Kadmon and Valeant ink global deal on ribavirn and taribavirin....

Valeant Pharmaceuticals and Kadmon Pharmaceuticals inked two separate agreements, worth a combined $12.5 million up front, covering the development and/or marketing of the hepatitis C drug ribavirin and the clinical-stage ribavirin prodrug candidate taribavirin. The deals come within a few days of Kadmon buying out Three Rivers Pharmaceuticals, which already markets the hepatitis C drugs Infergen™ (consensus interferon), Ribasphere® (ribavirin, USP), and RibaPak® (ribavirin).

The first new deal gives Kadmon an exclusive, worldwide license (excluding Japan) to taribavirin, which has successfully completed a Phase IIb trial for the treatment of chronic hepatitis C. Under terms of this agreement Kadmon will pay Valeant $5 million up front in addition to development milestones and future sales royalties.

The second agreement gives Valeant exclusive rights to all Kadmon dosage forms of ribavirin, including its 200 mg, 400 mg, and 600 mg capsules and tablets, in Poland, Hungary, the Czech Republic, Slovakia, Romania, and Bulgaria. Valeant paid Kadmon $7.5 million for the ribavirin portfolio and will source the products from Kadmon.

At first glance the combination of these two deals may seem counterintuitive. Valeant is passing further development of its ribavirin prodrug candidate virtually worldwide to Kadmon but is instead taking on rights to a marketed ribavirin portfolio in central Europe. However, as Valeant’s CEO, J. Michael Pearson, points out, while further development of taribavirin in house was halted in 2009 until a partner could be found, the firm wants to keep its hand in the branded generics market for hepatitis C drugs in some territories. “While participating in product development in the overall hepatitis C market no longer fits within our corporate development strategy, ribavirin could be a significant product for our branded generics portfolio in Central Europe.”

Kadmon, meanwhile, is making a more obvious push into the hepatitis C market globally, both through its deal with Valeant and with its recent acquisition of Three Rivers. “Kadmon is building upon its commercial platform in hepatitis C through expanded global distribution and the addition of complementary products,” notes Samuel D. Kalsal, CEO. “Our agreements with Valeant achieve milestones for both of these objectives. Taribavirin completes our ribavirin franchise and will ensure its future sustainability and growth. We have also expanded our global distribution network for ribavirin into markets in which Valeant is a leading provider.”

Excerpts from a "Hepatology" commentary on the future of Taribavirn - by Paul Kwo, MD and Rakesh Vinayek MD.... (Thank you NATAP.org)

The Next Step for Taribavirin - Commentary        Hepatology Sept 24 2010   Paul Y Kwo and Rakesh Vinayek   Excerpts:   In this issue of Hepatology, Poordad and colleagues report the SVR rates of weight-based TBV compared to weight-based RBV in naïve genotype I HCV-infected patients. In this US Phase 2b randomized open-label controlled parallel group study, 278 naïve genotype I subjects were randomized to TBV 20, 25, or 30 mg/kg/day or RBV 800-1400 mg, pegIFN alfa-2b for 48 weeks. An early virologic response (EVR) defined as undetectable HCV RNA (< 39 I.U. at Week 12) or a 2 log reduction in baseline HCV RNA, the primary endpoint of the study, was comparable across all treatment arms. The SVR rate was also preserved across all treatment arms, ranging between 27 and 28%. The overall response rates in this trial were low though the high percentage of African Americans (20%) and those with advanced fibrosis may explain the lower SVR rates. It would be interesting to know the IL-28 composition of the treatment population as there may have been a high prevalence of unfavorable Il-28 CT or TT genotype patients present which could also explain in part the low SVR rates.   While SVR rates were not different between treatment arms, a lower relapse rate was seen with an incremental increase in the dose of TBV, similar to that observed with RBV. In addition, the per protocol SVR rates were substantially higher again demonstrating the importance of adherence to therapy to provide optimal SVR rates in the genotype I population. Lower anemia rates (defined as hemoglobin < 10 grams/dL) were seen in the TBV arms throughout the entire 48 weeks, with cumulative anemia rates being significantly lower across the two lower TBV arms (20 mg and 25 mg/kg) compared to weight-based RBV. However, as the dose of TBV was increased to 30 mg/kg, the anemia rate was numerically lower than with RBV but was not significant, other than at week 4, suggesting that higher doses TBV may lead to similar rates of anemia and other side effects observed with RBV. The pharmacokinetic analysis showed that this effect correlated with RBV plasma exposure. Furthermore, within the first 12 weeks of treatment when maintaining the dose of RBV has been shown to be most critical, significantly lower rates of anemia were observed with TBV compared with RBV (7-15% vs 24%, respectively) within the first 12 weeks of treatment although this translated clinically into comparable, not superior SVR rates in the TBV arms. Even though, fewer patients treated with TBV required dose reduction (13-28%) compared to 32% patients treated with RBV, it should also be noted that dropout rates for anemia were not different amongst the TBV arms compared to the RBV arms in this study, though this may be due to relatively small sample size. There does appear to be an increased rate of diarrhea in the TBV arms compared to RBV. This may be significant as some DAA agents are also associated with increased GI side effects and, as we enter an era where DAA agents and other drugs are combined, side effects could limit the efficacy of multi-drug combinations. Finally, while not statistically significant, insomnia was numerically higher in the TBV arms and should be a side effect of some concern in future trials. Thus, as significantly fewer dose reductions were noted only in the TBV 20 mg/kg arm as compared to the higher doses of TBV and RBV with similar SVR rates, the dose of 20 mg/kg may also require study in the future with DAA agents  So what does the future hold for taribavirin? Phase 2 and ongoing Phase 3 trials strongly suggest that DAA agents will be added to pegIFN and RBV to obtain higher SVR rates, albeit at the expense of higher rates of anemia and other side effects. Currently, the role of ESAs in the treatment of HCV with DAA agents is not yet precisely defined, though we await the results of ongoing trials. The inclusion of TBV into the HCV armamentarium may serve as an opportunity to combine with pegIFN and DAA agents to reduce the rates of anemia and avoid RBV dose reduction or introduction of ESAs. As RBV reduction or removal of RBV is associated with increased rates of breakthrough and development of resistance to DAA agents, TBV may have a role in populations particularly sensitive to ribavirin-related anemia , including those with advanced liver disease, older patients, patients who have undergone liver transplantation, HIV/HCV coinfected individuals, patients with hemoglobulinopathies and chronic renal failure 20. However, with the commencement of several trials comprising of multiple combinations of DAA agents with and without pegIFN/RBV, and the development of newer protease inhibitors with potentially lower rates of anemia, the role of TBV remains less precisely defined and could potentially have a finite life cycle. Studies with combinations of DAA agents with PEGIFN/RBV have been initiated and these studies will multiply. Whether or not RBV (and TBV) can be eliminated altogether remains to be determined.  Particularly in those patients with unfavorable treatment characteristics, RBV may remain a part of our therapeutic armamentarium for years to come; and, if so, TBV could be an option which has the potential to limit toxicity and potentially reduce costs. The ideal study may be to combine TBV with a DAA agent and pegIFN and compare it to RBV, to see if SVR rates can be preserved or improved by minimizing dose reductions and reducing the emergence of resistance. Given the long wait between the approval of pegIFN and RBV and yet unapproved DAA agents, one should not discount the potential contribution of TBV. Many promising agents have already been stopped in development due to lack of efficacy or toxicity 21-22. Thus, if TBV can be shown to preserve or improve efficacy rates in combination with DAAs and Peg IFN, with lower rates of anemia, the use of TBV in these clinical settings would be a welcome addition to the HCV armamentarium as we begin to expand the HCV populations that we treat.