What Happened
- Zydus Lifesciences received Orphan Drug Designation (ODD) from the US Food and Drug Administration (USFDA) for Desidustat, an oral drug for the treatment of Sickle Cell Disease (SCD).
- Desidustat is a novel Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor (HIF-PHI) that works by increasing haemoglobin levels and red blood cell counts.
- Zydus has already completed a Phase II, double-blind, randomized, placebo-controlled, multi-centre proof-of-concept study evaluating Desidustat in SCD patients.
- The orphan drug designation provides eligibility for tax credits on clinical testing, FDA user fee exemptions, and potential seven-year marketing exclusivity upon USFDA approval.
Static Topic Bridges
Sickle Cell Disease: Prevalence and India's Elimination Mission
Sickle Cell Disease is an inherited blood disorder caused by a mutation in the beta-globin gene, leading to the production of abnormal haemoglobin (HbS). Under low-oxygen conditions, HbS polymerizes and causes red blood cells to become rigid and sickle-shaped, blocking small blood vessels and causing painful vasoocclusive crises, organ damage, and reduced life expectancy. India has the third-highest number of annual SCD births globally, after Nigeria and the Democratic Republic of the Congo.
- Approximately 73% of Indians with the sickle haemoglobin gene (HbS) belong to tribal (indigenous) communities, which constitute 8.6% of India's population.
- Prevalence of sickle cell trait (HbAS) in Indian tribal populations ranges from 1% to 40% depending on the region and ethnic group.
- In central India, approximately 1 in 86 births is affected by SCD, with around 20% of affected children dying before their second birthday.
- The National Sickle Cell Anaemia Elimination Mission was launched by the Prime Minister on July 1, 2023, with the goal of eliminating SCD as a public health problem by 2047.
- The mission initially covers 17 high-prevalence states and targets screening of the entire population aged 0-40 years.
- As of June 2024, over 3.37 crore individuals had been screened under the programme.
Connection to this news: Desidustat represents a potential new therapeutic option for SCD, which is significant given that India has one of the world's largest SCD patient populations, predominantly among vulnerable tribal communities with limited access to existing treatments.
Orphan Drug Designation Framework
The Orphan Drug Act of 1983 in the United States was enacted to incentivize pharmaceutical companies to develop treatments for rare diseases that would otherwise be commercially unviable. A rare disease under US law is defined as one affecting fewer than 200,000 persons in the United States, or one for which there is no reasonable expectation that the development cost will be recovered from sales.
- Benefits include: 25% tax credit on qualified clinical trial costs, exemption from FDA user fees (Prescription Drug User Fee Act), and seven years of marketing exclusivity upon approval.
- During the seven-year exclusivity period, the FDA cannot approve another application for the same drug for the same indication from a different manufacturer.
- An exception exists: the FDA may approve a competing orphan drug if the original manufacturer cannot supply sufficient quantities.
- India does not have a separate orphan drug legislation; the Drugs and Cosmetics Act, 1940 does not specifically address rare diseases, though the National Policy for Rare Diseases 2021 provides a framework for financial support.
Connection to this news: The USFDA orphan drug designation for Desidustat provides Zydus with significant regulatory and financial incentives to advance clinical development for SCD, a disease with limited therapeutic options despite affecting millions globally.
HIF Pathway and Prolyl Hydroxylase Inhibitors
Under normal oxygen conditions, Hypoxia-Inducible Factor (HIF) is rapidly degraded by prolyl hydroxylase enzymes that mark it for destruction. HIF-Prolyl Hydroxylase Inhibitors (HIF-PHIs) block this degradation, stabilizing HIF and mimicking the body's natural response to low oxygen (hypoxia). This triggers increased erythropoietin (EPO) production and enhanced iron absorption, stimulating red blood cell production.
- HIF-PHIs were initially developed for anaemia associated with chronic kidney disease (CKD); several are already approved for this indication in various countries.
- In sickle cell disease, HIF-PHI stabilization may also promote fetal haemoglobin (HbF) expression, which inhibits HbS polymerization and reduces sickling.
- Desidustat has shown ability to increase haemoglobin, RBC count, and haematocrit in preclinical models.
- In vitro studies demonstrated that Desidustat reduced sodium metabisulfite-induced sickling in RBCs from SCD patients.
Connection to this news: Desidustat's mechanism as a HIF-PHI addresses SCD through a different pathway than hydroxyurea (the current standard of care), potentially offering an alternative for patients who do not respond to or cannot tolerate existing treatments.
Key Facts & Data
- Drug: Desidustat (oral HIF-Prolyl Hydroxylase Inhibitor) by Zydus Lifesciences.
- Designation: USFDA Orphan Drug Designation for Sickle Cell Disease.
- Clinical status: Phase II proof-of-concept study completed.
- Orphan drug benefits: tax credits, user fee exemption, potential 7-year US market exclusivity.
- SCD in India: third-highest birth prevalence globally; 73% of carriers are from tribal communities.
- National Sickle Cell Anaemia Elimination Mission: launched July 1, 2023; target year 2047; covers 17 states.
- Over 3.37 crore individuals screened under the mission as of June 2024.
- Current SCD treatments: hydroxyurea (not universally effective; risk of neutropenia, thrombocytopenia), blood transfusions (costly; risks of iron overload, alloimmunization).
- Rare disease threshold (US): fewer than 200,000 affected persons.