Dextofisopam for IBS

Dextofisopam is Pharmos’ lead product for diarrhea predominant irritable bowel syndrome (IBS-d). The compound has been shown to have efficacy at a 200 mg dose level in both Phase 2a and Phase 2b trials with a high level of tolerability.

Dextofisopam, a non-serotonergic agent currently being evaluated for the treatment of irritable bowel syndrome (IBS), is the R-enantiomer of racemic tofisopam, a molecule marketed and used safely outside the United States for over three decades for multiple indications including IBS. Dextofisopam represents a novel, first-in-class opportunity with a positive proof-of-concept study in an arena where there are few compounds with unique approaches or positive efficacy results. By structure, Dextofisopam is a member of the homophthalazine class; Dextofisopam binds to specific receptors in areas of the brain affecting autonomic function, including gastrointestinal (GI) function. Unlike the two 5-HT3 or 5-HT4 mediated IBS therapies recently introduced into the market, and subsequently withdrawn because of safety concerns, Dextofisopam novel non-serotonergic activity offers a unique and innovative approach to IBS treatment.

While IBS is not a life threatening disease, it can be debilitating and represents a large unmet medical need. Previously approved treatments for IBS include Lotronex from GSK and Zelnorm from Novartis, both of which were both withdrawn after successful market launches because of unexpected and serious side effects. Lotronex was subsequently relaunched, but with a black box warning label. Dextofisopam is an enantiomer of racemic tofisopam, a drug that has been used safely for over 30 years, and has exhibited an excellent safety profile in clinical trials to date. Unlike Lotronex and Zelnorm, which are from the 5HT class of drugs, Dextofisopam structurally is a homophthalazine. It is a non-sedating, non-addicting molecule containing an “atypical” 2,3-benzodiazepine ring.

Pharmos, together with Vela Pharmaceuticals which merged with Pharmos in 2006, has advanced the compound through Phase 2b. The placebo-controlled Phase 2a trial (N=141) studied a 200mg dose of Dextofisopam and produced statistically significant results that formed the basis for a Phase 2b clinical trial.

The Phase 2b trial (N=324) studied 100 mg, 200 mg and 300 mg doses of Dextofisopam. The Phase 2b trial did not meet its primary endpoint of overall adequate relief, but the trial clearly showed drug activity, especially at the 200 mg dose level, confirming the efficacy seen in the Phase 2a trial. In addition, statistical significance was achieved in improvement in abdominal pain and discomfort and multiple variables in month 3, including overall relief. Statistical significance for the primary endpoint was not achieved because of a much higher than expected placebo response rate. The response rates in the Phase 2b trial were actually superior to the Phase 2a in many cases, but a higher placebo rate prevented a statistically significant separation.

The response rate for the primary endpoint of overall adequate relief was 57% in the Phase 2a trial and 56% for the 200 mg dose in the Phase 2b trial. The response rates for secondary endpoints all showed drug activity. These endpoints were abdominal pain / discomfort, overall IBS symptoms, stool frequency, abnormal bowel habits and stool consistency.

The Company switched CROs mid way through the trial to accelerate enrollment. Interestingly, practically all the efficacy resulted from one CRO. This information will be used in developing the next trial.

Patent Estate

An extensive patent estate is in place with Dextofisopam. This consists of an issued composition-of-matter patent, an issued manufacturing patent, and numerous additional pending patent applications in both the United States (including use of Dextofisopam for inflammatory disorders and immunomodulation) in both the United States and foreign counterparts.

Potential pharmaceutical market for Dextofisopam

The development of Dextofisopam for the treatment of Irritable Bowel Syndrome (IBS) is a major goal of Pharmos’ development activity. Direct medical costs associated with IBS have been estimated at $8 billion annually in the U.S. It has been estimated that indirect costs for IBS in the U.S. exceed $20 billion. The few recent products introduced in this market have been limited by poor safety profiles.

Irritable Bowel Syndrome: Disease Description and Diagnosis

Irritable bowel syndrome is defined by a constellation of symptoms that includes abdominal pain or discomfort accompanied by diarrhea, constipation, or an alternation between the two. IBS is classified as a functional disorder; it is diagnosed by symptom-based criteria following exclusion of organic diseases that may produce abdominal pain and altered bowel function.

Although the etiology of IBS is not completely understood, five factors have been proposed as playing a role in the development of IBS:

  1. Psychosocial factors
    1. impact of stress on motor function of the GI tract
    2. approximately 60% of patients seen at referral centers have psychiatric symptoms.
  2. Visceral hypersensitivity – lower threshold for abdominal pain
  3. Altered bowel motility – abnormal motility of the small intestine
  4. Infection and inflammation
  5. Autonomic nervous system dysfunction
    1. studies show that IBS patients have aberrant autonomic nervous system activity
    2. altering autonomic nervous system activity in volunteers produces symptoms of IBS.

This perspective on the pathophysiology of IBS suggests that a drug that improves altered bowel motility, decreases visceral hypersensitivity reduces stress-related impact on GI function, normalizes autonomic dysfunction, and possesses anti-inflammatory properties may provide a superior, broad-spectrum approach to the treatment of IBS. In preclinical studies, Dextofisopam exhibits all of these properties.

The diagnostic criteria for IBS have evolved over the years. Today, diagnosis for clinical trials and regulatory purposes is defined by the Rome III Criteria. Diagnosis is based on the patient having a) recurrent abdominal pain or discomfort for at least 6 months, and b) at least two of the following three features on at least 3 days per month over the past 3 months:

  1. Improvement with defecation
  2. Onset associated with a change in frequency of stool
  3. Onset associated with a change in form (appearance) of stool

Based on the clustering of symptoms, IBS patients are usually categorized as either “diarrhea-predominant,” “constipation-predominant,” or “alternating” (also termed “mixed”). For a diagnosis of IBS, specific “red flag” symptoms are usually excluded. These “red flag” symptoms may indicate the presence of organic disease, such as colon cancer (especially if onset is rapid or occurs over the age of 40), ulcerative colitis (rectal bleeding), or Crohn’s disease (weight loss, fever). For the diagnosis of IBS to be made, normal results must have been obtained for blood and stool tests, x-rays, endoscopy, and biopsies.

While not a life-threatening disease, IBS can have a large negative impact on the quality of life of patients. Even mild cases can be life-altering, and severe cases are often debilitating, with the frequency and severity of episodes seriously affecting work, school, and social schedules.

IBS is a leading cause of physician visits, accounting for approximately 3,000,000 visits annually in the U.S., representing 4% of all visits to office-based physicians and 49% of visits to office-based gastroenterologists. The need to eliminate other possible diagnoses (colon cancer, inflammatory bowel disease, and other GI diseases) necessitates expensive in-office procedures. As noted earlier, the annual direct medical costs for IBS in the U.S. have been estimated at $8 billion.

Prevalence of IBS

IBS is a very common disorder, with studies indicating prevalence in the range of 6-15% for North America, Europe, and Japan. Based on a prevalence rate of 12.5%, approximately 36 million individuals in the United States meet diagnostic criteria for IBS. Prevalence rates are similar in the major European markets (France, Germany, Italy, Spain, and the United Kingdom). While prevalence rates for other countries are not well established, published studies support the existence and recognition of IBS throughout the world, including China and India.

Irritable bowel syndrome, or IBS, is a chronic, recurring condition with symptoms that affect more often women than men. IBS is characterized by multiple symptoms that include bowel dysmotility-diarrhea, constipation, or alternating diarrhea and constipation-and abdominal discomfort. Studies have shown that diarrhea-predominant IBS appears to be the most common subtype. For patients with diarrhea-predominant and alternating-type IBS, there are no recently approved treatments for any but the most severely affected women, and none for men.

The prevalence of IBS varies with gender and age. Higher prevalence rates are consistently reported for women than for men (two to three times greater). While IBS is observed in all age groups, including pediatric and geriatric populations, it is more common in the age range of 20 to 60 years for both genders.

Current and Recent Therapies

Even with the introduction of two new therapies – Lotronex┬« (alosetron), a 5-HT3 antagonist, and Zelnorm┬« (tegaserod), a 5-HT4 partial agonist – the IBS market is still largely served by older products, with questionable efficacy and poor tolerability. These older products include antispasmodics, laxatives, and antidiarrheal agents. While antispasmodics at high doses may provide relief of specific symptoms, these drugs are poorly tolerated at those doses. The estimated sales of IBS drugs in the U.S. market totaled $348 M in 2009.

Lotronex was introduced into the U.S. IBS market in March 2000, and was withdrawn from the market in November 2000 due to safety issues. Lotronex was subsequently reintroduced in 2003 with a restricted marketing program (Physician Prescribing Program). The utility of Lotronex® is severely hampered both by its narrow indication (only for women with severe diarrhea-predominant IBS who have failed to respond to conventional therapy) and a major safety issue (the risk of potentially fatal ischemic colitis). Since its reintroduction, Lotronex has had minimal prescription volume.

Zelnorm was introduced into the U.S. IBS market in July 2002 for short-term use in women with constipation-predominant IBS. In April 2004, a precautionary statement was added to Zelnorm labeling regarding post-marketing cases of ischemic colitis and a warning for severe diarrhea. Despite these changes to the package insert, the strong marketing and educational efforts supporting Zelnorm appeared to have increased awareness and expanded utilization. Zelnorm achieved U.S. sales of $26 M in 2002, $132 M in 2003, $249 M in 2004, $357 M in 2005, and $488 M in 2006, with 2006 worldwide sales of $561 M. Zelnorm was approved in 30 countries, though not in major EU markets or in Japan. Zelnorm was voluntarily withdrawn from the market in March 2007 because of severe side effects.

Market Potential (United States and Rest of World)

The market potential for IBS is very large. IBS is a prevalent disorder for which there are currently no safe and broadly effective treatments. Investment research analysts estimate a U.S. market worth approximately $2.5 B. Market research reports project that the current full worldwide (WW) market potential for IBS therapies could be as high as $15 B (over $6 B in the United States alone). Based on its current clinical profile, Dextofisopam may have the potential to capture a significant portion of the IBS market.