Overcoming Patent barriers to hepatitis C treatment The Hepatitis C Treatment Revolution Expanding Access to HIV Co-Infected and Beyond UNITAID, MSF, WHO IAC, Melbourne 21 July, 2014

Drugs of Interest - Hepatitis C Sofosbuvir Will likely be backbone of HCV all-oral pan-genotypic regimens MSF planning to use in our treatment programs Daclatasvir Significantly strengthens sofosbuvir regimens and likely reduces duration Potential component (e.g. with sofosbuvir) of pan-genotypic all oral regimen Very good activity in genotype 3 Ledipasvir Potential for pan-genotypic all-oral regimen (e.g. with sofosbuvir) – but need to evaluate further studies that are on-going potential for FDC with sofosbuvir for GT 1 and 4 – data already available GS 5816 Very good pan-genotypic potential, but need to see results of on-going studies

Local Patents linked to Local Prices PatentNo patent One supplierMultiple producers No competition Competition High prices of imported medicines Access to low cost generic medicines

Study by Andrew Hill – Minimum cost to cure HCV with generic DAAs

Sofosbuvir (preventing evergreening) DESCRIPTIONPCT Number/ PCT Publication Number (WO) Patent No. 1 Base compound WO A2 Patent No. 2 Structural formula and pro-drugs of nucleoside derivatives + processes (ex: salts, hydrates, solvates, steroisomers, and crystalline forms) WO A2 Patent No. 3 Process WO A2 Patent No.4 Process for preparation of active compound WO A2 Patent No. 5 Product byprocess WO A1 Patent No. 6 Specific derivative in crystalline or crystal-like form WO A1 Patent No. 7 Combinations exhibiting synergistic effects + methods of use WO A2 Patent No. 8 Composition of sofosbuvir + at least one excipient WO A1

THE GROUNDS FOR OPPOSING PATENT APPLICATIONS ON SOFOSBUVIR 24 Nov 2013: opposition to the patent application on the pro-drug The opposition, filed at the Kolkata Patent Office by I-MAK targets Gilead’s patent application 3658/KOLNP/2009 (WO2008/121634). 19 March 2014: opposition to the patent application on the base compound The opposition, filed at the Delhi Patent Office by I- MAK and the Delhi Network of Positive People (DNP+) targets Gilead’s patent application 6087/DELNP/2005 (WO 2005/003147). Lack of novelty - The base compound has been disclosed in various earlier patents, which already reveal the free base compound that is used in sofosbuvir The complete patent opposition documents are available.

The treatment regime MSF doctors dream of! Which DAAs Sofosbuvir + Daclastavir (NUC + NS5a) pan-genotypic Better treatment outcomes for patients with advanced liver disease In what form? Co-blister Fixed dose combination Pediatric formulation

The barriers Clinical trials - Gilead won’t cooperate with BMS Then we wait for sofosbuvir and daclastavir to be registered separately Generic production of sofosbuvir in the pipeline Generic production of daclastavir? Dialogue with generic producers needed to stimulate interest. Likely scenario – sofosbuvir will not be patented in India. Daclastavir (at least compound) could be patented…(impact of new patent regime in India) Challenge – how do you ensure generic supply of sofosbuvir and daclastavir together for medical projects

What TRIPS flexibilities? Finding the patent applications (WHO and I-MAK) Filing pre-grant oppositions (starting with India) If and when a patent is granted on daclastavir, use of bolar provision will protect generic companies from infringement suits for developing, registering and pre-qualifying (BE & stability studies) of generic formulations of daclastavir (section 107A of Indian law) Compulsory licensing for daclastavir (building a dossier for Indian government and placing an order) Can the drug be produced in an LDC (using the LDC extension for opening up generic supply of new DAAs patented in India What are governments doing about this?

Generic competition or tiered pricing short term gain – long term pain

Marketing authorization/Registration status in India Registration in developed countries - On the two drugs (sofosbuvir & simeprevir) despite having completed phase II trials (phase 3 data is awaited), were considered for accelerated approval by the USFDA & EMA as they appear to offer significant advantages over available therapies. Another drug daclastavir is also likely to receive approval in August Local registration - For new oral drugs to be available in the India market, first companies (originator or Indian generic company) have to submit registration dossiers to the Indian Drug Regulatory Authority (Drug Controller General of India). This is yet to happen and therefore the drugs are not available locally. In India. Gilead is yet to apply for registration of sofosbuvir. As per the Indian law – the Drugs & Cosmetic Act - it is doing a local trial covering 100 patients. Therefore registration of sofosbuvir in India is unlikely in Maybe 2015 if the Indian FDA does not delay. Gilead will submit its dossier only after completion of the local trial. For other drugs like daclastavir and simeprevir we are unaware if the companies have initiated any steps to register these drugs or conducting clinical trials in India. Generic companies too could initiate the registration process but till now no company has stepped forward to do so.

More and more patients failing current treatment regimen (Peg inf+Ribavirin) are being prescribed new DAAs (Sofosbuvir) and asked to import from US if possible (cost 26,000 canadian $ for 28 tablets) Cases of denial of treatment starting to emerge (human rights issues).

Compassionate use What is the option for patients who need new HCV drugs immediately: Compassionate use allows the possibility to use (outside of clinical trials) by a clinician a new drug yet unregistered in India for patients suffering from a life threatening disease and for whom conventional therapies have failed. In other words, when no other treatments are available to a seriously ill patient, clinicians can sometimes use a new, unapproved drug. Such provisions are mainly used by Indian clinicians for diseases like cancer to provide access to treatments that are still under development and that have not yet received marketing authorization in India.

Compassionate use For patients who have either failed or cannot tolerate treatments based on interferon injections and are in urgent need of treatment there are legal safeguards in the Drugs & Cosmetic Act that allow access to new drugs which are yet to be registered in India. Please note that Indian law does not directly recognize the concept of compassionate use but clearly allows for use of new unregistered drugs imported under a special license in small quantities for life threatening diseases or such disease requiring therapies for unmet medical needs.

Compassionate use There are three steps to this process: Step 1 Applying to the company for compassionate use – does the company accepts the request for compassionate use for this we must identify whether the company (for sofosbuvir it is Gilead, for simeprevir its is Janssen and for daclastavir is it BMS) have a Compassionate Use program open to process requests. Gilead’s criteria for CU –only those who have had liver transplant are eligible Janssen setting up a compassionate use programme for Asia Daclastavir - BMS - ?

Compassionate use Step 2 Once the company responds affirmatively then the patient must apply to the Drug Controller General of India for permission – The new unregistered drug can be imported under Rule 36 (import of drugs for personal use), by filing and submiting form 12A (Application for the issue of a permit to import small quantities of drugs for personal use). Form 12A is to be filled by the patient (attaching the prescription of the doctor.) the DCGI grants permission under 12B (Permit for the import small quantities of drugs for personal use. Apply for waiver of custom tax to MoH If granted this will be sufficient to legally import the drugs. Step 3 Once the drug has been dispatched by the company, the import shipment (consignment of the drug) has to be custom cleared and picked up from the airport with the original Import Permit (12B Form) and other necessary documents.