Daniel Dhumeaux, Henri Mondor hospital Créteil, France HCV compassionate use programme The French experience Amsterdam, April 27,2013

CUPIC

- Evaluation of real-life safety and efficacy of triple therapy (including telaprevir or boceprevir associated with peginterferon plus ribavirin) in HCV genotype 1 patients with compensated cirrhosis who were non responders to previous dual therapy (Compassionate Use of Protease Inhibitors in viral C Cirrhosis) - National multicenter observatory in the setting of ATU * (promoter ANRS) * Autorisation temporaire d’utilisation (temporary authorisation for use) Early access programme

Treatment regimen Peg-IFN α-2a + RBV TVR + Peg-IFN α-2a + RBV Follow-up Weeks 72 BOC + Peg-IFN α-2b + RBVFollow-up Peg-IFN + RBV BOC: 800 mg/8h; Peg-IFNα-2b: 1.5 µg/kg/week; RBV: 800 to 1400 mg/day TVR: 750 mg/8h; Peg-IFNα-2a: 180 µg/week; RBV: 1000 to 1200 mg/day n=205 n=292

Serious adverse events (SAE)* Premature discontinuation of treatment due to SAE TelaprevirBoceprevir Safety (SVR12) 54.2%51.0% 21.3% 14.2% (*) % of patients with at least one event

Albumin ≥35g/L Albumin<35g/L Platelets >100,000/µL Platelets ≤100,000/µL Risk of occurrence of death or severe complications 3.3% 4.3% 7.1% 44.1%

Albumin ≥35g/L Albumin<35g/L Platelets >100,000/µL Platelets ≤100,000/µL Risk of occurrence of death or severe complications 3.3% 4.3% 7.1% 44.1%

Efficacy (SVR12) TelaprevirBoceprevir SVR (%) % 41% 53%51% 32% 40% All patients Relapsers Partial responders Fontaine et al. J Hepatol 2013;58(suppl.1):S27

- More than 1,000 medicinal products assessed since Availability 10 to 12 months before market authorisation application - Therapeutic areas. Oncology-haematology. Central nervous system diseases. Metabolic disorders. Infectious diseases including HIV infection and and viral hepatitis - Implemented in 1994 The French ATU system

Criteria for granting ATU 1. The product is a medicinal product (not a preparation) 3. There is no market authorisation application 2. ATU is given for treatment (not for investigation) 6. There is no available alternative therapeutic method 7. Efficacy and safety are presumed and benefit is expected for the patient 4. The patient cannot be included in a clinical trail 5. The disease is serious and/or rare

Two types of ATU : nominative and cohort ATU Nominative ATU. For one patient, on a name patient basis. On the request and responsibility of the clinician. ATU for the duration of treatment. Usually follow-up of patients and data collection according to a protocol for therapeutic use Cohort ATU. For a group of patients. Applied by the company commitment to submit a marketing authorisation. ATU for one-year duration, renewal possible. Always follow-up of patients and data collection according to a protocol of therapeutic use

The ATU system Success and limitations - The ATU system is extremely useful for covering public health needs :. it is strongly supported by patients ans physicians. it is contolled by competent authorities (*) - The risks are (a) to slow down clinical trials and marketing authorisation applications, (b) to overestimate efficacy and to underestimate safety (*) National agency for medicinal product safety

Short and middle-term perspectives for hepatitis C early access programme in France - A nominative ATU was recently implemented for patients having developed severe liver disease recurrence post-transplantation (sofosbuvir plus ribavirin) - A cohort ATU is in progress for (a) patients waiting liver transplantation, and (b) patients having developed severe liver disease recurrence post-transplantation (sofosbuvir plus ribavirin)

Summary  Use of first generation PI in real life is a major step forward in HCV treatment : –increases SVR in all genotype 1 patients including cirrhotics –is associated with more frequent SAEs, including death, severe infections and hepatic decompensation and difficult management of anemia in cirrhotics Patients with albumin <35 g/L and platelets <100,000 /mm 3 should not be treated Other patients need closer monitoring –TVR can be administrated twice daily –Triple therapy (TVR) for 12 weeks in CC, F0-F3 patients with RVR ?

The compassionate use of medicinal products. An example: the French ATU system

The ATU system Success and limits - The ATU system is extremely useful for covering public health needs :. It is strongly supported by patients ans physicians. It is contolled by competent authorities - The risks are (a) to slow down clinical trials and marketing autorisation applications, (b) to overestimate efficacy and to underestimate safety - Regarding nominative ATU :. Too many. Complex system. No strong regulatory long term status (no mandatory marketing authorisation application)