January 21, RE: Bristol-Myers Squibb Expanded Access Program for Daclatasvir. Dear Dr. Birnkrant,

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1 U.S. Food and Drug Administration Center for Drug Evaluation and Research Office of Antimicrobial Products New Hampshire Avenue Silver Spring, MD January 21, 2014 RE: Bristol-Myers Squibb Expanded Access Program for Daclatasvir Dear Dr. Birnkrant, The U.S. Food and Drug Administration s recent approval of sofosbuvir and simeprevir has given people living with hepatitis C important new options to achieve cure and reduce their risk of progression to liver failure and liver cancer. However, the patients with genotype 1 infection who were treated with a telaprevir or boceprevir-containing regimen and did not achieve sustained virological response (SVR) do not have any approved options for treatment right now. These patients often represent the most urgent-to-treat cases, including people with and liver transplantation. This serious unmet medical need for patients who had failed a previous PI-containing regimen could be addressed with a combination of sofosbuvir (SOF) plus daclatasvir (DCV). Sulkowski et al. have published data from 41 subjects who had failed a TVR or BOC containing regimen (protease inhibitor, PI), 80% of whom had moderate or higher fibrosis (no ), who received 24 weeks of SOF+DCV+/-RBV (NEJM 2014; 370: ). 98% of these subjects achieved SVR. Patients who have failed treatment with a PI-containing regimen need access to effective and safe treatment. The currently approved antiviral medicines do not have adequate data to support their use in these patients. There are no actual data on the combination of SOF, pegylated interferon alfa (Peg-IFN), and ribavirin (RBV) in patients who failed previous Peg-IFN+RBV, much less those with PI failure. We are concerned about the potency of this regimen in these patients given a sub-analysis done by the FDA showing a 71% SVR rate in naïve patients with non-cc IL-28B alleles, high HCV RNA levels, and F3 or F4 fibrosis. We anticipate that people who failed a PI-containing regimen may have an even lower SVR rate. There are also no data on SOF+RBV for 24 weeks in patients who failed a previous Peg- IFN+RBV or Peg-IFN+RBV+PI regimen. Difficult-to-cure subjects in the SPARE study had a 68% SVR rate, but they were treatment naïve. Currently approved drugs may be suboptimal in PI failures. Yet, many providers are prescribing SOF+simeprevir (SMV) +/- RBV in patients who failed Peg-IFN+RBV+PI. Again, there are no efficacy data for this combination in people who failed a previous PI-containing regimen, and there are theoretical concerns about cross-resistance with TVR or BOC and SMV.

2 In recognition of the need for additional treatment options especially for HCV genotype 1 patients who were unsuccessfully treated with a PI - the European Medicines Agency s Committee for Medicinal Products for Human Use (CHMP) issued a press release on November 22, It stated an opinion on the use of daclatasvir in combination with sofosbuvir in the treatment of chronic HCV infection in a compassionate-use program. The recommended compassionate use is intended for adult patients at a high risk of their liver being no longer able to function normally (decompensation) or death within 12 months if left untreated, and who have a genotype 1 infection. Further, it is recognized that the potential benefit of such combination therapy may extend to patients infected with other HCV genotypes. The press release also notes, these medicines have been studied in combination, with or without ribavirin, in a clinical trial which included treatment-naive (previously untreated) HCV genotype-1, -2 and -3 infected patients, as well as patients with genotype 1 infection who have previously failed telaprevir or boceprevir treatment. Results from the trial indicate high efficacy, also in those who have failed treatment with these protease inhibitors. Many such patients have very advanced liver disease and are in urgent need of effective therapy in order to cease the progression of liver injury. In addition, a press release issued by Bristol Myers Squibb on January 8, 2014 announced that the European Medicines Agency validated BMS s marketing application for the use of DCV for the treatment of adults with chronic hepatitis C with compensated disease, including genotypes 1, 2, 3 or 4, in combination with other agents, including sofosbuvir. The announcement specifically highlighted DCV use in patients who did not achieve an SVR with protease inhibitor treatment and patients with comorbidities. This press release also noted that DCV has been studied in over 5,500 patients in all-oral and interferon-containing regimens. In the Unites States, Bristol-Myers Squibb has a Named Patient/Compassionate Use program for DCV. This program could potentially meet the currently unmet medical needs of patients who have and who 1) failed a previous PI-containing regimen, 2) are unable to tolerate an IFN-containing regimen and are unable to receive simeprevir due to unavoidable drug-drug interactions, or 3) are genotype 3, treatment experienced patients with, for whom SOF+RBV x 24 weeks has only a 60% SVR rate. The current Named Patient/Compassionate Use Program is too limited in scope. Here is a link to general language on the BMS website to describe an expanded access program, and we would like the FDA to request & support an Expanded Access Program by BMS for daclatasvir plus Sofosbuvir. (accessed 07 January 2014) Expanded Access Programs (EAP) are generally: Limited to patients with a serious/life-threatening condition For patients for whom there is no real therapeutic alternative Outside of a clinical trial (i.e., the patient is ineligible to participate in a clinical trial or there is no ongoing clinical trial in the patient s country of residence.) In order to approve an EAP, all of the following criteria must be met:

3 Sufficient evidence of efficacy that a clinically meaningful benefit may be expected (i.e., available scientific evidence, taken as a whole, provides a reasonable basis to conclude that the drug may be effective.) Sufficient evidence of safety indicating that patients would not be exposed to unreasonable risk if prescribed the product. The patient has the serious or life-threatening disease for which the expanded access program is authorized. There is no comparable or satisfactory alternative therapy to diagnose, monitor or treat the disease or condition. The patient is ineligible for, or otherwise unable to participate in a clinical trial for the product (e.g., due to geographical constraints). There is nothing unique about a particular patient that suggests that a clinically meaningful benefit would not be expected or that there would be an unreasonable risk posed by prescribing the product drug to that patient. In their Named Patient/Compassionate Use program for DCV, BMS has taken the position that access to DCV can only be granted to patients with HCV infection who have less than a year to live (see attached request form). However, they do not have data to support dosing DVC in patients with decompensated. There are several other problems with this position, as follows. 1) Patients need to have an expectation of meaningful life expectancy if their HCV were cured. If a patient has less than a year to live due to a non-hcv-related complication, treating and curing the HCV will not provide a clinically meaningful outcome. 2) Compensated cirrhotic patients who have less than a year to live, and would benefit from curing their HCV are almost always patients with hepatocellular carcinoma. These patients have the option to receive SOF+RBV until transplant since achieving an undetectable viral load appears to be the important goal pre- and prior PI exposure should not impact this outcome. 3) Almost all other pre-transplant patients with less than a year to live have decompensated liver disease; there are no data on DCV use in this population. 4) Post-liver transplant patients with compensated are the one group that are likely to have less than a year to live and could qualify for SOF+DCV. 5) decompensation is a tragic complication for patients. Decompensation events are personally devastating for patients, expensive to manage, and may lead to death given the insufficient access to liver for transplantation in the US. Treatment intervention to prevent decompensation is an additional highly urgent medical need. Of note, the CHMP decision includes the cirrhotic population who is at risk for decompensation.

4 No Compensated Decompensat ed no compensated decompensat ed Patients that may meet BMS Expanded Access current criteria Although BMS is sponsoring Phase III Daclatasvir + Sofosbuvir in Cirrhotic Subjects and Subjects Post-liver Transplant (ALLY 1; NCT ), this trial excludes patients with HIV or HBV coinfection who also may have high unmet medical needs. We believe that BMS should expand their criteria for access to DCV via their Named Patient/Compassionate Use program for patients with compensated, with or without HIV or HBV coinfection, who failed a previous PI-containing regimen, have contraindications to interferon-alfa and simeprevir (precluding use of SOF+IFN+RBV and SOF+SMV), or are genotype 3, treatment experienced patients. In addition, because patients who have received a liver transplant can develop accelerated fibrosis progression, we are requesting access for DCV for all post-liver transplant patients with compensated liver disease who failed a previous PI-containing regimen, have contraindications to SOF+SMV, or are genotype 3, treatment experienced patients with. In addition, these patients would not have access to ALLY-1. No Compensat ed Decompens ated no compensat ed decompens ated Proposed patients that could benefit from BMS Expanded Access Patients urgently need additional treatment options, so we are requesting that the FDA: 1) Agree with the proposed expanded criteria of patients for a BMS Named Patient/Compassionate Use program for daclatasvir 2) Strongly encourage BMS to immediately expand their criteria for patients who qualify for daclatasvir under their Named Patient/Compassionate Use program

5 3) Encourage BMS to create an Expanded Access program and protocol now to facilitate patient access in the US Thank you for your consideration of this request. The authors below are signing this letter on behalf of the National Viral Hepatitis Roundtable, an umbrella organization of over 200 organizations dedicated to improving the lives of people living with viral hepatitis. Sincerely, Michael Ninburg Chair, NVHR Robert Gish, MD Vice Chair, NVHR Camilla S. Graham, MD, MPH Co-Director, Viral Hepatitis Center, Division of Infectious Disease, Beth Israel Deaconess Medical Center Tracy Swan Hepatitis/HIV Project Director, Co-Director, Viral Hepatitis Center Treatment Action Group