Tuesday, 13 August 2013

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)


24th 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.

Thursday, 8 August 2013

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.

Sunday, 4 August 2013

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.