A Promising Drug on horizon: Acadia Pharmaceutical (NASDAQ:ACAD) and treatment of Parkinson's disease psychosis

ACADIA Pharmaceuticals (NASDAQ: ACAD) is a biopharmaceutical company focused on innovative small molecule drugs that address unmet medical needs in neurological and related central nervous system disorders. They are developing pimavanserin, which is in Phase III development as a potential first-in-class treatment for Parkinson's disease psychosis (PDP).

Pimavanserin is a new chemical entity that can be taken orally as a tablet once-a-day. Pimavanserin selectively blocks the activity of the 5-HT2A receptor, a drug target that plays an important role in psychosis.

www.chemnet.com

Brief background on Parkinson’s disease Psychosis (PDP)

Parkinson’s disease is a chronic and progressive neurodegenerative disorder that affects about 1 million people in the United States and from 4-6 million people worldwide.

It is the second most common neurological disorder after Alzheimer’s disease.

Parkinson’s disease involves the death of neurons in a region of the brain that controls movement, creating a shortage of an important neurotransmitter known as dopamine, thereby rendering patients unable to direct or control their movements in a normal manner.

Parkinson’s disease is characterized by well known motor symptoms, including rest tremor, bradykinesia, rigidity, and disturbances of balance and posture, as well as by non-motor symptoms, including psychosis, depression, sleep disturbances, compulsive behaviors and dementia. Among these the onset of psychosis is considered a particularly poor prognostic sign.

Parkinson’s disease psychosis, or PDP, is a debilitating disorder that develops in up to 60 percent of patients with Parkinson’s disease. PDP is characterized by the presence of hallucinations and delusions.

Current standard of care is to reduce or withdraw dopaminergic therapy. Use of antipsychotics has been drug of choice for management of symptoms but they tend to counteract the anti-parkinson’s therapy making the therapy even worse. The drug currenly used are Clozapine, Seroquel (quetiapine) and Abilify (aripiprazole) but they come with very bad side effects mainly being agranulocytosis (severely low amount of white blood cell important for immune system and fighting infections)

cnsspectrums.com

Current State of Pimavanserin

In late 2009, Pimavanserin failed to show statistically significant result to prove its efficacy in Phase III trial for PDP when compared to placebo. That trial did not meet its primary endpoint but the key secondary endpoint of motoric tolerability and pimavanserin was generally safe and well tolerated in the study.

In July 2010, they started a new Phase III trial with new trial design. The redesigned study will include only patients from North America, and will exclude mildly psychotic patients. The main goal of the ongoing study is to reduce psychotic symptoms in Parkinson's disease patients. The secondary goal is to check tolerability to the drug pimavanserin. 

The study will now enhance the main goal, which Hacksell (CEO) said has already been approved by the U.S. Food and Drug Administration. The CEO Uli Hacksell, has repeatedly said , "We believe pimavanserin has an ideal profile to effectively treat PDP without impairing motor function and, therefore, provides the potential for an important advance in therapy for patients suffering from this large unmet medical need."

The Trial design can be viewed here (NCT01174004), “http://clinicaltrials.gov/ct2/show/NCT01174004?term=acadia&rank=3”

Reasons why I think the Phase III (-020) trial will be successful:

• The trial will test only 40mg pimavanserin vs. placebo in a 1:1 randomization compared to 3 arms in the previous phase failed trial. It should help reduce the statistical complexity

• This trial also has two-week lead-in period which include social therapy in order to help pull initial placebo responses ahead of the assessment period. This will help rule out placebo effect

• The trial has new Scale for the Assessment of Positive Symptoms (SAPS) endpoint through analysis of the two previous trials -012 and -014. The new trial will focus on 9 items compared to 20 items in previous failed trials. The SAPS endpoint was accepted by the FDA

• Most importantly, this trial will enroll a more homogeneous patient population (US patient population ONLY). The previous failed trial enrolled patients in seven different countries (U.S., U.K., France, Bulgaria, India, Russia, and Ukraine)

In my opinion, the stock prices should start to run as we approach August 31, 2012. According to their last quarterly result webcast they are projecting on clinical trial completion near end of August 31, 2012. The final data will be released 3 months after that so the final data release will be November 2012. Since we have strong timeline of data release, the stock price should go up considerably.

As we get closer to the mid 4Q 2012 we will start to see more news around ACAD. A recent PR was released on Reuters, http://www.reuters.com/finance/stocks/ACAD.O/key-developments/article/2573125. I am predicting more PRs like this will make this stock very volatile. 

Disclosure: May initiate position in next 72 hours

Resources: Reuters, Acadia Pharmaceutical Investor Relations, Google Images, Journal of Clinical Psychiatry, Abilify Package Insert

A great Biotech investment opportunity: Amicus Theraputics (NASDAQ: FOLD) - Migalastat HCl for Fabry Disease

Amicus Therapeutics (NASDAQ: FOLD) is a biopharmaceutical company focused on the discovery, development and commercialization of novel small molecule, orally administered drugs known as pharmacological chaperones, for the treatment of a range of human genetic diseases.

Amicus (NASDAQ: FOLD) is focused on three key strategic priorities:

• The Phase 3 development of its lead program, AT1001 (migalastat HCl) for the treatment of Fabry disease;

A Quick overview of Fabry Disease

• Fabry disease is an inherited lysosomal storage disorder caused by deficiency of an enzyme called α-galactosidase A (α-GAL). 

Nature.com

• The role of α-GAL within the body is to break down a complex lipid called globotriaosylceramide (GL-3).  Reduced or absent levels of α-GAL activity leads to the accumulation of GL-3 in the affected tissues, including the central nervous system, heart, kidneys, and skin. 

• This accumulation of GL-3 is believed to cause the various symptoms of Fabry disease, including

• Pain
• Kidney failure
• Increased risk of heart attack and stroke.

• Most individuals with Fabry disease have missense mutations in the GLA gene. Missense mutations can alter the structure of α-GAL, which results in the accumulation of the enzyme in endoplasmic reticulum (ER).

• As a result of the accumulation of α-GAL in the ER, the enzyme is unable to reach the lysosome, the part of the cell where α-GAL does its work of breaking down substrate.

Market opportunity 

• It is currently estimated that Fabry disease affects approximately 5,000 to 10,000 people worldwide. The market opportunity is endless with number of Fabry patients on treatment projected to grow by 12%.

• Fabry disease is an X-linked recessive genetic disorder that affects both men and women. 

Amigal (migalastat HCl)

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=47206758

Migalastat HCl bind to destabilized α-galactosidase A enzyme (α-GAL) and thereby restore its intended biological function of degrading globotriaosylceramide (GL-3) substrate in lysosomes. 

Amicus completed multiple Phase 2 studies of AT1001 for the treatment of Fabry disease. 
In total, 26 male and female subjects were treated for either 12 or 24 weeks. 
Twenty-three of the 26 subjects continued to receive treatment in an ongoing Phase 2 Extension Study designed to evaluate the long-term safety and efficacy of AT1001.
Results from the Phase 2 studies of Amigal indicated that there were no drug-related serious adverse events. The most common adverse events were headache, arthralgia and diarrhea.  
In subjects identified as responders to AT1001, treatment resulted in increased levels of the target enzyme (α-Gal A), as measured in white blood cells and in the kidney, and reduced levels of the target substrate (GL-3), as measured in renal interstitial capillary cells from kidney biopsies and in urine.
Additional preliminary results from Phase 2 extension study showed that eGFR has remained stable out to 2-3 years for all subjects continuing in the extension study and the average annual rate of change in eGFR in subjects identified as responders to migalastat HCl, excluding hyperfiltrators, was +2.0 mL/min/1.73m2.  Additionally, trends of reduced proteinuria continued to be observed in subjects identified as responders to AT1001

Phase 3 design:

• Purpose: compare the effect of AT1001 (migalastat hydrochloride) versus placebo on kidney globotriaosylceramide (GL-3).
• Study design: double-blind, randomized, placebo-controlled study will be conducted in 60 patients at approximately 40 sites worldwide. The study will consist of two stages and an open-label treatment extension phase
• Primary outcome: kidney GL-3 (assessed histologically in kidney biopsy samples)
• Secondary outcome:  urine GL-3 levels, renal function (assessed by iohexol GFR, eGFR, and 24-hour urine protein) , and safety and tolerability
• Estimated Primary completion date: July 2012
• For more info: http://clinicaltrial.gov/ct2/show/NCT00925301?term=NCT00925301&rank=1
• Results expected in 3Q of 2012. It is also being evaluated in different indication in Study 013 with results expected in 3Q-4Q of 2012.

In terms of fundamentals of this company, they have $108.2M in cash as of March 31, 2012. The company is planning on spending around $37-43M in R&D.  I do not believe the company will need additional capital through its Phase 3 data release and/or NDA submission. 

From the Phase 2 results, and the design of Phase 3 trial, I believe the data should be positive. Since 65% of the patients from phase 2 remained on the migalastat HCl monotherapy shows a strong efficacy and safety in this patient population. So far from the observation, there is low dropout rate which significantly strengthens the potential for positive data of phase 3 trial. In addition, GlaxoSmithKline invested additional $18.6million equity investment in this company which now brings their ownership to 19.9%. With positive phase 3 result, they may buyout this company due to its smaller size. 

In my opinion, this company should do well in near term as it approaches its phase 3 data release. I strongly believe that the share prices should reach $7-9 with positive result but once again we should see more momentum in share price as the company updates on specific date of data release.  Once again, this company can possibly be bought out by GlaxoSmithKline on a positive result and its deep pipeline with various candidates.

Price target: $8 

Disclosure: Long 

Resources: Amicus Theraputics Website, Reuters, Stockcharts, Clinicaltrial.gov, Pubmed Chemical, and nature.com

New Drug on Horizon: Linaclotide for Chronic Constipation and Irritable Bowel Syndrome - Constipation (Ironwood Pharmaceutical: IRWD)

Ironwood Pharmaceuticals, Inc., (NASDAQ: IRWD) an entrepreneurial pharmaceutical company, discovers, develops, and commercializes human medicines.

Its lead product candidate, linaclotide, is a guanylate cyclase type-C agonist that completed Phase III clinical trials for the treatment of patients with irritable bowel syndrome with constipation (IBS-C) and chronic constipation (CC).

 Ironwood Pharmaceuticals (NASDAQ: IRWD) has collaboration and license agreements with Forest Laboratories, Inc. to co-develop and co-market linaclotide in North America; Almirall, S.A to develop and commercialize linaclotide for the treatment of IBS-C, CC, and other lower gastrointestinal conditions; and Astellas Pharma Inc. to develop and commercialize linaclotide for the treatment of IBS-C, CC, and other gastrointestinal conditions in Japan, South Korea, Taiwan, Thailand, the Philippines, and Indonesia.

More about Linaclotide:

Linaclotide is a GC-C agonist in development for the treatment of irritable bowel syndrome with constipation (IBS-C) and chronic constipation (CC).

Complications of chronic constipation include haemorrhoids, faecal impaction (shown here on CT scan) and intestinal perforation | Photo: SPL

The clinical efficacy portion of the linaclotide development program is complete and two long-term safety studies are still ongoing.

Across four Phase 3 efficacy trials in patients with IBS-C or CC, linaclotide met all primary and secondary endpoints encompassing abdominal and bowel symptoms.

In these trials, diarrhea was the most commonly reported adverse event and the most commonly reported adverse event that led to study discontinuation. Most occurrences of diarrhea were reported as mild to moderate. More than 3,200 patients have enrolled in one of two ongoing 18-month open label safety studies.

In April 2012, US FDA notified the companies that it will require a three-month extension to complete its review of the data supporting the New Drug Application (NDA) for linaclotide for the treatment of irritable bowel syndrome with constipation (IBS-C) and chronic constipation (CC).

An additional analysis of existing data was recently requested by the FDA to further characterize the relative effect of the two doses of linaclotide that were studied in the Phase 3 CC clinical trials.

Since this analysis was submitted to the FDA within three months of the user fee goal date, the date has been extended by three months, in accordance with applicable regulation. No new data have been requested by the agency to complete the review. FDA action is now expected by September 2012. Ironwood and Forest continue to plan for a 2012 launch.

Ironwood is a relatively mid-cap pharmaceutical company with market capital of $1.43B as of July 2012. It currently has revenue of $71.22M with quarterly revenue growth of 29.70% and gross profit of $65.87M. In addition, it has total cash of $157.65millon which equates to about 1.47 cash per share. If the Linaclotide gets an FDA approval, Ironwood Pharmaceutical company will get $85M milestone payment from Forest Laboratories and $20M milestone from Almirall.

In my opinion, they have enough cash to reach their anticipated PDUFA date on September 2012. According to their recent 2^nd quarter highlights, they also have European MAA under review which we should be able to get a decision in the 2^nd half of 2012. They are also planning on gaining more market share by expanding global access to patient by filing CTA (FDA of China) which is also accepted for review.

I believe that management is very confident in launching the product commercially in 2^nd half of 2012. During Digestive Disease Week of 2012 which showcases more than 5,000 abstracts and lectures in Gastrointestinal research, medicine and technology also had positive reviews for the Linaclotide.

Market Need

IBS-C and Chronic constipation (CC) are chronic conditions characterized by frequent and bothersome abdominal and/or constipation symptoms. Patients with IBS-C experience frequent and recurrent abdominal pain and/or discomfort and constipation symptoms, such as infrequent bowel movements, hard/lumpy stools, and straining during defecation.

In 2010, approximately 40 million people in the U.S. suffered from symptoms of IBS-C or CC, of whom an estimated 18 million patients sought medical care. Patients are often treated with fiber and laxatives; however, according to market research, over 70 percent are not satisfied with current treatment options. This large, highly symptomatic, and dissatisfied patient population could benefit from new treatments.

In my opinion, this company should fare well in upcoming months. I definitely see an upside in stock price from this levels. After reading the recently published randomized trial results (http://www.nejm.org/doi/full/10.1056/NEJMoa1010863), I feel more confident in approval of this drug. There is definitely a need for new treatment in IBS-C and CC since current standard of therapy lacks patient satisfaction. After close consideration and research, my price target for this company is $16-17 in upcoming months with relative volatility due to its midcap.

Disclosure: May own shares in this company in next 72hours.

Sources: Ironwood Pharmaceutical, New England Journal of Medicine, Yahoo Finance, Reuters, Google images

GlaxoSmithKline to invest additional $18.6million in the Amicus Theraputics (NASDAQ:FOLD)

GlaxoSmithKline to invest additional $18.6million equity investment in the Amicus Therapeutics (NASDAQ: FOLD) for its experimental therapy for Fabry disease, bringing GSK’s total ownership stake to 19.9 percent. They invested $60millon in cash in 2010. 

Amicus will commercialize the drug (Migalastat HCL), currently in Phase II and III trials, in the U.S. and GSK will handle marketing in the rest of the world.

Fabry disease, estimated to affect 5,000 to 10,000 people worldwide, is caused by an enzyme deficiency and lists various symptoms – including kidney failure and increased risk of heart disorders.

Migalastat HCl is now in two late-stage studies for Fabry disease, with pivotal data expected in the third quarter. 

 Three Studies underway for NASDAQ: FOLD

 Sources: Amiscus Theraputics, Reuters, FierceBiotech

Vivus Pharma (NASDAQ: VVUS) awaits FDA approval for its obesity drug

Shares of weight-loss drug makers Vivus Inc (NASDAQ:VVUS) fell ahead of an anticipated deadline by the end of Tuesday for the U.S. Food and Drug Administration to decide on approval of Vivus's diet drug Qnexa.

The stock of VVUS has seen heavy, volatile trade in the days leading up to the decision on the second of three new drugs aimed at tackling America's obesity epidemic.

The FDA last month approved a rival obesity drug called Belviq from Arena Pharmaceuticals Inc (NASDAQ:ARNA), making it the first prescription weight-loss pill to receive U.S. approval in over 13 years. In addition, there was also rumor of possible buyout from Pfizer (NYSE: PFE)

Share of Vivus fell 9.8 percent to $25.90 in early trading on the Nasdaq. They recouped most of those losses midday after a USA Today story appeared online saying the drug had been approved. The story quoted Vivus President Peter Tam saying it would be available to consumers later this year

The story was removed from USA Today's website about an hour later and replaced by a statement that the story had been prepared "in anticipation of FDA approval, but at this hour that approval is still pending." Vivus shares traded down 2.9 percent.

"The timing of the USA today report fits with (Vivus shares) recovering that 10 percent briefly," said Jonathan Aschoff, analyst with Brean Murray Carret & Co.
FDA officials were not immediately available for comment. Vivus declined comment.


Source: Reuters, Google images

Alnylam Pharma (ALNY)'s ALN-TTR02 able to knockdown TTR proteins by 94%

Alnylam Pharmaceuticals Inc. (ALNY), the developer of a treatment for a rare genetic disorder, rose the most ever after the drug showed promise in an early clinical trial.

Alnylam Pharmaceuticals Inc announced the achievement of positive clinical results from its Phase I trial with ALN-TTR02, an RNAi therapeutic targeting the transthyretin (TTR) gene for the treatment of TTR-mediated amyloidosis (ATTR).

 

My analysis: As the pharmacogenomics and personalized medicine are coming in the forefront the companies like Alnylam Pharma (ALNY) are benefiting a lot from it. Due to smaller market capitalization of these companies, they tend to rise exponentially on positive press release.

I feel this rally will not last too long before investors realize that this is just the Phase I trial data which are mainly toxicity data. This data may get presented at various investor conferences but this drug still has lots of clinical inspection to go thru.

This company is certainly not a M&A target due to its specific focused pipeline. It will be intersteing to see in coming months how this company pans out.

TTR medicated amyloidosis

The disease is caused by a mutation in the gene responsible for producing the transthyretin protein. In people with the genetic defect, transthyretin made by the liver breaks apart, forms into clumps, and damages the nerves and heart. Currently a liver transplant is the only available treatment.

Alnylam’s drug, called ALN-TTR02, stops production of transthyretin. The company is focusing on patients with TTR-FAP, or transthyretin familial amyloid polyneuropathy. The company estimates that as many as 10,000 patients have the disease. In TTR-FAP, the protein attacks the body’s longest nerves first, often killing them within a decade as the body shuts down.

Results from this study show that administration of ALN-TTR02 leads to robust knockdown of serum TTR protein levels of up to 94%; the overall results were highly significant (p<0.00001 by ANOVA). Suppression of TTR, the disease-causing protein in ATTR, was found to be rapid, dose dependent, durable, and specific after just a single dose.

 Alnylam recently reported that it has initiated a Phase II study of ALN-TTR02 in patients with ATTR and has guided that its goal is to start a pivotal trial in 2013.

The primary objective of the study was to evaluate the safety and tolerability of a single dose of ALN-TTR02, with subjects being enrolled into five sequential cohorts of increasing doses ranging from 0.01 to 0.50 mg/kg. In addition, pharmacodynamic activity was evaluated with serial measurements of serum TTR protein levels through at least day 56.

Preliminary data from this study showed that a single dose of ALN-TTR02 resulted in rapid, dose-dependent, durable, and specific knockdown of serum TTR levels. Even at doses as low as 0.15 mg/kg, substantial serum TTR suppression was achieved, with a mean 81.9% knockdown at nadir.

Sources: Reuters and Bloomberg