Nabanita Das, PhD
Email: dasnabanita123@gmail.com
SERB-National Postdoctoral fellow, CSIR-Central Drug Research Institute, Sector-10, Jankipuram extension, Sitapur Road, Lucknow-22603, Uttar Pradesh. India.
Abstract
Development of a brand new drug takes enormous toll on time, money and effort, due to bottlenecks in therapeutic development. Strategically repurposing drugs for other uses can save time and money, as their pharmacology, formulation and potential toxicity are already known. The preclinical phase includes a demonstration of its efficacy in invitro or in vivo model system and then filing the experimental new drug application with the U.S. Food and Drug Administration (FDA), it typically enters into clinical phase II trials. The cost of launching a repurposed drug is approximately 85% less than for a de novo drug. Besides repurposed drugs, repositioned and rescued drugs generate 25% of annual revenues for the pharmaceutical industry as per the estimate. There are multiple illustrations of drug repurposing to date, the pioneer was the repurposing of thalidomide, initially a sedative and anti-leprosy, later approved for the treatment of multiple myeloma by USFDA in 2012.
Clofazimine (CFZ), primarily known for its anti-leprosy activity is shown to be effective against primary interventions for multidrug-resistant tuberculosis, chronic myelogenous leukemia (CML), and more recently SARS-CoV-2. CFZ was discovered during 1950s at Trinity College, Dublin, was approved for use in the United States in 1986, presently it is in WHO list of essential medicines.
The efficacy of CFZ against Mycobacterium Avium Complex (MAC) was demonstrated by Jarand et. al. from University of Calgary, Canada in 2016. CFZ administered in combination with macrolide and ethambutol was shown to be highly effective in treatment of MAC. The work was recognized and published in the renowned journal CHEST.
The research group at CSIR-Central Drug Research Institute, Lucknow in collaboration with Zydus Research Centre, Ahmedabad and King Georges Medical University, Lucknow has demonstrated that CFZ can defeat leukemic stem cells (LSCs) and resists relapse in CML patients.
CML, a type of cancer affecting blood and bone marrow developed due to chromosomal aberrations is one of most recurrent adult leukemia in Indian population, which accounts for 30%-60% of all leukemia. The management of CML was revolutionized by the targeted treatment with imatinib that has become the standard treatment of choice. The second-generation of medicine includes nilotinib, dasatinib administered to patients resistant or intolerant to first-generation of drugs. However, although effective, second-line therapy comes at a significant expense. It has been estimated that the cost can measure up to $800000 per quality-adjusted life-year compared to generic imatinib. Moreover, a considerable number of patients suffer from relapse and progression when the first/second-line therapy stops due to the activity of leukemic stem cells (LSCs).
The breakthrough research from the group shows CFZ is particularly effective in imatinib-resistant patients and terminates LSCs including notorious quiescent stem cells derived from CML patients without causing harm to hematopoietic cells derived from healthy individuals. The drug could successfully over empower cellular leukemic/oncogenic factors often associated with multidrug-resistant patients. Interestingly CFZ when administered in combination with imatinib at a significantly low physiological dose known so far, proved exceptionally effective in comparison to monotherapy. The outcome of the study was published in a reputed journal, HAEMATOLOGICA. Leukemic stem cells possess immense hindrance to the existing drugs, as they are incapable of targeting quiescent stem cells. The identified drug from the study could overcome this hindrance and can be proposed for its further clinical evaluation.
The future of this comprehensive study depends directly on clinical evaluation in humans because preclinical validations, pharmacokinetics and toxicity studies have already been performed in detail. Successful execution of clinical trials will render healthcare much more affordable for CML patients of Indian origin. The research team with their disease-centric viewpoint screened over most possible repurposing candidates for the treatment of chronic myeloid leukemia and has come across CFZ. Again, they have explored the use of novel combination therapies, where the repurposed drug increases the efficiency of imatinib, a well-known treatment and could dramatic improvements in outcomes. This research promises that in the future treatment of CML who are resistant to existing drugs or relapse patients will benefit from it as the cure will become within reach in economically backward parts of India. Clinicians can bank on CFZ repurposing for the treatment of chronic myeloid leukemia.
Most recently in 2020, researchers from Sanford Burnham Prebys Medical Discovery Institute and the University of Hong Kong demonstrated that CFZ was capable of inhibiting SARS-CoV-2 multiplication in hamsters. Their research published in the highly reputed journal NATURE reports CFZ to be effective against several coronaviruses in including the novel coronavirus. Novel emerging infectious diseases like the present COVID-19 possess extreme challenges to the healthcare systems. This creates an urgent need for effective pharmacological treatments. The demand can only be fulfilled by repurposing drugs due to the lack of available time for new drug formulation. The antiviral synergism between clofazimine and remdesivir, the first ever-pharmacological approach towards prevention of Covid-19 has a promising future. Repurposing clofazimine thus brings a ray of hope for combating the prevalent pandemic situation.
References:
1. Challenges and opportunities with drug repurposing: finding strategies to find alternative uses of therapeutics. Alan Talevi and Carolina L Bellera. Expert Opin Drug Discov. 2020 Apr;15(4):397-401.
2. Long-term Follow-up of Mycobacterium avium Complex Lung Disease in Patients Treated With Regimens Including Clofazimine and/or Rifampin. Julie Jarand, J Paul Davis, Robert L Cowie, Stephen K Field, Dina A Fisher. Chest. 2016 May;149(5):1285-93.
3. Leprosy drug clofazimine activates peroxisome proliferator-activated receptor-γ and synergizes with imatinib to inhibit chronic myeloid leukemia cells. Sabyasachi Sanyal et. al. Haematologica 2020 Apr;105(4):971-986.
4. Clofazimine broadly inhibits coronaviruses including SARS-CoV-2. Kwok-Yung Yuen et. al. Nature. 2021 May;593(7859):418-423.
