Upcoming FDA PDUFA: Auxilium Pharmaceuticals + Biospecifics Technologies - Xiaflex (collagenase clostridium histolyticum) - Peyronie's Disease

Auxilium Pharmaceuticals and Biospecifics Technologies announced a three-month FDA PDUFA date delay since the initial scheduled date of Sept 6, 2013. The next PDUFA date for Xiaflex's supplemental biologics license application (sBLA) for the treatment of Peyronie's disease is December 6, 2013. 

The delay was caused by the company, rather than by the FDA, and is related to changes made by Auxilium in relation to proposed Risk Evaluation and Mitigation Strategy (REMS) program and other aspects related to the proposed label. The changes were classified as a major amendment by the FDA, causing the delay in the scheduled PDUFA date. The FDA has not requested any additional clinical trials or information at this time. 

Date of FDA Decision (PDUFA): December 6, 2013
Company name: Auxilium Pharmaceuticals & Biospecifics Technologies
Stock ticker: AUXL and BSTC
Location: Malvern, Pennsylvania

Type of application: Supplemental BLA – novel indication
Name of drug: Xiaflex (Collagenase clostridium histolyticum)
Indication: Peyronie's Disease

23rd October 2013:

Auxilium Pharma:

Market Cap	$851.28 Mln
52-week range	13.87 – 21.60
Avg. volume	851,374

Q2 2013:

Net Income	$0.22 per share
Cash	$74.6 mln

Biospecifics Technologies:

Market Cap	$116.95 Mln
52-week range	12.52 - 19.99
Avg. volume	24,868

Q1 2013:

Net Income	$0.15 per share
Cash	$12.0 mln

Auxilium is an unmet niche specialist addressing rare and orphan diseases, mainly through biopharmaceuticals.  Auxilium has two products on the market and three currently in clinical development; all products in the Auxilium’s pipeline are for different indications of the same product – Xiaflex (collagenase clostridium histolyticum).

Auxilium Pharmaceuticals: Clinical Pipeline

Note: The Xiaflex Cellulite Study has recently entered phase 2a

Collagenase clostridium histolyticum is an enzyme produced by the bacterium Clostridium histolyticum that dismantles collagen. It is marketed and is being developed as a local injection into areas with overly high collagen accumulation, such as in the case of Dupuytren’s disease (severely clenched fingers) and Peyronie’s disease (penile curvature)—a connective tissue disorder involving the growth of fibrous plaques in the soft tissue of the penis affecting up to 10% of men. According to Auxilium, 65,000 to 120,000 new patients are diagnosed with Peyronie’s disease each year. Peyronie’s disease causes pain, abnormal curvature, erectile dysfunction, indentation, loss of girth and shortening, with no effective treatment to date. Xiaflex has already demonstrated efficacy in treating Peyronie’s disease in clinical trials, and, if approved, will be the first non-surgical treatment for the indication.

In two 400-patient trials Xiaflex was injected into the penile plaque over a period of several months. The company reported in a press release that the treatment yielded a 37.6 reduction in penile curvature in one trial and a 30.5% reduction in the second. The average deformity of the penis at the beginning of the study was 48.8 degrees in men receiving the drug and 49 degrees in those receiving placebo. After 52 weeks, the deformity was only 31 degrees in men receiving Xiaflex and 39 degrees in those receiving placebo. Although the results are not overwhelming, Xiaflex is the only available treatment currently in the pipeline, thus an automatic improvement over what is currently available.

According to the Auxilium company website, "During the course of recent product label discussions, Auxilium submitted revisions regarding the Company's proposed Risk Evaluation and Mitigation Strategy (REMS) program and other aspects related to the proposed label. The FDA determined that this submission qualified as a major amendment filed during the final three months of the review and extended the PDUFA goal date to December 6, 2013. The FDA has not requested that any additional clinical studies be performed prior to the revised PDUFA action date."

Xiaflex was developed by BioSpecifics Technologies, but its clinical trials were carried out by Auxilium. Along with Pfizer Auxilium is also responsible for Xiaflex’s marketing.

Ligand and Pfizer's Aprela (Duavee) approved despite government shutdown, Ligand stock up 10% intraday

The FDA kept its promise on delivering a verdict for Ligand (LGND) and Pfizer's (PFE) Aprela on Oct 3, 2013. The drug was approved despite low expectations.

Aprela (now known as Duavee) is a novel combination drug of Bazedoxifene and Conjugated estrogens (Premarin) for the treatment of moderate-to-severe vasomotor symptoms (VMS) and vulvar and vaginal atrophy (VVA) associated with menopause, as well as the prevention of postmenopausal osteoporosis in non-hysterectomized women.

The drug was approved amidst low hopes and safety speculations. Pfizer has previously struggled with gaining approval of bazedoxifene on its own, having had the drug previously rejected by the FDA. The new combination, however, includes conjugated estrogens isolated from pregnant mares' urine, sold under the name Premarin since 1942 indicated for hormone replacement therapy.

The drug may have a hard time appealing to physicians, particularly as non-hormonal competitors indicated for hot flushes have recently reached the market - OKed Hisamitsu Pharmaceutical's Brisdelle was approved by the FDA in June.

Ligand's stock gained nearly 10% on the news on Oct 3rd.

Government Shutdown May Delay FDA AdCom, PDUFA dates and Stock Catalysts

Advisory committee (Adcom) and Prescription Drug User Fee Act (PDUFA) drug approval dates may face unpredictable delays due to government shortages affecting the FDA. Several drugs are/were scheduled to receive FDA decisions in October 2013 but have so far not heard from the agency on whether their applications are being processed and whether their decision dates have been affected.

On Oct 3, 2013, Ligand Pharma and Pfizer did not hear from the FDA concerning the agency's decision on Aprela/ Duavive (bazedoxifene) for the treatment of moderate-to-severe vasomotor symptoms (VMS) and vulvar and vaginal atrophy (VVA) associated with menopause, as well as the prevention of postmenopausal osteoporosis in non-hysterectomized women. Several more drugs are in the queue for October's PDUFA decisions:

Oct 3	Ligand Pharmaceuticals (LGND); Pfizer (PFE)	Duavive (EU); Aprela	Bazedoxifene/Conjugated estrogens (BZA/CE)	Moderate-to-severe vasomotor symptoms (VMS) and vulvar and vaginal atrophy (VVA) associated with menopause, as well as the prevention of postmenopausal osteoporosis in non-hysterectomized women
Oct 14	Antares Pharma (ATRS)	Otrexup	Methotrexate (combination product for use with Medi-Jet™ technology)	Rheumatoid arthritis (RA), poly-articular-course juvenile RA and moderate to severe psoriasis
Oct 17	Alimera Sciences (ALIM), pSivida Corp (PSVD)	Iluvien	Fluocinolone acetonide intravitreal insert	Diabetic Macular Edema (DME)
Oct 21	Amag Pharmaceuticals (AMAG)	Feraheme (supplemental NDA – new formulation)	Ferumoxytol	Intravenous administration for Iron Deficiency Anemia Patients Who Cannot Take Oral Iron
Dec 18	Theravance (THRX), GlaxoSmithKline (GSK)	Anoro Ellipta	Umeclidinium bromide and vilanterol	Chronic Obstructive Pulmonary Disorder (COPD)
Dec 20	Amarin Corp (AMRN)	Vascepa (supplemental NDA)	Icosapent ethyl	Cardiovascular disease – triglyceride reducer during diet for adult patients with high triglycerides (TG ≥200 mg/dL and < 500 mg/dL) with mixed dyslipidemia

Until the FDA makes specific announcements, the investors are likely to be kept in the dark about October's PDUFA decisions. Delays are also likely to cause bottlenecks in the approval process and may delay the rest of the PDUFA calendar. 

To re-cap: 

Oct 3, 2013: Ligand Pharmaceuticals and Pfizer - Aprela (bazedoxifene and conjugated equine estrogens (Premarin)) - moderate-to-severe vasomotor symptoms (VMS) and vulvar and vaginal atrophy (VVA) associated with menopause, as well as the prevention of postmenopausal osteoporosis in non-hysterectomized women

Ligand is a biopharmaceutical company that develops and acquires assets it believes will generate royalty revenues and produce sustainable profitability. Ligand has a diverse asset portfolio addressing the unmet medical needs of patients for a broad spectrum of diseases including thrombocytopenia, multiple myeloma, diabetes, hepatitis, muscle wasting, dyslipidemia, anemia, and osteoporosis. Ligand has established multiple alliances with the world's leading pharmaceutical companies including GlaxoSmithKline, Merck, Pfizer, Eli Lilly & Company, Baxter International, Bristol-Myers Squibb, Celgene, Onyx Pharmaceuticals, Lundbeck Inc., and The Medicines Company, among others.

As a result of a series of successful licensing agreements, Ligand’s total revenue more than doubled in recent years, with royalties up 90% on higher sales of GlaxoSmithKline’s Promacta® and a contribution from Onyx Pharmaceuticals’ Kyprolis™, plus increases of 131% and 125% in sales and licensing revenues of Ligand’s proprietary patented drug delivery technology Captisol.

Aprela is a drug which combines Pfizer’s as-of-yet-unapproved drug Viviant (bazedoxifene), initially developed by Ligand and Wyeth (now Pfizer) in 1994 and Premarin, Pfizer’s conjugated estrogen compound. Bazedoxifene is a selective estrogen receptor modulator, which is a compound able to selectively act on estrogen receptors throughout the body. Aprela belongs to the novel class of tissue-selective estrogen complexes (TSECs), which pair SERM with conjugated estrogen (Premarin). So far, the combination drug has demonstrated positive efficacy and safety results in a series of Phase III clinical trials involving approximately 7,500 women.

The FDA accepted an NDA from Pfizer and Ligand in December 2012. The agency will deliver its verdict on Oct 3, 2013, but complications are expected, in light of the fact that bazedoxifene has been encountering obstacles with FDA approval since 2007.

  

Oct 14, 2013: – Antares pharma - Otrexup (Methotrexate - combination product for use with Medi-Jet™ self-injection technology)- Rheumatoid arthritis (RA), poly-articular-course juvenile RA and moderate to severe psoriasis

Antares Pharma is a developer of parenteral technologies, specializing in self-injectable drug delivery. Among the company’s proprietary products are Jet-injectors, Auto-injectors and Pen injectors which can be used with a wide array of oral and injectable medications. Among the companies to which Antares has licensed its technologies are Pfizer, Teva and Jazz Pharmaceuticals. Teva is Antares’s largest source of revenue, having licensed three technologies from the company.

Although Antares normally engages in risk-diluting partnerships with Big Pharma, it is developing Otrexup (methotrexate) on its own. Methotrexate is a rheumatoid arthritis (RA) drug used in 70% of 1.3 million RA cases in the US. Commonly, the drug is taken orally, but complications exist with this mode of delivery, namely poor absorption and gastrointestinal side effects.  A self-injectable formulation of methotrexate would lower the necessary dosage of the drug, and reduce side effects. In clinical studies, Antares found that 98% of patients found the self-injectable system easy to use. In addition to RA, the company intends to market Otrexup for moderate to severe psoriasis, an autoimmune skin pigmentation disorder, for which methotrexane is also commonly prescribed. The global psoriasis market was worth US$ 3.9 billion in 2010.

Oct 17, 2013: Alimera Sciences (ALIM) + Psivida Corp (PSVD) Iluvien (Fluocinolone acetonide intravitreal insert) - Diabetic Macular Edema (DME)

Alimera Sciences specializes in the research, development and commercialization of prescription ophthalmic pharmaceuticals. The company’s main focus is on diseases affecting the retina. pSivida corp specializes in developing sustained-release drug delivery systems and licensing them out. Iluvien is currently licensed out by pSivida to Alimera.

Iluvien (fluocinolone acetodine (FAc)) is a sustained-release eye implant which delivers a corticosteroid (anti-inflammatory agent) to the eye for up to 36 months. Iluvien is indicated for Diabetic Macular Edema (DME) – a diabetes-related disorder characterized by fluid and protein deposits on or under the macula of the eye (a yellow central area of the retina), causing it to thicken and swell (edema). The swelling may distort a person's central vision. Alimera has conducted two Phase 3 pivotal clinical trials (collectively known as the FAME Study) for Iluvien involving 956 patients in sites across the United States, Canada, Europe and India to assess the efficacy and safety of Iluvien with two doses, a high and low dose, in the treatment of diabetic macular edema. 

Although Alimera already obtained marketing approval of Iluvien in Austria, France, Germany, Portugal, Spain and the United Kingdom, and is going through the national phase in the approval process in Italy, the FDA has so far refused to grant Iluvien marketing approval, stating that “the NDA did not provide sufficient data to support that Iluvien is safe and effective in the treatment of patients with DME. The FDA stated that the risks of adverse reactions shown for Iluvien in the FAME® Study were significant and were not offset by the benefits demonstrated by Iluvien in these clinical trials. The FDA stated that Alimera will need to conduct two additional clinical trials to demonstrate that the product is safe and effective for the proposed indication.”[i]

The third PDUFA date for Iluvien is anticipated on Oct. 17^th, 2013.

Upcoming FDA PDUFA: Oct 14 2013 - Antares Pharma - Otrexup for Rheumatoid arthritis (RA), poly-articular-course juvenile RA and moderate to severe psoriasis

Antares Pharma (ATRS) is awaiting an FDA approval decision on Oct 14 2013 for Otrexup (Methotrexate - combination product for use with Medi-Jet™ self-injection technology) for the treatment of Rheumatoid arthritis (RA), poly-articular-course juvenile RA and moderate to severe psoriasis. 

Date of FDA Decision (PDUFA): October 3, 2013

Company name: Antares Pharma

Stock ticker: (ATRS)

Location: Ewing, NJ

Type of application: First Submission; combination of previously approved drug with novel self-injection technology

Indication: Rheumatoid arthritis (RA), poly-articular-course juvenile RA and moderate to severe psoriasis

01 Oct 2013:

Market Cap	$516.26 Mln
52-week range	3.35 – 4.67
Avg. volume	926,105

Q2 2013:

Net loss	$0.02 per share
Cash	$75.0 mln

Antares Pharma is a developer of parenteral technologies, specializing in self-injectable drug delivery. Among the company’s proprietary products are Jet-injectors, Auto-injectors and Pen injectors which can be used with a wide array of oral and injectable medications. Among the companies to which Antares has licensed its technologies are Pfizer, Teva and Jazz Pharmaceuticals. Teva is Antares’s largest source of revenue, having licensed three technologies from the company.

Although Antares normally engages in risk-diluting partnerships with Big Pharma, it is developing Otrexup (methotrexate) on its own. Methotrexate is a rheumatoid arthritis (RA) drug used in 70% of 1.3 million RA cases in the US. Commonly, the drug is taken orally, but complications exist with this mode of delivery, namely poor absorption and gastrointestinal side effects.  A self-injectable formulation of methotrexate would lower the necessary dosage of the drug, and reduce side effects. In clinical studies, Antares found that 98% of patients found the self-injectable system easy to use. In addition to RA, the company intends to market Otrexup for moderate to severe psoriasis, an autoimmune skin pigmentation disorder, for which methotrexane is also commonly prescribed. The global psoriasis market was worth US$ 3.9 billion in 2010.

Upcoming FDA PDUFA: Oct 3 2013 - Ligand Pharmaceuticals and Pfizer - Aprela (Duavive) for menopause

Ligand Pharmaceuticals (LGND) and Pfizer (PFE) are awaiting an FDA drug approval decision for Aprela - a novel combination drug of Bazedoxifene and Conjugated estrogens (Premarin) for the treatment of moderate-to-severe vasomotor symptoms (VMS) and vulvar and vaginal atrophy (VVA) associated with menopause, as well as the prevention of postmenopausal osteoporosis in non-hysterectomized women.

Date of FDA Decision (PDUFA): October 3, 2013
Company name: Ligand Pharmaceuticals and Pfizer
Stock ticker: LGND and PFE
Location: La Jolla, CA

Type of application: First NDA Submission; combination of an approved and an un-approved drug
Name of drug: Aprela

Indication: moderate-to-severe vasomotor symptoms (VMS) and vulvar and vaginal atrophy (VVA) associated with menopause, as well as the prevention of postmenopausal osteoporosis in non-hysterectomized women 

Ligand Pharmaceuticals: 01 Oct 2013

Market Cap	$884.64 Mln
52-week range	14.75 – 50.85
Avg. volume	262,502

Q1 2013:

Net Income	$0.30 per share
Cash	$10.1 mln

Ligand is a biopharmaceutical company that develops and acquires assets it believes will generate royalty revenues and produce sustainable profitability. Ligand has a diverse asset portfolio addressing the unmet medical needs of patients for a broad spectrum of diseases including thrombocytopenia, multiple myeloma, diabetes, hepatitis, muscle wasting, dyslipidemia, anemia, and osteoporosis. Ligand has established multiple alliances with the world's leading pharmaceutical companies including GlaxoSmithKline, Merck, Pfizer, Eli Lilly & Company, Baxter International, Bristol-Myers Squibb, Celgene, Onyx Pharmaceuticals, Lundbeck Inc., and The Medicines Company, among others.

As a result of a series of successful licensing agreements, Ligand’s total revenue more than doubled in recent years, with royalties up 90% on higher sales of GlaxoSmithKline’s Promacta® and a contribution from Onyx Pharmaceuticals’ Kyprolis™, plus increases of 131% and 125% in sales and licensing revenues of Ligand’s proprietary patented drug delivery technology Captisol.

Aprela is a drug which combines Pfizer’s as-of-yet-unapproved drug Viviant (bazedoxifene), initially developed by Ligand and Wyeth (now Pfizer) in 1994 and Premarin, Pfizer’s conjugated estrogen compound. Bazedoxifene is a selective estrogen receptor modulator, which is a compound able to selectively act on estrogen receptors throughout the body. Aprela belongs to the novel class of tissue-selective estrogen complexes (TSECs), which pair SERM with conjugated estrogen (Premarin). So far, the combination drug has demonstrated positive efficacy and safety results in a series of Phase III clinical trials involving approximately 7,500 women.

The FDA accepted an NDA from Pfizer and Ligand in December 2012. The agency will deliver its verdict on Oct 3, 2013, but complications are expected, in light of the fact that bazedoxifene has been encountering obstacles with FDA approval since 2007. 

Click here for a free report on the upcoming PDUFA stock catalysts in 2013.

FDA Calendar Events to Watch if you are a Biotech Stock Investor

We at Bioassociate have followed stock prices of public life science companies for some time, particularly stock behavior around notable events such as Investigational New Drug (IND) applications, New Drug Application (NDA), Biologics License Application (BLA), FDA Advisory Committee Meetings (AdCom) and Prescription Drug User Fee Act (PDUFA) dates. Below is a brief description of each of these events: 

• Investigational New Drug (IND): An IND application is the first step companies normally take in order to commence clinical trials of a compound. In essence, IND is the means by which a pharmaceutical company obtains permission to ship an experimental drug across state lines (usually to clinical investigators). Based on preclinical data, the FDA reviews the IND application for safety to assure that research subjects will not be subjected to unreasonable risk. If the application is cleared, the candidate drug usually enters a Phase 1 clinical trial.

• New Drug Application (NDA): An NDA is an application to market the drug. It is normally (with exceptions) filed with the FDA after all phases of the clinical trials have been completed and all data collected. Once the application is submitted, the FDA has 60 days to conduct a preliminary review which will assess whether the NDA is "sufficiently complete to permit a substantive review". If the NDA is found to be insufficiently complete (and reasons for this can vary from a simple administrative mistake in the application to a requirement to reconduct much of the testing), then the FDA rejects the application with the issue of a Refuse to File letter which is sent to the applicant explaining where the application has failed to meet requirements. If the NDA is complete, the FDA will accept the application and set a PDUFA (see below) date on which it will deliver its verdict.

• Supplemental NDA (sNDA): An application submitted for an already approved compound for any changes in packaging, labeling, dosages, ingredients or new indications

• Biologics License Application (BLA): A BLA is the equivalent of the NDA for biological drugs.

• Supplemental BLA (sBLA): An application submitted for an already approved biological drug for any changes in packaging, labeling, dosages, ingredients or new indications

• Advisory Committee Meeting (AdCom): An FDA Advisory Committee is a committee comprised of researchers and experts who lend their opinion to the FDA on key issues relating to new drug approvals. AdCom meetings are very common for first-time NDA applications, and are normally scheduled in the months running up to the FDA scheduled approval decision date. For supplemental applications, or for drugs which are re-submitting previously refused NDAs, AdCom meetings are uncommon. AdComs generate a lot of hype in the bio-investment world as they often foreshadow the FDA’s decision on new drugs. Although the FDA needn’t take AdCom advise, statistically the agency does follow the committee’s opinion, particularly if negative issues are raised during the meetings. Opportunity investors often closely follow live AdCom meetings, as they can momentarily influence a stock.

• Prescription Drug Free User Act (PDUFA): PDUFA is the date by which the FDA aims to deliver its marketing verdict for an NDA or BLA, following which the applicant may be granted or refused marketing approval, or requested to provide additional documentation and/or conduct further studies.

Of all the events on the FDA calendar, the PDUFA date arguably carries the most momentum, as it can signify the birth or death of a new medicine. PDUFA dates are also particularly relevant for biotech stock observers, as most life science companies will have had an IPO by the time their product is near to the marketing stage. To a pharma and biotech investor, an FDA marketing decision can potentially crash or soar a stock. PDUFA dates normally carry a significant stock run-up up to the date, and PDUFA-related intraday surges of up to 300% are not unheard of, which should be incentive enough to closely follow, and understand, the FDA calendar.

Upcoming FDA PDUFA: Delcath Systems - Melblez (melphalan) - Unresectable ocular melanoma metastatic to the liver

Delcath Systems is awaiting an FDA drug approval decision on Sept 13, 2013 for an application of a new drug as part of a two-component drug-device system - the Delcath Hepatic Delivery System

Date of FDA Decision (PDUFA): September 13, 2013
Company name: Delcath Systems
Stock ticker: DCTH
Location: Queensbury, NY

Type of application: first NDA
Name of drug: Melblez for Delcath Hepatic Delivery System
Indication: Unresectable ocular melanoma metastatic to the liver

24^th July 2013:

Market Cap	$34.77 Mln
52-week range	0.35 – 2.38
Avg. volume	2,367,750

Q1 2013:

Net Loss	$0.15 per share
Cash	$42.8 mln

Delcath Systems, Inc. is a specialty pharmaceutical and medical device company focused on oncology. The company’s lead product is a drug/device combination Delcath Hepatic Delivery System, designed to administer high dose chemotherapy and other therapeutic agents to diseased organs or regions of the body, while controlling the systemic (rest of body) exposure of those agents. The company's initial focus is on the treatment of primary and metastatic liver cancers. 

Melblez, the compound awaiting an FDA decision on September 13, is the drug component of the two-component Hepatic Delivery System. On May 2^nd, 2013, Delcath’s stock plunged when the FDA Oncologic Drugs Advisory Committee (ODAC) voted 16 to 0 with no abstentions that benefits of treatment with Delcath's Melblez Kit for the treatment of patients with unresectable ocular melanoma metastatic to the liver do not outweigh the risks associated with the procedure. 

The FDA has yet to deliver a decision on September 13, 2013. 

Click here for a free report on the upcoming PDUFA stock catalysts in 2013.