Interview with Professor Michel Revel - Inventor of Rebif (interferon-beta), Chief Scientist at Kadimastem

Professor Revel began his career in a laboratory associated with the Pasteur Institute in Paris, where he discovered the initiation factors of protein synthesis. This discovery opened up a field of research on the mechanisms controlling the translation of genetic information.

Prof Revel’s scientific path continued at the Weizmann Institute, where he conducted extensive research on the mechanisms of action and the isolation of the human Interferon-beta gene. These studies have led to the biotechnological development of recombinant Interferon-beta (Rebif) at Interpharm.  Rebif is today the lead product of Merck Serono, a $2.4 billion-a-year commercial drug, widely used to treat multiple sclerosis (MS), a disease that destroys the myelin coating of nerves in the brain.

Revel also discovered the human gene for the cytokine Interleukin-6, and elucidated its activity in protecting nerve functions and the nerve myelin coating in neuropathies. In recent years, Revel's laboratory focused on human embryonic stem cells (hESC) and succeeded to produce from them mature nerve myelinating cells that reconstitute the myelin coating after transplantation into myelin-deficient animals. Large scale culture technology for hESC can also be used to produce differentiated human cells such as insulin-producing pancreatic beta cells. This in recent years has lead Prof Revel to become involved in a novel commercial project—Kadimastem, a biotechnology company focused on the industrial development and commercialization of hESC-based products. One of their products, already in use by Merck-Serono, applies the hESC-derived myelinating cells in a drug-screening platform for new MS drugs.

A WORD WITH PROFESSOR REVEL:

Bioassociate: What do you feel has been the most rewarding accomplishment in your scientific career?

Prof Revel: The opportunity to pursue my basic science interests and to translate results into medical applications. I studied Interferons (IFN) as a translation control system which selectively inhibits viral protein synthesis. These studies required us to produce a lot of IFN and we therefore cloned the human gene for IFN-beta and developed the first efficient expression of this glycoprotein in mammalian cells. This attracted the attention of Serono, making it possible to develop IFN-beta production in their Israeli plant Interpharm, where I worked as Chief Scientist. Our studies on IFN-induced genes, in particular the HLA genes, shed new light on immuno-regulatory effects of IFN-beta which could be applied in autoimmune diseases. Serono’s clinical trials led to the registration of Rebif as an MS drug in 1998. To see one's research become a medication that helps hundreds of thousands of patients is indeed most rewarding.

Bioassociate: Tell us a little about your current project – KadimaStem

Prof Revel: This is really a continuation of our efforts to find new treatments for MS and other neurological diseases, by using pluripotent stem cells to produce cells that are damaged in such diseases.  We developed at the Weizmann Institute a procedure to derive human oligodendrocytes, and these myelinating cells can be applied to screen chemical libraries for molecules that stimulate nerve myelination. Present drugs for MS slow down the destruction of myelin by the immune system, but agents which stimulate the repair of myelin could be of great interest. The first product of Kadimastem, a three-year old biotechnology start-up at the Weizmann Science Park of which I am today the Chief Scientist, is such a drug screening platform already in use under contract with Merck Serono in their search for new oral drugs for treatment of MS.  A main project of Kadimastem is the production of pancreatic islet cells which could be applied in the future for cell replacement therapy in Diabetes. A third project is production of human astrocytes which hold promises for treatment of ALS, since ALS patients have abnormal astrocytes that do not anymore exert their neurotrophic functions. Kadimastem has a scientific staff of 25 (with 6 PhD researchers), and works with human embryonic stem cells and iPS cells licensed from Hadassah (from Prof. B. Reubinoff) and from Shaarei Zedek Medical centers.

Bioassociate: What do you think about the President’s recent initiative to make Israel a leading neurotech hub in 

the world?

Prof Revel: All initiatives to support and promote scientific research in Israel are welcome. A country is not measured by its size and Israel can be a big country by its contributions to Science and Technology. President Shimon Peres always understood this and his Israel Brain Hub initiative should therefore be taken seriously. Hopefully, the government, granting agencies and investment funds will listen to his appeal and make it happen. Financing academic and biotech research is one of the best investments for the State of Israel.

Bioassociate: Many people have said that Israel has been exceptionally successful at attaining scientific progress and commercializing scientific developments. Why do you think this is?

Prof Revel: The vision and support from generous donators in the Jewish Diaspora have given Israel the means to make important discoveries. Commercializing research is relatively easy in Israel, and technology transfer offices do help many scientists become involved in industry. Israel is excellent in the medical device sector, and it is no accident that analysts say that it is uniquely positioned to develop leadership in Brain-Machine interface and therapeutic neuro-stimulation devices. The pharmaceutical market is slower to grow mainly because it takes so much time to reach the market. But successes in developing new drugs can bring much larger returns, in the many billions of dollars, which should appeal to long-term investors. The two medications for multiple sclerosis coming out of Israel, Teva's Copaxone and Merck Serono/Interpharm’s Rebif, are examples that make the point. The Biotech drug, gene and cell therapy sector ought to be supported much more actively, with larger R&D budgets, and treated as national priority projects. Personally, I am proud that contributions to development of Israeli Biotechnology were mentioned in my Israel Prize and Emet prize awards.

Bioassociate: What do you think is today’s most important/pressing therapeutic area which neuroscience could address?

Prof Revel: Understanding the human brain is the new frontier following the genome project. For therapeutics, the main challenges are neuro-degenerative diseases like strokes, Alzheimer's disease, Parkinson's disease, ALS, neuropathies, spinal cord injuries and progressive forms of MS. There are many advances in these and other neurological diseases, with new drugs (e.g. Azilect of Teva, developed by Prof. Moussa Youdim), gene products (e.g. antisense RNA for myasthenia gravis of Prof. Hermona Soreq) and stem cell derived products (e.g. Hadassah stem cell pioneering trials in ALS patients of Prof. Karousis, BenHur and Slavin, and stem cell-derived astrocyte-like cells for ALS treatment being developed by Dr Daniel Offen at Brainstorm).

Bioassociate: Which obstacles do you perceive in Israel’s path to becoming a world leader in neurotechnology?

Prof Revel: The main obstacle is that the scientific potential of Israel is still not estimated at its real potential by government and Industry. Compared to other sectors in which receive millions of dollars in funding, many bio- laboratories and startups could thrive with five to ten millions, but lack the funds. Opportunities are lost due to lack of understanding of the needs of scientist. To become a world leader in neurotech, dedicated funds must be earmarked and long-term investments be encouraged by the Israeli government. The Industry and Trade Ministry's Chief Scientist Office is doing a marvelous job but it is not enough. The private business sector and large companies (e.g. Teva) ought to join hands with the government to create the real opportunities that will better exploit the human resources with which Israel is blessed. 

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.

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

Auxilium is awaiting an FDA drug approval decision on Sept 6, 2013 for an application of an existing drug for a novel indication (Peyronie's disease - penile curvature).

Date of FDA Decision (PDUFA): September 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

24^th July 2013 (Auxilium Pharma):

Market Cap	$892.06 Mln
52-week range	13.87 – 29.37
Avg. volume	900,897

Q1 2013:

Net Loss	$0.05 per share
Cash	$467.8 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

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.

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.

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

Pharma R&D in China: The Role of the "Hai Gui" - the returnees

A contingent the Chinese government is particularly fond of is the returnees—known as the Hai Gui, or Sea Turtles, in China. In the past five years, what was a trickle of returnees has become a steady flow,  as 340,000 Chinese students embarked on study abroad in 2011—a 20% increase over the previous year.  

Thus far, 818,400 have returned to China, including 150,000 life science graduates over the last five years, and the flow gained particular momentum recently. 186,000 have returned in 2011 alone, which was a 38% increase from 2010 (Fig. 1).

Figure 1. The number of Chinese returnees annually, 2005-2010

The practice is gaining popularity due to the benefits and privileges being a Hai Gui provides. Above all, returnees can now take advantage of significantly improved work opportunities upon their return: many are scouted into top management and executive positions, and already constitute the majority of senior positions in the corporate world. The Hai Gui constitute 78% of university presidents, 72% directors of key research centers and labs, 81% of academics of the Chinese Science Academy, and 54% engineering academics.

In 2009, only 10% of Chinese students had plans to remain in the United States, 52% believed that opportunities were greater in China than abroad, 68% planned to start a business and an overwhelming 74% anticipated a boom in China’s economy.  Only 7% of Chinese student in the US believed the best days of the US economy lay ahead.

The expectations are that, as MNCs pave the way for an innovative pharma industry in China, the highly-skilled returnees will initially be assimilated into the foreign player arena. However, this is not unanimously so: the prominent bio-startups Bei Gene, Hua Medicine and Ascletis were all founded by returnees in the recent past, and investor confidence in this contingent is evident in the amount of capital the three companies were able to raise. Setting a new fundraising record, Ascletis was able to attract a US$ 100 million investment from government and private sources, while Hua Medicine raised over US$ 50 million from well-known PE firms including ARCH Venture Partners, Fidelity Biosciences and Wuxi Pharmatech’s Venture Arm. Meanwhile, Bei Gene raised its funds from co-development deals with Janssen and Merck.

Check out "Pharmerging Markets: China - The Next Innovative Pharma Market?" for a free 53-page report on China's Innovative Pharma industry. 

Interview with Prof Marta Weinstock-Rosin, Israel's leading Neuroscientist, Inventor of Alzheimer's treatment Exelon (rivastigmine) and ladogstigil

PROFESSOR MARTA WEINSTOCK-ROSIN 

Professor Emeritus, School of Pharmacy-Institute for Drug Research, Hebrew University of Jerusalem

Professor Weinstock-Rosin received her B. Pharm. Hons, M.Sc. and Ph.D. degrees at London University, UK. At Hebrew University, she was Chairman of the Department of Pharmacology from 1983-1986, and President of the Israel Society for Neuroscience from 2003-2005.

Rosin was the developer of rivastigmine in 1985 (commercially available as Exelon), for the treatment of mild to moderate dementia and dementia due to Parkinson's disease. Rivastigmine was sold to Novartis through Hebrew University’s Yissum TTO and in 2009 the sales of Exelon neared US$ 1 billion worldwide.

Recently, together with Prof Moussa Youdim, Rosin developed ladostigil – a novel neuroprotective agent which combines the mechanisms of action of older drugs like rivastigmine and rasagiline into a single molecule. Ladostigil is currently in Phase II clinical trials carried out by Avraham Pharmaceuticals Ltd for the treatment of Alzheimer’s disease, Lewy Body disease and Parkinson’s. Avraham Pharmaceuticals recently completed a $9 million financing round from investors Yissum TTO, Prof Weinstock-Rosin, Eli Hurvitz’s Pontifax Fund and Clal Biotechnology.

In addition to drug development Professor Weinstock-Rosin’s major research for the past 27 years has centered on the neurochemical and hormonal mechanisms underlying the behavioral alterations induced by prenatal stress. In addition to Exelon and ladostigil, Professor Weinstock-Rosin is currently developing a new series of neuroprotective drugs with novel mechanisms of anti-inflammatory activity.

A WORD WITH PROFESSOR WEINSTOCK-ROSIN

Professor Rosin has dedicated her scientific career to understanding of the processes which take place in the ageing brain, and what causes accelerated neurodegeneration. She admits that at the time of rivastigmine discovery in 1985, the only known fact about Alzheimer’s disease was the correlation between memory loss and diminished amounts of acetylcholine – one of the most ubiquitous neurotransmitters in the brain. Rivastigmine’s mode of action is thought to be the blocking of acetylcholinesterase, an enzyme which breaks down acetylcholine, although the drug’s exact mode of action remains unknown. By the time rivastigmine was reaching the market, a substantial amount of new evidence emerged suggesting that the drug might be treating the symptom, rather than the cause, as a wide array of new underlying processes were attributed to impaired cognitive ability in rat models.

On the discovery of ladostigil:

Prof Rosin’s research has led to the isolation of a distinct change in the ageing brain, in Alzheimer’s disease and in Mild Cognitive Impairment (MCI)—a significant drop in the function of mitochondria, the cell’s power station. Because oxygen isn’t sufficiently utilized by the ageing cells, a decline in energy production results in oxidative stress and in the activation of microglial cells – cells in the brain and spinal cord which act as the first and main form of defense. It is the chronic over-activity of microglia which has been strongly implicated in neuronal damage and neurodegeneration. 

In numerous experiments in ageing rats, Prof Weinstock-Rosin discovered that administration of rivastigmine in much lower doses than those marketed under the Exelon name significantly lowered microglial inflammation, so much so that microglia of 16-months-old rats (a rat’s life span is on average two years) resembled those of young rats. Furthermore, aged rats exhibited substantially improved cognitive ability after lower-dosage rivastigmine administration.

Joining forces with Israel’s other Alzheimer’s drug, Azilect (rasagiline), Prof Weinstock worked with Prof Moussa Youdim on creating an amalgamated form of rasagiline and rivastigmine, creating ladostigil. If Prof Rosin’s laboratory studies are to be taken as an indication of ladostigil’s efficacy, we may expect excellent results in the drug’s clinical trials. Although, says Prof Rosin, ladostigil’s success may be a long way away—clinical trials of neurodegenerative diseases are notoriously difficult and lengthy to run, as patient selection is a tricky art in MCI and Alzheimer’s cases.

Speaking of the Israel Brain Technologies Initiative, Prof Rosin is perhaps more down-to-earth than her Israeli colleagues. With the right priorities, direction and financing, Israel has a great chance of becoming a world neurotech leader. But perseverance and motivation are a must, particularly because she anticipates this to be a rather costly project. 

Upcoming FDA PDUFA: Otsuka Pharmaceutical - Samsca (tolvaptan)

Date of FDA Decision (PDUFA): September 1, 2013
Company name: Otsuka Pharma
Stock ticker: TYO: 4578 OTK.F
Location: Tokyo, Japan
Type of application: Supplemental NDA; Novel Indication; Fast-Track Review
Name of drug: Samsca (tolvaptan)
Indication: Autosomal dominant polycystic kidney disease (ADPKD)

24^th July 2013:

Market Cap	$18.3 Bln
52-week range	$23.8 – 37.11
Avg. volume	889,570

Otsuka is a diversified pharmaceutical company based in Tokyo and Osaka, Japan. It is currently the second largest pharma player in Japan, and, despite its predominantly nutraceutical focus, Otsuka is actively looking to specialize in innovative pharmaceuticals targeting central nervous system disorders and oncology.

Tolvaptan is a selective, competitive vasopressin receptor 2 antagonist approved by the FDA in 2009 for the treatment of hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH). The drug is currently awaiting an FDA decision for a novel indication, Autosomal Dominant Polycystic Kidney Disease (ADPKD), a genetic illness characterized by the development of multiple cysts in the kidneys. ADPKD is the most common inherited kidney disease, accounting for about 5% of end-stage renal disease in the USA.

In a recently published tolvaptan trial the study met its primary and secondary end points. When given at an average dose of 95 mg per day over a 3-year period, tolvaptan slowed the usual increase in kidney volume by 50% compared to placebo (2.80% per year versus 5.51% per year, respectively, p<0.001) and reduced the decline in kidney function when compared with that of placebo-treated patients by approximately 30%. 

However, in April 2013 Samsca's clinical trials also revealed an increased risk of the drug to patients with underlying liver disease, and patients who take tolvaptan for extended period of time. Because of the findings, on May 1, 2013, the FDA limited the duration and dosage of Samsca by updating its drug label. In the new label the duration of treatment was limited to 30 days, the indication of cirrhosis has been removed, and increased liver risks were added. 

If approved by the FDA, tolvaptan will become the first pharmaceutical therapy for patients with ADPKD.

21st Century Thought Reading Technology May Soon Over-write Freud

Original article can be found here

Ever wondered what Google, Frankenstein, insulin and the theory of relativity have in common? Other than being some of our greatest creations and discoveries, they have all arisen from the swampy nether of the sleeping brain. Some of the humanity's most celebrated achievements were, literally, products of dreams. Ironically enough, the underlying mechanism of sleep and dreaming was dreamt up too, amongst a vast greatness of other, surprisingly numerous, slumbersome discoveries. Wouldn't it be wonderful if we could consciously immerse ourselves in this elusive underworld of dreams, exploring our hidden genius and treating a neurological disorder or two along the way? As frightening as this may sound, we may no longer be as distant from such a reality as we'd perhaps like to think.

And the reason for this is simple: as of late, we have gotten exceptionally nifty at invading the mind. Several neurotechnology leaps ago it was 1973 and doctors had to painfully drain blood vessels in the brain in order to X-ray the empty spaces left behind. Today, 20 minutes inside a non-invasive functional magnetic resonance imaging (fMRI) scanner is all it can take to unveil our emotional state, mood, and even basic thought. Combine this with other neuro-imaging techniques such as diffusion tensor imaging (DTI), electroencephalography (EEG), magnetoencephalography (MEG) and positron emission tomography (PET) and neuroscience can now paint a pretty picture of our brains' inner workings, detecting and treating psychological trauma and mental disease and exposing our deeply-rooted emotional responses to anything from our favorite show to our next-door neighbor.

The latest breakthroughs in fMRI imaging have been the most striking. Recently neuroscientists were able to "communicate" with patients previously believed to be long comatose by detecting activity spikes in brain areas responsible for visual processing, emotion, and so on, which are otherwise un-translated into visible signs of consciousness. A step further from this practice is actual visual "decoding" - reading and replicating vision from brain scans. In a series of visual decoding experiments, volunteers were asked to watch short clips inside an fMRI scanner. Scientists then used the external output to replicate clips of what the person was seeing. Below is a video demonstrating visual reconstruction from an fMRI scanner: 

 The incredibly discernible albeit unpolished, fMRI output attests to one frightfully simple fact: mind reading is at our doorstep. Whether we like it or not, growing data samples and meticulous calibration will continue to yield increasingly accurate brain reads until we can stream brains onto television screens.

But no need to panic just yet. The level of accuracy required to breach our darkest secrets is certainly a long way away, but this hasn't stopped the neuro-inquisitive from exploring all possible applications of our newfound mindreading ability. The subconscious is perhaps the ideal candidate for this, for the simple reason that we still seriously lack reliable psychoanalytical tools for penetrating such an elusive realm.

And what better starting point for this than dreaming. Dreams are so mysterious, liberating, frightening, life-changing and sometimes so outright odd that for centuries we have speculated on their message to no definitive avail. The famous "Interpretation of Dreams" by Sigmund Freud is a book of psychoanalysis and controversy, offering at times outlandish interpretations of shapes and figures inhabiting the dozing mind. According to Freud, "Dreams are the royal road to the unconscious", revealing glimpses of a secluded backdoor unbeknownst even to its beholder, but, on a large scale, riddled with sex symbolism and fueled by carnal instincts. Met with much skepticism, to this day "Interpretation of dreams" is lying in wait of more compelling evidence, something which our ever-expanding neurotech prowess is likely to soon afford.

If we were to trust the importance Freud attributed to dreaming, one can only imagine the untapped potential lurking in obscure cranial crevasses, offering anything from hugely ameliorated psychotherapy to unleashing hidden genius.

In the sphere of dream research, impressive progress is steadily being made. In an a series of fMRI sleep experiments Horikawa and colleagues from ATR Computational Neuroscience Laboratories, in Kyoto (Japan) caused a few seat stirs when they presented first-of-a-kind evidence of dream decoding. In what is now a peer-reviewed publication in Science, the team unveiled decoded readings of dreams achieved with an fMRI scanner much the same way as in the visual reconstruction experiments. Subjects were allowed to catch 10-minute z's inside an fMRI scanner. As soon as they entered REM sleep, they were awoken and questioned about the content of their dreams. Scientists then scoured the internet in search of images which would match the dream description. When these images were shown to the subjects inside an fMRI scanner, the brain activity spikes they induced were surprisingly similar to the spikes detected from the subjects' dreams. After appropriately calibrating the dream- and wake- signals, scientists scanned sleeping subjects once again, this time "decoding" the dreams and confirming their findings with the subjects, with a crude-but-impressive 60% accuracy on basic shapes and themes (ie -person, street, tree, etc).

For starters, the findings have unveiled a previously unknown fact: equivalent spikes generated in sleep and in waking suggest that dreams, like images, at least partially reside in the visual cortex (what happens in the case of blindness remains to be studied). Secondly, a 60% accuracy is certainly not bad for a first try, considering that the experiment was targeting dozens, if not hundreds of possible dream scenarios. Most importantly, the fact that calibration improves with every scan means that, when it comes to dream decoding, the only way is up. Perhaps dream reading will not go as far as to yield us downloadable dream databases every morning, but it will certainly give scientists the opportunity to study various dream patterns in disease, injury, and alongside a plethora of other parameters. And, with time, this research will doubtlessly begin to give meaning to the enigma which has vexed humanity for so long.

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.