-L-cysteinyl-нангиботидمانغيبوتيد南吉博肽

Sequence (one letter code)LQEEDAGEYGCM-amide
Sequence (three letter code)H-Leu-Gln-Glu-Glu-Asp-Ala-Gly-Glu-Tyr-Gly-Cys-Met-NH2
  • OriginatorInotrem
  • ClassAnti-infectives; Anti-inflammatories; Anti-ischaemics; Antivirals; Peptides
  • Mechanism of ActionTREML1 protein inhibitors
  • Phase II/IIICOVID 2019 infections
  • Phase IISeptic shock
  • Phase IMyocardial infarction
  • 12 Jul 2021Inotrem has patents pending for nangibotide use in severe forms of COVID-19
  • 12 Jul 2021Inotrem receives funding from French government by Bpifrance for nangibotide development in COVID-2019 infections
  • 12 Jul 2021Inotrem receives authorization from both the French and Belgian authorities to proceed with clinical development of nangibotide up to registration in COVID-2019 infections

Nangibotide, also referred as LR12, is an antagonist of triggering receptor expressed on myeloid cells (TREM)-1, and was derived from residues 94 to 105 of TREM-like transcript-1 (TLT-1).

TREM-1 plays a crucial role in the onset of sepsis by amplifying the host immune response. TLT-1– and TLT-1–derived peptides therefore exhibit anti-inflammatory properties by dampening TREM-1 signalling.  LR12 blocks TREM-1 by binding to the TREM-1 ligand and provides protective effects during sepsis such as inhibiting hyper-responsiveness, organ damage, and death, without causing deleterious effects. The protective effects of modulating TREM-1 signalling are also evident in other models of inflammation such as: pancreatitis; haemorrhagic shock; inflammatory bowel diseases and inflammatory arthritis

Inotrem is developing the peptide nangibotide, a triggering receptor expressed on myeloid cells 1 inhibitor, for treating sepsis and septic shock. In July 2021, this drug was reported to be in phase 3 clinical development.

Nangibotide is an inhibitor of TREM-1, a receptor found on certain white blood cells. Activation of TREM-1 stimulates inflammation. Nangibotide is therefore being investigated as a treatment for the overwhelming inflammation typically seen in severe sepsis.

Mode of action

TREM-1 is a receptor found on neutrophilsmacrophages and monocytes, key elements of the immune system. Activation of TREM-1 results in expression of NF-κB, which promotes systemic inflammation. Nangibotide inhibits TREM-1, thereby preventing the inflammatory activation. Absence of TREM-1 results in vastly reduced inflammation without impairing the ability to fight infection.[2]

Animal models

LR17, a mouse equivalent of nangibotide, improves survival in mouse models of severe sepsis.[3] In a pig model of sepsis, LR12 – another animal equivalent of nangibotide – resulted in significantly improved haemodynamics and less organ failure.[4] In monkeys, LR12 also reduced the inflammatory and hypotensive effects of sepsis.[5]

Human studies

Nangibotide has demonstrated safety in Phase 1 (healthy volunteers)[6] and Phase 2 (sick patients with septic shock)[7] studies. The ASTONISH trial will examine clinical efficacy in 450 patients with septic shock.[8]

Inotrem Receives Approval to Expand Nangibotide Clinical Trial in Critically Ill COVID-19 Patients and Receives Additional Public Funding of €45 Million

  • Inotrem’s phase 2/3 clinical trial “ESSENTIAL” will enroll up to 730 patients in Europe to demonstrate the safety and efficacy of nangibotide to treat critically ill COVID-19 patients with respiratory failure.
  • Recent preclinical studies have strengthened the body of evidence for targeting the TREM-1 pathway which is activated in a subset of patients suffering from severe COVID-19.

July 12, 2021 03:00 AM Eastern Daylight Time

PARIS–(BUSINESS WIRE)–Inotrem S.A., a biotechnology company specializing in the development of immunotherapies targeting the TREM-1 pathway, announces that it has obtained authorization to pursue the clinical development of nangibotide up to registration in COVID-19 patients from both the French and Belgian competent authorities.

As part of this program, Inotrem receives additional 45 million euros in public funding under the “Capacity Building” Call for Expression of Interest, operated on behalf of the French government by Bpifrance, the French national investment bank, as part of the Programme d’investissements d’avenir (PIA) and the France Recovery Plan, bringing French state support for the project to a total of 52,5 million euros. This public funding will support Inotrem’s clinical program including the phase 2/3 study “ESSENTIAL” which aims to demonstrate the efficacy and safety of nangibotide in treating patients in respiratory distress with severe forms of COVID-19.

The primary endpoint is evaluation of the impact of nangibotide on the progression of disease in patients receiving ventilatory support due to COVID-19 as well as on the severity of the respiratory failure, duration of mechanical ventilation, length of stay in intensive care and mortality. In “ESSENTIAL”, a Phase 2/3 clinical program, up to 730 patients will be enrolled initially in France and Belgium and, possibly in other European countries. Pre-defined interim analyses will be conducted by an independent Data Monitoring Board to test futility and to allow for the study design to be adapted as necessary. “ESSNTIAL” is the continuation of a 60 patients phase 2a evaluating the safety and efficacy of nangibotide in patients suffering from severe COVID-19. In July 2020, the CoviTREM-1 consortium, which includes the Nancy and Limoges university hospitals and Inotrem, obtained public funding of 7,5 million euros under the “PSPC-COVID” call for projects, operated on behalf of the French government by Bpifrance

New pre-clinical studies with nangibotide have demonstrated that the administration of nangibotide in murine models infected with SARS-CoV-2 was associated with a decrease in inflammatory mediators and an improvement of clinical signs, in particular respiratory function, and survival. Inotrem also confirmed in 3 different and independent cohorts that sTREM-1, a marker of the activation of the TREM-1 biological pathway, is associated with both severity and mortality in critically ill COVID-19 patients.

Leveraging the results of these preclinical studies and the implications for the role of the TREM-1 pathway in COVID-19, Inotrem has filed additional patents to cover nangibotide use in severe forms of COVID-19 as well as the use of sTREM-1 as a biomarker and companion diagnostic. This significantly strengthens Inotrem’s already broad patent estate.

Jean-Jacques Garaud, Executive Vice-President, Head of Scientific and Medical Affairs and Inotrem’s co-founder said :“We are eager to pursue the development of nangibotide in these severe forms of COVID-19. Nangibotide is a TREM-1 inhibitor which has already demonstrated a trend towards efficacy in septic shock patients and has the potential to modulate the dysregulated immune response in critically ill COVID-19 patients. With this large clinical study, we can demonstrate efficacy for nangibotide in a further indication with the goals of reducing the duration of hospitalization and mortality.”

Sven Zimmerman, CEO of Inotrem, also declared: “The size of the financial support awarded to us as part of the French government’s initiative against COVID-19 is a testimony to the relevance of targeting the TREM-1 pathway with nangibotide in these severely ill patients. We are delighted by the confidence placed in our technology and our team. Everyone at Inotrem is fully committed to deliver on this ambitious program alongside nangibotide’s ongoing Phase 2b trial in septic shock patients.”

About Inotrem
Inotrem S.A. is a biotechnology company specialized in immunotherapy for acute and chronic inflammatory syndromes. The company has developed a new concept of immunomodulation that targets the TREM-1 pathway to control unbalanced inflammatory responses. Through its proprietary technology platform, Inotrem has developed the first-in-class TREM-1 inhibitor, LR12 (nangibotide), with potential applications in a number of therapeutic indications such as septic shock and myocardial infarction. In parallel, Inotrem has also launched another program to develop a new therapeutic modality targeting chronic inflammatory diseases. The company was founded in 2013 by Dr. Jean-Jacques Garaud, a former head of research and early development at the Roche Group, Prof. Sébastien Gibot and Dr. Marc Derive. Inotrem is supported by leading European and North American investors.

www.inotrem.com

About TREM-1 pathway
TREM-1 pathway is an amplification loop of the immune response that triggers an exuberant and hyperactivated immune state which is known to play a crucial role in the pathophysiology of septic shock and acute myocardial infarction.

About Nangibotide
Nangibotide is the formulation of the active ingredient LR12, which is a 12 amino-acid peptide prepared by chemical synthesis. LR12 is a specific TREM-1 inhibitor, acting as a decoy receptor and interfering in the binding of TREM-1 and its ligand. In preclinical septic shock models, nangibotide was able to restore appropriate inflammatory response, vascular function, and improved animals’ survival post septic shock.

About ESSENTIAL study:
The Efficacy and Safety Study Exploring Nangibotide Treatment in COVID-19 pAtients with ventiLatory support, is a randomized, double-blind, placebo-controlled confirmatory study with adaptive features that will be performed in Europe. This is a pivotal study and it is expected that based on its results, nangibotide could be registered in this indication. The first part of the study (i.e.: 60 patients) has been already finalized and assessed by an independent data monitoring committee with excellent safety results. The study will recruit up to 730 patients in up to 40 sites. Several interim and futility analyses are foreseen as part of the adaptive design of the study.

About Bpifrance
Bpifrance is the French national investment bank: it finances businesses – at every stage of their development – through loans, guarantees, equity investments and export insurances. Bpifrance also provides extra-financial services (training, consultancy.). to help entrepreneurs meet their challenges (innovation, export…).

PATENT

WO-2021144388

Process for preparing nangibotide by solid phase synthesis, useful for treating acute inflammatory disorders such as septic shock. Also claims novel peptide fragments, useful in the synthesis of nangibotide.

Example 1

Preparation of nangibotide by full SPPS (Reference)

Step 1 : Loading of the first amino acid onto the Rink Amide Resin

2 g of MBHA resin (1.0-1.3 mmol/g) was swelled using 16 mL of DMF for 30 min. 2 eq Fmoc-Met-OH (2.4 mmol, 2.67 g), 2 eq DIC (2.4 mmol, 1.136 mL) and 2 eq OxymaPure (2.4 mmol, 1.023 g) were dissolved in 8 mL of DMF at 0.3 M cone, and added to the resin after 5 min. All the coupling steps were conducted in this way unless described differently. The loading step was carried out for 1.5 hour. After the loading, the resin was filtered and washed 3 times with 12 mL of DMF. The Fmoc deprotection step was carried out by addition of 12 mL of 20% piperidine solution in DMF for two 10 min cycles. This step was performed analogously for all the amino acid residues. The loading, calculated by UV absorption for the peptidyl resin, was 0.8 mmol/g.

Step 2: peptide elongation

For the coupling of all the amino acids involved in the synthesis of nangibotide, 3 eq of each amino acid were activated by 3 eq of DIC and OxymaPure dissolved in DMF at 0.3 M cone. At the end of the peptide elongation, a final Fmoc deprotection, as already described, was performed before moving to the cleavage step.

Step 3: Cleavage and precipitation of crude nangibotide

The cleavage of nangibotide off the resin was carried out using a solution of 16 mL of TFA/DODT/TIPS/water in 90/4/3/3 ratio cooled at 0°C. The peptidyl resin was added portionwise in 30 min keeping the internal temperature under 25°C. The cleavage was run for 3.5 hours, then the resin was filtered and washed by 10 mL of TFA for 10 min.

DIPE was used for the precipitation of the peptide, adding 12 volumes (300 mL) dropwise to the peptide TFA solution, keeping the temperature under 20°C. The suspension with nangibotide was filtered on a gooch funnel, the peptide washed again with 100 mL of DIPE and then dried under vacuum overnight. Molar yield 40%. Purity 61%.

Example 2

Preparation of nangibotide by three-fragment condensation

In the approach using three fragments, only the cysteine residue was coupled to the methionine on rink amide resin to prepare fragment 11-12, whereas protected peptide fragments 1-7 and 8-10 were synthesized using 2-CTC resin.

Step 1: Synthesis of fragment 11-12

2 g of MBHA resin (1.0-1.3 mmol/g) was swelled using 16 mL of DMF for 30 min 2 eq of Fmoc-Met-OH (2.4 mmol, 2.67 g), 2 eq DIC (2.4 mmol, 1.136 mL) and 2 eq OxymaPure (2.4 mmol, 1.023 g) were dissolved in 8 mL of DMF at 0.3 M cone, and added to the resin. The loading step was carried out for 1 and half hour. After the loading, the resin was filtered and washed 3 times with 12 mL of DMF. The Fmoc deprotection step was carried out by

addition of 12 mL of a 20% piperidine solution in DMF for two 10 min cycles. Same procedure was repeated for the coupling of Fmoc-Cys(Trt)-OH to obtain resin-attached Fmoc-deprotected fragment 11-12. The loading, calculated by UV absorption for the peptidyl resin relative to the first amino acid inserted, was 0.8 mmol/g.

Step 2: Synthesis of fragments 1-7 and 8-10

For the synthesis of both fragments the loading of 2-chloro trityl chloride resin was performed on 5 g (1.6 mmol/g) using 0.8 eq Fmoc-Gly-OH (6.40 mmol, 1.90 g) dissolved in 30 mL of DCM and addition of 3 eq DIPEA (24 mmol, 4.19 mL). The loading step was carried out for 1 hour, then the resin was washed by 30 mL DCM for three times and eventual Cl-groups were capped by two different capping solutions: first by 30 mL of methanol/DIPEA/DCM (1:2:7) and then by 30 mL AC2O/DIPEA/DCM in the same ratio. After the treatment with these solutions for 15 min and subsequent washing with DCM, the resin was washed three times with DMF, before deprotection of Fmoc and evaluation of the resin loading. Generally, this protocol gave a resin loaded with 1.1 mmol/g Fmoc-Gly-OH. The Fmoc deprotection and coupling step protocols were equally performed with all the amino acids in the respective sequences: Fmoc-Tyr(tBu)-OH and Fmoc-Glu(tBu)-OH for fragment 8-10, and Fmoc-Ala-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Glu(OtBu)-OH twice, Fmoc-Gln(Trt)-OH and Fmoc-Leu-OH for fragment 1-7.

For each coupling, 3 eq amino acid were activated by 3 eq DIC and 3 eq OxymaPure dissolved in DMF at 0.3 M cone.

Fragment Fmoc-Glu(tBu)-Tyr(tBu)-Gly-OH (8-10) was obtained by cleavage off the resin using 6 volumes (30 mL) of a TFA 1.5 % solution in DCM, 5 times for 2 min. The final TFA solution was neutralized by 1.2 eq pyridine (15.89 mmol, 1.3 mL) diluted in 30 mL methanol. The final solution was concentrated to 50 mL under vacuum then washed by water and brine. The organic layer was dried by anhydrous sodium sulphate, filtered and further concentrated before crystallization of the tripeptide with 5 volumes of petroleum ether at 0°C. The peptide was filtered, washed by petroleum ether and dried overnight in a vacuum oven at 37°C. Molar yield 65%. Purity 90%.

Fragment Fmoc-Leu-Gln(Trt)-Glu(OtBu)-Glu(OtBu)-Asp(OtBu)-Ala-Gly-OH (1-7) was obtained by cleavage off the resin using 6 volumes (30 mL) of a TFA 1.5 % solution in DCM, 5 times for 2 min. The final TFA solution was neutralized by 1.2 eq pyridine (15.89 mmol, 1.3 mL) diluted in 30 mL methanol. The DCM was evaporated and replaced by methanol, adding and evaporating 30 mL methanol a couple of times till one third of the volume. The peptide fragment was precipitated by adding 5 volumes (150 mL) water to the methanol solution at 0°C and filtered after stirring for 30 min. The full protected heptapeptide was washed by water and dried overnight in a vacuum oven at 37°C. Molar yield 85%. Purity 89%.

Step 3: Synthesis of fragment 8-12 (Fragment condensation 1)

The fragment condensation between Fmoc-Glu(tBu)-Tyr(tBu)-Gly-OH (8-10) and H-Cys(Trt)-Met-MBHA resin (11-12) was carried out activating 2 eq (1.6 mmol, 1.12 g) of fragment 8-10 dissolved in 6 mL of DMF at 40°C by using 2 eq OxymaPure (1.6 mmol, 0.22 g) and 2 eq DIC (1.6 mmol, 0.25 mL) for 10 min. The activated ester of tripeptide 8-10 was added to the resin-attached fragment 11-12 and stirred for 3 hours at 40°C. After filtration, the resin was washed three times by 15 mL DMF and then capped by 12 mL of AC2O 10% in DMF for 15 min. The resin was washed three timed by 12 mL DMF before deprotection of Fmoc to finally obtain resin-attached Fmoc-protected fragment 8-12. Molar yield 91%. Purity 89%.

Step 4: Synthesis of nanaibotide (Fragment condensation 2)

The fragment condensation between fragment 1-7 and H-Glu(OtBu)-Tyr(tBu)-Gly-Cys(Trt)-Met-MBHA resin (8-12) was carried out activating 1.5 eq (2.25 mmol, 2.64 g) of fragment 1-7 dissolved in 25 mL DMF at 40°C by using 2 eq OxymaPure (2.25 mmol, 0.32 g) and 2 eq DIC (2.25 mmol, 0.35 mL) for 15 min. The activated ester of fragment 1-7 was added to the resin-attached fragment 8-12 and stirred for 3.5 hours at 40°C. After filtration, the resin was washed three times by 12 mL DMF before deprotection of Fmoc with the standard procedure described above. After Fmoc deprotection, the resin was washed again by DMF and DCM and then dried at vacuum pump.

Step 5: Cleavage and precipitation of crude nanaibotide

The cleavage of nangibotide off the resin was carried out using a solution of 16 mL of TFA/DODT/TIPS/water in 90/4/3/3 ratio cooled at 0°C. The peptidyl resin was added portionwise in 30 min keeping the internal temperature under 25°C. The cleavage was run for 3.5 hours, then the resin filtered and washed by 10 mL of TFA for 10 min.

DIPE was used to precipitate the peptide, adding 12 volumes (300 mL) dropwise to the peptide TFA solution, keeping the temperature under 20°C. The suspension with nangibotide was filtered on a gooch funnel, the peptide washed again with 100 mL of DIPE and then dried at vacuum pump overnight. Molar yield 61%. Purity 73%.

Example 3

Preparation of nangibotide by two-fragment condensation

In the approach using two fragments, the SPPS elongation onto MBHA resin, as described in Example 2, step 1, was continued until Glu8 was attached to provide fragment 8-12, then fragment 1-7, synthesized on 2-CTC resin as described in example 2, step 2, was coupled to the resin-attached fragment 8-12 as described in example 2, step 4.

Step 1: Synthesis of fragment 8-12

2 g of MBHA resin (1.0-1.3 mmol/g) was swelled using 16 mL of DMF for 30 min 2 eq of Fmoc-Met-OH (2.4 mmol, 2.67 g), 2 eq DIC (2.4 mmol, 1.136 mL) and 2 eq OxymaPure (2.4 mmol, 1.023 g) were dissolved in 8 mL of DMF at 0.3 M cone, and added to the resin. The loading step was carried out for 1 and half hour. After the loading, the resin was filtered and washed 3 times with 12 mL of DMF. The Fmoc deprotection step was carried out by addition of 12 mL of a 20% piperidine solution in DMF for two 10 min cycles. Same procedure was repeated for the coupling of Fmoc-Cys(Trt)-OH; Fmoc-Glu(OtBu)-OH; Fmoc-Tyr(tBu)-OH; Fmoc-Gly-OH to obtain fragment 8-12. The loading, calculated by UV absorption for the peptidyl resin relative to the first amino acid inserted, was 0.8 mmol/g. Molar yield 88%. Purity 83%.

Step 2: Synthesis of nanaibotide (Fragment condensation 2)

The final fragment condensation was performed as described in example 2, step 4.

Step 3: Cleavage and precipitation of crude nanaibotide

The cleavage of nangibotide off the resin was carried out as described in example 2, step 5. Molar yield 60%. Purity 70%.

PAPER

Methods in enzymology (2000), 312, 293-304

 Journal of the American College of Cardiology (2016), 68(25), 2776-2793

PATENT

https://patents.google.com/patent/WO2011124685A1/en

Product pat, WO2011124685 ,protection in the EU states and the US  April 2031

References

  1. ^ Cuvier V, Lorch U, Witte S, Olivier A, Gibot S, Delor I, Garaud JJ, Derive M, Salcedo-Magguilli M (2018). “A first-in-man safety and pharmacokinetics study of nangibotide, a new modulator of innate immune response through TREM-1 receptor inhibition”Br J Clin Pharmacol84 (10): 2270–2279. doi:10.1111/bcp.13668PMC 6138490PMID 29885068.
  2. ^ Weber B, Schuster S, Zysset D, Rihs S, Dickgreber N, Schürch C, Riether C, Siegrist M, Schneider C, Pawelski H, Gurzeler U, Ziltener P, Genitsch V, Tacchini-Cottier F, Ochsenbein A, Hofstetter W, Kopf M, Kaufmann T, Oxenius A, Reith W, Saurer L, Mueller C (2014). “TREM-1 deficiency can attenuate disease severity without affecting pathogen clearance”PLOS Pathog10 (1): e1003900. doi:10.1371/journal.ppat.1003900PMC 3894224PMID 24453980.
  3. ^ Derive M, Bouazza Y, Sennoun N, Marchionni S, Quigley L, Washington V, Massin F, Max JP, Ford J, Alauzet C, Levy B, McVicar DW, Gibot S (1 June 2012). “Soluble TREM-like transcript-1 regulates leukocyte activation and controls microbial sepsis”Journal of Immunology188 (11): 5585–5592. doi:10.4049/jimmunol.1102674PMC 6382278PMID 22551551.
  4. ^ Derive M, Boufenzer A, Bouazza Y, Groubatch F, Alauzet C, Barraud D, Lozniewski A, Leroy P, Tran N, Gibot S (Feb 2013). “Effects of a TREM-like transcript 1-derived peptide during hypodynamic septic shock in pigs”Shock39 (2): 176–182. doi:10.1097/SHK.0b013e31827bcdfbPMID 23324887S2CID 23583753.
  5. ^ Derive M, Boufenzer A, Gibot S (April 2014). “Attenuation of responses to endotoxin by the triggering receptor expressed on myeloid cells-1 inhibitor LR12 in nonhuman primate”Anaesthesiology120 (4): 935–942. doi:10.1097/ALN.0000000000000078PMID 24270127S2CID 10347527.
  6. ^ Cuvier V, Lorch U, Witte S, Olivier A, Gibot S, Delor I, Garaud JJ, Derive M, Salcedo-Magguilli M (2018). “A first-in-man safety and pharmacokinetics study of nangibotide, a new modulator of innate immune response through TREM-1 receptor inhibition”Br J Clin Pharmacol84 (10): 2270–2279. doi:10.1111/bcp.13668PMC 6138490PMID 29885068.
  7. ^ François B, Wittebole X, Ferrer R, Mira JP, Dugernier T, Gibot S, Derive M, Olivier A, Cuvier V, Witte S, Pickkers P, Vandenhende F, Garaud JJ, Sánchez M, Salcedo-Magguilli M, Laterre PF (July 2020). “Nangibotide in patients with septic shock: a Phase 2a randomized controlled clinical trial”Intensive Care Medicine46 (7): 1425–1437. doi:10.1007/s00134-020-06109-zPMID 32468087S2CID 218912723.
  8. ^ “Efficacy, Safety and Tolerability of Nangibotide in Patients With Septic Shock (ASTONISH)”ClinicalTrials.gov. US National Library of Medicine. Retrieved 13 July 2020.

Derive et al (2013) Effects of a TREM-Like Transcript 1–Derived Peptide During Hypodynamic Septic Shock in Pigs. Shock39(2) 176 PMID: 23324887

Derive et al (2014) Attenuation of Responses to Endotoxin by the Triggering Receptor Expressed on Myeloid Cells-1 Inhibitor LR12 in Nonhuman Primate. Anesthesiology120(4) 935 PMID: 24270127

Derive et al (2012) Soluble Trem-like Transcript-1 Regulates Leukocyte Activation and Controls Microbial Sepsis. J. Immunol.188(11) 5585 PMID: 22551551

Clinical data
Routes of
administration
Intravenous; intraperitoneal
Physiological data
ReceptorsTREM-1
MetabolismEnzymatic in bloodstream
Pharmacokinetic data
MetabolismEnzymatic in bloodstream
Elimination half-life3 minutes
Identifiers
showIUPAC name
CAS Number2014384‐91‐7
ChemSpider64835227
UNII59HD7BLX9H
ChEMBLChEMBL4297793
Chemical and physical data
FormulaC54H82N14O22S2
Molar mass1343.439
3D model (JSmol)Interactive image
showSMILES
showInChI

//////////////Nangibotide, phase 3, нангиботид , مانغيبوتيد , 南吉博肽 , INOTREM, SEPTIC SHOCK, PEPTIDE

wdt-9

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Tralokinumab


(Heavy chain)
QVQLVQSGAE VKKPGASVKV SCKASGYTFT NYGLSWVRQA PGQGLEWMGW ISANNGDTNY
GQEFQGRVTM TTDTSTSTAY MELRSLRSDD TAVYYCARDS SSSWARWFFD LWGRGTLVTV
SSASTKGPSV FPLAPCSRST SESTAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ
SSGLYSLSSV VTVPSSSLGT KTYTCNVDHK PSNTKVDKRV ESKYGPPCPS CPAPEFLGGP
SVFLFPPKPK DTLMISRTPE VTCVVVDVSQ EDPEVQFNWY VDGVEVHNAK TKPREEQFNS
TYRVVSVLTV LHQDWLNGKE YKCKVSNKGL PSSIEKTISK AKGQPREPQV YTLPPSQEEM
TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL DSDGSFFLYS RLTVDKSRWQ
EGNVFSCSVM HEALHNHYTQ KSLSLSLGK
(Light chain)
SYVLTQPPSV SVAPGKTARI TCGGNIIGSK LVHWYQQKPG QAPVLVIYDD GDRPSGIPER
FSGSNSGNTA TLTISRVEAG DEADYYCQVW DTGSDPVVFG GGTKLTVLGQ PKAAPSVTLF
PPSSEELQAN KATLVCLISD FYPGAVTVAW KADSSPVKAG VETTTPSKQS NNKYAASSYL
SLTPEQWKSH RSYSCQVTHE GSTVEKTVAP TECS
(Disulfide bridge: H22-H96, H149-H205, H263-H323, H369-H427, H228-H’228, H231-H’231, L22-L87, L136-L195, H136-L213)

Tralokinumab

トラロキヌマブ (遺伝子組換え)

FormulaC6374H9822N1698O2014S44
CAS1044515-88-9
Mol weight143873.2167

EU APPROVED, Adtralza, 2021/6/17

Antiasthmatic, Anti-inflammatory, Anti-IL-13 antibody

Tralokinumab is a human monoclonal antibody which targets the cytokine interleukin 13,[1] and is designed for the treatment of asthma and other inflammatory diseases.[2] Tralokinumab was discovered by Cambridge Antibody Technology scientists, using Ribosome Display, as CAT-354[3] and taken through pre-clinical and early clinical development.[4] After 2007 it has been developed by MedImmune, a member of the AstraZeneca group, where it is currently in Ph3 testing for asthma and Ph2b testing for atopic dermatitis.[5][6] This makes it one of the few fully internally discovered and developed drug candidates in AstraZeneca’s late stage development pipeline.

Discovery and development

Tralokinumab (CAT-354) was discovered by Cambridge Antibody Technology scientists[7] using protein optimization based on Ribosome Display.[8] They used the extensive data sets from ribosome display to patent protect CAT-354 in a world-first of sequence-activity-relationship claims.[7] In 2004, clinical development of CAT-354 was initiated with this first study completing in 2005.[9] On 21 July 2011, MedImmune LLC initiated a Ph2b, randomized, double-blind study to evaluate the efficacy of tralokinumab in adults with asthma.[10]

In 2016, MedImmune and AstraZeneca were developing tralokinumab for asthma (Ph3) and atopic dermatitis (Ph2b) while clinical development for moderate-to-severe ulcerative colitis and idiopathic pulmonary fibrosis (IPF) have been discontinued.[9] In July of that year AstraZeneca licensed Tralokinumab to LEO Pharma for skin diseases.[11]

A phase IIb study of Tralokinumab found that treatment was associated with early and sustained improvements in atopic dermatitis symptoms and tralokinumab had an acceptable safety and tolerability profile, thereby providing evidence for targeting IL-13 in patients with atopic dermatitis.[12]

On 15 June 2017, Leo Pharma announced that they were starting phase III clinical trials with tralokinumab in atopic dermatitis.[13]

Society and culture

Legal status

On 22 April 2021, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Adtralza, intended for the treatment of moderate‑to‑severe atopic dermatitis.[14]

The applicant for this medicinal product is LEO Pharma A/S.

References

  1. ^ Kopf M, Bachmann MF, Marsland BJ (September 2010). “Averting inflammation by targeting the cytokine environment”. Nature Reviews. Drug Discovery9 (9): 703–18. doi:10.1038/nrd2805PMID 20811382S2CID 23769909.
  2. ^ “Statement On A Nonproprietary Name Adopted By The USAN Council: Tralokinumab” (PDF). American Medical Association.
  3. ^ Thom G, Cockroft AC, Buchanan AG, Candotti CJ, Cohen ES, Lowne D, et al. (May 2006). “Probing a protein-protein interaction by in vitro evolution” [P]. Proceedings of the National Academy of Sciences of the United States of America103 (20): 7619–24. Bibcode:2006PNAS..103.7619Tdoi:10.1073/pnas.0602341103PMC 1458619PMID 16684878.
  4. ^ May RD, Monk PD, Cohen ES, Manuel D, Dempsey F, Davis NH, et al. (May 2012). “Preclinical development of CAT-354, an IL-13 neutralizing antibody, for the treatment of severe uncontrolled asthma”British Journal of Pharmacology166 (1): 177–93. doi:10.1111/j.1476-5381.2011.01659.xPMC 3415647PMID 21895629.
  5. ^ “Pipeline”MedImmune. Retrieved 11 June 2013.
  6. ^ “Studies found for CAT-354”ClinicalTrials.gov. Retrieved 11 June 2013.
  7. Jump up to:a b Human Antibody Molecules for Il-13, retrieved 2015-07-26
  8. ^ Jermutus L, Honegger A, Schwesinger F, Hanes J, Plückthun A (January 2001). “Tailoring in vitro evolution for protein affinity or stability”Proceedings of the National Academy of Sciences of the United States of America98 (1): 75–80. Bibcode:2001PNAS…98…75Jdoi:10.1073/pnas.98.1.75PMC 14547PMID 11134506.
  9. Jump up to:a b “Tralokinumab”Adis Insight. Springer Nature Switzerland AG.
  10. ^ Clinical trial number NCT01402986 for “A Phase 2b, Randomized, Double-blind Study to Evaluate the Efficacy of Tralokinumab in Adults With Asthma” at ClinicalTrials.gov
  11. ^ “AstraZeneca enters licensing agreements with LEO Pharma in skin diseases”.
  12. ^ Wollenberg A, Howell MD, Guttman-Yassky E, Silverberg JI, Kell C, Ranade K, et al. (January 2019). “Treatment of atopic dermatitis with tralokinumab, an anti-IL-13 mAb”The Journal of Allergy and Clinical Immunology143 (1): 135–141. doi:10.1016/j.jaci.2018.05.029PMID 29906525.
  13. ^ “LEO Pharma starts phase 3 clinical study for tralokinumab in atopic dermatitis”leo-pharma.com. AstraZeneca. 1 July 2016.
  14. ^ “Adtralza: Pending EC decision”European Medicines Agency. 23 April 2021. Retrieved 23 April 2021.
Tralokinumab Fab fragment bound to IL-13. From PDB 5L6Y​.
Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetIL-13
Clinical data
ATC codeD11AH07 (WHO)
Identifiers
CAS Number1044515-88-9 
ChemSpidernone
UNIIGK1LYB375A
KEGGD09979
Chemical and physical data
FormulaC6374H9822N1698O2014S44
Molar mass143875.20 g·mol−1
  (what is this?)  (verify)

/////////Tralokinumab, Adtralza, EU 2021, APPROVALS 2021, Antiasthmatic, Anti-inflammatory, Anti-IL-13 antibody, MONOCLONAL ANTIBODY, PEPTIDE, トラロキヌマブ (遺伝子組換え) ,

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EpiVacCorona


Russia approves 2nd coronavirus vaccine "EpiVacCorona"

Origin of EpiVacCorona antigenes

  1. MKIEEGKLVIWINGDKGYNGLAEVGKKFEKDTGIKVTVEHPDKLEEKFPQVAATGDGPDIIFWAHDRFGGYAQSGLLAEITPDKAFQDKLYPFTWDAVRYNGKLIAYPIAVEALSLIYNKDLLPNPPKTWEEIPALDKELKAKGKSALMFNLQEPYFTWPLIAADGGYAFKYENGKYDIKDVGVDNAGAKAGLTFLVDLIKNKHMNADTDYSIAEAAFNKGETAMTINGPWAWSNIDTSKVNYGVTVLPTFKGQPSKPFVGVLSAGINAASPNKELAKEFLENYLLTDEGLEAVNKDKPLGAVALKSYEEELAKDPRIAATMENAQKGEIMPNIPQMSAFWYAVRTAVINAASGRQTVDEALKDAQTNSSSNNNNNNNNNNLGDNGPQNQRNAPRITFGGPSDSTGSNQNGERSGARSKQRRPQGLPNNTASWFTALTQHGKEDLKFPRGQGVPINTNSSPDDQIGYYRRATRRIRGGDGKMKDLSPRWYFYYLGTGPEAGLPYGANKDGIIWVATEGALNTPKDHIGTRNPANNAAIVLQLPQGTTLPKGFYAEGSRGGSQASSRSSSRSRNSSRNSTPGSSRGTSPARMAGNGGDAALALLLLDRLNQLESKMSGKGQQQQGQTVTKKSAAEASKKPRQKRTATKAYNVTQAFGRRGPEQTQGNFGDQELIRQGTDYKHWPQIAQFAPSASAFFGMSRIGMEVTPSGTWLTYTGAIKLDDKDPNFKDQVILLNKHIDAYKTFPPTEPKKDKKKKADETQALPQRQKKQQTVTLLPAADLDDLSKQLQQSMSSADSTQA. “Carrier protein sequence”.

EpiVacCorona

Federal Budgetary Research Institution State Research Center of Virology and Biotechnology

peptide, russia

PATENT https://www.fips.ru/registers-doc-view/fips_servlet?DB=RUPAT&DocNumber=2743594&TypeFile=htmlRU 2 743 594 RU 2 743 593RU 2 743 595 RU 2 738 081 Science (Washington, DC, United States) (2021), 372(6538), 116-117. 

EpiVacCorona (Russian: ЭпиВакКорона, tr. EpiVakKorona) is a peptide-based vaccine against COVID-19 developed by the VECTOR center of Virology.[1][2][3] It consists of three chemically synthesized peptides (short fragments of a viral spike protein) that are conjugated to a large carrier protein. This protein is a fusion product of a viral nucleocapsid protein and a bacterial MBP protein.The third phase of a clinical trial, which should show whether the vaccine is able to protect people from COVID-19 or not, was launched in November 2020 with more than three thousand participants.[2] It is assumed it will be completed in August 2021.[2] According to the vaccine developers, the peptides and the viral part of the chimeric protein should immunize people who received this vaccine against SARS-CoV-2 and trigger the production of protective antibodies. However, some experts in the field have expressed concerns about the selection of peptides for use as vaccine antigens.[3][4] In addition, there are also serious concerns about the vaccine immunogenicity data, which have fueled independent civic research efforts[5][6][7] and criticism by some experts.[3][8][4][9][10] Meanwhile, the EpiVacCorona has received vaccine emergency authorization in a form of government registration and is available for vaccination outside the clinical trials.[11] The vaccine delivered via intramuscular route and aluminum hydroxide serves as an immunological adjuvant.

Description[edit]

Origin of EpiVacCorona antigenes

Composition

The vaccine includes three chemically synthesized short fragments of the viral spike protein – peptides, which, according to the developers of EpiVacCorona represent the protein regions containing B-cell epitopes that should be recognized by the human immune system.

These peptides are represented by following amino acid sequences:

1) CRLFRKSNLKPFERDISTEIYQAGS, 2) CKEIDRLNEVAKNLNESLIDLQE, 3) CKNLNESLIDLQELGKYEQYIK.[1][12][13]

In the vaccine all peptides are conjugated to a carrier protein, which is an expression product of the chimeric gene. This chimeric gene was created by fusion of two genes originating from different organisms, namely a gene encoding a viral nucleocapsid protein and a gene encoding a bacterial maltose-binding protein (MBP). The fusion chimeric gene expressed in Escherichia coli. The sequence of the chimeric protein is available from the patent.[4] The genetic construct of the chimeric gene also includes a short genetic fragment encoding a polyhistidine-tag, which is used to purify the chimeric protein from E. coli lysate. After the purification, the protein is conjugated with three peptides in a way that only one variant of the peptide molecule is attached to each protein molecule. As a result, three types of conjugated molecules are created: chimeric protein with attached peptide number 1, the same protein with peptide number 2, and finally the same protein with peptide number 3. All three types of conjugated molecules are included in the vaccine.[citation needed]

EpiVacCorona: antigens origin and composition

Vaccine antigens and antibodies

According to the developers’ publications,[14][5][6] vaccine antigens are three peptides of the spike protein and a chimeric protein consisting of two parts (viral nucleocapsid protein and bacterial maltose-binding protein). In addition, the polyhistidine-tag – a short peptide that is introduced into a vaccine composition to purify a chimeric protein from a bacterial lysate – is also a vaccine antigen against which antibodies can form in those who have received the vaccine. A person vaccinated with EpiVacCorona can develop antibodies not only to the peptides of the spike protein, but also to other antigens present in the vaccine. According to Anna Popova who is a head of the Federal Service for Supervision of Consumer Rights Protection and Human Welfare, it takes 42 days for those vaccinated with EpiVacCorona to develop immunity.[15]

figure2

Development

Immunogenic peptide screening in rabbits for EpiVacCorona design

Preclinical studies

The primary screening of peptides for the search for the most immunogenic ones was carried out in animals. The level of antibodies that was triggered by each tested peptide after administration to rabbits was measured. In the test, hemocyanin protein was used as a carrier protein for the studied peptides. Further, on six species of animals (mice, rats, rabbits, African green monkeys, rhesus monkeys, guinea pigs), the vaccine was shown to be harmless in terms of such parameters as general toxicity, allergic properties, and mutagenic activity. In four species of animals (hamsters, ferrets, African green monkeys, rhesus monkeys), specific activity was shown: immunogenicity and protective properties against SARS-CoV-2. The main results of preclinical studies are published in the “Bulletin of the Russian Academy of Medical Sciences”.[12][13]

Clinical studies

The studies development timeline was reported in Russian media in January 2021.[16] There are currently two clinical trials of EpiVacCorona registered in the ClinicalTrials.gov database.[17][18][2]

Phase I-II

The trial “Study of the Safety, Reactogenicity and Immunogenicity of “EpiVacCorona” Vaccine for the Prevention of COVID-19 (EpiVacCorona)”[18] was registered in clinical trial database with ClinicalTrials.gov identifier: NCT04780035. Another trial with the same title was registered with ClinicalTrials.gov Identifier: NCT04527575. Results of the trial that included data on 86 participants were published in Russian Journal of Infection and Immunity, indicating preliminary evidence of safety and an immune response.[1] The publication reports preliminary results of the first two phases of clinical trials of the vaccine in volunteers, of which 14 people aged 18-30 years participated in the first phase, and 86 volunteers aged 18-60 years in the second phase. It is claimed that antibodies were formed in 100% of the volunteers, and the vaccine is also claimed to be safe.[1]

EpiVacCorona Vaccine Development Timeline

Phase III

The third phase of a clinical trial, which should show whether the vaccine is able to protect people from COVID-19 or not, was launched in November 2020 with more than three thousand participants planned. It is expected to be completed in September 2021.[2] In the clinical trials database the phase III trial etitled “Study of the Tolerability, Safety, Immunogenicity and Preventive Efficacy of the EpiVacCorona Vaccine for the Prevention of COVID-19[2]” was registered only in March 2021 with ClinicalTrials.gov Identifier: NCT04780035. Phase 3-4 trial was registered in Russia at 18.11.2020 with 4991 participants planned.[19]

Intellectual property

The following patents of the Russian Federation for invention have been published, which protect the EpiVacCorona vaccine:

Peptide immunogens and vaccine composition against coronavirus infection COVID-19 using peptide immunogens” (No. 2738081). There are 7 peptides in patented vaccine compositions.

Peptide immunogens and vaccine composition against coronavirus infection COVID-19 using peptide immunogens” (No. 2743593). The patented vaccine composition contains 2 peptides.

Peptide immunogens used as a component of a vaccine composition against coronavirus infection COVID-19″ (No. 2743594). The patented vaccine composition contains 3 peptides.

Vaccine composition against coronavirus infection COVID-19″ (No. 2743595). The patented vaccine composition contains 3 peptides.

In all of these patents, the carrier protein is referred to as a chimeric fusion protein with an amino acid sequence derived from two parts, a bacterial maltose binding protein and a viral nucleocapsid protein.[20]

EpiVacCorona vaccine registration certificate

Authorization

 
  Full authorization  Emergency authorization

See also: List of COVID-19 vaccine authorizations § EpiVacCorona

The VECTOR has received vaccine emergency authorization in a form of government registration in October 2020.[21]

In Russia phase III clinical study is called post-registration study. Therefore, government registration of the vaccine means permission to perform phase III clinical research and public vaccination outside of clinical trials as well.[21] Since December 2020, the vaccine has been released for public vaccination in Russia.[22]

As of March 2021, Turkmenistan is the only foreign state to register EpiVacCorona with full authorization.[23][24]

Russia’s Chief Health Officer Anna Popova said: “In December 2020 the EpiVacCorona documents were presented to the World Health Organization, and we are expecting a decision from WHO.”[25] However, Deutsche Welle reports “As of March 1, the WHO had yet to receive an Expression of Interest (EOI) from EpiVacCorona’s developers, “VECTOR,” to enable WHO experts to evaluate their vaccine.”[26]

Export

The Deputy Director-General of the World Health Organization (WHO) Dr. Soumya Swaminathan during news conference in Geneva that took place in October 2020, told: “We will only be able to have a position on a vaccine when we see results of the phase III clinical trials.”[27] According to the center’s director Rinat Maksyutov, many government and non-government organizations want to test or be involved in the production of the vaccine.[28] As of March 30, Venezuela obtained 1000 doses of the Russian EpiVacCorona vaccine for a trial.[29] Venezuela also has reached a deal to purchase doses of the vaccine, as well as manufacture it locally, Vice President Delcy Rodriguez provided this information on June 4, 2021.[30] Turkmenistan expects to receive EpiVacCorona, as the vaccine has already been approved for use in that country.[31]

Controversy

Independent study of clinical trial participants

Ministry of Health’s response to a request from trial participants to perform independent antibody screening tests

English translation of Ministry of Health’s response to a request from trial participants to perform independent antibody screening tests.

At the start of the Phase III, trial participants and those vaccinated outside the trial began to form a community through the Telegram messenger network. On January 18, 2021, the members of the community turned to the Ministry of Health of the Russian Federation with an open letter, in which they stated that the production of antibodies after vaccination among them is much lower than declared by vaccine developers. Study participants claimed that antibodies were not found in more than 50% of those who documented their participation in the study, although only 25% of the participants should have had a placebo according to the study design. The trial participants also claimed that negative results were obtained using the a special ELISA test developed and recommended by VECTOR for EpiVacCorona detection.[5][6][4] More questions about the quality and protectiveness of antibodies induced by EpiVacCorona appeared along with the first results of a special antibody VECTOR’s test, when, with a positive special test, negative results of all other commercially available tests were otained: LIAISON SARS-CoV-2 S1 / S2 IgG – DiaSorin, IgM / IgG – Mindray, SARS-CoV-2 IgG – Abbott Architect, Anti-SARS-CoV-2 ELISA (IgG) – Euroimmun, Access SARS-CoV-2 IgG (RBD) – Beckman Coulter, “SARS-CoV-2-IgG-ELISA -BEST “-” Vector-Best “,” Anti-RBD IgG “- Gamaleya Research Center.[5][6][4][8] Clinical trial participants conducted their own antibody mini-study that was performed in independent Russian laboratory. The study participants asked Dr. Alexander Chepurnov, the former head of the infectious diseases department at VECTOR, who now works at another medical institute, to check neutralizing antibodies presence in their serum samples.[3] They also sent to Dr. Chepurnov control serum samples from former COVID-19 patients or people vaccinated with another Russian vaccine, Sputnik V, which is known to trigger the production of neutralizing antibodies.[32] All serum samples were blinded before antibody tests. On 23 March 2021, the participants reported the results of their mini-study in an open letter to the Ministry of Health of the Russian Federation.[6][7] According to the letter, even with the help of the VECTOR antibody detection system, antibodies were detected only in 70-75% of those vaccinated with EpiVacCorona. However, the level of antibodies was very low. Moreover, according to the letter, virus-neutralizing antibodies were not detected in the independent research Dr. Alexander Chepurnov laboratory at all.[3][6][7] The trial participants asked Ministry of Health in their open letter to perform independent study for the verification of their findings.[3][6][7] In addition, the letter reports 18 cases of COVID-19 cases as of March 22, 2021 among those who received the vaccine and became ill (sometimes severe) three weeks or later after the second dose of EpiVacCorona.[33][6][7] April 20, 2021 the study participants got a reply, with refusal of performing any additional verification antibody tests or investigation of sever COVID-19 cases among vaccinated individuals. The reply include the following text: “Considering that the listed immunobiological preparations (vaccines) for the prevention of COVID-19 are registered in the prescribed manner, their effectiveness and safety have been confirmed.”

Vaccine criticism by independent experts

Some independent experts criticized the vaccine design[3][4] and clinical data presentation in the publication.[8][9][10] The experts are saying that peptide selection is “crucial” for the innovative peptide approach, which VECTOR uses for EpiVacCorona design. However, some researchers are not convinced that the viral spike protein peptides selected for the vaccine are actually “visible” by human immune system.[3][4][34] They stated that these peptides do not overlap[35] with peptides that have been shown in several publications to contain human linear B cell epitopes in spike protein of SARS-CoV-2.[36][37][38][39][40] Moreover, the study was criticized for the lack of positive control of convalescent plasma samples in reports related to neutralizing antibody titers in vaccinated individuals.[1][10] The same study was also criticized for presence of detectable antibodies in negative controls samples that were not discussed by authors.[1][10] In addition, vaccine developers have been criticized for aggressively advertising their vaccine efficacy prior to the completion of phase III clinical trial. The most substantial criticism came from Dr. Konstantin Chumakov, who currently serves as the Associate Director for Research at the FDA Office of Vaccines Research and Review. Dr. Chumakov said: “I would not be in a hurry to call this peptide formulation a vaccine yet, because its effectiveness has not yet been proven…For the introduction of such a vaccine, the level of evidence must be much higher, and therefore the developers of EpiVacCorona, before launching their vaccine on the market, had to conduct clinical trials and prove that their vaccine actually protects against the disease. However, such tests were not carried out, which is absolutely unacceptable.”[41]

The title page of the “EpiVacCorona” patent with Anna’s Popova name among inventors

Conflict of interest

The vaccine design was protected by several already issued patents (see section above). In each patent one of its co-authors is a namesake of Anna Popova who is a head of the Federal Service for Supervision of Consumer Rights Protection and Human Welfare. This patent authorship represents an issue as far as Anna Popova is a head of the Russian agency that is charged with overseeing vaccine safety and efficacy. As a co-author of these patents, she might have an interest in promoting the vaccine despite its shortcomings.

References

  1. Jump up to:a b c d e f Ryzhikov AB, Ryzhikov EA, Bogryantseva MP, Usova SV, Danilenko ED, Nechaeva EA, Pyankov OV, Pyankova OG, Gudymo AS, Bodnev SA, Onkhonova GS, Sleptsova ES, Kuzubov VI, Ryndyuk NN, Ginko ZI, Petrov VN, Moiseeva AA, Torzhkova PY, Pyankov SA, Tregubchak TV, Antonec DV, Gavrilova EV, Maksyutov RA (2021). “A single blind, placebo-controlled randomized study of the safety, reactogenicity and immunogenicity of the “EpiVacCorona” Vaccine for the prevention of COVID-19, in volunteers aged 18–60 years (phase I–II)”Russian Journal of Infection and Immunity11 (2): 283–296. doi:10.15789/2220-7619-ASB-1699.
  2. Jump up to:a b c d e Federal Budgetary Research Institution State Research Center of Virology and Biotechnology “Vector” (2 March 2021). “Multicenter Double-blind Placebo-controlled Comparative Randomized Study of the Tolerability, Safety, Immunogenicity and Prophylactic Efficacy of the EpiVacCorona Peptide Antigen-based Vaccine for the Prevention of COVID-19, With the Participation of 3000 Volunteers Aged 18 Years and Above (Phase III-IV)”.
  3. Jump up to:a b c d e f g DobrovidovaApr. 6, Olga; 2021; Am, 11:05 (6 April 2021). “Russia’s COVID-19 defense may depend on mystery vaccine from former bioweapons lab—but does it work?”Science | AAAS. Retrieved 24 April 2021.
  4. Jump up to:a b c d e f Dobrovidova, Olga (9 April 2021). “Latest Russian vaccine comes with a big dose of mystery”Science372 (6538): 116–117. doi:10.1126/science.372.6538.116ISSN 0036-8075PMID 33833104S2CID 233191522.
  5. Jump up to:a b c Staff, Reuters (26 March 2021). “Volunteers break rank to raise doubts in trial of Russia’s second COVID-19 vaccine”Reuters. Retrieved 23 April 2021.
  6. Jump up to:a b c d e f g “”ЭпиВакКорона” глазами участников клинических испытаний и ученых-биологов”Троицкий вариант — Наука (in Russian). 23 March 2021. Retrieved 23 April 2021.
  7. Jump up to:a b c d e https://epivakorona.com/openletter.htm
  8. Jump up to:a b c “EpiVacCorona’s race to the finish line Meduza speaks to the developer and manufacturer about concerns surrounding Russia’s latest coronavirus vaccine”meduza.io. Retrieved 23 April2021.
  9. Jump up to:a b “Нет антител, вопросы к составу, непрозрачность данных. Что не так с вакциной “ЭпиВакКорона””BBC News Русская служба (in Russian). Retrieved 23 April 2021.
  10. Jump up to:a b c d “Sputnik V’s ugly cousin Clinical results for Russia’s EpiVacCorona vaccine are finally here, but developers published in an obscure local journal, raising questions and concerns”meduza.io. Retrieved 23 April 2021.
  11. ^ “About 200,000 EpiVacCorona vaccine doses go into civil circulation in Russia”TASS. Retrieved 25 April 2021.
  12. Jump up to:a bhttps://www.researchgate.net/publication/350822775_Immunogenicity_and_protectivity_of_the_peptide_candidate_vaccine_against_SARS-CoV-2
  13. Jump up to:a b Ryzhikov AB, Ryzhikov EA, Bogryantseva MP, Usova SV, Danilenko ED, Imatdinov IR, Nechaeva EA, Pyankov OV, Pyankova OG, Gudymo AS, Bodnev SA, Onkhonova GS, Sleptsova ES, Kuzubov VI, Ryndyuk NN, Ginko ZI, Petrov VN, Moiseeva AA, Torzhkova PY, Pyankov SA, Tregubchak TV, Antonec DV, Sleptsova ES, Gavrilova EV, Maksyutov RA (2021). “Immunogenicity and Protectivityof the Peptide Vaccine againstSARS-CoV-2”Annals of the Russian Academy of Medical Sciences76 (1): 5–19. doi:10.15690/vramn1528.
  14. ^ Ryzhikov, A. B.; Ryzhikov, Е. А.; Bogryantseva, M. P.; Usova, S. V.; Danilenko, E. D.; Nechaeva, E. A.; Pyankov, O. V.; Pyankova, O. G.; Gudymo, A. S. (24 March 2021). “A single blind, placebo-controlled randomized study of the safety, reactogenicity and immunogenicity of the “EpiVacCorona” Vaccine for the prevention of COVID-19, in volunteers aged 18–60 years (phase I–II)”Russian Journal of Infection and Immunity. Retrieved 23 April 2021.
  15. ^ “People vaccinated with Russia’s EpiVacCorona need 42 days to develop immunity – watchdog”TASS. Retrieved 25 April 2021.
  16. ^ “Что ждать от “ЭпиВакКороны”. Все о пептидной вакцине против COVID-19″РИА Новости(in Russian). 1 January 2021. Retrieved 24 April 2021.
  17. ^ s.r.o, Direct Impact. “AIM database substance – EpiVacCorona”AIM. Retrieved 25 April 2021.
  18. Jump up to:a b Federal Budgetary Research Institution State Research Center of Virology and Biotechnology “Vector” (20 February 2021). “Simple, Blind, Placebo-controlled, Randomized Study of the Safety, Reactogenicity and Immunogenicity of Vaccine Based on Peptide Antigens for the Prevention of COVID-19 (EpiVacCorona), in Volunteers Aged 18-60 Years (I-II Phase)”.
  19. ^ Реестр Клинических исследований COV/pept-03/20[1]
  20. ^MKIEEGKLVIWINGDKGYNGLAEVGKKFEKDTGIKVTVEHPDKLEEKFPQVAATGDGPDIIFWAHDRFGGYAQSGLLAEITPDKAFQDKLYPFTWDAVRYNGKLIAYPIAVEALSLIYNKDLLPNPPKTWEEIPALDKELKAKGKSALMFNLQEPYFTWPLIAADGGYAFKYENGKYDIKDVGVDNAGAKAGLTFLVDLIKNKHMNADTDYSIAEAAFNKGETAMTINGPWAWSNIDTSKVNYGVTVLPTFKGQPSKPFVGVLSAGINAASPNKELAKEFLENYLLTDEGLEAVNKDKPLGAVALKSYEEELAKDPRIAATMENAQKGEIMPNIPQMSAFWYAVRTAVINAASGRQTVDEALKDAQTNSSSNNNNNNNNNNLGDNGPQNQRNAPRITFGGPSDSTGSNQNGERSGARSKQRRPQGLPNNTASWFTALTQHGKEDLKFPRGQGVPINTNSSPDDQIGYYRRATRRIRGGDGKMKDLSPRWYFYYLGTGPEAGLPYGANKDGIIWVATEGALNTPKDHIGTRNPANNAAIVLQLPQGTTLPKGFYAEGSRGGSQASSRSSSRSRNSSRNSTPGSSRGTSPARMAGNGGDAALALLLLDRLNQLESKMSGKGQQQQGQTVTKKSAAEASKKPRQKRTATKAYNVTQAFGRRGPEQTQGNFGDQELIRQGTDYKHWPQIAQFAPSASAFFGMSRIGMEVTPSGTWLTYTGAIKLDDKDPNFKDQVILLNKHIDAYKTFPPTEPKKDKKKKADETQALPQRQKKQQTVTLLPAADLDDLSKQLQQSMSSADSTQA. “Carrier protein sequence”.
  21. Jump up to:a b “Russia begins post-registration trials of EpiVacCorona Covid-19 vaccine”http://www.clinicaltrialsarena.com. Retrieved 25 April 2021.
  22. ^ “Вакцина “ЭпиВакКорона” поступила в гражданский оборот”РИА Новости (in Russian). 11 December 2020. Retrieved 23 April 2021.
  23. ^ “Turkmenistan registers vaccines for the prevention of infectious diseases”Turkmenistan Today. 29 January 2021.
  24. ^ “Turkmenistan: Master Berdymukhamedov goes to Moscow | Eurasianet”eurasianet.org. Retrieved 25 April 2021.
  25. ^ “Russia submits EpiVacCorona vaccine documents to WHO – Rospotrebnadzor head Popova”interfax.com. Retrieved 23 April 2021.
  26. ^ Welle (www.dw.com), Deutsche. “Two more Russian vaccines: What we do and don’t know | DW | 09.03.2021”DW.COM. Retrieved 23 April 2021.
  27. ^ “COVID-19 vaccine: WHO in talks with Russia on its second vaccine EpiVacCorona”mint. 16 October 2020. Retrieved 9 June 2021.
  28. ^ “Vector Center says has over 45 inquiries from abroad about its EpiVacCorona vaccine”TASS. Retrieved 25 April 2021.
  29. ^ Foundation, Thomson Reuters. “Venezuela receives doses of Russian EpiVacCorona vaccine for trials”news.trust.org. Retrieved 25 April 2021.
  30. ^ “Venezuela to purchase and manufacture Russia’s EpiVacCorona vaccine”Reuters. 5 June 2021. Retrieved 13 June 2021.
  31. ^ turkmenportal. “Turkmenistan Approves Use of Russia’s EpiVacCorona Vaccine | Society”Business Turkmenistan Information Center. Retrieved 25 April 2021.
  32. ^ Jones, Ian; Roy, Polly (20 February 2021). “Sputnik V COVID-19 vaccine candidate appears safe and effective”The Lancet397 (10275): 642–643. doi:10.1016/S0140-6736(21)00191-4ISSN 0140-6736PMC 7906719PMID 33545098.
  33. ^ “Участники КИ “ЭпиВакКороны” продолжают исследовать эффективность вакцины”pcr.news. Retrieved 24 April 2021.
  34. ^ Li, Yang; Ma, Ming-Liang; Lei, Qing; Wang, Feng; Hong, Wei; Lai, Dan-Yun; Hou, Hongyan; Xu, Zhao-Wei; Zhang, Bo; Chen, Hong; Yu, Caizheng (30 March 2021). “Linear epitope landscape of the SARS-CoV-2 Spike protein constructed from 1,051 COVID-19 patients”Cell Reports34 (13): 108915. doi:10.1016/j.celrep.2021.108915ISSN 2211-1247PMC 7953450PMID 33761319.
  35. ^ “Вакцина “ЭпиВакКорона” в иллюстрациях”Троицкий вариант — Наука (in Russian). 23 March 2021. Retrieved 24 April 2021.
  36. ^ Yi, Zhigang; Ling, Yun; Zhang, Xiaonan; Chen, Jieliang; Hu, Kongying; Wang, Yuyan; Song, Wuhui; Ying, Tianlei; Zhang, Rong; Lu, HongZhou; Yuan, Zhenghong (December 2020). “Functional mapping of B-cell linear epitopes of SARS-CoV-2 in COVID-19 convalescent population”Emerging Microbes & Infections9 (1): 1988–1996. doi:10.1080/22221751.2020.1815591ISSN 2222-1751PMC 7534331PMID 32844713.
  37. ^ Poh, Chek Meng; Carissimo, Guillaume; Wang, Bei; Amrun, Siti Naqiah; Lee, Cheryl Yi-Pin; Chee, Rhonda Sin-Ling; Fong, Siew-Wai; Yeo, Nicholas Kim-Wah; Lee, Wen-Hsin; Torres-Ruesta, Anthony; Leo, Yee-Sin (1 June 2020). “Two linear epitopes on the SARS-CoV-2 spike protein that elicit neutralising antibodies in COVID-19 patients”Nature Communications11 (1): 2806. doi:10.1038/s41467-020-16638-2ISSN 2041-1723PMC 7264175PMID 32483236.
  38. ^ Li, Yang; Lai, Dan-Yun; Zhang, Hai-Nan; Jiang, He-Wei; Tian, Xiaolong; Ma, Ming-Liang; Qi, Huan; Meng, Qing-Feng; Guo, Shu-Juan; Wu, Yanling; Wang, Wei (October 2020). “Linear epitopes of SARS-CoV-2 spike protein elicit neutralizing antibodies in COVID-19 patients”Cellular & Molecular Immunology17 (10): 1095–1097. doi:10.1038/s41423-020-00523-5ISSN 2042-0226PMC 7475724PMID 32895485.
  39. ^ Farrera-Soler, Lluc; Daguer, Jean-Pierre; Barluenga, Sofia; Vadas, Oscar; Cohen, Patrick; Pagano, Sabrina; Yerly, Sabine; Kaiser, Laurent; Vuilleumier, Nicolas; Winssinger, Nicolas (2020). “Identification of immunodominant linear epitopes from SARS-CoV-2 patient plasma”PLOS ONE15 (9): e0238089. doi:10.1371/journal.pone.0238089ISSN 1932-6203PMC 7480855PMID 32903266.
  40. ^ Shrock, Ellen; Fujimura, Eric; Kula, Tomasz; Timms, Richard T.; Lee, I.-Hsiu; Leng, Yumei; Robinson, Matthew L.; Sie, Brandon M.; Li, Mamie Z.; Chen, Yuezhou; Logue, Jennifer (27 November 2020). “Viral epitope profiling of COVID-19 patients reveals cross-reactivity and correlates of severity”Science370 (6520): eabd4250. doi:10.1126/science.abd4250ISSN 1095-9203PMC 7857405PMID 32994364.
  41. ^ “Константин Чумаков: “Даже если человек переболел COVID-19, ему все равно нужно привиться. Иммунный ответ на прививку лучше и долговечнее, чем на саму болезнь””republic.ru (in Russian). Retrieved 24 April 2021.

External links

EpiVacCorona vaccine
Vaccine description
TargetSARS-CoV-2
Vaccine typePeptide subunit
Clinical data
Trade namesEpiVacCorona
Routes of
administration
Intramuscular
ATC codeNone
Legal status
Legal statusRegistered in Russia on 14 October 2020 RU Registered.TU approved.Full list : List of EpiVacCorona COVID-19 vaccine authorizations
Identifiers
DrugBankDB16439
Part of a series on the
COVID-19 pandemic
COVID-19 (disease)SARS-CoV-2 (virus)
showTimeline
showLocations
showInternational response
showMedical response
showImpact
 COVID-19 portal

EpiVacCorona Vaccine, developed by the Vektor State Research Center of Virology and Biotechnology in Russia, is based on peptide-antigens that facilitate immunity to the SARS-CoV-2 virus1. It is currently being tested in Phase I/II clinical trials for safety and immunogenicity (NCT04527575)1,2.

  1. Precision Vaccinations: VACCINE INFO EpiVacCorona Vaccine [Link]
  2. The Pharma Letter: Russia’s EpiVacCorona vaccine post-registration trials started [Link]

//////EpiVacCorona, SARS-CoV-2, RUSSIA, CORONA VIRUS, COVID 19, VACCINE, PEPTIDE

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Pegcetacoplan


Sequence:

1ICVWQDWGAH RCTXK

Sequence:

1ICVWQDWGAH RCTXK

Sequence Modifications

TypeLocationDescription
terminal mod.Lys-15C-terminal amide
terminal mod.Lys-15′C-terminal amide
bridgeCys-2 – Cys-12disulfide bridge, dimer
bridgeLys-15 – Lys-15′covalent bridge, dimer
bridgeCys-2′ – Cys-12′disulfide bridge, dimer
uncommonOaa-14
uncommonOaa-14′

Pegcetacoplan

ペグセタコプラン;

FDA APPROVED Empaveli, 2021/5/14

Protein Sequence

Sequence Length: 30, 15, 15multichain; modifiedPoly(oxy-1,2-ethanediyl), α-hydro-ω-hydroxy-, 15,15′-diester with N-acetyl-L-isoleucyl-L-cysteinyl-L-valyl-1-methyl-L-tryptophyl-L-glutaminyl-L-α-aspartyl-L-tryptophylglycyl-L-alanyl-L-histidyl-L-arginyl-L-cysteinyl-L-threonyl-2-[2-(2-aminoethoxy)ethoxy]acetyl-N6-carboxy-L-lysinamide cyclic (2→12)-(disulfide)Polymer

Poly(oxy-1,2-ethanediyl), alpha-hydro-omega-hydroxy-, 15,15′-diester with N-acetyl-Lisoleucyl-L-cysteinyl-L-valyl-1-methyl-L-tryptophyl-L-glutaminyl-L-alpha-aspartyl-L-tryptophylglycyl-L-alanyl-L-histidyl-L-arginyl-L-cysteinyl-L-threonyl-2-(2-(2-aminoethoxy)ethoxy)acetyl-N6-carboxy-L-lysinamide cyclic (2�-&gt;12)-(disulfide)

O,O’-bis((S2,S12-cyclo(N-acetyl-L-isoleucyl-L-cysteinyl-L-valyl-1-methyl-Ltryptophyl-L-glutaminyl-L-alpha-aspartyl-L-tryptophylglycyl-L-alanyl-L-histidyl-L-arginyl-L-cysteinyl-L-threonyl-2-(2-(2-aminoethoxy)ethoxy)acetyl-L-lysinamide))-N6.15-carbonyl)polyethylene glycol(n = 800-1100)

  • APL-2
  • WHO 10743
FormulaC170H248N50O47S4. (C2H4O)n3872.40 g·mol−1
EfficacyDiseaseComplement inhibitorParoxysmal nocturnal hemoglobinuria
  CAS2019171-69-6
CommentTreatment of paroxysmal nocturnal hemoglobinuria (PNH), complement-mediated nephropathies, and age-related macular degeneration (AMD)
  • OriginatorApellis Pharmaceuticals
  • ClassAnti-inflammatories; Anti-ischaemics; Antianaemics; Cyclic peptides; Eye disorder therapies; Polyethylene glycols; Urologics
  • Mechanism of ActionComplement C3 inhibitors
  • Orphan Drug StatusYes – Paroxysmal nocturnal haemoglobinuria; Autoimmune haemolytic anaemia; Glomerulonephritis
  • RegisteredParoxysmal nocturnal haemoglobinuria
  • Phase IIIAge-related macular degeneration
  • Phase IIAmyotrophic lateral sclerosis; Autoimmune haemolytic anaemia; Glomerulonephritis; IgA nephropathy; Lupus nephritis; Membranous glomerulonephritis
  • Phase I/IIWet age-related macular degeneration
  • DiscontinuedIschaemia
  • 02 Jun 2021Apellis Pharmaceuticals plans a phase III trial for Glomerulonephritis in the second half of 2021
  • 25 May 2021Top-line efficacy and safety results from the phase III PRINCE trial for Paroxysmal nocturnal haemoglobinuria released by Apellis Pharmaceuticals
  • 18 May 2021Registered for Paroxysmal nocturnal haemoglobinuria in USA (SC) – First global approval

Pegcetacoplan, sold under the brand name Empaveli, is a medication used to treat paroxysmal nocturnal hemoglobinuria (PNH).[1][2]

The most common side effects include injection-site reactions, infections, diarrheaabdominal pain, respiratory tract infection, viral infection, and fatigue.[2]

Paroxysmal nocturnal hemoglobinuria is characterized by red blood cell destruction, anemia (red blood cells unable to carry enough oxygen to tissues), blood clots, and impaired bone marrow function (not making enough blood cells).[1]

Pegcetacoplan is the first treatment for paroxysmal nocturnal hemoglobinuria that binds to complement protein C3.[1] Pegcetacoplan was approved for medical use in the United States in May 2021.[1][3]

Pegcetacoplan is a complement inhibitor indicated in the treatment of paroxysmal nocturnal hemoglobinuria (PNH).5,7 Prior to its FDA approval, patients with PNH were typically treated with the C5 inhibiting monoclonal antibody eculizumab.5 Patients given eculizumab experienced less hemolysis caused by the membrane attack complex, but were still somewhat susceptible to hemolysis caused by C3b opsonization.5,6 Pegcetacoplan was developed out of a need for an inhibitor of complement mediated hemolysis further upstream of C5.5,6 Pegcetacoplan is a pegylated C3 inhibitor that can disrupt the processes leading to both forms of hemolysis that threaten patients with PNH.5

Pegcetacoplan was granted FDA approval on 14 May 2021.7

Medical uses

Pegcetacoplan is indicated to treat adults with paroxysmal nocturnal hemoglobinuria (PNH).[1][2]

EMPAVELI contains pegcetacoplan, a complement inhibitor. Pegcetacoplan is a symmetrical molecule comprised of two identical pentadecapeptides covalently bound to the ends of a linear 40-kiloDalton (kDa) PEG molecule. The peptide portions of pegcetacoplan contain 1-methyl-L-tryptophan (Trp(Me)) in position 4 and amino(ethoxyethoxy)acetic acid (AEEA) in position 14.

The molecular weight of pegcetacoplan is approximately 43.5 kDa. The molecular formula is C1970H3848N50O947S4. The structure of pegcetacoplan is shown below.

EMPAVELI™ (pegcetacoplan) Structural Formula - Illustration

EMPAVELI injection is a sterile, clear, colorless to slightly yellowish aqueous solution for subcutaneous use and is supplied in a 20-mL single-dose vial. Each 1 mL of solution contains 54 mg of pegcetacoplan, 41 mg of sorbitol, 0.384 mg of glacial acetic acid, 0.490 mg of sodium acetate trihydrate, and Water for Injection USP. EMPAVELI may also contain sodium hydroxide and/or additional glacial acetic acid for adjustment to a target pH of 5.0.

FDA approves new treatment for adults with serious rare blood disease..

https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-new-treatment-adults-serious-rare-blood-disease

FDA has approved Empaveli (pegcetacoplan) injection to treat adults with paroxysmal nocturnal hemoglobinuria (PNH), a rare, life-threatening blood disease. Empaveli is the first PNH treatment that binds to compliment protein C3.

PNH is characterized by red blood cell destruction, anemia (red blood cells unable to carry enough oxygen to tissues), blood clots, and impaired bone marrow function (not making enough blood cells). The disease affects 1-1.5 people per million. Individuals are typically diagnosed around ages 35 to 40. PNH can be serious, with median survival of 10 years after diagnosis. However, some patients live for decades with only minor symptoms.

PNH is caused by gene mutations that affect red blood cells. Red blood cells in people with these mutations are defective and can be destroyed by the immune system, which causes anemia.

The effectiveness of Empaveli was evaluated in a study enrolling 80 patients with PNH and anemia who had been taking eculizumab, a treatment previously approved for PNH. Patients first completed a four-week period during which they received Empaveli 1,080 mg twice weekly in addition to eculizumab at their previous dose. After the first four weeks, patients were randomly assigned to receive either Empaveli or their current dose of eculizumab for 16 weeks.

After 16 weeks, the severity of anemia was compared in the two treatment groups on the basis of hemoglobin concentration (a laboratory measure of anemia). In both treatment groups, the average hemoglobin was 8.7 g/dL at baseline, indicating severe anemia. (Normal hemoglobin values in adult men are 14 g/dL or above; normal values in adult women are 12 g/dL or above.) During the 16 weeks of treatment, patients in the Empaveli group had an average increase in their hemoglobin of 2.4 g/dL. Meanwhile, patients in the eculizumab group had an average decrease in their hemoglobin of 1.5 g/dL.

Empaveli is available only through a restricted program under a risk evaluation and mitigation strategy. Meningococcal (a type of bacteria) infections can occur in patients taking Empaveli and can become life-threatening or fatal if not treated early. Empaveli may also predispose individuals to serious infections, especially infections caused by encapsulated bacteria. Patients should be monitored for infusion-related reactions. Empaveli can interfere with certain laboratory tests. The most common side effects are injection site reactions, infections, diarrhea, abdominal pain, respiratory tract infection, viral infection, and fatigue.

Empaveli received priority reviewfast track and orphan drug designations for this indication.

FDA granted the approval of Empaveli to Apellis Pharmaceuticals.

Adverse effects

Meningococcal (a type of bacteria) infections can occur in people taking pegcetacoplan and can become life-threatening or fatal if not treated early.[1] Pegcetacoplan may also predispose individuals to serious infections, especially infections caused by encapsulated bacteria.[1]

History

The effectiveness of pegcetacoplan was evaluated in a study enrolling 80 participants with paroxysmal nocturnal hemoglobinuria and anemia who had been taking eculizumab, a treatment previously approved for paroxysmal nocturnal hemoglobinuria.[1]

References

  1. Jump up to:a b c d e f g h i “FDA approves new treatment for adults with serious rare blood disease”U.S. Food and Drug Administration (FDA). 14 May 2021. Retrieved 14 May 2021.  This article incorporates text from this source, which is in the public domain.
  2. Jump up to:a b c d https://pi.apellis.com/files/PI_Empaveli.pdf
  3. ^ “Apellis Announces U.S. Food and Drug Administration (FDA) Approval of Empaveli (pegcetacoplan) for Adults with Paroxysmal Nocturnal Hemoglobinuria (PNH)” (Press release). Apellis Pharmaceuticals. 14 May 2021. Retrieved 14 May 2021 – via GlobeNewswire.

External links

  • “Pegcetacoplan”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT03500549 for “Study to Evaluate the Efficacy and Safety of APL-2 in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH)” at ClinicalTrials.gov
Clinical data
Trade namesEmpaveli
Other namesAPL-2
License dataUS DailyMedPegcetacoplan
Routes of
administration
Subcutaneous infusion
Drug classComplement inhibitor
ATC codeNone
Legal status
Legal statusUS: ℞-only [1][2]
Identifiers
CAS Number2019171-69-6
UNIITO3JYR3BOU
KEGGD11613
ChEMBLChEMBL4298211
Chemical and physical data
FormulaC170H248N50O47S4
Molar mass3872.40 g·mol−1

/////////Pegcetacoplan, ペグセタコプラン , FDA 2021, APPROVALS 2021, APL-2, WHO 10743, Apellis Pharmaceuticals, Empaveli, priority reviewfast track,  orphan drug

https://www.sec.gov/Archives/edgar/data/1492422/000156459020007350/apls-10k_20191231.htm

wdt-7

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Imdevimab


(Heavy chain)
QVQLVESGGG VVQPGRSLRL SCAASGFTFS NYAMYWVRQA PGKGLEWVAV ISYDGSNKYY
ADSVKGRFTI SRDNSKNTLY LQMNSLRTED TAVYYCASGS DYGDYLLVYW GQGTLVTVSS
ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS
GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG
PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN
STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE
LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW
QQGNVFSCSV MHEALHNHYT QKSLSLSPGK
(Light chain)
QSALTQPASV SGSPGQSITI SCTGTSSDVG GYNYVSWYQQ HPGKAPKLMI YDVSKRPSGV
SNRFSGSKSG NTASLTISGL QSEDEADYYC NSLTSISTWV FGGGTKLTVL GQPKAAPSVT
LFPPSSEELQ ANKATLVCLI SDFYPGAVTV AWKADSSPVK AGVETTTPSK QSNNKYAASS
YLSLTPEQWK SHRSYSCQVT HEGSTVEKTV APTECS
(Disulfide bridge: H22-H96, H147-H203, H223-L215, H229-H’229, H264-H324-H370-H428, H’22-H’96, H’147-H’203, H’223-L’215, H’264-H’324, H’370-H’428, L22-L90, L138-L197, L’22-L’90, L’138-L’197)

Imdevimab

イムデビマブ;

  • Immunoglobulin G1, anti-​(severe acute respiratory syndrome coronavirus 2 spike glycoprotein) (human monoclonal REGN10987 γ1-​chain)​, disulfide with human monoclonal REGN10987 λ-​chain, dimer
FormulaC6396H9882N1694O2018S42
CAS2415933-40-1
Mol weight144141.7693

Monoclonal antibody
Treatment and prophylaxis of SARS-CoV-2 infection

ANTIVIRAL

SARS-CoV-2 spike glycoprotein

  • REGN 10987
  • RG 6412

Fact Sheet – US Food and Drug Administration

https://www.fda.gov › media › download 
 PDFBenefit of treatment with casirivimab and imdevimab has not been observed in patients hospitalized due to COVID-19. Monoclonal antibodies, such as casirivimab.

Casirivimab/imdevimab, sold under the brand name REGEN-COV,[1] is an experimental medicine developed by the American biotechnology company Regeneron Pharmaceuticals. It is an artificial “antibody cocktail” designed to produce resistance against the SARS-CoV-2 coronavirus responsible for the COVID-19 pandemic.[3][4] It consists of two monoclonal antibodies, casirivimab (REGN10933) and imdevimab (REGN10987) that must be mixed together.[1][5][6] The combination of two antibodies is intended to prevent mutational escape.[7]

Trials

In a clinical trial of people with COVID-19, casirivimab and imdevimab, administered together, were shown to reduce COVID-19-related hospitalization or emergency room visits in people at high risk for disease progression within 28 days after treatment when compared to placebo.[2] The safety and effectiveness of this investigational therapy for use in the treatment of COVID-19 continues to be evaluated.[2]

The data supporting the emergency use authorization (EUA) for casirivimab and imdevimab are based on a randomized, double-blind, placebo-controlled clinical trial in 799 non-hospitalized adults with mild to moderate COVID-19 symptoms.[2] Of these participants, 266 received a single intravenous infusion of 2,400 milligrams casirivimab and imdevimab (1,200 mg of each), 267 received 8,000 mg casirivimab and imdevimab (4,000 mg of each), and 266 received a placebo, within three days of obtaining a positive SARS-CoV-2 viral test.[2]

The prespecified primary endpoint for the trial was time-weighted average change in viral load from baseline.[2] Viral load reduction in participants treated with casirivimab and imdevimab was larger than in participants treated with placebo at day seven.[2] However, the most important evidence that casirivimab and imdevimab administered together may be effective came from the predefined secondary endpoint of medically attended visits related to COVID-19, particularly hospitalizations and emergency room visits within 28 days after treatment.[2] For participants at high risk for disease progression, hospitalizations and emergency room visits occurred in 3% of casirivimab and imdevimab-treated participants on average compared to 9% in placebo-treated participants.[2] The effects on viral load, reduction in hospitalizations and ER visits were similar in participants receiving either of the two casirivimab and imdevimab doses.[2]

As of September 2020, REGEN-COV is being evaluated as part of the RECOVERY Trial.[8]

On 12 April 2021, Roche and Regeneron announced that the Phase III clinical trial REGN-COV 2069 met both primary and secondary endpoints, reducing risk of infection by 81% for the non-infected patients, and reducing time-to-resolution of symptoms for symptomatic patients to one week vs. three weeks in the placebo group.[9]

Authorization

On 21 November 2020, the U.S. Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for casirivimab and imdevimab to be administered together for the treatment of mild to moderate COVID-19 in people twelve years of age or older weighing at least 40 kilograms (88 lb) with positive results of direct SARS-CoV-2 viral testing and who are at high risk for progressing to severe COVID-19.[2][10][11] This includes those who are 65 years of age or older or who have certain chronic medical conditions.[2] Casirivimab and imdevimab must be administered together by intravenous (IV) infusion.[2]

Casirivimab and imdevimab are not authorized for people who are hospitalized due to COVID-19 or require oxygen therapy due to COVID-19.[2] A benefit of casirivimab and imdevimab treatment has not been shown in people hospitalized due to COVID-19.[2] Monoclonal antibodies, such as casirivimab and imdevimab, may be associated with worse clinical outcomes when administered to hospitalized people with COVID-19 requiring high flow oxygen or mechanical ventilation.[2]

The EUA was issued to Regeneron Pharmaceuticals Inc.[2][10][12]

On 1 February 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) started a rolling review of data on the REGN‑COV2 antibody combination (casirivimab/imdevimab), which is being co-developed by Regeneron Pharmaceuticals, Inc. and F. Hoffman-La Roche, Ltd (Roche) for the treatment and prevention of COVID‑19.[13][14] In February 2021, the CHMP concluded that the combination, also known as REGN-COV2, can be used for the treatment of confirmed COVID-19 in people who do not require supplemental oxygen and who are at high risk of progressing to severe COVID-19.[15]

The Central Drugs Standards Control Organisation (CDSCO) in India, on 5 May 2021, granted an Emergency Use Authorisation to Roche (Genentech)[16] and Regeneron[17] for use of the casirivimab/imdevimab cocktail in the country. The announcement came in light of the second wave of the COVID-19 pandemic in India. Roche India maintains partnership with Cipla, thereby permitting the latter to market the drug in the country.[18]

Deployment

Although Regeneron is headquartered in Tarrytown, New York (near New York City), REGEN-COV is manufactured at the company’s primary U.S. manufacturing facility in Rensselaer, New York (near the state capital at Albany).[19] In September 2020, to free up manufacturing capacity for REGEN-COV, Regeneron began to shift production of its existing products from Rensselaer to the Irish city of Limerick.[20]

Regeneron has a deal in place with Roche (Genentech)[21]to manufacture and market REGEN-COV outside the United States.[10][22]

On 2 October 2020, Regeneron Pharmaceuticals announced that US President Donald Trump had received “a single 8 gram dose of REGN-COV2” after testing positive for SARS-CoV-2.[23][24] The drug was provided by the company in response to a “compassionate use” (temporary authorization for use) request from the president’s physicians.[23]

References

  1. Jump up to:a b c “REGEN-COV- casirivimab and imdevimab kit”DailyMed. Retrieved 18 March 2021.
  2. Jump up to:a b c d e f g h i j k l m n o p q “Coronavirus (COVID-19) Update: FDA Authorizes Monoclonal Antibodies for Treatment of COVID-19”U.S. Food and Drug Administration (FDA) (Press release). 21 November 2020. Retrieved 21 November 2020.  This article incorporates text from this source, which is in the public domain.
  3. ^ Kelland K (14 September 2020). “Regeneron’s antibody drug added to UK Recovery trial of COVID treatments”Reuters. Retrieved 14 September 2020.
  4. ^ “Regeneron’s COVID-19 Response Efforts”Regeneron Pharmaceuticals. Retrieved 14 September 2020.
  5. ^ Morelle R (14 September 2020). “Antibody treatment to be given to Covid patients”BBC News Online. Retrieved 14 September2020.
  6. ^ “Safety, Tolerability, and Efficacy of Anti-Spike (S) SARS-CoV-2 Monoclonal Antibodies for Hospitalized Adult Patients With COVID-19”ClinicalTrials. 3 September 2020. Retrieved 14 September2020.
  7. ^ Baum A, Fulton BO, Wloga E, Copin R, Pascal KE, Russo V, et al. (August 2020). “Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies”Science369 (6506): 1014–1018. Bibcode:2020Sci…369.1014Bdoi:10.1126/science.abd0831PMC 7299283PMID 32540904.
  8. ^ “RECOVERY COVID-19 phase 3 trial to evaluate Regeneron’s REGN-COV2 investigational antibody cocktail in the UK”Recovery Trial. Retrieved 14 September 2020.
  9. ^ “Phase III prevention trial showed subcutaneous administration of investigational antibody cocktail casirivimab and imdevimab reduced risk of symptomatic COVID-19 infections by 81%”streetinsider.comArchived from the original on 2021-04-12. Retrieved 2021-04-12.
  10. Jump up to:a b c “Regeneron Reports Positive Interim Data with REGEN-COV Antibody Cocktail used as Passive Vaccine to Prevent COVID-19”(Press release). Regeneron Pharmaceuticals. 26 January 2021. Retrieved 19 March 2021 – via PR Newswire.
  11. ^ “Fact Sheet For Health Care Providers Emergency Use Authorization (EUA) Of Casirivimab And Imdevimab” (PDF). U.S. Food and Drug Administration (FDA).
  12. ^ “Casirivimab and Imdevimab”Regeneron Pharmaceuticals. Retrieved 19 March 2021.
  13. ^ “EMA starts rolling review of REGN‑COV2 antibody combination (casirivimab / imdevimab)” (Press release). European Medicines Agency (EMA). 1 February 2021. Retrieved 1 February 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  14. ^ “EMA reviewing data on monoclonal antibody use for COVID-19” (Press release). European Medicines Agency (EMA). 4 February 2021. Retrieved 4 March 2021.
  15. ^ “EMA issues advice on use of REGN-COV2 antibody combination (casirivimab / imdevimab)” (Press release). European Medicines Agency (EMA). 26 February 2021. Retrieved 5 March 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  16. ^https://www.businesswire.com/news/home/20200818005847/en/Genentech-and-Regeneron-Collaborate-to-Significantly-Increase-Global-Supply-of-REGN-COV2-Investigational-Antibody-Combination-for-COVID-19
  17. ^ https://timesofindia.indiatimes.com/india/india-approves-roche/regeneron-antibody-cocktail-to-treat-covid-19/articleshow/82407551.cms
  18. ^ “Roche receives Emergency Use Authorisation in India for its investigational Antibody Cocktail (Casirivimab and Imdevimab) used in the treatment of Covid-19 | Cipla”http://www.cipla.com. Retrieved 2021-05-06.
  19. ^ Williams, Stephen (3 October 2020). “Experimental drug given to President made locally”The Daily Gazette.
  20. ^ Stanton, Dan (11 September 2020). “Manufacturing shift to Ireland frees up US capacity for Regeneron’s COVID antibodies”BioProcess International.
  21. ^https://www.businesswire.com/news/home/20200818005847/en/Genentech-and-Regeneron-Collaborate-to-Significantly-Increase-Global-Supply-of-REGN-COV2-Investigational-Antibody-Combination-for-COVID-19
  22. ^ “Roche and Regeneron link up on a coronavirus antibody cocktail”CNBC. 19 August 2020. Retrieved 14 September 2020.
  23. Jump up to:a b Thomas K (2 October 2020). “President Trump Received Experimental Antibody Treatment”The New York TimesISSN 0362-4331. Retrieved 2 October 2020.
  24. ^ Hackett DW (3 October 2020). “8-Gram Dose of COVID-19 Antibody Cocktail Provided to President Trump”http://www.precisionvaccinations.comArchived from the original on 3 October 2020.

External links

REGN10933 (blue) and REGN10987 (orange) bound to SARS-CoV-2 spike protein (pink). From PDB6VSB6XDG.
Combination of
CasirivimabMonoclonal antibody against spike protein of SARS-CoV-2
ImdevimabMonoclonal antibody against spike protein of SARS-CoV-2
Clinical data
Trade namesREGEN-COV
Other namesREGN-COV2
AHFS/Drugs.comMonograph
License dataUS DailyMedCasirivimab
Routes of
administration
Intravenous
ATC codeNone
Legal status
Legal statusUS: Unapproved (Emergency Use Authorization)[1][2]
Identifiers
DrugBankDB15691
KEGGD11938D11939

////////Imdevimab, ANTI VIRAL, PEPTIDE, CORONA VIRUS, COVID19, APPROVALS 2020, FDA 2020, イムデビマブ, REGN 10987, RG 6412, 

wdt

NEW DRUG APPROVALS

one time

$10.00

Casirivimab with Imdevimab

Casirivimab


(Heavy chain)
QVQLVESGGG LVKPGGSLRL SCAASGFTFS DYYMSWIRQA PGKGLEWVSY ITYSGSTIYY
ADSVKGRFTI SRDNAKSSLY LQMNSLRAED TAVYYCARDR GTTMVPFDYW GQGTLVTVSS
ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS
GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG
PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN
STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE
LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW
QQGNVFSCSV MHEALHNHYT QKSLSLSPGK
(Light chain)
DIQMTQSPSS LSASVGDRVT ITCQASQDIT NYLNWYQQKP GKAPKLLIYA ASNLETGVPS
RFSGSGSGTD FTFTISGLQP EDIATYYCQQ YDNLPLTFGG GTKVEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
(Disulfide bridge: H22-H96, H147-H203, H223-L214, H229-H’229, H232-H’232, H264-H324, H370-H428, H’22-H’96, H’147-H’203, H’223-L’214, H’264-H’324, H’370-H’428, L23-L88, L134-L194, L’23-L’88, L’134-L’194)

Casirivimab

カシリビマブ;

  • Immunoglobulin G1, anti-​(severe acute respiratory syndrome coronavirus 2 spike glycoprotein) (human monoclonal REGN10933 γ1-​chain)​, disulfide with human monoclonal REGN10933 κ-​chain, dimer
FormulaC6454H9976N1704O2024S44
CAS2415933-42-3
Mol weight145233.3296

Monoclonal antibody
Treatment and prophylaxis of SARS-CoV-2 infection (COVID-19)

SARS-CoV-2 spike glycoprotein

  • Protein Sequence
  • Sequence Length: 1328, 450, 450, 214, 214
  • REGN 10933
  • RG 6413

https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-monoclonal-antibodies-treatment-covid-19 November 21, 2020

Today, the U.S. Food and Drug Administration issued an emergency use authorization (EUA) for casirivimab and imdevimab to be administered together for the treatment of mild to moderate COVID-19 in adults and pediatric patients (12 years of age or older weighing at least 40 kilograms [about 88 pounds]) with positive results of direct SARS-CoV-2 viral testing and who are at high risk for progressing to severe COVID-19. This includes those who are 65 years of age or older or who have certain chronic medical conditions.

In a clinical trial of patients with COVID-19, casirivimab and imdevimab, administered together, were shown to reduce COVID-19-related hospitalization or emergency room visits in patients at high risk for disease progression within 28 days after treatment when compared to placebo. The safety and effectiveness of this investigational therapy for use in the treatment of COVID-19 continues to be evaluated.

Casirivimab and imdevimab must be administered together by intravenous (IV) infusion.

Casirivimab and imdevimab are not authorized for patients who are hospitalized due to COVID-19 or require oxygen therapy due to COVID-19. A benefit of casirivimab and imdevimab treatment has not been shown in patients hospitalized due to COVID-19. Monoclonal antibodies, such as casirivimab and imdevimab, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high flow oxygen or mechanical ventilation.

“The FDA remains committed to advancing the nation’s public health during this unprecedented pandemic. Authorizing these monoclonal antibody therapies may help outpatients avoid hospitalization and alleviate the burden on our health care system,” said FDA Commissioner Stephen M. Hahn, M.D. “As part of our Coronavirus Treatment Acceleration Program, the FDA uses every possible pathway to make new treatments available to patients as quickly as possible while continuing to study the safety and effectiveness of these treatments.” 

Monoclonal antibodies are laboratory-made proteins that mimic the immune system’s ability to fight off harmful pathogens such as viruses. Casirivimab and imdevimab are monoclonal antibodies that are specifically directed against the spike protein of SARS-CoV-2, designed to block the virus’ attachment and entry into human cells.

“The emergency authorization of these monoclonal antibodies administered together offers health care providers another tool in combating the pandemic,” said Patrizia Cavazzoni, M.D., acting director of the FDA’s Center for Drug Evaluation and Research. “We will continue to facilitate the development, evaluation and availability of COVID-19 therapies.”

The issuance of an EUA is different than an FDA approval. In determining whether to issue an EUA, the FDA evaluates the totality of available scientific evidence and carefully balances any known or potential risks with any known or potential benefits of the product for use during an emergency. Based on the FDA’s review of the totality of the scientific evidence available, the agency has determined that it is reasonable to believe that casirivimab and imdevimab administered together may be effective in treating patients with mild or moderate COVID-19. When used to treat COVID-19 for the authorized population, the known and potential benefits of these antibodies outweigh the known and potential risks. There are no adequate, approved and available alternative treatments to casirivimab and imdevimab administered together for the authorized population.

The data supporting this EUA for casirivimab and imdevimab are based on a randomized, double-blind, placebo-controlled clinical trial in 799 non-hospitalized adults with mild to moderate COVID-19 symptoms. Of these patients, 266 received a single intravenous infusion of 2,400 milligrams casirivimab and imdevimab (1,200 mg of each), 267 received 8,000 mg casirivimab and imdevimab (4,000 mg of each), and 266 received a placebo, within three days of obtaining a positive SARS-CoV-2 viral test.

The prespecified primary endpoint for the trial was time-weighted average change in viral load from baseline. Viral load reduction in patients treated with casirivimab and imdevimab was larger than in patients treated with placebo at day seven. However, the most important evidence that casirivimab and imdevimab administered together may be effective came from the predefined secondary endpoint of medically attended visits related to COVID-19, particularly hospitalizations and emergency room visits within 28 days after treatment. For patients at high risk for disease progression, hospitalizations and emergency room visits occurred in 3% of casirivimab and imdevimab-treated patients on average compared to 9% in placebo-treated patients. The effects on viral load, reduction in hospitalizations and ER visits were similar in patients receiving either of the two casirivimab and imdevimab doses.

Under the EUA, fact sheets that provide important information about using casirivimab and imdevimab administered together in treating COVID-19 as authorized must be made available to health care providers and to patients and caregivers. These fact sheets include dosing instructions, potential side effects and drug interactions. Possible side effects of casirivimab and imdevimab include: anaphylaxis and infusion-related reactions, fever, chills, hives, itching and flushing.

The EUA was issued to Regeneron Pharmaceuticals Inc.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Related Information

Casirivimab/imdevimab, sold under the brand name REGEN-COV,[1] is an experimental medicine developed by the American biotechnology company Regeneron Pharmaceuticals. It is an artificial “antibody cocktail” designed to produce resistance against the SARS-CoV-2 coronavirus responsible for the COVID-19 pandemic.[3][4] It consists of two monoclonal antibodies, casirivimab (REGN10933) and imdevimab (REGN10987) that must be mixed together.[1][5][6] The combination of two antibodies is intended to prevent mutational escape.[7]

Trials

In a clinical trial of people with COVID-19, casirivimab and imdevimab, administered together, were shown to reduce COVID-19-related hospitalization or emergency room visits in people at high risk for disease progression within 28 days after treatment when compared to placebo.[2] The safety and effectiveness of this investigational therapy for use in the treatment of COVID-19 continues to be evaluated.[2]

The data supporting the emergency use authorization (EUA) for casirivimab and imdevimab are based on a randomized, double-blind, placebo-controlled clinical trial in 799 non-hospitalized adults with mild to moderate COVID-19 symptoms.[2] Of these participants, 266 received a single intravenous infusion of 2,400 milligrams casirivimab and imdevimab (1,200 mg of each), 267 received 8,000 mg casirivimab and imdevimab (4,000 mg of each), and 266 received a placebo, within three days of obtaining a positive SARS-CoV-2 viral test.[2]

The prespecified primary endpoint for the trial was time-weighted average change in viral load from baseline.[2] Viral load reduction in participants treated with casirivimab and imdevimab was larger than in participants treated with placebo at day seven.[2] However, the most important evidence that casirivimab and imdevimab administered together may be effective came from the predefined secondary endpoint of medically attended visits related to COVID-19, particularly hospitalizations and emergency room visits within 28 days after treatment.[2] For participants at high risk for disease progression, hospitalizations and emergency room visits occurred in 3% of casirivimab and imdevimab-treated participants on average compared to 9% in placebo-treated participants.[2] The effects on viral load, reduction in hospitalizations and ER visits were similar in participants receiving either of the two casirivimab and imdevimab doses.[2]

As of September 2020, REGEN-COV is being evaluated as part of the RECOVERY Trial.[8]

On 12 April 2021, Roche and Regeneron announced that the Phase III clinical trial REGN-COV 2069 met both primary and secondary endpoints, reducing risk of infection by 81% for the non-infected patients, and reducing time-to-resolution of symptoms for symptomatic patients to one week vs. three weeks in the placebo group.[9]

Authorization

On 21 November 2020, the U.S. Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for casirivimab and imdevimab to be administered together for the treatment of mild to moderate COVID-19 in people twelve years of age or older weighing at least 40 kilograms (88 lb) with positive results of direct SARS-CoV-2 viral testing and who are at high risk for progressing to severe COVID-19.[2][10][11] This includes those who are 65 years of age or older or who have certain chronic medical conditions.[2] Casirivimab and imdevimab must be administered together by intravenous (IV) infusion.[2]

Casirivimab and imdevimab are not authorized for people who are hospitalized due to COVID-19 or require oxygen therapy due to COVID-19.[2] A benefit of casirivimab and imdevimab treatment has not been shown in people hospitalized due to COVID-19.[2] Monoclonal antibodies, such as casirivimab and imdevimab, may be associated with worse clinical outcomes when administered to hospitalized people with COVID-19 requiring high flow oxygen or mechanical ventilation.[2]

The EUA was issued to Regeneron Pharmaceuticals Inc.[2][10][12]

On 1 February 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) started a rolling review of data on the REGN‑COV2 antibody combination (casirivimab/imdevimab), which is being co-developed by Regeneron Pharmaceuticals, Inc. and F. Hoffman-La Roche, Ltd (Roche) for the treatment and prevention of COVID‑19.[13][14] In February 2021, the CHMP concluded that the combination, also known as REGN-COV2, can be used for the treatment of confirmed COVID-19 in people who do not require supplemental oxygen and who are at high risk of progressing to severe COVID-19.[15]

The Central Drugs Standards Control Organisation (CDSCO) in India, on 5 May 2021, granted an Emergency Use Authorisation to Roche (Genentech)[16] and Regeneron[17] for use of the casirivimab/imdevimab cocktail in the country. The announcement came in light of the second wave of the COVID-19 pandemic in India. Roche India maintains partnership with Cipla, thereby permitting the latter to market the drug in the country.[18]

Deployment

Although Regeneron is headquartered in Tarrytown, New York (near New York City), REGEN-COV is manufactured at the company’s primary U.S. manufacturing facility in Rensselaer, New York (near the state capital at Albany).[19] In September 2020, to free up manufacturing capacity for REGEN-COV, Regeneron began to shift production of its existing products from Rensselaer to the Irish city of Limerick.[20]

Regeneron has a deal in place with Roche (Genentech)[21]to manufacture and market REGEN-COV outside the United States.[10][22]

On 2 October 2020, Regeneron Pharmaceuticals announced that US President Donald Trump had received “a single 8 gram dose of REGN-COV2” after testing positive for SARS-CoV-2.[23][24] The drug was provided by the company in response to a “compassionate use” (temporary authorization for use) request from the president’s physicians.[23]

References

  1. Jump up to:a b c “REGEN-COV- casirivimab and imdevimab kit”DailyMed. Retrieved 18 March 2021.
  2. Jump up to:a b c d e f g h i j k l m n o p q “Coronavirus (COVID-19) Update: FDA Authorizes Monoclonal Antibodies for Treatment of COVID-19”U.S. Food and Drug Administration (FDA) (Press release). 21 November 2020. Retrieved 21 November 2020.  This article incorporates text from this source, which is in the public domain.
  3. ^ Kelland K (14 September 2020). “Regeneron’s antibody drug added to UK Recovery trial of COVID treatments”Reuters. Retrieved 14 September 2020.
  4. ^ “Regeneron’s COVID-19 Response Efforts”Regeneron Pharmaceuticals. Retrieved 14 September 2020.
  5. ^ Morelle R (14 September 2020). “Antibody treatment to be given to Covid patients”BBC News Online. Retrieved 14 September2020.
  6. ^ “Safety, Tolerability, and Efficacy of Anti-Spike (S) SARS-CoV-2 Monoclonal Antibodies for Hospitalized Adult Patients With COVID-19”ClinicalTrials. 3 September 2020. Retrieved 14 September2020.
  7. ^ Baum A, Fulton BO, Wloga E, Copin R, Pascal KE, Russo V, et al. (August 2020). “Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies”Science369 (6506): 1014–1018. Bibcode:2020Sci…369.1014Bdoi:10.1126/science.abd0831PMC 7299283PMID 32540904.
  8. ^ “RECOVERY COVID-19 phase 3 trial to evaluate Regeneron’s REGN-COV2 investigational antibody cocktail in the UK”Recovery Trial. Retrieved 14 September 2020.
  9. ^ “Phase III prevention trial showed subcutaneous administration of investigational antibody cocktail casirivimab and imdevimab reduced risk of symptomatic COVID-19 infections by 81%”streetinsider.comArchived from the original on 2021-04-12. Retrieved 2021-04-12.
  10. Jump up to:a b c “Regeneron Reports Positive Interim Data with REGEN-COV Antibody Cocktail used as Passive Vaccine to Prevent COVID-19”(Press release). Regeneron Pharmaceuticals. 26 January 2021. Retrieved 19 March 2021 – via PR Newswire.
  11. ^ “Fact Sheet For Health Care Providers Emergency Use Authorization (EUA) Of Casirivimab And Imdevimab” (PDF). U.S. Food and Drug Administration (FDA).
  12. ^ “Casirivimab and Imdevimab”Regeneron Pharmaceuticals. Retrieved 19 March 2021.
  13. ^ “EMA starts rolling review of REGN‑COV2 antibody combination (casirivimab / imdevimab)” (Press release). European Medicines Agency (EMA). 1 February 2021. Retrieved 1 February 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  14. ^ “EMA reviewing data on monoclonal antibody use for COVID-19” (Press release). European Medicines Agency (EMA). 4 February 2021. Retrieved 4 March 2021.
  15. ^ “EMA issues advice on use of REGN-COV2 antibody combination (casirivimab / imdevimab)” (Press release). European Medicines Agency (EMA). 26 February 2021. Retrieved 5 March 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  16. ^https://www.businesswire.com/news/home/20200818005847/en/Genentech-and-Regeneron-Collaborate-to-Significantly-Increase-Global-Supply-of-REGN-COV2-Investigational-Antibody-Combination-for-COVID-19
  17. ^ https://timesofindia.indiatimes.com/india/india-approves-roche/regeneron-antibody-cocktail-to-treat-covid-19/articleshow/82407551.cms
  18. ^ “Roche receives Emergency Use Authorisation in India for its investigational Antibody Cocktail (Casirivimab and Imdevimab) used in the treatment of Covid-19 | Cipla”http://www.cipla.com. Retrieved 2021-05-06.
  19. ^ Williams, Stephen (3 October 2020). “Experimental drug given to President made locally”The Daily Gazette.
  20. ^ Stanton, Dan (11 September 2020). “Manufacturing shift to Ireland frees up US capacity for Regeneron’s COVID antibodies”BioProcess International.
  21. ^https://www.businesswire.com/news/home/20200818005847/en/Genentech-and-Regeneron-Collaborate-to-Significantly-Increase-Global-Supply-of-REGN-COV2-Investigational-Antibody-Combination-for-COVID-19
  22. ^ “Roche and Regeneron link up on a coronavirus antibody cocktail”CNBC. 19 August 2020. Retrieved 14 September 2020.
  23. Jump up to:a b Thomas K (2 October 2020). “President Trump Received Experimental Antibody Treatment”The New York TimesISSN 0362-4331. Retrieved 2 October 2020.
  24. ^ Hackett DW (3 October 2020). “8-Gram Dose of COVID-19 Antibody Cocktail Provided to President Trump”http://www.precisionvaccinations.comArchived from the original on 3 October 2020.

External links

REGN10933 (blue) and REGN10987 (orange) bound to SARS-CoV-2 spike protein (pink). From PDB6VSB6XDG.
Combination of
CasirivimabMonoclonal antibody against spike protein of SARS-CoV-2
ImdevimabMonoclonal antibody against spike protein of SARS-CoV-2
Clinical data
Trade namesREGEN-COV
Other namesREGN-COV2
AHFS/Drugs.comMonograph
License dataUS DailyMedCasirivimab
Routes of
administration
Intravenous
ATC codeNone
Legal status
Legal statusUS: Unapproved (Emergency Use Authorization)[1][2]
Identifiers
DrugBankDB15691
KEGGD11938

//////////// Casirivimab, ANTI VIRAL, PEPTIDE, SARS-CoV-2, MONOCLONAL ANTIBODY, FDA 2020, 2020APPROVALS, CORONA VIRUS, COVID 19, カシリビマブ, REGN-COV2, REGN10933+REGN10987 combination therapy, REGN 10933, RG 6413

wdt-7

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Casirivimab with Imdevimab

Evinacumab


(Heavy chain)
EVQLVESGGG VIQPGGSLRL SCAASGFTFD DYAMNWVRQG PGKGLEWVSA ISGDGGSTYY
ADSVKGRFTI SRDNSKNSLY LQMNSLRAED TAFFYCAKDL RNTIFGVVIP DAFDIWGQGT
MVTVSSASTK GPSVFPLAPC SRSTSESTAA LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP
AVLQSSGLYS LSSVVTVPSS SLGTKTYTCN VDHKPSNTKV DKRVESKYGP PCPPCPAPEF
LGGPSVFLFP PKPKDTLMIS RTPEVTCVVV DVSQEDPEVQ FNWYVDGVEV HNAKTKPREE
QFNSTYRVVS VLTVLHQDWL NGKEYKCKVS NKGLPSSIEK TISKAKGQPR EPQVYTLPPS
QEEMTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT PPVLDSDGSF FLYSRLTVDK
SRWQEGNVFS CSVMHEALHN HYTQKSLSLS LGK
(Light chain)
DIQMTQSPST LSASVGDRVT ITCRASQSIR SWLAWYQQKP GKAPKLLIYK ASSLESGVPS
RFSGSGSGTE FTLTISSLQP DDFATYYCQQ YNSYSYTFGQ GTKLEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
(Disulfide bridge: H22-H96, H140-L214, H153-H209, H232-H’232, H235-H’235, H267-H327, H373-H431, H’22-H’96, H’140-L’214, H’153-H’209, H’267-H’327, H’373-H’431, L23-L88, L134-L194, L’23-L’88, L’134-L’194)

Evinacumab

エビナクマブ (遺伝子組換え)

Immunoglobulin G4, anti-​(human protein ANGPTL3 (angiopoietin-​like 3)​) (human monoclonal REGN1500 heavy chain)​, disulfide with human monoclonal REGN1500 light chain, dimer

FormulaC6480H9992N1716O2042S46
CAS1446419-85-7
Mol weight146081.9345

Protein Sequence

Sequence Length: 1334, 453, 453, 214, 214multichain; modified (modifications unspecified)

FDA APPROVED,  2021/2/11, EVKEEZA

Antihyperlipidemic, Anti-angiopietin like 3

Monoclonal antibody
Treatment of dyslipidemia

  • REGN 1500
  • REGN-1500
  • REGN1500

Sequence:

1EVQLVESGGG VIQPGGSLRL SCAASGFTFD DYAMNWVRQG PGKGLEWVSA51ISGDGGSTYY ADSVKGRFTI SRDNSKNSLY LQMNSLRAED TAFFYCAKDL101RNTIFGVVIP DAFDIWGQGT MVTVSSASTK GPSVFPLAPC SRSTSESTAA151LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS201SLGTKTYTCN VDHKPSNTKV DKRVESKYGP PCPPCPAPEF LGGPSVFLFP251PKPKDTLMIS RTPEVTCVVV DVSQEDPEVQ FNWYVDGVEV HNAKTKPREE301QFNSTYRVVS VLTVLHQDWL NGKEYKCKVS NKGLPSSIEK TISKAKGQPR351EPQVYTLPPS QEEMTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT401PPVLDSDGSF FLYSRLTVDK SRWQEGNVFS CSVMHEALHN HYTQKSLSLS451LGK

Sequence:

1EVQLVESGGG VIQPGGSLRL SCAASGFTFD DYAMNWVRQG PGKGLEWVSA51ISGDGGSTYY ADSVKGRFTI SRDNSKNSLY LQMNSLRAED TAFFYCAKDL101RNTIFGVVIP DAFDIWGQGT MVTVSSASTK GPSVFPLAPC SRSTSESTAA151LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS201SLGTKTYTCN VDHKPSNTKV DKRVESKYGP PCPPCPAPEF LGGPSVFLFP251PKPKDTLMIS RTPEVTCVVV DVSQEDPEVQ FNWYVDGVEV HNAKTKPREE301QFNSTYRVVS VLTVLHQDWL NGKEYKCKVS NKGLPSSIEK TISKAKGQPR351EPQVYTLPPS QEEMTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT401PPVLDSDGSF FLYSRLTVDK SRWQEGNVFS CSVMHEALHN HYTQKSLSLS451LGK

Sequence:

1DIQMTQSPST LSASVGDRVT ITCRASQSIR SWLAWYQQKP GKAPKLLIYK51ASSLESGVPS RFSGSGSGTE FTLTISSLQP DDFATYYCQQ YNSYSYTFGQ101GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV151DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG201LSSPVTKSFN RGEC

Sequence:

1DIQMTQSPST LSASVGDRVT ITCRASQSIR SWLAWYQQKP GKAPKLLIYK51ASSLESGVPS RFSGSGSGTE FTLTISSLQP DDFATYYCQQ YNSYSYTFGQ101GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV151DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG201LSSPVTKSFN RGEC

Sequence Modifications

TypeLocationDescription
bridgeCys-22 – Cys-96disulfide bridge
bridgeCys-140 – Cys-214”disulfide bridge
bridgeCys-153 – Cys-209disulfide bridge
bridgeCys-232 – Cys-232′disulfide bridge
bridgeCys-235 – Cys-235′disulfide bridge
bridgeCys-267 – Cys-327disulfide bridge
bridgeCys-373 – Cys-431disulfide bridge
bridgeCys-22′ – Cys-96′disulfide bridge
bridgeCys-140′ – Cys-214”’disulfide bridge
bridgeCys-153′ – Cys-209′disulfide bridge
bridgeCys-267′ – Cys-327′disulfide bridge
bridgeCys-373′ – Cys-431′disulfide bridge
bridgeCys-23” – Cys-88”disulfide bridge
bridgeCys-134” – Cys-194”disulfide bridge
bridgeCys-23”’ – Cys-88”’disulfide bridge
bridgeCys-134”’ – Cys-194”’disulfide bridge

PATENTS

WO 2017024062

 US 20170305999 

Evinacumab, sold under the brand name Evkeeza, is a monoclonal antibody medication for the treatment of homozygous familial hypercholesterolemia (HoFH).[1][2]

Evinacumab is a recombinant human IgG4 monoclonal antibody targeted against angiopoietin-like protein 3 (ANGPTL3) and the first drug of its kind. The ANGPTL family of proteins serve a number of physiologic functions – including involvement in the regulation of lipid metabolism – which have made them desirable therapeutic targets in recent years.2 Loss-of-function mutations in ANGPTL3 have been noted to result in hypolipidemia and subsequent reductions in cardiovascular risk, whereas increases in function appear to be associated with cardiovascular risk, and it was these observations that provided a rationale for the development of a therapy targeted against ANGPTL3.3

In February 2021, evinacumab became the first-and-only inhibitor of ANGPTL3 to receive FDA approval after it was granted approval for the adjunctive treatment of homozygous familial hypercholesterolemia (HoFH) under the brand name “Evkeeza”.8 Evinacumab is novel in its mechanism of action compared with other lipid-lowering therapies and therefore provides a unique and synergistic therapeutic option in the treatment of HoFH.

Common side effects include nasopharyngitis (cold), influenza-like illness, dizziness, rhinorrhea (runny nose), and nausea. Serious hypersensitivity (allergic) reactions have occurred in the Evkeeza clinical trials.[2]

Evinacumab binds to the angiopoietin-like protein 3 (ANGPTL3).[2] ANGPTL3 slows the function of certain enzymes that break down fats in the body.[2] Evinacumab blocks ANGPTL3, allowing faster break down of fats that lead to high cholesterol.[2] Evinacumab was approved for medical use in the United States in February 2021.[2][3]

NAMEDOSAGESTRENGTHROUTELABELLERMARKETING STARTMARKETING END  
EvkeezaInjection, solution, concentrate150 mg/1mLIntravenousRegeneron Pharmaceuticals, Inc.2021-02-11Not applicableUS flag 
EvkeezaInjection, solution, concentrate150 mg/1mLIntravenousRegeneron Pharmaceuticals, Inc.2021-02-11Not applicableUS flag 
EVKEEZA™ (evinacumab-dgnb) INJECTION | Regeneron Corporate

History

The effectiveness and safety of evinacumab were evaluated in a double-blind, randomized, placebo-controlled, 24-week trial enrolling 65 participants with homozygous familial hypercholesterolemia (HoFH).[2] In the trial, 43 participants received 15 mg/kg of evinacumab every four weeks and 22 participants received the placebo.[2] Participants were taking other lipid-lowering therapies as well.[2]

The primary measure of effectiveness was the percent change in low-density lipoprotein (LDL-C) from the beginning of treatment to week 24.[2] At week 24, participants receiving evinacumab had an average 47% decrease in LDL-C while participants on the placebo had an average 2% increase.[2]

The U.S. Food and Drug Administration (FDA) granted the application for evinacumab orphan drugbreakthrough therapy, and priority review designations.[2] The FDA granted approval of Evkeeza to Regeneron Pharmaceuticals, Inc.[2]

References

  1. Jump up to:a b https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761181s000lbl.pdf
  2. Jump up to:a b c d e f g h i j k l m n “FDA approves add-on therapy for patients with genetic form of severely”U.S. Food and Drug Administration (FDA). 11 February 2021. Retrieved 12 February 2021.  This article incorporates text from this source, which is in the public domain.
  3. ^ “FDA Approves First-in-class Evkeeza (evinacumab-dgnb) for Patients with Ultra-rare Inherited Form of High Cholesterol” (Press release). Regeneron Pharmaceuticals. 11 February 2021. Retrieved 12 February 2021 – via PR Newswire.

Further reading

External links

Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetAngiopoietin-like 3 (ANGPTL3)
Clinical data
Trade namesEvkeeza
Other namesREGN1500, evinacumab-dgnb
License dataUS DailyMedEvinacumab
Routes of
administration
Intravenous
ATC codeNone
Legal status
Legal statusUS: ℞-only [1][2]
Identifiers
CAS Number1446419-85-7
DrugBankDB15354
ChemSpidernone
UNIIT8B2ORP1DW
KEGGD11753
Chemical and physical data
FormulaC6480H9992N1716O2042S46
Molar mass146083.95 g·mol−1

//////////////

#Evinacumab, #Peptide, #APPROVALS 2021, #FDA 2021, #Monoclonal antibody, #dyslipidemia, #エビナクマブ (遺伝子組換え) , #REGN 1500, #REGN-1500, #REGN1500, #Anthony melvin crasto, #world drug tracker. # new drug approvals, #pharma

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