Unmet needs spur innovative drug development for Hepatitis C...

Article I authored for TrendSlate blog.

Large, unmet needs in medicine have always spurred innovation in novel drug development. A textbook case of this can be found in the effort to fight Hepatitis C (HCV) infection. Hepatitis C is a blood borne virus that primarily affects the liver. The virus triggers an immune response – one that the virus almost always successfully evades– causing liver inflammation and scarring. Slowly, over a period of 20-30 years in most cases, the scarring can progress to decompensated cirrhosis, liver cancer and eventually liver failure. Lack of general knowledge regarding the disease in both the patient and healthcare provider population has created an environment of chronic underscreening, underdiagnosis and lack of proper treatment.

By the most conservative of estimates, researchers have put the worldwide number of HCV infected at 180 million, with 3 to 5 million here in the United States. With large portion of the infections occurring before the early 90’s when an effective technology came out to screen the blood donor pool, most of the burden of the disease sits squarely on the shoulders of those born between 1946 and 1964 – the baby boomer generation. Given that the progression of disease from infection to liver damage is roughly 20 years, there has been a correlating recent uptick in the worldwide incidence of liver disease. Without an effective therapy, experts expect a four fold increase in the incidence of Hepatitis C-related liver disease in the next 20 years. Inextricably linked are healthcare costs… a highly regarded 2009 forecast from the Milliman Consulting Group pegs an increase in healthcare costs from the current $30 billion to over $85 billion in 2027. Most of that burden is forecasted to fall in the lap of already-cash strapped government payors. That is one financial tidal wave to be avoided.

The current treatment for Hepatitis C is arduous for both patient and provider, costly and comes with a largely insufficient cure rate, especially genotype 1, the most common genotype found in the United States. With a 50% cure rate at best (called ‘SVR’ or ‘Sustained Viral Response’), the current treatment of pegylated interferon and nucleoside analog ribavirin is also fraught with side events and tolerability issues that make it not unlike a 48 week endurance contest. Pegylated interferon works by stimulating the host immune response and ribavirin is thought to work by preventing relapse, although it’s exact mechanism of action is unknown. Using the two together means 48 weeks of flu-like symptoms, depression and fatigue. With 50% of patients not responding and/or tolerating this regimen, there is certainly a lot of room for improvement. This fact, coupled with a refocused FDA prioritizing reviews with an eye out for compounds that meet unmet disease states, make HCV an attractive target for intrepid drug developers.

From the scrappiest of the little Biopharma startups to the biggest of behemoth Big Pharma companies, there is plenty of innovation going in developing drugs to effectively treat HCV. As I’m typing this, there are currently over 120 compounds in all stages of development with new ones being added as others undoubtedly falter. Most of these new compounds fall under the umbrella of “STAT-C Drugs” or “Specifically Targeted Antiviral Therapy for Hepatitis C”, Unlike the non-specific method of action of pegylated interferon and ribavirin, STAT-C drugs are a new class of compounds that customized to target specific areas integral to the life cycle of Hepatitis C virus. The goal is to terminate that life cycle, thereby preventing viral replication.

Nearest to market are Vertex Pharmaceuticals and Merck with HCV protease inhibitors Telaprevir and Boceprevir respectively, due to hit the market at about the same time in 2011. Some experts even predict a dual FDA review which will surely test the mettle of both companies. It is fitting, however, that Vertex is amongst the leaders in STAT-C development. They fired the first shot in the equivalent of a drug development revolution when Vertex scientists first published the structure of the HCV protease in 1996 and then used computer-generated modeling to design molecules to bind to the protease. Unlike the HIV protease, HCV didn’t present a nice, big pocket to fit a molecule in. The binding site of the HCV protease was described as more of a “dent in a dinner plate”, making the design more difficult. That program created the Telaprevir molecule. Vertex did it again in 1998, identifying the 3D structure of the NS3 HCV Helicase. This, however, has been a less successful target than the protease. No doubt that both discoveries lead to a industry-wide gold rush in HCV drug development. The forecasted revenue for these two novel drugs? Between 2-3 billion by 2014 for Vertex’s Telaprevir alone, according to some market oracles.

In terms of competition, it looks as if both Vertex and Merck look to have the STAT-C market to themselves for two or three years. Both companies have additional STAT-C compounds in in the pipeline. Looming closely behind are companies like Roche, Bristol Meyers Squibb, Gilead, Boehringer Ingelheim and Tibotec with their own compounds and no shortage of capital to get them to market. Yet despite the leaps in drug development innovation for HCV, a big, yet unanswered question remains. All the trials with both Telaprevir and Boceprevir were done in combination with the current standard of care, pegylated interferon and ribavirin. The addition of either compound provided an average increase in SVR of around 20% and cut the duration of therapy by 50% compared to pegylated interferon and ribavirin alone. Both compounds added additional leverage in boosting the SVRs of patients that had been previously treated but were not cured as well as making significant inroads in populations that have significant genetic barriers to treatment success such as Hispanics and African Americans. A 20% increase in SVR in half the time is remarkable achievement. The fact remains however, that even 12-16 weeks of treatment may be rough to get through given the side effect baggage of pegylated interferon and ribavirin combined with the additional side effects of the new compounds. If a combination of better-tolerated STAT-C drugs can be robust enough to prevent viral resistance and breakthrough without the non-virus specific immune modulating effects of peyglated interferon and ribavirin, even more patients could be treated.

Don’t think drug developers haven’t dreamed of ditching pegylated interferon and ribavirin. Many of the aforementioned companies are doing trials using their STAT-C regimens in combination both with and without pegylated interferon and ribavirin to explore the possibilities. Is it reasonable to think a virus that mutates so rapidly as to create every single possible mutation of itself every day be outwitted by drugs that target multiple points of the virus life cycle? The jury is still out. Vertex recently discontinued an arm in their trial pairing Telaprevir with a low dose of their non-nucleoside polymerase inhibitor VX-222 without pegylated interferon and ribavirin because some patients experienced viral breakthrough. In the higher dose arms, they paired Telaprevir plus VX-222 as well as pegylated interferon and ribavirin and at the time of the press release, those patients remained undetectable. Other trials with different combinations of drugs are currently progressing, so that particular question remains without a definitive answer.

Whatever the ultimate outcome for the STAT-C drugs, it’s clear that a significant milestone has been achieved in terms of drug development. Science and innovation are addressing a clear unmet need. We have an upcoming armory of novel compounds aimed at turning the $85 billion dollar tidal wave into a mere ripple by cutting the down the duration of therapy, increasing SVR and ultimately saving lives. Drugs will continue to improve as developers work to reduce adverse events, increase efficacy and make dosing more convenient. We’ll also witness dramatic shifts in the marketplace due to cost – how will the evolving managed care environment embrace the STAT-C drugs? What effects will STAT-C drugs have on utilization and provider reimbursement? How will patient assistance programs be designed? What role will support groups, community advocates and politics play in educating the masses on the disease and it’s treatment? What are the barriers to access to care? What about drug interactions and resistance profiles? What does HCV viral resistance mean? It is indeed a very exciting time for drug development, but definitely not for the faint of heart