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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Generic approval FDA- Travatan ZTravoprost Ophthalmic Solution/Drops 0.004% – Par Pharmaceutical, Inc.
Travoprost is a synthetic prostaglandin F analogue.
Its chemical name is [1R-[lα(Z),2β(lE,3R*),3α,5α]]-7-[3,5-Dihydroxy-2-[3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1 -butenyl]cyclopentyl]-5-heptenoic acid, 1 -methylethylester.
It has a molecular formula of C26H35F3O6 and a molecular weight of 500.55.
The chemical structure of travoprost is:
Travoprost is a clear, colorless to slightly yellow oil that is very soluble in acetonitrile, methanol, octanol, and chloroform. It is practically insoluble in water.
TRAVATAN® (travoprost ophthalmic solution) 0.004% is supplied as sterile, buffered aqueous solution of travoprost with a pH of approximately 6.0 and an osmolality of approximately 290 mOsmol/kg.
TRAVATAN® contains Active: travoprost 0.04 mg/mL; Preservative: benzalkonium chloride 0.15 mg/mL; Inactives: polyoxyl 40 hydrogenated castor oil, tromethamine, boric acid, mannitol, edetate disodium, sodium hydroxide and/or hydrochloric acid (to adjust pH) and purified water.
GENERIC APPROVAL MARCH 2013
- Travoprost Ophthalmic Solution/Drops 0.004%
Approved: March 1, 2013 – Par Pharmaceutical, Inc.
Generic for: Travatan Z
Travoprost ophthalmic solution is a topical medication used for controlling the progression of glaucoma or ocular hypertension, by reducing intraocular pressure. It is a synthetic prostaglandin analog (or more specifically, an analog of prostaglandin F2α)[1][2] that works by increasing the outflow of aqueous fluid from the eyes.[3] It is also known by the brand names of Travatan and Travatan Z, manufactured by Alcon, and Travo-Z, manufactured by Micro Labs.
- Alcon Laboratories, Inc. (September 2011). “TRAVATAN – travoprost solution”. DailyMed. Bethesda, MD: U.S. National Library of Medicine. Retrieved 2011-09-30.
- Alcon Laboratories, Inc. (September 2011). “TRAVATAN Z (travoprost) solution”. DailyMed. Bethesda, MD: U.S. National Library of Medicine. Retrieved 2011-09-30.
- AHFS Consumer Medication Information (2011-01-01).“Travoprost Ophthalmic”. MedlinePlus. Bethesda, MD: U.S. National Library of Medicine. Retrieved 2011-09-30.
NDA –Sefelsa (gabapentin) Extended Release Tablets – formerly Serada
GABAPENTIN
Sefelsa (gabapentin) Extended Release Tablets – formerly Serada
Company: Depomed, Inc.
Treatment for: Menopausal Hot Flashes
Sefelsa (gabapentin) is an investigational extended-release formulation of gabapentin in development for the treatment of menopausal hot flashes.
- Depomed Provides Update on Sefelsa FDA Advisory Committee – March 4, 2013
- Depomed Announces Serada NDA Acceptance and FDA Advisory Committee Meeting – October 15, 2012
- Depomed Announces Submission Of Serada NDA – August 17, 2012
- Depomed Announces Intent to File NDA for Serada for Treatment of Menopausal Hot Flashes – April 18, 2012
NEWARK, Calif., March 4, 2013
Depomed, Inc., a specialty pharmaceutical company, announced today that the Reproductive Health Drugs Advisory Committee (RHDAC) of the U.S. Food and Drug Administration (FDA) voted 2-12 against approval for Sefelsa, Depomed’s investigational, oral, twice daily formulation of gabapentin, to treat moderate to severe vasomotor symptoms due to menopause. Sefelsa is the proposed trade name for the medication and was formerly referred to as Serada. Based on the outcome of committee meeting, the company will not have a conference call today as previously indicated.
“Depomed today is a product-focused, growth-oriented specialty pharmaceutical company with a growing franchise of treatments for pain and potentially other CNS indications. With revenues from two marketed products, Gralise and Zipsor, significant royalty income from our partnered products and technology, a strong balance sheet and potential to turn cash flow positive in the second half of this year, we believe that 2013 has the potential to be a landmark year in our company’s history,” said Jim Schoeneck, President and Chief Executive Officer of Depomed. “We recognize and appreciate the concerns that were raised by the members of the Advisory Committee. Based on today’s meeting we believe the hurdles for approval of a non-hormonal treatment for hot flashes remain high. Until we believe there is a positive direction for Sefelsa, we will cease all spending relating to the product candidate.”
Data presented at today’s Advisory Committee Meeting included results from the Phase 3 clinical program, which enrolled 1706 patients in three studies.
The FDA will consider the Advisory Committee recommendation in its review of the New Drug Application (NDA) for Sefelsa that Depomed submitted on July 31, 2012, though the FDA is not bound to follow it. The Prescription Drug User Fee Act (PDUFA) date for Sefelsa is May 31, 2013. The PDUFA date is the goal date for the FDA to complete its review of the NDA.
About Vasomotor Symptoms
Vasomotor symptoms include hot flashes and night sweats. A hot flash is a sudden flushing and sensation of heat caused by dilation of skin capillaries. Currently, the leading prescription drug product for the treatment of hot flashes associated with menopause is hormone replacement therapy (HRT). HRT involves the administration of the hormone estrogen, either alone or in combination with the hormone progestin.
About Depomed
Depomed, Inc. is a specialty pharmaceutical company with three approved and marketed products. Gralise® (gabapentin) is a once-daily treatment approved for the management of postherpetic neuralgia (PHN). Zipsor® (diclofenac potassium) Liquid Filled Capsules is a non-steroidal anti-inflammatory drug (NSAID) indicated for relief of mild to moderate acute pain in adults. Glumetza® (metformin hydrochloride extended release tablets) is approved for use in adults with type 2 diabetes and is commercialized by Santarus, Inc. in the United States. Depomed formulates its products and product candidates with its proven, proprietary Acuform® drug delivery technology, which is designed to improve existing oral medications, allowing for extended release of medications to the upper gastrointestinal tract when dosed with food. Additional information about Depomed may be found on its website, www.depomed.com.
Gabapentin (Neurontin) is a pharmaceutical drug, specifically a GABA analog. It was originally developed for the treatment of epilepsy, and currently is also used to relieve neuropathic pain. There are, however, concerns regarding the quality of the trials conducted for a number of conditions.[1]
Web Site: http://www.depomed.com
- Vedula, SS; Bero L; Scherer RW; Dickersin K (November 2009). “Outcome reporting in industry-sponsored trials of gabapentin for off-label use”. The New England Journal of Medicine 361 (20): 1963–71. doi:10.1056/NEJMsa0906126. PMID 19907043.
- “Gabapentin”. The American Society of Health-System Pharmacists. http://www.drugs.com/monograph/gabapentin.html. Retrieved 3 April 2011.
- Vedula, SS; Bero L; Scherer RW; Dickersin K (November 2009). “Outcome reporting in industry-sponsored trials of gabapentin for off-label use”. The New England Journal of Medicine 361 (20): 1963–71. doi:10.1056/NEJMsa0906126. PMID 19907043.
- Moore, RA; Wiffen PJ; Derry S; McQuay HJ (2011-03-16). Moore, R Andrew. ed. “Gabapentin for chronic neuropathic pain and fibromyalgia in adults”. Cochrane database of systematic reviews (Online) (3): CD007938. doi:10.1002/14651858.CD007938.pub2. PMID 21412914.
- Ho, KY; Gan TJ; Habib AS (2006-12-15). “Gabapentin and postoperative pain–a systematic review of randomized controlled trials”. Pain 126 (1–3): 91–101. doi:10.1016/j.pain.2006.06.018. PMID 16846695.
Phase III Study of Teva’s Milprosa (Progesterone) Vaginal Ring Published in Fertility and Sterility
Progesterone
Data Demonstrated Once-Weekly Milprosa™ Provides Similar Pregnancy Rates to Daily 8 Percent Progesterone Vaginal Gel
Mar 4, 2013 –
Teva Pharmaceutical Industries Ltd. today announced the publication of results of the Phase III clinical trial of Milprosa™ (progesterone) vaginal ring in Fertility and Sterility. The study compared the efficacy and safety of once-weekly Milprosa™ to daily 8 percent progesterone vaginal gel for luteal phase support in in vitro fertilization (IVF) and found that clinical pregnancy rates per retrieval at eight and 12 weeks were comparable between patient groups. Adverse event (AE) profiles were similar between the two treatment groups and consistent with known AEs associated with progesterone.
“The study results demonstrate that Milprosa™ may be an effective and safe option for progesterone supplementation during the luteal phase among women undergoing IVF,” said Laurel Stadtmauer, M.D., Ph.D., professor of Obstetrics and Gynecology at Jones Institute for Reproductive Medicine at Eastern Virginia Medical School and study author. “Since normal luteal function may be compromised among women undergoing IVF, progesterone supplementation is essential and the more options patients have, the better. If approved, the once-weekly dosing of Milprosa™ may offer convenience for patients.”
The Phase III randomized, single-blinded, multicenter, noninferiority study was conducted at 22 clinical sites in the U.S. and included 1,297 patients between the ages of 18 and 42. Of enrolled patients, 646 were randomized to Milprosa™ and 651 to the 8 percent progesterone vaginal gel.
“The Fertility and Sterility publication of the Milprosa™ Phase III data is a significant milestone for Teva, especially because fertility is a meaningful new area of specialization for the company and one in which significant unmet need exists,” said Jill DeSimone, senior vice president & general manager, Global Teva Women’s Health. “We look forward to continuing to share important updates about Milprosa™ and demonstrating our investment in and commitment to women’s health.”
About the Study
The Phase III study randomized patients into two treatment groups: one group received once-weekly Milprosa™ and the other received daily 8 percent progesterone vaginal gel. Milprosa™ and the vaginal gel were initiated on the day following egg retrieval and continued through 12 weeks’ gestation. Efficacy was evaluated by comparing clinical pregnancy rates of patients at eight and 12 weeks gestation.
- At week eight, clinical pregnancy rates per retrieval were 48.0 percent for the Milprosa™ group and 47.2 percent for the vaginal gel group (between-group difference, 0.8%; 95% CI, -4.6%, 6.3%).
- At week 12, clinical pregnancy rates per retrieval for Milprosa™ and the vaginal gel were 46.4 percent and 45.2 percent respectively (between-group difference, 1.3%; 95% CI, -4.1%, 6.7%).
A secondary efficacy endpoint was the rate of live birth.
- The overall live birth rate per retrieval for women using Milprosa™ was 45.2 percent; among women using the vaginal gel, the rate was 43.3 percent.
- The majority of patients pregnant at week 12, when progesterone treatment ended, went on to have a live birth: 97.4 percent for the Milprosa™ group and 96.5 percent for the vaginal gel group.
The most commonly reported adverse events (those greater than or equal to 10% in the Milprosa™ treatment group) were nausea, headache, abdominal pain, post-procedural discomfort, abdominal distension, back pain, fatigue, vomiting and constipation. Serious adverse events (SAEs) occurred in approximately 12 percent of all patients, with no significant difference in the rate between treatment groups. The majority of SAEs that occurred were mild to moderate in severity and not related to treatment. Rates of discontinuation of treatment due to AEs were low and similar between both groups (approximately 6%).
About Milprosa™ (Progesterone) Vaginal Ring
Milprosa™ is an investigational, once-weekly progesterone ring inserted in the vagina. It is flexible and designed to continuously release a steady dose of micronized progesterone. Milprosa™ is in development to support embryo transplantation and early pregnancy (up to 10 weeks post-embryo transfer) by supplementation of corpus luteal function as part of an Assisted Reproductive Technology (ART) treatment program for infertile women.
About Supplementation of Corpus Luteal Function
The corpus luteum is a temporary endocrine gland that develops during the luteal phase of a woman’s menstrual cycle. It is an important contributor of progesterone and is critical for the maintenance of early pregnancy. During in vitro fertilization, progesterone supplementation is needed because natural levels of the hormone may be insufficient. This supplementation improves implantation rates and thus pregnancy rates. Additionally, progesterone supplementation supports early pregnancy.
About Teva
Teva Pharmaceutical Industries Ltd. (NYSE: TEVA) is a leading global pharmaceutical company, committed to increasing access to high-quality healthcare by developing, producing and marketing affordable generic drugs as well as innovative and specialty pharmaceuticals and active pharmaceutical ingredients. Headquartered in Israel, Teva is the world’s leading generic drug maker, with a global product portfolio of more than 1,000 molecules and a direct presence in about 60 countries. Teva’s branded businesses focus on CNS, oncology, pain, respiratory and women’s health therapeutic areas as well as biologics. Teva currently employs approximately 46,000 people around the world and reached $20.3 billion in net revenues in 2012.
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.
Dainippon Sumitomo receives approval for Surepost, Repaglinide in combination with biguanides and thiazolidenediones
Repaglinide is an antidiabetic drug in the class of medications known as meglitinides, and was invented in 1983. It is sold by Novo Nordisk under the name of Prandin in theU.S., GlucoNorm in Canada, Surepost in Japan,Repaglinide in Egypt by EIPICO, andNovoNorm elsewhere. In Japan it is produced by Dainippon Sumitomo Pharma.
Repaglinide lowers blood glucose by stimulating the release of insulin from the pancreas. It achieves this by closing ATP-dependent potassium channels in the membrane of the beta cells. This depolarizes the beta cells, opening the cells’ calcium channels, and the resulting calcium influx induces insulin secretion.
Precursor drugs to repaglinide were invented in late 1983 by scientists at Dr Karl Thomae GmbH, a German drug manufacturer located at Biberach an der Riß in southern Germany which was acquired by Boehringer Ingelheim in 1990. The drug that became repaglinide was later licensed by Boehringer to Novo Nordisk, which filed an Investigational New Drugapplication for the compound with the Food and Drug Administration (FDA) in April 1992. Novo Nordisk filed its New Drug Application (NDA) for Prandin in July 1997 and it was quickly approved, gaining FDA approval in December 1997. The drug was the first of the meglitinide class. It was branded Prandin because its quick onset and short duration of action concentrates its effect around meal time (the prandium was the Roman meal which is comparable to the modern lunch).
After several attempts to file for U.S. patent protection, a filing was made in March 1990 which eventually became U.S. Patents 5,216,167 (June 1993), 5,312,924 (May 1994) and 6,143,769 (November 2000). After filing its NDA for repaglinide in 1997, Novo Nordisk applied for patent extension under the Hatch-Waxman Act. This process, called patent term restoration, allows drug patents to be extended based on the time that a drug spent in clinical trials and in the approval process. Previously it had been decided by the U.S. Patent and Trademark Office that the expiration date of U.S. Patents 5,216,167 and 5,312,924 would be 5 September 2006. In February 2001 Prandin’s patent life was extended to 14 March 2009 in response to Novo Nordisk’s patent term restoration application, with U.S. Patent 5,216,167 having been reissued as RE37035.[1]
Prior to the end of repaglinide’s patent term, Novo Nordisk obtained a new patent, U.S. Patent 6,677,358 (January 2004), covering the combination therapy of repaglinide together with the generic anti-diabetic drug metformin. This new patent was due to expire June 2018. In January 2011, a federal court ruled Novo Nordisk’s new patent invalid on the grounds of obviousness, and unenforceable on the grounds of inequitable conduct on the part of Novo Nordisk’s patent attorneys.[2]
- “Details for Patent: RE37035”.
- Frankel, Alison (2011-01-27). “Judge Finds Novo Nordisk Diabetes Drug Patent Invalid and Unenforceable, Questions In-House Patent Lawyer’s Conduct”. Retrieved 2011-02-05.
KYTHERA Biopharmaceuticals, Inc. Announces Positive Interim Results from Open-Label Study of ATX-101 in the Reduction of Unwanted Submental Fat (SMF) or “Double Chin”
http://clinicaltrials.gov/ct2/show/NCT01426373
synthesis………..https://newdrugapprovals.org/2014/07/14/some-thing-for-your-chin-fda-accepts-kytheras-atx-101-new-drug-application/
The drug is sodium deoxycholate for injection, code-named ATX-101 was developed for the treatment of lipomas – benign tumors of subcutaneous adipose tissue, as well as other unwanted fatty growths, such as a double chin. This substance, which is a salt of one of the bile acids, emulsifies fats, destroying their excess deposits
ATX-101 (a first-in-class injectable drug being studied for the reduction of localized fat. ATX-101 is a proprietary formulation of deoxycholate a well-studied endogenous compound that is present in the body), a facial injectable drug for the reduction of unwanted fat under the chin, or submental fat. V. Leroy Young, MD, FACS, presented the initial results at the American Society for Aesthetic Plastic Surgery (ASAPS) 45th Annual Aesthetic Meeting in Vancouver, British Columbia, on May 4, 2012.
In August 2010 Bayer Consumer Care AG signed a licensing and development collaboration agreement with KYTHERA, thereby obtaining commercialization rights to ATX-101 outside the US and Canada. KYTHERA and Bayer are collaborating on the development of ATX-101 in Europe.
KYTHERA Biopharmaceuticals Inc. 02 MAR 3013, announced positive interim results from a Phase IIIb multi-center open-label study (ATX-101-11-26) to evaluate the safety and efficacy of ATX-101 an investigational injectable drug for the reduction of unwanted submental fat (SMF) commonly known as double chin. The results presented at the Late Breaking Research Symposium at the 71st American Academy of Dermatology (AAD) Annual Meeting in Miami Beach Fla. found that ATX-101 is well-tolerated and may be effective in reducing SMF by both clinician and patient reported outcome measures. The ATX-101 global clinical development program has enrolled more than 2500 total patients of which more than 1500 have been treated with ATX-101.
“In my practice patients often request a non-surgical way to treat their submental fat or undesirable double chin” said investigator Susan Weinkle MD FAAD a board certified dermatologist and affiliate clinical professor at the University of South Florida. “For these patients double chin is often resistant to diet and exercise. The results of this study suggest that microinjections of ATX-101 can reduce submental fat without worsening skin laxity.”
ATX-101 is a proprietary synthetically-derived formulation of deoxycholic acid (DCA) a naturally-occurring molecule found in the body that aids in fat metabolism. In this open-label Phase IIIb study interim results three months after the last ATX-101 treatment found:
- Reduction of submental fat
- 87 percent of patients achieved at least a one-grade improvement from baseline on the Clinician-Reported Submental Fat Rating Scale (CR-SMFRS)
- Similarly 83 percent of patients achieved at least a one-grade improvement on the Patient-Reported Submental Fat Rating Scale (PR-SMFRS)
- 96 percent of patients had unchanged or improved skin laxity based on the clinician rated Submental Skin Laxity Grading Scale (SMSLG)
- 95 percent of patients were satisfied with treatment based on the Global Post Treatment Satisfaction Scale
- Adverse events were of mild to moderate intensity transient and primarily associated with the treatment area
Topline results from this study were announced in November 2012. As previously announced 71.3 percent of subjects had at least a one-grade improvement on the CR-SMFRS / PR-SMFRS composite and 14.0 percent had at least a two-grade improvement on the same composite measure.
These results are based on a multicenter 12-month open-label Phase IIIb study conducted at 21 sites across the United States evaluating 165 adults who received injections of ATX-101 for up to six treatments at four-week intervals. Patients received ATX-101 (2 mg/cm2) by subcutaneous microinjections directly into their SMF and were evaluated three months after their last treatment. The study population includes females (77.6 percent) and males (22.4 percent) with a mean age of 47 who report at least moderate SMF and dissatisfaction with the appearance of their chin. All Fitzpatrick Skin Types an industry standard scale to categorize skin tone are represented.
“We are pleased with these ATX-101 study results” said Patricia S. Walker M.D. Ph.D. chief medical officer KYTHERA Biopharmaceuticals Inc. “These results along with efficacy analyses in double-blind placebo-controlled studies support ATX-101 entering the market as potentially the first medical aesthetic drug approved for the reduction of submental fat.”
About ATX-101
ATX-101 is a potential first-in-class injectable drug candidate under clinical investigation for the reduction of unwanted submental fat. ATX-101 is a proprietary formulation of synthetic deoxycholic acid a well-characterized endogenous compound that is present in the body to promote the natural breakdown of dietary fat. ATX-101 is designed to be a locally-injected drug that causes proximal preferential destruction of adipocytes or fat cells with minimal effect on surrounding tissue. Based on clinical trials conducted to date ATX-101 has exhibited significant meaningful and durable results in the reduction of submental fat which commonly presents as an undesirable “double chin.” These results correspond with subject satisfaction measures demonstrating meaningful improvement in perceived chin appearance.
In August 2010 Bayer signed a licensing and collaboration development agreement with KYTHERA thereby obtaining development and commercialization rights to ATX-101 outside of the U.S. and Canada. Bayer recently completed two pivotal Phase III trials of ATX-101 in Europe for the reduction of submental fat. Topline results from these trials were reported in the second quarter of 2012. KYTHERA completed enrollment in its pivotal Phase III clinical program for ATX-101 in more than 1000 subjects randomized to ATX-101 or placebo in 70 centers across the United States and Canada in August 2012. The Company expects to release topline results in mid-2013.
About KYTHERA Biopharmaceuticals Inc.
KYTHERA Biopharmaceuticals Inc. is a clinical-stage biopharmaceutical company focused on the discovery development and commercialization of novel prescription products for the aesthetic medicine market. KYTHERA initiated its pivotal Phase III clinical program for ATX-101 in March 2012 and completed enrollment of more than 1000 patients randomized to ATX-101 or placebo in 70 centers across the U.S. and Canada in August 2012. KYTHERA also maintains an active research interest in hair and fat biology. Find more information at www.kytherabiopharma.com.
Celgene phase 3 – Oral Apremilast Achieves Statistical Significance for the Primary Endpoint of PASI-75 in the First Phase III Study in Patients with Psoriasis
APREMILAST, N-{2-[(1S)-1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide
mar02,2013
Celgene International Sàrl, a subsidiary of Celgene Corporation (NASDAQ: CELG) today presented the results from ESTEEM 1, the Company’s first phase III study in psoriasis, at the American Academy of Dermatology annual meeting in Miami, Florida.
“I see this as a prime candidate for future management of psoriasis that allows us to treat a range of patients, including more moderate cases earlier on”
The company previously announced statistical significance for the primary and major secondary endpoint of PASI-75 at Week 16 and the Static Physician Global Assessment for patients receiving apremilast in the ESTEEM 1&2 phase III studies. ESTEEM 1&2 are the phase III registrational randomized, placebo-controlled studies evaluating the Company’s oral small-molecule inhibitor of phosphodiesterase-4 (PDE4) in patients with moderate-to-severe chronic plaque psoriasis.
ESTEEM 1, presented today, evaluated efficacy and safety in a range of patients. Approximately one-third of the study population was systemic and/or phototherapy treatment-naïve. Nearly 30 percent of the overall study population had prior biologic therapy, which included biologic-failures.
In the ESTEEM 1 study, a significantly higher percentage of apremilast-treated patients demonstrated PASI-75 at week 16 than did placebo patients (33.1% vs. 5.3%; P<0.0001). Significantly higher PASI-75 scores at week 16 were demonstrated across all patient segments enrolled in this study, including systemic-naïve and biologic-naïve patients receiving apremilast 30 mg BID compared with placebo (38.7% vs. 7.6%; P<0.0001 and 35.8% vs. 5.9%; P<0.0001 respectively). Apremilast demonstrated maintenance of effect over time, as measured by the Mean Percent Change from Baseline in PASI score over 32 weeks, with apremilast demonstrating a 54.9% reduction at week 16 and a 61.9% reduction at week 32.
Statistical significance at week 16 was also demonstrated in the major secondary endpoint, Static Physician Global Assessment (sPGA) of clear or almost clear (P<0.0001), and other key secondary endpoints (change in BSA, Pruritus VAS, DLQI), as well as in assessments of difficult to treat areas (nail and scalp psoriasis).
“I see this as a prime candidate for future management of psoriasis that allows us to treat a range of patients, including more moderate cases earlier on,” said Kristian Reich, M.D., SCIderm Research Institute and Dermatologikum Hamburg, Germany.
The overall safety and tolerability profile was consistent with results from previously reported phase III psoriatic arthritis trials. No cases of tuberculosis or lymphoma were observed through week 16, and there was no increased risk of cardiovascular events or serious opportunistic infection. Apremilast was generally well tolerated. The most common adverse events (AEs) greater than placebo were diarrhea, nausea and headache. Greater than 96% of patients in the study reported no AEs or mild to moderate AEs. A similar percentage of patients reported both serious AEs and severe AEs in the apremilast 30 mg BID treatment group compared to placebo (2.1% vs. 2.8% and 3.6% vs. 3.2%, respectively).
An NDA submission to the U.S. Food and Drug Administration, based on the combined ESTEEM 1&2 studies for psoriasis, is expected in the second half of 2013. The Company previously announced it expects to file a separate NDA for psoriatic arthritis in the first quarter of 2013. A combined PsA/psoriasis MAA submission in Europe is also planned for the second half of 2013.
Top-line positive results from the two pivotal, randomized, placebo-controlled phase III studies of apremilast in psoriasis (ESTEEM 1&2) were released in January 2013. The studies included more than 1,200 patients with moderate-to-severe psoriasis and are ongoing. Results from PSOR-005, a phase IIb dose-range study, were recently published in The Lancet (http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60642-4/fulltext).
About ESTEEM 1 & 2
ESTEEM 1 & 2 are two pivotal phase III randomized, placebo-controlled studies evaluating apremilast in subjects with a diagnosis of moderate-to-severe chronic plaque psoriasis for at least 12 months prior to the screening, and at baseline, and who were also candidates for phototherapy and/or systemic therapy. Approximately 1,250 patients were randomized 2:1 to receive either apremilast 30 mg BID or placebo for the first 16 weeks, followed by a maintenance phase from weeks 16-32 in which placebo subjects were switched to apremilast 30 mg BID through week 32, and a randomized withdrawal phase for responders from Week 32-Week 52 based on their initial apremilast randomization and PASI response.
Apremilast, an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4), works intracellularly to modulate a network of pro-inflammatory and anti-inflammatory mediators. PDE4 is a cyclic adenosine monophosphate (cAMP)-specific PDE and the dominant PDE in inflammatory cells (see http://discoverpde4.com/). PDE4 inhibition elevates intracellular cAMP levels, which in turn down-regulates the inflammatory response by modulating the expression of TNF-α, IL-23, and other inflammatory cytokines. Elevation of cAMP also increases anti-inflammatory cytokines such as IL-10. To learn more go to www.discoverpde4.com/.
Top-line positive results from three pivotal randomized, placebo-controlled phase III studies of apremilast in PsA (PALACE 1, 2 & 3) were released in September 2012. PALACE 1 was also presented as an oral presentation at the ACR annual meeting in November 2012. Taken together, the PALACE program comprises the most comprehensive psoriatic arthritis studies to date intended for regulatory submission.
Results from PSA-001, the phase II study of apremilast in psoriatic arthritis, were recently published online in the journal Arthritis & Rheumatism (http://onlinelibrary.wiley.com/doi/10.1002/art.34627/abstract).
A randomized, placebo-controlled phase III study (POSTURE) of apremilast in ankylosing spondylitis (AS) began enrolling patients in April 2012. AS, a debilitating disease, which may cause fusion of the spine, arthritis, inflammation of the eye and damage to the heart, affects approximately 1.5 million people in the U.S. and Europe. The trial will randomize approximately 450 patients to receive 20 mg or 30 mg apremilast BID, or placebo BID.
Psoriasis is an immune-mediated, non-contagious chronic inflammatory skin disorder of unknown cause. The disorder is a chronic recurring condition that varies in severity from minor localized patches to complete body coverage. Plaque psoriasis is the most common type of psoriasis. About 80 percent of people who develop psoriasis have plaque psoriasis, which appears as patches of raised, reddish skin covered by silvery-white scales. These patches, or plaques, frequently form on the elbows, knees, lower back, and scalp. Psoriasis occurs nearly equally in males and females. Recent studies show that there may be an ethnic link. Psoriasis is believed to be most common in Caucasians and slightly less common in other ethnic groups. Worldwide, psoriasis is most common in Scandinavia and other parts of northern Europe. About 10 percent to 30 percent of patients with psoriasis also develop a condition called psoriatic arthritis, which causes pain, stiffness and swelling in and around the joints.
Celgene International Sàrl, located in Boudry, in the Canton of Neuchâtel, Switzerland, is a wholly owned subsidiary and international headquarters of Celgene Corporation. Celgene Corporation, headquartered in Summit, New Jersey, is an integrated global pharmaceutical company engaged primarily in the discovery, development and commercialization of innovative therapies for the treatment of cancer and inflammatory diseases through gene and protein regulation. For more information, please visit the Company’s website at www.celgene.com.
Apremilast is an orally available small molecule inhibitor of PDE4 being developed by Celgene for ankylosing spondylitis, psoriasis, and psoriatic arthritis.[1][2] The drug is currently in phase III trials for the three indications. Apremilast, an anti-inflammatory drug, specifically inhibits phosphodiesterase 4. In general the drug works on an intra-cellular basis to moderate proinflammatory and anti-inflammatory mediator production.
Apremilast is being tested for its efficacy in treating “psoriasis, psoriatic arthritis and other chronic inflammatory diseases such as ankylosing spondylitis, Behcet’s disease, and rheutmatoid arthritis.”
- “Apremilast Palace Program Demonstrates Robust and Consistent Statistically Significant Clinical Benefit Across Three Pivotal Phase III Studies (PALACE-1, 2 & 3) in Psoriatic Arthritis” (Press release). Celgene Corporation. 6 September 2012. Retrieved 2012-09-10.
- “US HOT STOCKS: OCZ, VeriFone, Men’s Wearhouse, AK Steel, Celgene”. The Wall Street Journal. 6 September 2012. Retrieved 2012-09-06
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
Otsuka receives FDA approval for ABILIFY MAINTENA to treat schizophrenia
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| 7-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy}-3,4-dihydroquinolin-2(1H)-one |
aripiprazole
mar 1, 2013
Otsuka Pharmaceutical Co., Ltd. (Otsuka) and H. Lundbeck A/S (Lundbeck) announced the U.S. Food and Drug Administration (FDA) has approved ABILIFY MAINTENA™ (aripiprazole) for extended- release injectable suspension, an intramuscular (IM) depot formulation indicated for the treatment of schizophrenia.
ABILIFY MAINTENA is the first dopamine D2 partial agonist approved as a once- monthly injection. It contributes a new treatment option to address the ongoing need for relapse prevention in patients with schizophrenia – a chronic, debilitating disease.
Efficacy was demonstrated in a 52-week, placebo-controlled, double-blind, randomized-withdrawal, Phase 3 maintenance trial of ABILIFY MAINTENA in patients with schizophrenia. The time to relapse was the primary endpoint. In the trial, ABILIFY MAINTENA>1 In a key secondary endpoint, the percentage of subjects experiencing relapse (i.e., meeting clinical trial criteria for exacerbation of psychotic symptoms/relapse) was also significantly lower with ABILIFY MAINTENA compared to placebo at the end of the study (10% vs. 40%, respectively; p<0.0001). Additional support for efficacy was derived from oral aripiprazole trials.
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. ABILIFY MAINTENA is not approved for the treatment of patients with dementia-related psychosis. ABILIFY MAINTENA is contraindicated in patients with a known hypersensitivity reaction to aripiprazole. Reactions have ranged from pruritus/urticaria to anaphylaxis (see Important Safety Information below).
ABILIFY MAINTENA will be the first commercialized product from the long-term global alliance between Otsuka and Lundbeck to develop CNS medicines worldwide. The companies expect the product will start becoming available in the U.S. on March 18.
Aripiprazolebrand names: Abilify, Aripiprex) is a partial dopamine agonist of the second generation class of atypical antipsychoticswith additional antidepressant properties that is used in the treatment of schizophrenia,bipolar disorder, and clinical depression. It was approved by the U.S. Food and Drug Administration (FDA) for schizophrenia on November 15, 2002 and the European Medicines Agency on 4 June 2004; for acute manic and mixed episodes associated with bipolar disorder on October 1, 2004; as an adjunct for major depressive disorder on November 20, 2007; and to treat irritability in children with autism on 20 November 2009.[1][2] Aripiprazole was developed by Otsuka in Japan, and in the United States,Otsuka America markets it jointly with Bristol-Myers Squibb.
EU OKs Lundbeck’s Selincro, Nalmefene to cut alcoholic urges
Nalmefene
17-cyclopropylmethyl-4,5α-epoxy-6-methylenemorphinan-3,14-diol
march 1 2013
Lundbeck will be celebrating news that European regulators have issued a green light for Selincro, making it the first therapy approved for the reduction of alcohol consumption in dependent adults.
Selincro (nalmefene) is a unique dual-acting opioid system modulator that acts on the brain’s motivational system, which is dysregulated in patients with alcohol dependence.
The once daily pill has been developed to be taken on days when an alcoholic feels at greater risk of having a drink, in a strategy that aims to reduce – rather than stop – alcohol consumption, which some experts believe is a more realistic goal.
Clinical trials of the drug have shown that it can reduce alcohol consumption by approximately 60% after six months treatment, equating to an average reduction of nearly one bottle of wine per day.
In March last year, data was published from two Phase III trials, ESENSE 1 and ESENSE 2, showing that the mean number of heavy drinking days decreased from 19 to 7 days/month and 20 to 7 days/month, while TAC fell from 85 to 43g/day and from 93 to 30g/day at month six. However, the placebo effect was also strong in the studies.
According to Anders Gersel Pedersen, Executive Vice President and Head of Research & Development at Lundbeck, Selincro “represents the first major innovation in the treatment of alcohol dependence in many years,” and he added that its approval “is exciting news for the many patients with alcohol dependence who otherwise may not seek treatment”.
Alcohol dependence is considered a major public health concern, and yet it is both underdiagnosed and undertreated, highlighting the urgent need for better management of the condition.
In Europe, more than 90% of the 14 million patients with alcohol dependence are not receiving treatment, but research suggests that treating just 40% of these would save 11,700 lives each year.
The Danish firm said it expects to launch Selincro in its first markets in mid-2013, and that it will provide the drug as part of “a new treatment concept that includes continuous psychosocial support focused on the reduction of alcohol consumption and treatment adherence”.
Nalmefene (Revex), originally known as nalmetrene, is an opioid receptor antagonistdeveloped in the early 1970s, and used primarily in the management of alcoholdependence, and also has been investigated for the treatment of other addictions such aspathological gambling and addiction to shopping.
Nalmefene is an opiate derivative similar in both structure and activity to the opiate antagonist naltrexone. Advantages of nalmefene relative to naltrexone include longer half-life, greater oral bioavailability and no observed dose-dependent liver toxicity. As with other drugs of this type, nalmefene can precipitate acute withdrawal symptoms in patients who are dependent on opioid drugs, or more rarely when used post-operatively to counteract the effects of strong opioids used in surgery.
Nalmefene differs from naltrexone by substitution of the ketone group at the 6-position of naltrexone with a methylene group (CH2), which considerably increases binding affinity to the μ-opioid receptor. Nalmefene also has high affinity for the other opioid receptors, and is known as a “universal antagonist” for its ability to block all three.
- US patent 3814768, Jack Fishman et al, “6-METHYLENE-6-DESOXY DIHYDRO MORPHINE AND CODEINE DERIVATIVES AND PHARMACEUTICALLY ACCEPTABLE SALTS”, published 1971-11-26, issued 1974-06-04
- Barbara J. Mason, Fernando R. Salvato, Lauren D. Williams, Eva C. Ritvo, Robert B. Cutler (August 1999). “A Double-blind, Placebo-Controlled Study of Oral Nalmefene for Alcohol Dependence”. Arch Gen Psychiatry 56 (8): 719.
- Clinical Trial Of Nalmefene In The Treatment Of Pathological Gambling
- http://www.fda.gov/cder/foi/label/2000/20459S2lbl.pdf
- “Efficacy of Nalmefene in Patients With Alcohol Dependence (ESENSE1)”. “Lundbeck submits Selincro in EU; Novo Nordisk files Degludec in Japan”. thepharmaletter. 22 December 2011.
- Nalmefene Hydrochloride Drug Information, Professional
New Drug Approvals 