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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Biogen submits haemophilia A drug to FDA
Mar 14 2013
Biogen Idec has filed the first long-lasting Factor VIII treatment for haemophilia A with the US Food and Drug Administration.
The US biotech major has submitted recombinant factor VIII Fc fusion protein (rFVIIIFc), the first haemophilia A product candidate “in a new class of long-lasting clotting factor therapies being developed with the goal of reducing the burden of treatment for this condition”. If approved, rFVIIIFc will be the first major advance in haemophilia A treatment in more than two decades, Biogen claims.
The regulatory submission is based on results from A-LONG, the largest Phase III study in haemophilia A to date. Glenn Pierce, Biogen’s head of global medical affairs, noted that in that trial, patients were able to inject rFVIIIFc once-weekly to twice-weekly, “which creates the potential for those currently on prophylactic treatment to reduce injections by 50 to 100 per year”. Moreover, patients currently treating bleeding episodes could potentially dose once per week “and maintain significant protection from bleeding with about the same total number of injections each year they use to treat bleeding episodes today”, he added.
Earlier this month, the FDA accepted for review the company’s BLA for its factor IX candidate, rFIXFc, for use in patients with haemophilia B.
Links
Phase III trial of Merck’s Vytorin passes vital safety test
mar 13 2013
Merck & Co’s stock enjoyed a boost yesterday after it revealed it has been given permission to continue a late-stage trial of its cholesterol buster Vytorin.
The Whitehouse Station, New Jersey-based firm must have a breathed a sigh of relief when the Data Safety Monitoring Board issued a green light for the Phase III IMPROVE for a second time, having found no significant safety concerns raised by the data.
After an earlier planned review of data last year, the Board, rather unusually, said it would undertake a second interim analysis at a later date, which had led to some concerns that there may be issues that could lead to the trial being halted, according to media reports.
However, it seems these fears are unfounded at this point, as the18,000-plus patient study – which is designed to determine whether Vytorin is more effective at reducing the risk of heart attack, stroke and death in patients with heart disease than simvastatin alone – has been cleared to conclude.
The drugmaker said the trial should finish in September next year, and it will no doubt be hoping for a positive outcome to prove the benefits of Vytorin – a combination of the generic simvastatin and the still-patented Zetia (ezetimibe) – and breathe a little new life into its heart franchise.
Citi Investment Research analyst Andrew Baum, however, expressed doubt in a research note the final analysis will show Merck’s drug is more effective than generic competition, according to the Associated Press.
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|---|---|
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| Combination of | |
| Ezetimibe | via Niemann-Pick C1-Like 1 protein |
| Simvastatin | Statin HMG-CoA reductase inhibitor |
Health Canada approval-aHUS Canada applauds approval of Soliris® (eculizumab) first treatment for fatal, ultra-rare disease affecting children and adults
CAS number 219685-50-4
Soliris is a formulation of eculizumab which is a recombinant humanized monoclonal IgG2/4;κ antibody produced by murine myeloma cell culture and purified by standard bioprocess technology. Eculizumab contains human constant regions from human IgG2 sequences and human IgG4 sequences and murine complementarity-determining regions grafted onto the human framework light- and heavy-chain variable regions. Eculizumab is composed of two 448 amino acid heavy chains and two 214 amino acid light chains and has a molecular weight of approximately 148 kDa.
TORONTO, March 7, 2013
Atypical Hemolytic Uremic Syndrome (aHUS) Canada is thrilled by Health Canada’s recent approval of Soliris® (eculizumab) for the treatment of patients with atypical Hemolytic Uremic Syndrome (aHUS), 1 a very rare, chronic and life-threatening genetic condition affecting fewer than 60 patients in Canada.
aHUS leaves a part of the immune system (known as the complement system) uncontrolled and always active. As a result, the immune system attacks the body’s unhealthy and healthy cells which can cause blood vessel damage, abnormal blood clotting 2,3 and progressive damage to the body’s major organs, leading to heart attack, stroke, kidney failure and death.4
The management of aHUS has relied on plasma infusion and plasma exchange therapies with variable results.5 These lifelong therapies are costly, painful and time-consuming, and have not been studied or approved for the treatment of aHUS.6 If kidney failure has already occurred as a result of aHUS, dialysis is required, though it is not a curative treatment.7 Within a year of diagnosis, over half of patients will need dialysis, will have irreversible kidney damage, or will not survive.6 The majority of patients progress to end-stage kidney failure within three years of diagnosis.8,9
With the approval of Soliris, aHUS patients and their families finally have a reason for hope.
Sonia DeBortoli knows all too well the destructive force of the disease. Sonia’s 11-year-old son Joshua was diagnosed with aHUS in March 2012 and experienced kidney failure, internal bleeding and a blood clot in his groin as a result. He endured several painful hours of daily dialysis and plasma therapy, and was on prednisone and oxygen. Then, a chance to join a clinical trial for Soliris restored Joshua’s health so that he no longer needed the other therapies.
“Our whole world changed when Joshua was given Soliris – we now believe he has a long and healthy future. He is back at school, taking karate lessons and playing soccer,” Sonia says. “We got our little boy back, he got his life back, and we want the same for anyone who has to deal with this rare and devastating disease.”
A groundbreaking treatment advance for aHUS patients
Soliris (eculizumab) is the first and only pharmaceutical treatment for aHUS, and is being hailed by experts worldwide as a critical breakthrough in treating the disease. It has been shown to significantly improve patients’ health and quality of life.10 In clinical trials, Soliris has been proven effective in preventing blood vessel damage and abnormal blood clotting,11,12 leading to remission and significant improvement in kidney function.5,4 Soliris has also allowed patients to discontinue dialysis and plasma exchange therapies.10
Soliris is also indicated, and proven safe and effective, for the treatment of another rare and life-threatening disorder called paroxysmal nocturnal hemoglobinuria (PNH).13 Canadians living with PNH already have access to Soliris through private health insurance and provincial drug plans.
Immediate and sustained access to treatment urgently needed
Now that this new treatment option has been approved for the small number of Canadians living with the devastating symptoms of aHUS, Soliris must be made immediately accessible to all aHUS patients whose lives depend on this treatment.
“We are so hopeful that the Common Drug Review will recognize the urgent need for access to Soliris, and that provincial governments will act swiftly to provide reimbursement to patients who are in urgent need of this life-saving treatment,” says Tracy MacIntyre, a founder of aHUS Canada whose daughter is living with aHUS. “Immediate access to the drug would have a profoundly positive impact on the few Canadians living with aHUS, while any delay in funding treatment could lead to devastating consequences.”
About aHUS Canada
aHUS Canada was formed in November 2012 to support Canadian patients and families living with aHUS. In addition to establishing a Canadian aHUS community, the group is committed to building public awareness and understanding of aHUS and advocating for the best possible care and treatment for patients. For more information, please visit http://www.ahuscanada.org.
Eculizumab (INN and USAN; trade name Soliris®) is a humanized monoclonal antibody that is a first-in-class terminal complement inhibitor and the first therapy approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), a rare, progressive, and sometimes life-threatening disease characterized by excessive destruction of red blood cells (hemolysis).[1] It costs £400,000 ($US 600,000) per year per patient.[1]
Eculizumab also is the first agent approved for the treatment of atypical hemolytic uremic syndrome (aHUS), an ultra-rare genetic disease that causes abnormal blood clots to form in small blood vessels throughout the body, leading to kidney failure, damage to other vital organs and premature death.[2][3]
In clinical trials in patients with PNH, eculizumab was associated with reductions in chronic hemolysis, thromboembolic events, and transfusion requirements, as well as improvements in PNH symptoms, quality of life, and survival.[1][4][5][6] Clinical trials in patients with aHUS demonstrated inhibition of thrombotic microangiopathy (TMA),[7] the formation of blood clots in small blood vessels throughout the body,[1][3][4] including normalization of platelets and lactate dehydrogenase (LDH), as well as maintenance or improvement in renal function.[7]
Eculizumab was discovered and developed by Alexion Pharmaceuticals and is manufactured by Alexion. It was approved by the United States Food and Drug Administration (FDA) on March 16, 2007 for the treatment of PNH, and on September 23, 2011 for the treatment of aHUS. It was approved by the European Medicines Agency for the treatment of PNH on June 20, 2007, and on November 24, 2011 for the treatment of aHUS. Eculizumab is currently being investigated as a potential treatment for other severe, ultra-rare disorders
- Hillmen, Young, Schubert, P, N, J, et al (2006). “The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria”. N Engl J Med 355 (12): 1233–1243. doi:10.1056/NEJMMoa061648. PMID 16990386.
- Noris, Caprioli, Bresin, M, J, E, et al. (2010). “Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype”. Clin J Am Soc Nephrol 5: 1844–1859.
- Caprioli, Noris, Brioschi, J, M, S, et al (2006). “Genetics of HUS: the impact of MPC, CFH, and IF mutations on clinical presentation, response to treatment, and outcome”. Blood 108: 1267–1279.
- Hillman, Hall, Marsh, P, C, JC, et al (2004). “Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria”. N Eng J Med 350: 552–559.
- Ray, Burrows, Ginsberg, Burrows, JG, RF, JS, EA (2000). “Paroxysmal nocturnal hemoglobinuria and the risk of venous thrombosis: review and recommendations for management of the pregnant and nonpregnant patient”. Haemostasis 30: 103–107.
- Kelly, Hill, Arnold, RJ, A, LM, et al (2011). “Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival”. Blood 117: 6786–6792.
- .Soliris® (eculizumab) prescribing information (2011). Cheshire, CT: Alexion Pharmaceuticals. http://www.soliris.net/sites/default/files/assets/soliris)pi.pdf.
Phase 2 Drug: Ustekinumab A monoclonal antibody against the p40 subunit of IL-12/23 Other Name: Stelara
| Monoclonal antibody | |
|---|---|
| Type | Whole antibody |
| Source | Human |
| Target | IL-12 and IL-23
|
Ustekinumab, CAS number 815610-63-0, is also known by it’s brand name Stelara, which is marketed by Janssen Biotech, Inc. Developed as a treatment for adults with moderate to severe plaque psoriasis
Rockefeller University, MAR 2013
http://clinicaltrials.gov/ct2/show/NCT01806662
Atopic dermatitis (AD) is a chronic disease associated with intense itching, which affects most aspects of everyday life in the majority of patients. Acute inflammation and extensor/facial involvement is common in infants, whereas chronic inflammation increases in prevalence with age, as do localization to flexures. AD has a complex background characterized by immune activation, increased epidermal thickness in chronic diseased skin, and defective barrier function. In normal, healthy skin, the outer layer of the epidermis, the stratum corneum is made up flattened dead cells called corneocytes held together by a mixture of lipids and proteins. The stratum corneum and, in particular, the lipid layer are vital in providing a natural barrier function that locks water inside the skin and keeps allergens and irritants out. In people with AD, the barrier function is defective, which leads to dry skin. As the skin dries out, it cracks allowing allergens and irritants to penetrate.
Mild AD can be controlled with emollients and topical medications. However, moderate to severe AD is extremely difficult to control and requires systemic treatment that is often unsatisfactory due to impracticality and lack of effectiveness. Only three therapeutic options exist for moderate to severe AD, including: 1) oral steroids 2) cyclosporine A (CsA), that is not widely used in the US as it is not FDA approved for AD and 3) ultraviolet phototherapy. Oral steroids and CsA treatments have major side effects and UV radiation therapy is highly inconvenient for patients. Several biologic medications, such as TNF-alpha inhibitors, are effective, convenient, and relatively safe therapies for psoriasis, but have thus far not shown efficacy in AD. Ustekinumab is a unique biologic medication that may specifically target AD.
The investigators study will determine whether there is a reversal of the skin thickness and the immune pathways involved in the disease during treatment with Ustekinimab and what specific immune cells are involved. The investigators are also interested to understand how the clinical reversal of the disease will correlate with tissue reversal of the disease.
Detailed Description:
In psoriasis, epidermal hyperplasia is driven by underlying immune activation, whether as a direct response to IL-20 family cytokines that induces hyperplasia and inhibits keratinocyte terminal differentiation or as an indirect response to immune-mediated injury to keratinocytes. The epidermal reaction in psoriasis is largely restored to normal with selective immune suppression. Hence, one might hypothesize that similar epidermal responses should occur in the presence of “generalized” cellular immune activation, in diseases with similar inflammatory infiltrate and epidermal hyperplasia, such as AD. In fact, psoriasis and AD share features of dense T-cells and dentritic cell infiltrates, as well as over-expression of IL-22 in skin lesions. These diseases also share similar epidermal hyperplasia in their chronic phases.
Work from the investigators group showed that IL-22 is a key cytokine in the pathogenesis of both AD and psoriasis. The investigators have demonstrated that in psoriasis, ustekinumab suppresses the production of IL-12, IL-23, and IL-22. Additionally, by RT-PCR the investigators demonstrated that the mRNA expression of p40 cytokine and the IL23R is up-regulated in AD as compared to both normal skin and psoriasis. The investigators therefore hypothesize that ustekinumab will suppress IL-22 and possibly also p40 production in AD lesions and reverse both the epidermal growth/differentiation defects and the underlying immune activation, and hence will suppress disease activity. Interestingly, p40 was also found to be significantly up-regulated in non-lesional AD skin as compared with normal skin.
Although AD is thought to be predominately a disease of Th2-type cells, in the chronic stage, there is large Th1 component. To date, the precise mechanism by which sequential activation of Th2 and Th1 cells in AD is achieved remains unknown. IL-12 induces the differentiation and maturation of human Th cells into Th1-type cells. Recent circumstantial evidence suggests that in AD patients IL-12 may facilitate a change from the Th2-type to a Th1 cytokine profile. IL-12 was recently shown to be highly elevated in pediatric AD and its levels were strongly associated with disease severity.
Expression of IL-12 p40 mRNA is significantly enhanced in lesional skin from AD, suggesting that the enhanced local production of IL-12 in dendritic cells and macrophages may be responsible for the increased production of IFN-γ in chronic lesions potentially suggesting that IL-12 may have a pivotal role in promoting inflammation in atopic dermatitis. Topical steroids which constitute a mainstay of therapy in AD are known to strongly down-regulate IL-12 expression, possibly also indicating that targeted anti IL-12 therapy might important role in treating AD.
Recently, the Th1/Th2 paradigm in autoimmunity and allergy has been revisited to include a role for a new population of IL-17-producing Th cells known as Th17. Th17 cells are characterized by the production of inflammatory cytokines such as IL-17A, IL-17F, IL-22, and IL-26. One of the key factors involved in naive Th-cell commitment to a Th17 phenotype is IL-23.
Patients with acute AD were found to have increased Th17 T-cells in peripheral blood by flow cytometry and intracellular cytokine staining 26 as well as by immunohistochemistry (IHC) in lesions. Since IL-23 is the major inducer of Th17 T-cells, as well as “T22” T-cells, neutralization of IL-23 could potentially result in both decreased Th17 signal in acute AD as well as decreased “T22/IL22″ signal. Therefore the investigators postulate that ustekinumab in AD will act both inhibiting the IL-12-dependent Th1 shift in chronic AD stage as well as the pathogenic IL-22/”T22” axis in this disease.
Ustekinumab [1] (INN, experimental name CNTO 1275, proprietary commercial name Stelara,[2] Centocor) is a human monoclonal antibody. It is directed against interleukin 12 and interleukin 23, naturally occurring proteins that regulate the immune system and immune-mediated inflammatory disorders.[3]
In two Phase III trials for moderate to severe psoriasis, the longest >76 weeks, ustekinumab was safe and effective.[4][5]
A third Phase III trial, ACCEPT, compared the efficacy and safety of ustekinumab with etanercept in the treatment of moderate to severe plaque psoriasis.[6] This trial found a significantly higher clinical response with ustekinumab over the 12-week study period compared to high-dose etanercept.[6] It also demonstrated the clinical benefit of ustekinumab among patients who failed to respond to etanercept.[6]
Ustekinumab is approved in Canada, Europe and the United States to treat moderate to severe plaque psoriasis.[7]
As of November 2009, the drug is being investigated for the treatment of psoriatic arthritis.[8][9] It has also been tested in Phase II studies for multiple sclerosis[10] and sarcoidosis, the latter versus golimumab (Simponi).[11]
- Cingoz, Oya (2009). “Ustekinumab”. MAbs 1 (3): 216–221. doi:10.4161/mabs.1.3.8593. PMC 2726595. PMID 20069753.
- ^ European Medicines Agency, 20 November 2008, http://www.emea.europa.eu/pdfs/human/opinion/Stelara_58227008en.pdf
- ^ Reddy M, Davis C, Wong J, Marsters P, Pendley C, Prabhakar U (May 2007). “Modulation of CLA, IL-12R, CD40L, and IL-2Ralpha expression and inhibition of IL-12- and IL-23-induced cytokine secretion by CNTO 1275”. Cell. Immunol. 247 (1): 1–11. doi:10.1016/j.cellimm.2007.06.006. PMID 17761156.
- ^ Leonardi CL, Kimball AB, Papp KA, et al. (May 2008). “Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1)”. Lancet 371 (9625): 1665–74. doi:10.1016/S0140-6736(08)60725-4. PMID 18486739.
- ^ Papp KA, Langley RG, Lebwohl M, et al. (May 2008). “Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2)”. Lancet 371 (9625): 1675–84. doi:10.1016/S0140-6736(08)60726-6. PMID 18486740.
- ^ a b c Griffiths C, Strober B, van de Kerkhof P et al. (2010). “Comparison of Ustekinumab and Etanercept for Moderate-to-Severe Psoriasis”. N Engl J Med 362 (2): 118–28. doi:10.1056/NEJMoa0810652. PMID 20071701.
- ^ Medarex to Receive Milestone Payment for Approval of STELARA(TM) (Ustekinumab) for the Treatment of Moderate to Severe Plaque Psoriasis
- ^ ClinicalTrials.gov NCT00267956 A Study of the Safety and Efficacy of CNTO 1275 in Patients With Active Psoriatic Arthritis
- ^ ClinicalTrials.gov NCT01009086 A Study of the Safety and Efficacy of Ustekinumab in Patients With Psoriatic Arthritis
- ^ ClinicalTrials.gov NCT00207727 A Safety and Efficacy Study of CNTO1275 in Patients With Multiple Sclerosis
- ^ ClinicalTrials.gov NCT00955279 A Study to Evaluate the Safety and Effectiveness of Ustekinumab or Golimumab Administered Subcutaneously (SC) in Patients With Sarcoidosis
- ^ http://www.empr.com/stelara-approved-for-moderate-to-severe-psoriasis/article/149760/
- ^ a b Centocor 12/19/08 Press Release, http://www.centocor.com/centocor/i/press_releases/FDA_ISSUES_COMPLETE_RESPONSE_LETTER_TO_CENTOCOR_FOR_USTEKINUMAB_BIOLOGIC_LICENSE_APPLICATION_
- ^ Johnson LL. “Study: Drug for serious psoriasis tops competition” The Associated Press. 18 Sept 2008.[dead link]
- ^ Wild, David (November 2011), “Novel IL-12/23 Antagonist Shows Potential in Severe Crohn’s”, Gastroenterology & Endoscopy News 62 (11), retrieved 2011-12-04
- ^ a b c Weber J, Keam SJ (2009). “Ustekinumab”. BioDrugs 23 (1): 53–61. doi:10.2165/00063030-200923010-00006. PMID 19344192.
- ^ Segal BM, Constantinescu CS, Raychaudhuri A, Kim L, Fidelus-Gort R, Kasper LH (September 2008). “Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study”. Lancet Neurol 7 (9): 796–804. doi:10.1016/S1474-4422(08)70173-X. PMID 18703004.
- ^ “Important Safety Information”. STELARA® (ustekinumab). Janssen Biotech.
External links
- Centocor Ortho Biotech official site
- CNTO 1275 research studies registered with U.S. National Institutes of Health:
- ClinicalTrials.gov NCT00207727 Phase II Study on Multiple Sclerosis
- ClinicalTrials.gov NCT00320216 Phase II Study on Psoriasis
- ClinicalTrials.gov NCT00267969 Phase III Study on Psoriasis
- ClinicalTrials.gov NCT00307437 Phase III Study on Psoriasis
- ClinicalTrials.gov NCT00267956 Phase II Study on Psoriatic Arthritis
- Sylvester, Bruce (2006-03-06). “CNTO 1275 Shows Efficacy for Psoriasis: Presented at AAD”. Doctor’s Guide Publishing. Retrieved 2007-01-25.
NDA FDA-Nuvo reports FDA response to PENNSAID 2% , diclofenac sodium topical solution, 2% w/w
DICLOFENAC
PENNSAID 2%
7 MAR 2013
The US Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) to Nuvo Research’s US licensing partner, Mallinckrodt, following the review of Mallinckrodt’s New Drug Application (NDA) for diclofenac sodium topical solution, 2% w/w (PENNSAID 2%).
FDA in the letter mentioned that it requires Mallinckrodt’s complete pharmacokinetic study comparing PENNSAID 2% to original PENNSAID 1.5%.
FDA denied to review the similar pharmacokinetic studies submitted by Mallinckrodt with the NDA, as the reserve samples were not retained at the clinical site.
Pharmacokinetic studies are standard studies conducted during a drug development program to identify the total exposure or the amount of drug that reaches the blood stream after a patient receives both single and multiple doses of the product.
Mallinckrodt has suggested Nuvo that it expects to complete the study and submit the results to the FDA in the third quarter of 2013, and that it anticipates the FDA will provide a formal response to the filing within 6 months thereafter.
Nuvo’s Pain Group president Dr. Bradley Galer said with the new FDA’s letter the firm was disappointed that PENNSAID 2% will not be approved in this review cycle.
“We are pleased that the FDA has outlined a clear pathway to approval that we believe can be completed in a relatively short time frame,” Galer added.
“Upon approval, PENNSAID 2% will be the first and only topical NSAID in the U.S. featuring twice per day dosing and a metered dose pump bottle.”
Ziopharm Oncology will be releasing its Phase III results for its drug Palifofsamide towards the end of March 2013
(Zymafos; ZIO-201) is a cytotoxic, active metabolite of the alkylating agent ifosfamide, which causes irreparable DNA interstrand cross-linking in cancer cells. This prevents DNA replication and cell division, leading to cell death.
In contrast to ifosfamide, palifosfamide is not metabolised to the toxins acrolein and chloracetaldehyde, which are associated with haemorrhagic cystitis, and neuro- and nephro-toxicities respectively. Also, palifosfamide is not a substrate for aldehyde dehydrogenase (ALDH), an important mediator of drug resistance
Cyclophosphamide and ifosfamide are nitrogen mustard alkylating agents that act by crosslinking DNA strands at the guanine N-7 position, resulting in cell death. Both of these are prodrugs that are metabolised in the liver to phosphoramide mustard active metabolites, but their use is limited by toxic side-effects. They are also prone to tumour resistance, which results from numerous mechanisms, including DNA repair.
In an attempt to overcome some of these problems, Ziopharm Oncology has developed palifosfamide tromethamine, which is a salt formulation of isophosphoramide mustard, the active metabolite of isofosfamide.1
isofosamide
In a Phase I trial, it was given in combination with doxorubicin to 13 patients with advanced refractory tumours – eight with soft tissue sarcoma and the remainder with small cell lung cancer – for whom there was no available standard therapy.2 It was given on the first three days of a three-week cycle, with a starting dose of 150mg/m2, and doxorubicin given on the first day at a starting dose of 60mg/m2. The doses were escalated to a maximum tolerated dose of 150mg/m2 for palifosfamide and 75mg/m2 for doxorubicin. It was well tolerated, and three of the 12 assessable patients had a partial response, two of whom were from the sarcoma group, and the median progression free survival was 20 weeks.
references
1. S. Jung and B. Kasper, IDrugs 2010, 13, 38
2. L.J. Camacho et al. J. Clin. Oncol. 2009, 27 (Suppl.), Abst. 10577
3. C.F. Verschraegen et al. J. Clin. Oncol. 2010, 28 (Suppl.), A
Palifosfamide, A Novel Molecule for the Treatment of Soft Tissue Sarcoma
Palifosfamide (Zymafos™ or ZIO-201) references a novel composition (tris formulation) that is the functional active metabolite of ifosfamide (IFOS), a bi-functional DNA alkylator being investigated as a potential therapy for the treatment of soft tissue sarcoma (STS). Palifosfamide is formulated by combining the tris (hydroxymethyl) amino methane (tris) salt of palifosfamide and a number of excipients to create the final drug product. Preclinical development of palifosfamide has included in vitro and in vivo studies demonstrating activity against various sarcomas, breast cancers, other solid tumors and leukemias, including several that are resistant to IFOS. Several clinical studies have been initiated in a variety of cancer types. A Phase I study in advanced cancers, using the original lysine formulation, has been completed. A two-stage Phase I/II Study in advanced sarcomas, introducing the tris salt formulation, has completed enrollment and data retrieval is ongoing. A Phase I study in combination with doxorubicin evaluating patients with advanced, refractory solid tumors for whom treatment with doxorubicin is considered medically acceptable, has completed enrollment and data retrieval is ongoing. Based on the result of the Phase I combination study, an international randomized Phase II study comparing palifosfamide in combination with doxorubicin versus doxorubicin alone in 1st and 2nd line patients with advanced STS has been completed. phase 3 on now also
What is Soft Tissue Sarcoma, and what are the currently available treatments?
Soft-tissue sarcomas (STS) represent a rare and diverse group of tumors that are not very well understood. Although soft-tissue sarcomas account for <1% of all cancers, they represent a high percentage of cancer-related deaths worldwide (Ref. 3, Ref. 4, Ref. 5). STS tumors can occur anywhere within the body, originating in various soft tissues including fat, smooth or striated muscle, nerve/nerve sheath, vascular tissue, and other connective tissues; the extremities are the most common site of origin, accounting for approximately 50% of cases
Sanofi And Regeneron Report Positive Proof-of-Concept Data For Dupilumab, An IL-4R Alpha Antibody, In Atopic Dermatitis
| Monoclonal antibody | |
|---|---|
| Source | Human |
| Target | IL4 receptor alpha |
Treatment of atopic diseases
Immunoglobulin, anti-(human interleukin 4 receptor α) (human REGN668 heavy chain),
disulfide with human REGN668 κ-chain, dimer
Immunoglobulin G4, anti-(human interleukin-4 receptor subunit alpha (IL-4R-alpha,
CD124)); human monoclonal REGN668 des-452-lysine{CH3107K>-}-[233-
proline{H10S>P}]γ4 heavy chain (139-219′)-disulfide with human monoclonal REGN668
κ light chain, dimer (231-231”:234-234”)-bisdisulfide
1190264-60-8 cas no
REGN668, SAR231893
MOLECULAR FORMULA- C6512H10066N1730O2052S46
Dupilumab is a monoclonal antibody designed for the treatment of atopic diseases.[1]
This drug was developed by Regeneron Pharmaceuticals.
- Statement On A Nonproprietary Name Adopted By The USAN Council – Dupilumab,American Medical Association.
Phase 1b Data Presented at Late Breaking Session of 71st Annual Meeting of the American Academy of Dermatology
PARIS and TARRYTOWN, N.Y., March 2, 2013 – Sanofi and Regeneron Pharmaceuticals, Inc. today announced that pooled data from two Phase 1b trials with dupilumab (REGN668/SAR231893), an investigational, high-affinity, subcutaneously administered, fully-human antibody targeting the alpha subunit of the interleukin 4 receptor (IL-4R alpha), were presented at the 71st Annual Meeting of the American Academy of Dermatology (AAD) in Miami.
The primary objective of the Phase 1b studies was to assess the safety profile of dupilumab. Other exploratory endpoints included pharmacokinetic, biomarker, and efficacy parameters. The efficacy data showed that treatment with four weekly subcutaneous injections of dupilumab at either 150 milligrams (mg) or 300mg per week, significantly improved the signs and symptoms of patients with moderate-to-severe atopic dermatitis (AD) whose disease was not adequately controlled with topical medications. Specifically, patients treated with dupilumab had significant improvements in body surface area (BSA) score, Investigator Global Assessment (IGA) score, and Eczema Area Severity Index (EASI) from baseline to week 4 compared to placebo (p<0.05 vs. placebo for all measures and doses). The significant improvements in BSA, IGA, and EASI scores were maintained at week 8 in the 300mg dose group (p<0.05 vs. placebo). A responder analysis demonstrated that at week 4, 54.5% of patients treated with the 150mg dose and 71.4% of patients treated with the 300mg dose achieved a reduction in EASI score of 50% or greater compared to 18.8% with placebo (p<0.05). The most common adverse events (AEs) were nasopharyngitis (19.6% vs 12.5% for placebo) and headache (11.8% vs 6.3% for placebo).
“Despite existing therapies, a significant proportion of patients with moderate-to-severe atopic dermatitis continue to suffer from inflamed skin and intractable itch, which significantly impacts their quality of life,” said Dr. Eric Simpson, Associate Professor, Director of Clinical Studies, Oregon Health and Science University, Portland, Oregon, USA, and Principal Investigator of the study. ”The early phase results with this biologic therapy, which has a novel mechanism of action, are encouraging to those of us who treat these patients and warrant further clinical investigation.”
“Through blockade of IL-4R alpha, dupilumab modulates signaling of both the IL-4 and IL-13 pathway, which have been implicated in the pathophysiology of allergic disease,” said George D. Yancopoulos, M.D., Ph.D., Chief Scientific Officer of Regeneron and President of Regeneron Laboratories. ”We look forward to presenting additional data from a 12-week, Phase 2a trial in atopic dermatitis, as well as starting a larger Phase 2b trial with dupilumab in patients with atopic dermatitis, later this year.”
Presented today in a late-breaking clinical trials session at the AAD meeting, the Phase 1b trials included 67 patients randomized to three different doses of dupilumab (75mg, n=8; 150mg, n=22; 300mg, n=21) and placebo (n=16). The primary objective of the Phase 1b studies was to assess the safety profile of dupilumab. Other endpoints included pharmacokinetic, biomarker, and efficacy parameters. Following the 4-week treatment period, patients in the studies were followed for an additional 4 weeks for a total of 8 weeks.
About IL-4R and the IL-4/IL-13 Pathway
Atopic dermatitis and some types of asthma are characterized by the induction of a specific type of an immune response that is driven by a subset of immune cells called Type 2 helper T cells, or Th2 cells. IL-4 and IL-13 are key cytokines that are required for the initiation and maintenance of this Th2 immune response. Both IL-4 and IL-13 signaling occurs through two different IL-4 receptors (Type I and II), which both contain a common IL-4R alpha subunit.
About Dupilumab (SAR231893/REGN668)
Dupilumab is a fully human monoclonal antibody directed against IL-4R alpha and is administered via subcutaneous injection. By blocking IL-4R alpha dupilumab modulates signaling of both IL-4 and IL-13, drivers of a Th2 immune response. Dupilumab was created using Regeneron’s pioneering VelocImmune® technology and is being co-developed with Sanofi. Dupilumab is currently being studied in both atopic dermatitis and asthma.
About Atopic Dermatitis
Atopic dermatitis (AD) is a chronic, immune-mediated, inflammation of the skin that is characterized by poorly defined erythema (redness) with edema (swelling), weeping in the acute stage, and skin thickening (lichenification) in the chronic stage. Chronic and/or relapsing lesions, along with pruritus (itching) and scratching are the hallmarks of the disease. The prevalence of AD is estimated to be between 1% and 3% of adults. For many patients, topical therapies are not effective for keeping the disease under control and the only approved systemic therapies to treat AD are prednisone and cyclosporine (in Europe). Moderate-to-severe atopic dermatitis can negatively impact patients’ lives and is associated with a high burden to society both in terms of direct costs of medical care and prescription drugs, as well as loss of productivity.
About Sanofi
Sanofi, a global and diversified healthcare leader, discovers, develops and distributes therapeutic solutions focused on patients’ needs. Sanofi has core strengths in the field of healthcare with seven growth platforms: diabetes solutions, human vaccines, innovative drugs, consumer healthcare, emerging markets, animal health and the new Genzyme. Sanofi is listed in Paris (EURONEXT: SAN) and in New York (NYSE:SNY).
About Regeneron Pharmaceuticals, Inc.
Regeneron is a leading science-based biopharmaceutical company based in Tarrytown, New York that discovers, invents, develops, manufactures, and commercializes medicines for the treatment of serious medical conditions. Regeneron markets medicines for eye diseases, colorectal cancer, and a rare inflammatory condition and has product candidates in development in other areas of high unmet medical need, including hypercholesterolemia, rheumatoid arthritis, asthma, and atopic dermatitis. For additional information about the company, please visitwww.regeneron.com.
Taiho Pharma seeks Japanese nod to manufacture,market novel anti-tumour agent TAS-102
TRIFLURIDINE
TIPIRACIL
TAS-102 is an anti-cancer drug under development for colorectal cancer.[1]
| Combination of | |
|---|---|
| Trifluridine | cytotoxin |
| Tipiracil | thymidine phosphorylase inhibitor |
Clinical trials
A phase II trial reported in 2011[2] and a phase III trial is due to end in 2014.[1][3]
Mechanism
TAS-102 consists of the cytotoxin trifluridine and the thymidine phosphorylase inhibitor (TPI) tipiracil.[4] Trifluridine is incorporated into DNA during DNA synthesis and inhibits tumor cell growth. Tipiracil protects trifluridine from being broken down when taken orally.
| February 28, 2013, |
|
Taiho Pharmaceutical Co., Ltd. has submitted an application to the Japanese Ministry of Health, Labour and Welfare for approval of the manufacture and marketing of the novel oral nucleoside anti-tumour agent TAS-102 (combination of trifluorothymidine [FTD] and tipiracil hydrochloride [TPI]). Taiho is seeking approval of TAS-102 for the indication of unresectable, advanced, recurrent colorectal cancer. The application for approval is based on the results of a phase II clinical trial (Study 10040030) conducted at 20 facilities throughout Japan. It was a randomized, double-blind comparative study of TAS-102 and a placebo involving 172 patients with unresectable, advanced, recurrent colorectal cancer that was refractory to the standard chemotherapy of at least two or more regimens containing fluoropyrimidine, irinotecan, and oxaliplatin. The results indicated that the group administered TAS-102 had improved overall survival rates (median overall survival: 9.0 months vs. 6.6 months) and a significantly reduced risk of mortality (HR: 0.56, p=0.0011). The most frequently reported adverse drug reaction with a CTCAE grade of 3 or higher was neutropenia. Grade 3 or higher diarrhea, fatigue, nausea, and other adverse reactions were no more than 10 per cent. Taiho Pharmaceutical is currently proceeding with a global phase III clinical trial of TAS-102 in a similar colorectal cancer population (RECOURSE) with the ultimate goal of global registration and commercialization of the agent. Taiho Pharmaceutical believes that TAS-102 will make a significant contribution to cancer patients and will continue its development efforts to broaden its use. TAS-102 is an anti-tumour agent composed of a combination of trifluorothymidine (FTD), a nucleoside that incorporates into DNA and inhibits a variety of genetic functions required for the proliferation of cancer cells, and tipiracil hydrochloride (TPI), an inhibitor of thymidine phosphorylase (which degrades FTD) that maintains an effective blood concentration of FTD. TAS-102 is administered twice daily to achieve a total daily dose of 70mg/m2 for five days followed by two days of rest and then repeated a second time. This is followed by a 14-day rest period to make a 28-day schedule for one course. |
- “New Drug for Colorectal Cancer Shows Promise in Phase II Trial”. 28 Aug 2012.
- “Novel Drug TAS-102 Makes Headway in Refractory Colorectal Cancer”. 4 Oct 2011.
- “Phase II study of TAS-102 for pretreated metastatic colorectal cancer”. 29 Aug 2012.
- “A novel combination antimetabolite, TAS-102, exhibits antitumor activity in FU-resistant human cancer cells through a mechanism involving FTD incorporation in DNA.”. Sept 2004.
|
|
|---|---|
| TRIFLURIDINE | |
| 1-[4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5- (trifluoromethyl) pyrimidine-2,4-dione |
Trifluridine (also called trifluorothymidine or TFT) is an anti-herpesvirus antiviral drug, used primarily on the eye. It was sold under the trade name, Viroptic, by Glaxo Wellcome, now merged into GlaxoSmithKline. The brand is now owned by Monarch Pharmaceuticals, which is wholly owned by King Pharmaceuticals.
It is a nucleoside analogue, a modified form of deoxyuridine, similar enough to be incorporated into viral DNA replication, but the -CF3 group added to the uracil component blocks base pairing.
It is a component of the experimental anti-cancer drug TAS-102.
TIPIRACIL
| NAME | 5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]pyrimidine-2,4-(1H,3H)-dione | |||
| CAS | 183204-74-2 | |||
| MOL F | C9H11ClN4O2 | |||
| STR | |
|||
| USE | potentiator of antineoplastics; | |||
Taiho Pharmaceutical, a subsidiary of Otsuka Holdings Co., Ltd., is an R&D-driven specialty pharma focusing on the three fields of oncology, allergies and immunology, and urology.
Novartis’ Ilaris canakizumab has become the first biologic drug to be approved in the EU to treat the symptoms of gouty arthritis
| Monoclonal antibody | |
|---|---|
| Type | Whole antibody |
| Source | Human |
| Target | IL-1β |
Novartis’ Ilaris has become the first biologic drug to be approved in the EU to treat the symptoms of gouty arthritis in another gain for the interleukin-1 beta inhibitor.
march01,2013
First biologic drug approved for condition in Europe
The European Commission (EC) cleared llaris (canakizumab) for the treatment of adult patients who have suffered at least three gouty arthritis attacks in the previous 12 months, but who are unsuitable for treatment with non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine or repeated courses of corticosteroids.
Gouty arthritis – commonly known as gout – is an “excruciating condition”, according to Novartis division head David Epstein, who noted that Ilaris offers new hope to patients who do not currently have treatment options.
Data from two phase III trials of Ilaris in acute gouty arthritis attacks showed that patients treated with the drug experienced significantly greater pain relief compared to the injectable steroid triamcinolone acetonide, while most adverse events were mild to moderate in severity.
The most frequent side effects were infections, and particularly upper respiratory tract infections and nasopharyngitis.
Ilaris was launched in the US and EU in 2009 as a treatment for an auto-inflammatory condition called cryopyrin-associated periodic syndrome (CAPS). The rarity of that condition has meant sales have been relatively small, coming in at $72m last year, albeit a 56 per cent gain over 2011.
Gouty arthritis is a much bigger market for the drug and, along with a juvenile arthritis indication Novartis is pursuing, could push Ilaris towards blockbuster status with sales in excess of $1bn a year.
“Our vision is to realise the potential of Ilaris wherever IL-1 beta plays a key role and available treatment options don’t give patients the help they need,” said Epstein.
EU approval comes after the US FDA knocked back Ilaris for gouty arthritis, saying in 2011 that Novartis needed to provide more data on the drug’s risk-benefit profile, specifically its potential to leave patients vulnerable to infections.
Gout has been a tricky indication for drug developers to crack, with the FDA turning down another CAPS treatment – Regeneron’s IL-1 inhibitor Arcalyst (rilonacept) – in 2012 on the grounds of inadequate safety data and concern about a risk of malignancy.
One success came in 2010 when Savient secured approval for its Krystexxa (pegloticase) drug as a second-line treatment after oral xanthine oxidase inhibitors in patients with severe debilitating chronic tophaceous gout.
However, the drug has failed to make significant inroads because of a high price and tendency to stimulate neutralising antibodies that limit its therapeutic effect, according to Decision Resources.
There is still a great demand for safer and more effective therapies with the phase III pipeline featuring another potential blockbuster in the form of AstraZeneca/Ardea Biosciences URAT1 inhibitor lesinurad.
Canakinumab (INN, trade name Ilaris, previously ACZ885)[1] is a human monoclonal antibody targeted at interleukin-1 beta. It has no cross-reactivity with other members of the interleukin-1 family, including interleukin-1 alpha.[2]
Canakinumab was approved for the treatment of cryopyrin-associated periodic syndromes (CAPS) by the US FDA on June 2009[3] and by the European Medicines Agency in October 2009.[4] CAPS is a spectrum of autoinflammatory syndromes including familial cold autoinflammatory syndrome, Muckle–Wells syndrome, and neonatal-onset multisystem inflammatory disease.
Canakinumab was being developed by Novartis for the treatment of rheumatoid arthritis but this trial has been discontinued.[5] Canakinumab is also in phase I clinical trials as a possible treatment for chronic obstructive pulmonary disease.[6]
References
- Dhimolea, Eugen (2010). “Canakinumab”. MAbs 2 (1): 3–13. doi:10.4161/mabs.2.1.10328. PMC 2828573. PMID 20065636.
- Lachmann, HJ; Kone-Paut I, Kuemmerle-Deschner JB et al. (4 June 2009). “Use of canakinumab in the cryopyrin-associated periodic syndrome”. New Engl J Med 360 (23): 2416–25. doi:10.1056/NEJMoa0810787. PMID 19494217.
- “New biological therapy Ilaris approved in US to treat children and adults with CAPS, a serious life-long auto-inflammatory disease” (Press release). Novartis. 18 June 2009. Retrieved 28 July 2009.
- Wan, Yuet (29 October 2009). “Canakinumab (Ilaris) and rilonacept (Arcalyst) approved in EU for treatment of cryopyrin-associated periodic syndrome”. National electronic Library for Medicines. Retrieved 14 April 2010.
- “clinicaltrials.gov, Identifier NCT00784628: Safety, Tolerability and Efficacy of ACZ885 (Canakinumab) in Patients With Active Rheumatoid Arthritis”. Retrieved 2010-08-21.
- Yasothan U, Kar S (2008). “Therapies for COPD”. Nat Rev Drug Discov 7 (4): 285. doi:10.1038/nrd2533.
Monoclonal Antibody Therapeutic Uses
Sanofi Pasteur has received a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) recommending market approval for Sanofi Pasteur’s 6-in-1 pediatric vaccine Hexyon/Hexacima (DTaP-IPV-Hib-HepB vaccine).
FEB22,2013
French drug major Sanofi’s vaccines subsidiary Sanofi Pasteur has received a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) recommending market approval for Sanofi Pasteur’s 6-in-1 pediatric vaccine Hexyon/Hexacima (DTaP-IPV-Hib-HepB vaccine).
Hexyon/Hexacima is the only fully liquid, ready-to-use, 6-in-1 vaccine to protect infants against diphtheria, tetanus, pertussis (whooping cough), Hepatitis B, poliomyelitis and invasive infections caused by Haemophilus influenzae type b.
The new vaccine will be commercialized under the brand name Hexyon in Western European countries by Sanofi Pasteur MSD, the joint venture between US pharma giant Merck & Co and Sanofi Pasteur, and under the brand name Hexacima in Eastern European countries by Sanofi Pasteur.
“Availability of Hexyon/Hexacima ready-to-use, 6-in-1 pediatric vaccine will raise the standard of care of vaccination for millions of children. It reduces the number of vaccination visits for infants and it is more convenient for parents to complete the recommended vaccination schedule and thus better protect their children against six major childhood diseases,” said Olivier Charmeil, president and chief executive of Sanofi Pasteur, adding: “Upon licensure, we intend to introduce Hexyon/Hexacima vaccine in countries that are looking for improved and effective solutions for public immunization programs.”
Key benefits of Hexyon/Hexacima vaccine
According to Sanofi, the key benefits of Hexyon/Hexacima include the following:
• Hexyon/Hexacima is a fully liquid, ready-to-use vaccine; no reconstitution is needed prior to administration, which improves convenience for health care professionals. It is available in vial and pre-filled syringe presentations;
• by combining six vaccines into one, the vaccine reduces the number of injections, which improves comfort and vaccination compliance for infants, and
• the use of acP (acellular pertussis) antigens and IPV (inactivated poliovirus vaccine) improves safety and reduces reactogenicity as compared to wcP (whole cell pertussis)-containing vaccines and OPV (oral polio vaccine).
Assuming licensure, Hexyon/Hexacima would be indicated for primary and booster vaccination of infants from six weeks of age in accordance with official recommendations. The CHMP positive opinion is supported by results of multi-center clinical studies involving around 5,000 infants. Phase III clinical studies comparing Hexyon/Hexacima to licensed combination vaccines demonstrated that the vaccine is safe and induces a robust immune response against all six targeted diseases.
New Drug Approvals 
