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The recent hoopla surrounding Pharmasset (VRUS), as well as the excitement regarding two NDAs for hepatitis C, made me take a closer look at this disease and what is coming down the pipeline.

Hepatitis C virus (HCV), along with alcoholism, is one of the most important causes of chronic liver disease in the United States. Sixty to 70 percent of chronic hepatitis, and up to 50 percent of cirrhosis, end-stage liver disease, and liver cancer are caused by the virus. It is estimated that 4.1 million Americans have antibody to HCV (anti-HCV), and 1.2 million have active disease. Approximately three quarters of those infected develop chronic infection. The disease is responsible for about 10,000 deaths a year in the US alone. More details can be found at the NIH NIDDK website.

The present standard of care is a combination therapy of interferon alpha and ribavirin for 24 – 48 weeks. Approximately 55% of subjects (combined virus types 1, 2, and 3) respond to 48 weeks of therapy. Virus types 2 and 3 have response rates of 70 – 80%, whereas type 1 has a response rate around 40%. Doses required for type I are higher (1000 - 1200 mg of ribavirin a day) compared with types 2 and 3 (800 mg a day). Responders are measured as rapid virus response (RVR - where the virus is undetectable after 4 weeks of treatment) and sustained virus response (SVR - where the virus is undetectable 24 weeks after therapy). Complicating the picture is the presence of cirrhosis, co-infection with HIV, etc. But in general, patients with viral load of 400,000 IU/ml or lower respond better.

Therapy is also complicated by the side effect profile of both drugs. Interferon causes depression, exacerbation of auto-immune diseases and bone marrow suppression. Ribavirin causes red cell hemolysis and so cannot be used in those with coronary artery disease, strokes, or renal dysfunction. It also releases histamine, resulting in symptoms akin to allergic rhinitis and asthma. This side effect profile is important as we shall see in a moment.

It is clear that Hepatitis C is an important disease, and a lucrative opportunity for the pharmaceutical industry. Therefore it is no surprise that clinicaltrials.gov has more than 360 trials listed, and more than 20 drugs are in development. Of these, the first two out of the gate have been from Merck (MRK) and Vertex (VRTX).

MERCK: Merck filed an NDA for boceprevir earlier this year. The filing was based on phase III studies - RESPOND2 study was in subjects who had failed prior therapy, whereas SPRINT2 study was in treatment naïve subjects. Boceprevir was added to the background of interferon and ribavirin, and approximately 65% of subjects responded as measured by SVR. Placebo response rate was in the 25% - 35% range. Anemia was reported in approximately twice the number of subjects who received boceprevir compared with placebo, and was managed by administration of erythopoeisis stimulating agents (such as EPO, etc. Keep in mind that ribavirin also causes anemia. The FDA has granted Merck six month priority review.

VERTEX: Shortly after Merck, Vertex filed an NDA for telaprevir. The filing was based on three studies – ADVANCE, ILLUMINATE, and ADVANCE. Telaprevir was added to the background of interferon and ribavirin, and approximately 75% of subjects responded as measured by SVR, compared with 45% on placebo. Vertex showed that the time required to treat was also half that of the conventional 48 weeks. Another differentiating feature is that telaprevir was shown to be effective in those with high viral load (800,000 IU/ml) and with cirrhosis. From a side effect profile, rash and anemia were more common in the telaprevir cohort than the placebo cohort, and anemia was managed by reducing the dose of ribavirin rather than by administrating erythopoeisis stimulating agents (such as EPO, etc), but I could not find the exact numbers from the Vertex website. The FDA has granted Vertex six month priority review

Assuming that both drugs get approved by the middle of this year, it will pose a challenge to further drug development of other candidates. If one or both of these drugs become the standard of care, it will make it harder to conduct a placebo study like the one conducted by Merck and Vertex. The way around that is by new combinations that don’t use interferon as background therapy. Another issue is if the drugs prove to be as effective in clinical practice as in the trials, it will also make it harder to find patients to participate in the trials, at least in the US. With that in mind, here are some other companies that have drugs in the pipeline (based on clinicaltrials.gov, accessed on March 13, 2011) – this is not an exhaustive list by any means.

Company

Compound

Phase

Genotype

Janssen

TMC435

III

I

Boehringer

B1201335

III

I

BMS (BMY)

IL-29

II

?

Vertex (VRTX)

VX222 + telaprevir

II

I

Pfizer (PFE)

Filibuvir

II

I

BMS

790052 + 650032

II

I

Novartis (NVS)

DEB025

II

2, 3

Gilead (GILD)

9190/9256

II

I

Gilead

9190/9541

II

I

Hoffman

05303253

I

I

Merck (MRK)

7009

I

I

Okairos

AdCh3NSmut

I

I

Okairos

Ad6NSmut

I

I

Merck

5172

I

?

So, what about Pharmasset? While the data that caused the stock to rocket has not been published, rumor has it that the combination of PSI-938 and PSI-7977 “eliminated the virus” (such a short duration does not even come under RVR) in 15 out of 16 subjects in a matter of 14 days. Just keep in perspective that the primary endpoint for approval is SVR. And that 14 days is too short a time for the virus to become resistant to drugs. Similar efficacy has been seen at such early stage with other combinations as well. Now if that efficacy holds in SVR after 24 weeks of therapy, it will be a totally different story.

Source: Who Will Win the Hepatitis C Market?