New Delhi: Citing the unmet need, the Subject Expert Committee (SEC) functional under the Central Drug Standard Control Organisation (CDSCO) has granted approval to drug major MSD for a Phase III clinical trial waiver involving the retroviral drugs Doravirine tablet 100mg and Doravirine bulk drug in support of Emcure Pharmaceuticals’ proposal for manufacturing and marketing permission of Doravirine tablet 100mg and Doravirine bulk drug.
This came after drug maker MSD and Emcure Pharmaceuticals presented their proposal for a Phase III clinical trial waiver with the drug Doravirine tablet 100mg and Doravirine bulk drug before the committee.
However, the approval is dependent on a number of conditions, such as the requirement that the drug’s proposed indication be “indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and paediatric patients weighing at least 35 kg and without a history of antiretroviral treatment only.” (treatment-naive).
Doravirine is a non-nucleoside reverse transcriptase inhibitor used in combination with other antiretrovirals to treat HIV-1 infections. Doravirine is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment history. It is also indicated to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no history of treatment failure and no known substitutions associated with resistance to doravirine.
Doravirine is a pyridinone non-nucleoside reverse transcriptase inhibitor of HIV-1. Reverse transcriptase is the enzyme with which HIV generates complementary DNA (cDNA) to its RNA genome; this cDNA is then inserted into the host cell genome, where it can be transcribed into viral RNA for the purposes of replication.
Doravirine inhibits HIV-1 replication by non-competitively inhibiting HIV-1 reverse transcriptase. Doravirine does not, however, inhibit the human cellular DNA polymerases α, ß, and mitochondrial DNA polymerase γ.
At the recent SEC meeting for antimicrobial and antiviral drugs held on February 28, 2023, the expert panel reviewed the presentation made by the pharma majors Emcure and MSD Pharmaceuticals for manufacturing and marketing the antiretroviral drug Doravirine.
After detailed deliberation, the committee noted that:
(i) M/s. MSD submitted this application to support the application submitted by M/s. Emcure Pharmaceuticals for obtaining manufacturing and marketing permission for Doravirine tablet 100mg and Doravirine bulk drug.
(ii) M/S MSD entered into an exclusive agreement with M/S Emcure Pharmaceuticals to accelerate the availability of the drug Doravirine in India.
(iii)M/s Emcure has been granted permission to bioequivalence permission no. BE/ND/21/2022 dated 12.08.2022.
(iv)M/s MSD has presented safety and efficacy data of DRIVE-FORWARD, DRIVE-AHEAD and DRIVE-SHIFT Phase III clinical studies data with Doravirine drug.
(v) There were no treatment-emergent RT K103N, G190A, or Y181C substitutions in any DOR clinical trial, supporting the distinctive resistance profile of DOR.
(vi) M/s MSD also presented non-clinical toxicity data, including genotoxicity, carcinogenicity, antigenicity, immunotoxicity, or dependence, and reproductive and developmental toxicology data.
(vii) Doravirine tablets for oral use are approved in more than 70 countries, including the USA, EU, Japan, UK, Australia, and Canada.
Considering the foregoing, the committee identified that there is an unmet need in the country.
In view of the above, the expert panel recommended for the grant of a Phase III clinical trial waiver to support the application of M/s Emcure Pharmaceuticals for the manufacturing and marketing permission of Doravirine tablet 100mg and Doravirine bulk drug, subject to the following conditions:
i. M/s Emcure should submit a bioequivalence (BE) study report before the committee.
ii. M/s Emcure should conduct a Phase IV clinical trial study, for which the firm should submit the Phase IV clinical trial protocol within 3 months of approval.
iii. M/s Emcure should submit pharmaceutical equivalence data with the innovator product, i.e., PIFELTRO.
iv. M/s MSD should submit CMC data to support pharmaceutical equivalence with M/s Emcure’s Doravirine tablet, 100 mg, and bulk drug.
v. The proposed indication should be “indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 35 kg with no prior antiretroviral treatment history only” (treatment-naive).