Rare Diseases: Awaiting renewed focus

India needs to make significant investments in R&D, policy reforms, and measures to enable affordability and accessibility of medicines and healthcare to manage the burden posed by rare diseases
By Usha Sharma

The global rare disease drug market is expected to touch $242 billion by 2024 with a Compound annual growth rate (CAGR) of 12.3 per cent between 2019-2024. Globally, the definition of rare disease (RD) is at nascent stage although it is evolving constantly. It is assumed that there are approximately 8,000 different types of RDs, with more being discovered each day. Particularly in India, nearly 450 RDs have been enlisted. Due to its poor diagnosis mechanism, low prevalence and limited treatment options, often it is addressed as an ‘orphan’ disease.

Rare diseases in India
The Ministry of Health and Family Welfare, Government of India announced that so far only about 450 rare diseases have been recorded in India from tertiary care hospitals. The most common rare diseases include haemophilia, thalassemia, sickle-cell anaemia, primary immunodeficiency in children, auto-immune diseases, lysosomal storage disorders such as Pompe disease, Hirschsprung disease, Gaucher’s disease, cy

stic fibrosis, hemangiomas and certain forms of muscular dystrophies.

Dr Prashanth L K,Consultant Movement Disorders Specialist, Vikram Hospital informs, “ According to the definition, a rare movement disorder is one whose prevalence is less than 50 per 100,000 population. India constitutes 1/5th of this global scenario. Many of these disorders require dedicated healthcare services and some of them have dramatic medical care. Because of the rarity of these disorders, most of them are usually misdiagnosed and do not get proper interventions.”

Dr Sudheendra Rao,NR Scientific Advisor, Organisation for Rare Diseases India (ORDI) gives more update as he elaborates, “Due to lack of comprehensive national registry for RD or genetic disorders there is no exact data available in India. But, the clinical consensus is that apart from rare cancers, Duchenne Muscular Dystrophy, Limb Girdle Muscular Dystrophy, Spinal Muscular Atrophy, Primary Immunodeficiency disorders, Inborn errors of metabolism, Lysosomal Storage Disorders, Cystic Fibrosis

, Hirschsprung’s Disease, Haemangiomas and Genetically Determined Epilepsies certainly top the chart in the non-oncological orphan diseases. They have varied onset, high mortality depending on the underlying cause whereas, some such as muscular dystrophies are chronic in nature causing a loss in quality of life for one or two decades. It is essential to remember that each of the diseases mentioned above have multiple subtypes as well as genotypes.”

US FDA has designated orphan drug status to nearly 5198 drugs since 1983. There has been a six-fold increase in the orphan drug designations by US FDA in the last decade. This includes drugs developed for 363 different health conditions including some rare genetic diseases. However, the striking feature is that nearly 81 per cent of filing (4208) for orphan drug designation came from the US.

The rising number of rare disease profile indicates that it needs more research and development focus. Since India has a large population, it needs to give this subject considerable attention, especially in terms of research.

Significance of research 
India is 21st in the line of drugs developement of rare disease and between 2003-2019, it has filed 10 drugs for orphan drug designation covering 13 different conditions. The US has had the first-mover advantage with well laid regulatory processes, sufficiently funded R&D centres in both academia and industry and with the insurance industry bearing the cost of the treatments. All these factors have ensured that any investment in developing newer drugs remained lucrative. Therefore, what is apparent is that the focus for developing new drugs for rare diseases is very sharp in the US, however, the rest of the world is yet to catch up. Some of the countries for e.g., the UK, Switzerland, Canada, France, Israel, Sweden, Italy, South Korea and China are increasingly focusing on this growing need.

Rao comments, “Indians need to remember that even though we did not have the privilege of a stable and powerful economy like the US, within 60 years, we have captured 30 per cent (by volume) of the generic market of the US. Together these suggest that R&D funding and patents and licenses majorly guard the focus on developing newer drugs for rare disease portfolio. Purchase power parity and incomplete health insurance coverage are the other two factors dissuading novel formulation research in India.”

To overcome the rare disease burden in India, besides pharma companies, research institutes are also engaging themselves.

Research projects initiatives in India 
Indian Council for Medical Research (ICMR) has been working on a national registry for a while now that is reported to include lysosomal storage disorders, neuromuscular disorders, skeletal dysplasia, haematological disorders, inborn errors of metabolism and primary immunodeficiency disorders.

Rao highlights that knowing the fact that around 70 per cent of rare disorders are due to genetic mutations. Therefore, if we talk about rare genetic disorders, then one of the rarest is genetically documented ribose-5-phosphate isomerase (RPIA) deficiency caused by mutations in RPIA gene. He further elaborates, “RPIA mutations lead to developmental delays, psychomotor regression by seven years, seizures and abnormalities in the nervous system including white matter changes in the brain. There have been only four reported cases worldwide. Apart from symptomatic, rehabilitative and supportive care, there is no specific treatment for this disorder even today. However, for research purposes, genetically modified mice having mutations in RPIA gene have been developed and archived.”

Recently, an official circular issued by the ICMR states that the research body among other things has proposed forming the task force to explore gene editing based therapeutic approaches to treat illnesses. ICMR has narrowed down on genetic diseases affecting the brain and muscles, eye disorders affecting the retina and cornea, heart diseases and blood disorders like thalassemia, sickle cell disease and haemophilia. It has also stressed on diseases like cancer, diabetes and lung diseases. The strategies proposed should have a possibility of translation into future human trials. While the western world has made considerable strides with regards to gene therapy over the past 30 years, ICMR stated that drugs like Luxuturna for Retinitis Pigmentosa, a condition which leads to breakdown of retinal cells in the eye, and leads to low vision, or Yescarta which is a cell therapy for cancer, are currently in clinical trial phase.

Besides ICMR, other research bodies like Council of Scientific and Industrial Research (CSIR) are also working aggressively tracking down the gene sequencing. Recently, CSIR announced the launched of an ambitious project, IndiGen, to sequence whole genomes of diverse ethnic Indian population to develop public health technology applications. It has mentioned that sequencing of 1,008 Indian genomes as part of the project. It aims to complete sequencing of at least 10,000 Indian genomes over the next three years. Many countries around the world have developed rules and guidelines to regulate gene therapy trials. Taking cognizance of situation, it was felt necessary to frame national guidelines and regulations to direct scientists and clinicians including industry regarding the procedures and requirements to be followed for performing gene therapy in India.

These is an indication of developing disease model systems, stem cell products to cheaper and reliable diagnostic methodologies. Rao emphasises, “The onus always falls on the orphan drug sponsor who has to sift through literature or available patient registries to justify the designation. Hence some of the well-kept disease-specific patient registries are with pharma companies and not with governments.”

Market trend
According to Evaluate Pharma- Worldwide Orphan Drug Report, the top 10 multinational pharma companies by 2020 would be Celgen, Novartis, BMS, Roche, Alexion Pharma, Pfizer, Vetex Pharma, Merck AbbVie and J&J. To beat the hit of the market competition, Indian origin companies like Sun Pharma, Biocon, ReGrow Bioscience, Piramal, Natco and Cadila Pharma have at least one designated orphan drug by US FDA. There are several other pharma companies from domestic as well as from the international market who are involved in different profile of rare disease. In addition, there are at least 14 different orphan drug related organisations in India developing therapeutic products or working towards diagnostics.

Rare diseases provide an opportunity to pharma companies for innovation because in contrast to lifestyle diseases, majority of them have discernible elements such as genetic mutations. This leads to an enormous room for novel targets, formulations, dosage all providing opportunities for intellectual property generation. “There are thousands of rare diseases and to tackle some of the rare diseases therapeutically, pharma companies had to resort to advanced therapies, including cell therapy, gene therapy, gene editing, RNA therapy etc., suggests Rao”. However, these newer therapy modalities provide unique advantages to pharma in terms of novelty, efficacy and achieving success and miracles in hard to tackle healthcare problems, thus positively affecting company finances.

While making a comparison of global scenario with Indian context, particularly in research and development of rare disease, it indicates that pharma companies in the US, Europe and Japan have been investing more on the rare disease portfolio. Analysing the possible reason for the thrust there could be the support from government/regulatory agencies!
To name a few, a move of US FDA granting a research grant for rare disease research is an example!

Research grants for rare disease
Recently, the US Food and Drug Administration (US FDA) has awarded 12 new clinical trial research grants totalling more than $15 million over the next four years to enhance the development of medical products for patients with rare diseases. The FDA awarded the grants through the Orphan Products Clinical Trials Grants Programme, funded by Congress to encourage clinical development of drugs, biologics, medical devices and medical foods for the treatment of rare diseases. The grants are intended to substantially contribute to marketing approval of products to treat rare diseases or provide essential data needed for development of such products. The grants awarded are focused on supporting product development to meet the needs of patients impacted by a variety of rare diseases, mainly those affecting children and cancers.

“For more than 35 years, the FDA has been providing much-needed financial support for clinical trials of potentially life-changing treatments for patients with rare diseases. To date, the Orphan Products Clinical Trials Grants Program’s grants have supported research that led to the marketing approval of more than 60 treatments for rare diseases,” informs Amy Abernethy, FDA Principal Deputy Commissioner.

Besides this, there is also a provision for developing orphan drug (OD) which has been financially incentivised through US law via the Orphan Drug Act (ODA) on 4 January, 1983. The enactment of ODA in the US and EU emerged as ground breaking and provided the necessary support to guide research focused