FDA Stock Catalysts: Drug Approval Calendar August - December 2013

Following up from Bioassociate’s last white paper covering the upcoming FDA stock catalysts in Q1 2013, we have published a new report covering the upcoming notable events on the FDA calendar in August-December 2013.

Whether it be for an avid investor or for an occasional follower of the pharmaceutical industry, significant FDA events pose some of the greatest interest, and act as some of the most explosive catalysts of change in a company’s share price. For a small biotech located anywhere in the world, a marketing approval granted by the FDA is arguably the most contested prize in the industry.

Bioassociate's latest report covers the current drug approval landscape for 2013, important changes to the FDA regulatory environment, including changes to rare and orphan disease approval pathways, and the introduction of Breakthrough Therapy Designation, followed by descriptions of each of the drugs remaining on the 2013 FDA drug approval calendar.

Below is an introduction: 

In 2013 Biotech has steadily continued to outperform other sectors in the number of deals and IPOs, capital raised and stock performance. Since 2008, deal-making potential in the biotech industry is at its highest level yet, particularly as R&D departments are shrinking and in-licensing departments grow.

It has been raining biotech IPOs in 2013, with already more than twice the 2012 number of biotechs gone public. The 2013 biotech IPO number now stands at 24, with at least 5 more lined up over the rest of the year. As a general rule of thumb, biotechs go public in order to raise funds for the late-stage development or marketing phases of their compounds. It is thus likely that the FDA drug approval calendar will closely follow the sharp rise in IPO activity over the next year.

The NASDAQ biotechnology index, which comprises a multitude of leading biotechs, continues to soar above the other indices (fig. 1), and this is well represented in the abundance of promising compounds in the pipeline.

Figure 1. Stock performance of the NASDAQ Composite Index (Nasd), the Dow Jones Industrial Average (DJIAJT), S&P 500 and the NASDAQ Biotechnology Index (IBB), Jan-Jul 2013

FDA Calendar Events to Watch

Whether for an avid investor or for an occasional follower of the pharmaceutical industry, significant FDA events pose some of the greatest interest, and act as some of the most explosive catalysts of change in a company’s share price. For a small biotech located anywhere in the world, a marketing approval granted by the FDA is arguably the most contested prize in the industry.

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.  This report focuses exclusively on PDUFA dates.

2013 FDA Decisions to Date 

Table 1 is a brief summary of the status of drugs with PDUFA dates in 2013. The dates include new drug applications, as well as supplemental NDAs and BLAs for marketed drugs targeting novel indications or formulations. In the majority of cases, the FDA will either approve the drug for marketing or issue a Complete Response Letter (CRL) to the company, letting the company know that the drug application cannot be approved in its present form, accompanied with reasons for the agency’s decision. It is then up to the drug developers to address the issues raised by the FDA, and to re-submit the application or to abandon the development of the drug.

Table 1. FDA PDUFA outcomes: January-July, 2013

Date	Company (NASDAQ Ticker)	Drug			Indication	FDA Decision
		Brand Name	Generic Name
Jan 2	Salix Pharmaceuticals (SLXP)	Fulyzaq	Crofelemer		Diarrhea associated with anti-HIV drugs such as nucleoside analog reverse transcriptase inhibitors and protease inhibitors	Approval Granted
Jan 14	Santarus (SNTS)	UCERIS	Budesonide (novel formulation)		Induction of remission in patients with active, mild to moderate Ulcerative Colitis –	Approval Granted
Jan 17	NuPathe (PATH)	Zecurit (Zelrix)		Sumatriptan (novel delivery)	Migraine Patch	Approval Granted
Jan 21	Impax Laboratories (IPXL)	Rytary (IPX066)		Carbidopa and Levodopa (extended release)	Idiopathic Parkinson’s Disease (PD)	Complete Response Letter
Jan 23	Hyperion Therapeutics (HPTX)	Ravicti		Glycerol phenylbutyrate	Urea Cycle Disorders	Approval Granted
Jan 29	Isis Pharmaceuticals, (ISIS), Genzyme	KYNAMRO		Mipomersen sodium	Homozygous Familial Hypercholesterolemia	Approval Granted
Feb 2	Hemispherx Pharma (HEB)	Ampligen®		Rintatolimod	Double stranded RNA drug for Chronic Fatigue Syndrome (CFS)	Complete Response Letter
Feb 24	Dynavax Technologies (DVAX)	HEPLISAV		Hepatitis B vaccine	Biologic intended for immunization against infection caused by all known subtypes of hepatitis B virus	Complete Response Letter
Feb 26	ImmunoGen (IMGN) Roche	T-DM1		Trastuzumab emtansine	HER2+ Metastatic Breast Cancer (mBC)	Approval Granted
Mar 1	Zogenix (ZGNX)	Zohydro ER		Hydrocodone bitartrate (extended release)	Moderate to severe chronic pain	Postponed
Mar 25	United Therapeutics (UTHR)	UT-15C		Treprostinil diolamine (oral, sustained release)	Pulmonary arterial hypertension	Complete Response Letter
Mar 27	A.P. Pharma (APPA)	APF530		Granisetron (sustained release)	Acute- and delayed-onset chemotherapy-induced nausea and vomiting (CINV)	Complete Response Letter
Mar 27	Biogen Idec (BIIB)	Tecfidera (BG-12)		Dimethyl fumarate	Multiple Sclerosis	Approval Granted
Apr 16	MAP Pharmaceuticals (now Allergan – AGN)	Levadex		Dihydroergotamine (inhaler)	Migraine	Complete Response Letter
Apr 23	Sucampo Pharma & Takeda (SCMP)	Amitiza		Lubiprostone	Opioid-induced constipation (novel indication)	Approval Granted
Apr 30	Raptor Pharmaceutical Corp (RPTP)	Procysbi		Cysteamine bytartrate	Management of nephropathic cystinosis in children and adults	Approval Granted
Apr 30	Titan Pharmaceuticals (TTNP)(now…	Probuphine		Buprenorphine implant	Treatment of opioid dependence	Complete Response Letter
May 12	Theravance (THRX), GlaxoSmithKline	Breo Ellipta		Fluticasone furoate + vilanterol	Chronic obstructive pulmonary disorder (COPD)	Approval Granted
May 26	Valeant (VRX)			Efinaconazole	Toenail & Fingernail Onychomycosis	Complete Response Letter
May 31	Depomed (DEPO)	Sefelsa		Gabapentin	Non-hormonal treatment for menopause symptoms	Complete Response Letter, development ceased
May 31	Flamel Technologies (FLML)	Bloxiverz		Neostigmine methylsulfate	Reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery	Approval Granted
Jun 5	Celgene (CELGZ)	Revlimid		Lenalidomide	Novel indication:  B-cell chronic lymphocytic leukemia (CLL)	Complete Response Letter, development ceased

FDA approvals Aug-Nov 2013: Overview

12 promising compounds remain to be reviewed by the FDA in the second half of the year (Table 2). Among them are Ligand Pharmaceutials’ Aprela for the treatment of menopause-related disorders, Auxilium Pharmaceuticals’ Peyronie’s disease treatment Xiaflex, and Amarin’s triglyceride buster Vascepa, targeting cardiovascular disease. One of the drug’s on the next quarter’s calendar, Tivopath (by AVEO Pharma) already received a Complete Response Letter from the FDA 1.5 months ahead of time, following a negative AdCom meeting.

Table 2. Scheduled PDUFA dates on the FDA calendar; August-December 2013

Date	Company (NASDAQ Ticker)	Drug		Indication
		Brand Name	Generic Name
Jul 28	AVEO Pharmaceuticals (AVEO)	Tivopath	Tivozanib	Renal Cell Carcinoma – CRL received June 10
Sep 1	Otsuka Pharmaceutical (TYO: 4578)	Samsca (supplemental NDA, fast-track review)	Tolvaptan	Autosomal dominant polycystic kidney disease (ADPKD)
Sep 6	Auxilium Pharmaceuticals (AUXL) - Biospecifics Technologies (BSTC)	Xiaflex (supplemental BLA)	Collagenase clostridium histolyticum	Peyronie’s disease
Sep 13	Delcath Systems (DCTH)	Melblez	Melphalan	To complement Delcath Hepatic Delivery System in the drug/device combination for the treatment of patients with unresectable ocular melanoma metastatic to the liver
Sep 14	Seattle Genetics (SGEN)	Adcetris (supplemental BLA)	Brentuximab vedotin	Retreatment and Extended Duration of Therapy in Relapsed Hodgkin Lymphoma and Systemic ALCL
Sep 21	Celgene (CELG)	ABRAXANE (supplemental NDA – novel indication; priority review)	Paclitaxel protein-bound (injectable), combination with gemcitabine	Advanced pancreatic cancer
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

Six of the compounds on the remainder of the FDA calendar this year are supplemental applications for existing compounds which offer novel modes of delivery or target novel indications. Two of the compounds on the calendar are adjunct components to multi-component treatment systems. Two of the drugs awaiting approval are biologics, but both are a part of supplemental applications for existing drugs. One of the compounds (Xiaflex) targets an orphan disorder, and two (Melblez and Samsca) a rare one.

Therapeutic focus of drugs awaiting FDA approval in August - December 2013

In comparison with the first half of 2013, where CNS disorders dominated the therapeutic field on the FDA approvals calendar, the second half of the year is primarily led by Oncology, Cardiovascular health and Autoimmune disorders (fig. 1). More and more orphan and life-threatening indications are being targeted by drug developers as a result of recent regulatory changes to the FDA approval pathway, and as a result of increased competition in other therapeutic niches.

Figure 2. Drugs awaiting FDA approval decisions in Aug-Dec 2013, by therapeutic area

Market Capitalization of drugs awaiting FDA approval in August - December 2013

In line with widely emerging trends in the pharmaceutical industry, more and more mid-, small- micro- and even  nano- cap biotechs are reaching the market on their own, without the help of powerful large-cap partners. 2013 has been a record year for biotech IPOs, which is indicative of two general trends: more biotechs are reaching the market on their own, and more Big Pharma players are looking to acquire or in-license late-stage or even approved compounds.

Unsurprisingly, the 2013 FDA drug approval calendar featured only 2 Big Pharma applicants – the American biotech giant Celgene and the Japanese multinational Otsuka Pharmaceutical. As usual, all of the companies on the 2013 FDA PDUFA calendar are public, and all except Otsuka are traded on the Nasdaq.

The majority of the companies on the August – November 2013 FDA calendar are small-cap, with a market capitalization of under $2 billion (fig. 3). Two of the companies are large-cap ($10billion+), two are mid-cap, three are micro-cap, and one, Delcath Systems, is nano-cap, with a market capitalization of under $50 million.

Figure 3. Market capitalization of companies awaiting FDA approval in Aug-Nov of 2013 (US$)

Continue reading here for a full list of upcoming PDUFAs, with descriptions and prognosis.