Rare Disease R&D: one step forward, but a long road ahead

With over 40% of all medicines in the pipeline aimed at rare diseases, the future looks positive for increasing the number of treatments available. However, as Ben Hargreaves discovers, research into the area has only scratched the surface, amid calls for greater funding and greater collaboration to accelerate progress.

There are approximately 7,000 different types of rare disease and researchers estimate that there are more than 300 million people worldwide living with such a condition. When taken proportionately, the impact on health for people worldwide is much larger than might be thought for diseases that are classified as rare, with between 3.5 and 5.9% of the global population affected.

The problem in effectively treating rare diseases is that the incidence within a country’s population is usually low – the definition of a rare disease is a condition that affects 200,000 people or fewer. As a result, even the most basic tasks, such as correctly identifying such a disease, can be made extremely difficult. Many rare diseases require a specialist to accurately make the diagnosis, and some rare diseases do not offer specific symptoms, instead they can cause broader health problems, such as pain, weakness, and dizziness.

This means that patients average more than seven years in the US and five years in the UK before receiving an accurate diagnosis, with this journey often taking years. During this wait, people living with rare diseases are faced with the difficulty of living with a condition without the correct treatment. Once diagnosed, only 5% of rare diseases actually have an effective treatment.

The outlook for rare disease R&D

Many of the small challenges that face individual doctors and patients in seeking to find a solution for a rare disease also contribute to the difficulty of researching and developing an effective treatment. The sheer number of different rare diseases means that the battle to provide a treatment for each and every condition will be a long one. Once a target has been selected, the new battle begins in terms of being able to gather enough patients to progress a clinical trial as rare diseases, by nature, mean few people to select from. Once identified, there is also the challenge of the geographic spread of individuals living with the same rare disease and then finding a means to ensure that each person can reach the clinical trial site.

The highlighted issues are just a few of reasons that make developing treatments in the area of rare diseases a challenging one. However, the outlook is changing for rare disease R&D, as the unmet need in this area is being increasingly recognised. Regulatory bodies worldwide have introduced measures to encourage development of treatments for rare diseases, or orphan drugs, as they are known. Both the US Food and Drug Administration (FDA), through the Orphan Drug Act, and the European Medicines Agency (EMA), through the Orphan Medicinal Product Regulation, encouraged the development of orphan drugs, by providing extra support to companies working in the area, or through the offering of financial incentives to pursue rare disease R&D.

The result of this approach has seen a number of breakthroughs in the development of orphan drugs. In 2021, orphan drugs accounted for 52% of all novel drugs approved by the FDA, which had been preceded by 58% of all approvals in 2020.

A growing pipeline

However important the breakthroughs made in the recent past, the future of R&D in the space is crucial to determine how much progress is being made towards providing treatments to the 95% of diseases that are unaddressed. The positive news is that the pipeline of treatments for rare diseases is healthy, with 40% of new medicines in development being orphan drugs, a spokesperson for the European Federation of Pharmaceutical Industries and Associations (EFPIA) told pharmaphorum.

The spokesperson added that due to the regulations introduced by the EMA, “Between 2000 and 2020, 190 new medicines were approved by the EMA, addressing the needs of up to 6.3 million rare disease patients. This represents a massive jump from the 8 orphan-like medicines approved in the years leading to 2000. These incentives help drive the €39 billion a year industry invests in European research and development.”

Virginie Hivert, Therapeutic Development Director, and Simone Boselli, Public Affairs Director, of EURORDIS, an alliance of patient organisations focused on rare diseases, agreed on the progress achieved in recent years, saying: “We have witnessed great progress in research, discovery of treatment for rare diseases in the past twenty years in Europe. Scientific advancements in the understanding of different diseases, coupled with developments in therapies design means that many diseases previously untreated are now looking at potentially having their genetic root causes addressed.”

Being able to ascertain the genetic root of a rare disease has caused a boom in research into gene therapies, which has seen three significant approvals for rare diseases in recent years: Luxturna (voretigene neparvovec), Zynteglo (betibeglogene autotemcel ), and Zolgensma (onasemnogene abeparvovec). The benefits of gene therapies is some are able to offer a one-time cure for a monogenic disorder, as with each of these three approvals. Due to the viability and the recent success seen with gene therapies, there is now a growing pipeline under development – there are currently approximately 179 trials on going for gene therapies targeting rare diseases.

Work to be done

In terms of what the R&D process looks like in developing a treatment for a rare disease, pharmaphorum reached out to Vertex Pharmaceuticals to learn more about its general development process and specifically why rare diseases present such a challenge. The company has had success developing four treatments for cystic fibrosis, which is classified as a rare disease as there are approximately 70,000 people living with the disease worldwide.

“We only focus on diseases in which we understand the causal human biology, where there are validated targets, and translational assays and biomarkers that translate from bench to bedside. Our confidence in the targets and assays leads us to invest in advancing multiple clinical candidates into early clinical trials in parallel, maximising the chance of ultimate success,” a spokesperson for the company said, when explaining the company’s R&D approach.

The spokesperson continued to outline that what makes R&D in rare diseases particularly difficult, especially where fully understanding ‘causal human biology’ is integral to its R&D model, is that often there is only a limited understanding of the root cause or causes of each rare disease. When developing its clinical candidates, Vertex will develop multiple candidates based upon ‘predictive biomarkers’ and then once a candidate has been found that combines both causal human biology with a ‘compelling clinical profile,’ the candidate be progressed further, the spokesperson added.

Understanding the human biology that underpins each rare disease has been one of the long standing challenges to the development of treatments. Hivert and Boselli of EURORDIS suggested that the rare disease research community has been ‘very fragmented’ due to the large range of rare diseases, as well as due to a lack of funding for research in each disease and a “lack of concerted efforts to organise research and thus reach the requisite threshold for progress.” This stance calling for greater research and greater collaboration was echoed by the spokesperson for EFPIA, who suggested that “fundamental research is effectively non-existent” in many rare diseases.

A call for greater support

What can be done to address this lack of fundamental research? From the spokespeople of EFPIA, EURORDIS and Vertex, there was a unified call for greater dialogue and cooperation by all stakeholders. The spokesperson for Vertex called specifically for earlier dialogue between drug developers, regulators and health technology assessment bodies to have ‘an open and transparent dialogue’ through the development process.

As a practical example of the ways multiple stakeholders could work together, the EFPIA’s spokesperson provided an example: “Europe-wide patient registries, set up in collaboration with policymakers, hospitals, patients, and industry, could help track epidemiology and nature of these diseases, as well as characterise burden and unmet needs.” While EURORDIS actually created an orphan drug development guidebook, alongside the International Rare Diseases Research Consortium, to facilitate drug development wherein the guidebook describes the available tools and initiatives specific to rare diseases to aid researchers.

More than collaboration, Hivert and Boselli of EURORDIS called for greater funding to be dedicated to R&D into rare diseases: “Basic, clinical, social and translational research on rare diseases should be maintained as a priority by increasing the funds for competitive and pre-competitive research, establishing greater incentives in more neglected areas (or in areas of high unmet needs), and supporting infrastructures required to expedite discovery and knowledge acquisition.”

According to a study published by the National Institutes of Health, the yearly medical care cost for the 25 to 30 million people living with rare diseases is approximately $400 billion in the US alone. Worldwide, this cost only increases and suggests that any investment that can be made to create new, effective treatments for these individuals has the potential to reduce this cost to healthcare systems and to the individuals living with the disease. In the case of gene therapies, where there is the possibility to develop ‘one and done’ treatments, whereby patients only need one dose to be cured, the potential is even higher. With a burgeoning pipeline of such treatments, as well as a healthy proportion of the overall pharmaceutical pipeline being dedicated to rare diseases, the number of approved treatments emerging could increase even further still. However, with 95% of rare diseases still requiring treatments, there is still a lot of work, and R&D, left to be done.