Trials and tribulations of drug development: What does it take to establish new treatment for rare diseases?

rare diseases

Rare diseases are a complex and challenging area of medicine, affecting millions of people worldwide. Currently, between 7,000 and 10,000 rare diseases have been identified, with vast and varied symptoms, presenting significant diagnostic and treatment hurdles for both patients and healthcare practitioners.

“A rare disease is defined as occurring in less than one in 2,000 people. Now, that doesn't sound like something many of us will experience. However, if we think that about 1 in 17 of us will experience a rare disease in our lifetime, it means that collectively they are common,” prefaced Alistair Grenfell, President of Europe, Middle East, Africa, and South Asia at IQVIA, during a recent pharmaphorum webinar.  

During the ’Trials and tribulations of drug development’ webinar, sponsored by IQVIA, Dr Joanne Hackett, Vice President, Head of Genomic and Precision Medicine at IQVIA was joined by genetic and rare diseases expert, Dr Melita Irving, Specialist in Clinical Genetics and Skeletal Dysplasia at Guy’s and St Thomas’ NHS Foundation Trust, London, UK, and David H Tegay, Senior Medical Director and Head of the Pediatric and Rare Disease Center of Excellence, Therapeutic Science & Strategy Unit at IQVIA. 

Together, the webinar panellists explored the future of rare disease therapies and what it takes to develop effective medicines. The discussion covered highlights of the multiple steps required to develop new treatments for rare diseases, including examples of illustrative clinical trial studies, and explored new methodologies and emerging opportunities to transform the lives of those affected by rare genetic disorders. 

Rare diseases landscape

During the introduction, Alistair Grenfell highlighted that “75% of rare diseases affect children, and sadly, more than 30% of children with a rare disease do not live beyond their fifth birthday. This means that an early-stage diagnosis is critical. It is also one of the first challenges patients face. Innovations in diagnosis have led to a better understanding of the underlying causes of genetically driven diseases and the mechanisms involved.”

Indeed, one of the most significant challenges for patients with a rare disease is the lengthy diagnosis odyssey, involving multiple healthcare professionals and a variety of tests (sometimes invasive). Often, patients endure years of uncertainty, misdiagnosis, and ineffective treatments before receiving a proper diagnosis. 

Dr Melita Irving, clinical geneticist working in the rare disease space for over a decade, discussed that, as the majority of rare diseases have a genetic origin and the costs of sequencing has dropped down tremendously in recent years, this has opened opportunities for faster and more accurate diagnosis: “Precise diagnosis gives knowledge of the underlying disorder not only to the patient and their family, but also for healthcare professionals. That will allow accurate genetic counselling to be undertaken, including future family planning, current options for disease management, and which specialists need to be involved increasingly in treatment”.

The International Rare Disease Consortium (IRDiRC) was established in 2011 by the European Commission and the US National Institute of Health to tackle the rare disease landscape through research. This international collaboration between funders, companies, patient advocacy groups, and researchers set inspiring goals for advancing diagnosis, care, and access to treatments, while improving our understanding of the impact on people living with rare diseases. 

Clinical trials for rare diseases

Strategies to treat rare diseases can be grouped into two main categories: (a) repurposing existing medications approved for similar disorders or diseases with the same underlying mechanisms and (b) developing new treatment from scratch. One of the biggest barriers for a personalised approach in treating rare diseases is the small number of patients and lack of knowledge around the cause of a rare disease, and a lack of natural history data and effective end points that would predict a successful treatment.

Dr Irving shared successful examples of drug repurposing for paediatric achondroplasia and a rare skeletal dysplasia condition. Lengthy collaborative international trials start as an observational, natural history study to establish baseline data, medical, social, and surgical impacts of achondroplasia affecting children on a day-to-day basis. Notably, not only research institutes and companies are initiating clinical trials, but patient advocacy groups also play a leading role and drive studies on drug repurposing for rare diseases - such as the Alkaptonuria Society and a successful label extension for nitisinone in 2020 in treating alkaptonuria based on the clinical trial data run by a consortium of 12 European partners (DevelopAKUre trials). 

New treatments for rare diseases are being developed from scratch using novel methodologies such as cell and gene therapy, gene editing, and personalised medicines in general. The challenges here are around safety and off-target effects. Even though the pipeline for innovative treatments looks promising, there are many ultra-rare diseases with thousands of people being diagnosed with a genomic disorder in which they are the only person with that genetic variant. For these types of diseases, it is not feasible to put together a traditional clinical trial, so, in the future small (N=1) trials are being looked at for a truly personalised approach:

“Luckily, there is a commitment from industry to develop pipelines for rare diseases and there are lots of start-up companies who are looking into possibilities of N=1 approach,” concluded Dr Irving.

Market access challenges for rare disease treatments

In the second half of the webinar, David H Tegay hosted an interactive session, engaging with the audience so as to discuss the main challenges in developing treatments for rare diseases. 

Based on the evaluation of 46 new FDA approved orphan drugs, the development of orphan drugs takes 20% more time (16 years from first patent filing to product launch) than for non-orphan products (taking on average 13 years): “The length of time to launch generally correlates to the rarity of diseases with particular problems for ultra-rare disorders,” noted Tegay. 

Not only can development timelines be lengthy, but market approval can pose additional challenges in the rare disease space. Notable, a minority of the orphan drug designations result in ultimate market approvals. Additional legislations, such as the Orphan Drug Act (ODA), help to incentivise orphan drug development and have already demonstrated positive statistics.

Together with the audience, Tegay agreed that using the power of genomic technologies to enable broad-based genome testing and newborn screening initiatives might spur the greatest near-term impact in increasing orphan drug development and approval for rare disease indication. The advancements in the development of cell and gene/RNA therapies, as well as increasing real-world data evidence support “do provide powerful impetus and optimism for overcoming challenges in orphan drug development and enabling increased success in achieving new therapeutic options for rare disease patients who cannot afford to lose time to otherwise surmountable hurdles,” ended Tegay.

Harnessing modern technologies and AI for rare diseases

The panel also discussed the potential for artificial intelligence and machine learning applications in the rare diseases space. Dr Irving hopes “that machine learning and artificial intelligence will allow [healthcare professionals] to be able to discern which genetic variants are relevant and which ones can be discarded”, and that using machine learning will help predict which approved drugs can be repurposed for new indications based on thorough analysis of newly discovered interactions and pathways.

Tegay added: “Certainly, AI/ML is revolutionary in our industry. With natural language processing to review medical records and tease out potential aspects of the clinical history in patient populations for rare diseases, [it] can be very helpful in establishing more information about new important clinical endpoints and markers of early diagnosis that we might not be aware of.”

Despite the challenges presented and discussed during this webinar, there is much progress being made in the field of rare disease research and treatment. Innovative technologies, such as cell and gene therapy and precision and personalised medicine, are offering new opportunities to improve patient outcomes. With collaborative efforts between patients, healthcare professionals, researchers, and industry, there is hope for a brighter future for those living with rare diseases.

Maryia T
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Maryia Trubitsyna