Friday, January 29, 2010

Fall out from Merck's announcement that vicriviroc has failed in phase III treatment experienced trials

In 2008, antiretroviral sales across the seven major markets totaled $10.7 billion, growing at a CAGR of 12.8% between 2005 and 2008. This expansion is expected to slow down. Despite drivers such as new product launches, earlier treatment initiation, decreasing mortality and an increase in HIV prevalence, a series of patent expiries will impact branded sales from 2011. [See Forecast Insight: HIV - Cross-class fixed dose combinations drive continued growth]

The dynamic nature of the HIV market has been further evidenced by Merck's announcement last week that it will not, for the moment, be submitting an NDA for vicriviroc in treatment-experienced HIV-infected patients. This news came with the disclosure that two Phase III studies in this patient population failed to meet their primary efficacy endpoint.

Results from these studies will be presented at CROI in February.

Cowen and Co had already expected vicriviroc to achieve modest sales, $75 million in 2012, growing to $150 million in 2015. These figures will have to be revised.

Patients were recruited to the two Phase III trials, VICTOR-E3 and VICTOR-E4, only if they had documented resistance to at least two antiretroviral drug classes. Patients were treated with an optimized background regimen (ritonavir boosted protease inhibitor plus at least two active drugs) with or without vicriviroc.

Even with resistance to at least two antiretroviral drug classes, efficacy rates of 90% can nowadays be achieved with antivirals such as Merck's Isentress (raltegravir) or Tibotec/Johnson & Johnson's Prezista (darunavir) and Intelence (etravirine).

This supports Merck's explanation that the trials failed because many patients enrolled had three or more active drugs in their optimized background therapy regimen. Unsurprisingly therefore, this would leave little room for newer agents such as vicriviroc to show any additional benefits. While plausable we can't help but ask why this potential problem wasn't foreseen when the studies were designed and alternatives sought.

Despite the recent disappointment vicriviroc may still join the first in class CCR5 antagonist, Selzentry on the market as it will not be shelved according to Merck.

Merck continues to evaluate vicriviroc in treatment-naïve HIV-infected patients and patient enrollment has now been completed. In fact the experiences of Selzentry would suggest that the treatment-naïve population may represent the best target for vicriviroc.

Selzentry was initially approved for experienced patients, of whom only 50-60% are CCR5 tropic. As a result patients have to be tested prior to treatment to determine whether they are likely responders. The cost of testing presented a hurdle to Selzentry uptake. In contrast, approximately 80% of treatment-naïve patients have CCR5 trophic virus. Even though testing is still required its cost is less likely to represent wasted expense. In light of this, Merck is continuing the development of vicriviroc for treatment-naive patients.

Interestingly, the company is taking a novel approach in this setting by investigating vicriviroc in combination with Bristol-Myers Squibb's Reyataz (atazanavir) and eliminating the traditional nucleoside backbone. Concerns over NRTI toxicity have led to a renewed interest in such regimens, and prescribing two agents instead of the traditional three is also likely to have cost benefits. Moreover, this strategy may be highly effective in countering the threat from developmental fixed-dose combinations such as Gilead's Quad Pill and Gilead and Tibotec/Johnson & Johnson's Truvada/rilpivirine combination.

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