End of the Road for Cannabinoid Blockers in Obesity

November 06, 2008 End of the road for cannabinoid blockers in obesity

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Pfizer’s decision yesterday to terminate ongoing phase III trials for its cannabinoid type 1 (CB1) antagonist candidate CP-945,598 (otenabant) to treat obesity is hardly surprising given the pharma giant’s recent streamlining of its research efforts, which signalled a move away from a number of therapeutic areas including obesity.

However, following the high profile failures of Sanofi-Aventis’ Acomplia (rimonabant) and Merck and Co’s MK- 0364 (taranabant) due to serious risk of adverse psychiatric events, the future for the use of cannabinoid antagonists to treat obesity looks very bleak. These failures mean that, compared to analyst forecasts just 18 months ago when hopes remained reasonably high for these types of drugs, a staggering $14.4bn in potential cumulative revenues have been wiped out between 2007 and 2012 (see table below).

Cannabinoid type 1 antagonists WW annual sales ($m)

Product Company Archive date 2007 2008 2009 2010 2011 2012

Acomplia/Zimulti Sanofi-Aventis Oct 2008 108 121 actual sales

Apr 2007 562 1,193 1,833 2,489 3,017 3,426

CP-945,598 Pfizer Apr 2007 - - - 142 383 681

MK-0364 Merck & Co Apr 2007 - - 18 154 304 459

Annual missed sales 454 1,072 1,851 2,784 3,703 4,565

Total missed sales 14,430

Although Pfizer claims the reasons behind abandoning otenabant was not due to any safety concerns at this stage and was down to “changing regulatory perspectives on the risk/benefit profile of the CB1 class and likely new regulatory requirements for approval”, the suspicion must be that the company feared similar psychiatric side effects to those seen with Acomplia and taranabant would eventually emerge.

Meanwhile, following the recent withdrawal of Acomplia from European markets, Sanofi-Aventis confirmed yesterday that it is ending all further trials of the drug, including phase III studies in diabetes.

Few left standing

These late-stage failures mean just eight CB1 antagonists remain in development for obesity, matching the eight candidates that have been abandoned, mainly due to adverse side effects.

Of the remaining CB1 antagonists in development, none are in phase III and slim hopes for the class eventually proving successful now rest on SLV 319 (ibipinabant), a compound discovered by Solvay and licensed to Bristol-Myers Squibb.

Cannabinoid type 1 antagonists in development for obesity

Current Generic Therapeutic WW sales in Product Company Phase Name Subcategory 2014 ($m)

Bristol-Myers Anti-obesity Phase II SLV 319 ibipinabant 50 Squibb / Solvay agents

Anti-obesity AZD2207 - AstraZeneca - agents

Anti-obesity Phase I V24343 - Vernalis - agents

Anti-obesity AZD1175 - AstraZeneca - agents

Pre- Cannabinoid receptor-1 Johnson Anti-obesity - - clinical inverse agonist & Johnson agents

Anti-obesity SLV 326 - Solvay - agents

ACADIA Anti-obesity CB1 Program - - Pharmaceuticals agents

Research OSI Anti-obesity CB-1 Antagonist - - project Pharmaceuticals agents

In light of recent events, it is very likely all companies with active CB1 antagonists for obesity must be seriously reviewing whether further development is warranted.

Slim chances

With big pharma seemingly admitting defeat and washing its hands of attempting to develop the ultimate diet pill, a major holy grail for the industry, it now looks as if it is up to smaller companies such as Vivus, Arena Pharmaceuticals and Orexigen Therapeutics, with considerably smaller budgets to support the large and expensive trials required, to come up with a fat-busting solution.

However, with the overall therapeutic area now littered with more pipeline failures (103) than active projects (84), the chances of success are looking slim right now (Fewer opportunties for companies to get fat off obesity products, October 24, 2008)