Vertical 3: Development of Repurposed Drugs/New Drugs & Vaccine

Objective

Given the recent emergence of the COVID19, worldwide there are no drugs available for the treatment. However, given that developing new drugs against Coronavirus will take several years, efforts are on globally to fast track and test the drugs approved or tested for non-coronavirus diseases such as HIV or Ebola (called as repurposing). India is also participating some of these global trials and will also carry out its own clinical trials. The main focus of this vertical is on enabling quick access to drugs against coronavirus for Indian patients as soon as they are developed in India or globally. CSIR is exploring all possible options ranging from repurposed drugs to new drugs to Ayush products and biological therapeutics including Vaccines.

Towards that CSIR is working on the synthesis of the top 'potential' repurposed drugs in case India goes for compulsory licensing such that India can quickly launch the drugs in the country for patients. For this CSIR has tied up with top pharmaceutical Industries such as Cipla and CSIR has well established credentials in synthesis of drugs and having worked closely with industry and having been the fountain head of processes for generic drugs for which India is globally renowned.

  • Clinical trials of Mw: CSIR and Cadila have received regulatory approval for clinical trials to evaluate efficacy of an existing gram-negative sepsis drug, called Sepisvac for COVID19 patients. The drug contains heat-killed Mycobacterium (Mw) and is found to be extremely safe in patients and no systemic side effects are associated with its use. Sepsivac has been clinically developed and approved for gram negative sepsis, a severe infection. The drug has been shown to reduce the mortality of critically ill patients by more than half. It also leads to faster recovery of organ dysfunction seen in this condition. It is now approved for marketing in India and will be available commercially as Sepsivac® from Cadila Pharmaceuticals Ltd. The drug now will be tested in three different trials to combat Covid-19.
    • On critically ill Covid19 patients: "A clinical trial to evaluate the safety and efficacy of Mw in critically ill patients suffering from COVID 19 infectionā€¯ vide Protocol Number: CRSC20004 Version-02, was approved by DCGI. This will be a randomized, blinded, two arms, active comparator-controlled clinical trial and will evaluate the efficacy of the drug for reducing mortality (deaths) in critically ill COVID-19 patients. The trial will be conducted in AIIMS-New Delhi, AIIMS-Bhopal and PGI, Chandigarh and is expected to be completed in the next few months.
    • Hospitalized (but not critically ill) Covid19 patients: Permission for conducting a Phase III clinical trial titled " A Randomized, Double-blind, two arm, controlled clinical trial to compare the Efficacy and Safety of Mycobacterium w (Mw) administered along with Standard of care versus Placebo administered along with Standard of care, in adult, COVID 19 positive patients hospitalized but not critically ill.ā€¯ vide Protocol Number: CRSC20006 Version-02, dated 15th April 2020 was provided by DCGI. This trial will assess quicker recovery of hospitalized COVID-19 patients, who are not critically ill. This will also look at prevention of the progression of disease wherein patients will need ICU management.
    • High Risk Contacts of Covid19: "A Randomized, Double-blind, two arm, Placebo Controlled Clinical Trial to Evaluate the Efficacy and Safety of Mycobacterium w in preventing COVID-19 in subjects at risk of getting infected with COVID-19ā€¯ vide Protocol Number: CRSC20005 Version-02, dated 15th April 2020 was also approved. This trial aims to see if Mw can protect the close contacts of COVID-19 patients and health care staff by boosting their innate response and thereby preventing them from acquiring the disease.
    In Gram-negative sepsis as well as in critically ill COVID-19 patients, there is an altered immune response leading to a massive change in their cytokine profile. The drug modulates the immune system of the body and thereby inhibits the cytokine storm leading to reduced mortality and faster recovery. It can be used concurrently with any other therapies required in the management of such critically ill patients without any restriction. Its unique properties include boosting protective immunity (Th1, TLR2 agonist) and suppressing non-protective response (Th2).
  • Small Molecules and Active Pharmaceutical Ingredients (APIs): CSIR's focus is on the repurposing of existing drugs in the advanced clinical trials world over, synthesis of key intermediates of these drugs as well as Hydroxychloroquine to reduce India's dependence on imports, initiate trial on indigenous repurposed drug, and clinical trials of Phytopharmaceuticals and AYUSH drugs. Following drugs are being developed:

      Name Indication for which it is approved/ under trial Is under trial for COVID-19 IP Status/ Company Industrial partner in India TRL level Present Status
      FavipiravirInfluenza/ Russia/, China, JapanYes Expired in 2019/ Fujifilm Yes 8 Cipla has received approval for clinical trials of Favipiravir which are set to begin soon and CSIR-IICT is working with Cipla
      RemdesivirCDFDYes Patent valid till 2035/ Gilead Yes 5 Received emergency approval by FDA and Gilead has given voluntary license to several Indian companies
      Umifenovir (Arbidol)University of HyderabadYes Patent expired Yes 7 CSIR made process development and industrial partners scaling up studies
      Chloroquine/ Hydroxychloroquine (intermediate)CSIR-IICTYes Generic Yes 6 Gram scale synthesis completed with starting materials available in India
  • New Drug Discovery and Development: In addition to repurposed drugs, it is important that new drugs specific to coronavirus are discovered and taken up for development.
    • CSIR labs, CSIR-CDRI, CSIR-NCL, CSIR-IICT, CSIR-CLRI, CSIR-IIIM and others are working on this aspect and are utilizing molecular modeling based approach followed by screening and testing.
  • Phytopharmaceutical Formulation: CSIR and Sun Pharma are developing ACQH, a formulation developed for dengue being repositioned for coronavirus. The application for the clinical trial has been submitted to DCGI and approval is expected soon.
  • Supplements: CSIR has filed an application for Trademark for developing Zinc Gluconate and Vitamin C as nutraceutical, which have been found beneficial in patients with coronavirus infection.
  • Traditional Medicine: CSIR is working with the Department of AYUSH and the joint efforts of CSIR-Ministry of AYUSH have been planned in as prophylactic, symptom management, and add-on interventions to the modern medicine treatments. Following AYUSH botanicals/formulations have been taken up by CSIR and Min. of AYUSH for clinical trials:
    • Glycyrrhiza glabra (CSIR, Medanta Hospital, Min. of AYUSH)
    • Tinospora cordifolia (CSIR and Medanta Hospital, Min. of AYUSH)
    • Withania somnifera (CSIR, Pune University, Min. of AYUSH)
    • AYUSH-64 (Min. of AYUSH and CSIR) This is a four-herb formulation comprising of Alstonia scholaris, Picrorhiza kurroa, Swertia chirayita, and Caesalpinia crista
    • Biological Therapeutics and Vaccines
  • Inactivated Corona Vaccine: CSIR-CCMB and Bharat Biotech are working together for inactivated coronavirus vaccine development under the aegis of CSIR-NMITLI Program.
  • Convalescent Plasma Therapy: The U.S. Food and Drug Administration has approved the use of convalescent plasma therapy as an experimental treatment in clinical trials, and for critically ill COVID-19 patients without other treatment options. The therapy, which takes antibodies from the blood of a person who has recovered from a virus and transfuses those antibodies into a person sick with that virus, has long been used as a way to help kick start a person's immune system. The CSIR-IICB proposal on convalescent plasma therapy has been approved by the West Bengal State Govt. on April 9, 2020.
    • The trial has been planned involving CSIR-IICB, Medical College Hospital, and ID & BG Hospital. Applications were made to the Human Ethics Committees and the approval has been received from all three institutes. The trial has been submitted for registration at the Clinical Trial Registry of India and would be submitted for regulatory approval. A dedicated 'Epidemic Immune Monitoring Lab' has been prepared for this program.
  • Corona Viral Cultures and Cell lines for Screening Assays and Testing: In order to take forward new drug discovery, a critical step is the establishment of viral cultures and assays for testing. CSIR-CCMB has made considerable progress towards that and all the identified small molecules, natural products and phyto-pharmaceuticals will be tested once the platform is ready. It will also help in vaccine development.