The opportunities and challenges facing rare disease therapies developers

To mark upcoming Rare Disease Day, pharmaphorum asked a panel of experts to give their thoughts on the opportunities and challenges facing developers of rare disease therapies in 2024.

The panel comprised: Jean-Philippe Combal, CEO of Vivet Therapeutics; Dr Jörg Thomas Dierks, CEO of Neuraxpharm; Catherine Pickering, CEO of iOnctura; Jeremy Skillington, CEO, of Poolbeg Pharma; and Miquel Vila-Perelló, CEO and co-founder at SpliceBio.

What does the landscape for rare disease therapies look like in 2024?

Jean-Philippe Combal (JPC): There are global challenges with financing of rare and ultra-rare disease therapies, while in the EU there are uncertainties as to whether payers are able to assess the value of uncertain long-time outcomes.

It’s going to be increasingly important to create patient support frameworks to win over payers and collaborate with regulators to find early clinical benefit biomarker approaches for accelerated approvals.

Miquel Vila-Perelló (MVP): We are off to an excellent start, with the approval of three orphan drugs in three different rare disease areas. Hopefully, we can sustain the trend observed in the last decade, whereby approximately 50% of approved drugs are orphan and aimed at rare diseases.

Jeremy Skillington (JS): In 2024, advancements in rare disease therapies continue, with increased focus on precision medicine, gene therapies, and personalised treatment approaches. Research collaborations and innovative technologies play crucial roles in addressing the unique challenges of rare diseases. Access to these therapies may improve, but affordability and availability remain ongoing concerns.

How significant was the first FDA approval of a CRISPR gene therapy in late 2023, and what other promising and cutting-edge developments are on the horizon?

JPC: It was a turning point, but there is much more to be done. The ex-vivo CRISPR-based therapy adoption by patients will be an important next step, while the next cutting-edge step will be in-vivo CRISPR-based therapy - likely for a more limited number of indications.

MVP: It was fantastic news for patients and an endorsement to all gene therapy modalities. The approval demonstrates the pace at which gene therapies are being developed and the clear unmet medical need (10 years from company foundation to first approval). Another development is the recent reports of AAV gene therapies capable of restoring hearing in patients born with mutations in the gene otoferlin. What’s significant is the notable therapeutic effect of the approach, considering the fact that the otoferlin gene exceeds the packaging capacity of AAV vectors. The otoferlin gene needs to be split in two and delivered in a dual AAV modality. It demonstrates that gene therapy can work extraordinarily well and that dual AAV gene therapy is feasible in the clinic.

JS: The first FDA approval of a CRISPR gene therapy in late 2023 marked a significant milestone, showcasing the potential of gene editing for treating genetic disorders. This breakthrough has spurred further research and development in the field. Ongoing efforts include expanding CRISPR applications, improving precision, and addressing ethical considerations. Additionally, advancements in RNA-based therapies, stem cell treatments, and AI-assisted drug discovery show promise in shaping the future of medical interventions.

How has AI contributed to our understanding and treatment of rare diseases, and how will it affect research in the future?

JPC: It will and can certainly help in rare disease, although it’s difficult to understand the impact on the treatment of rare diseases today. It could help protocol design through the design of virtual arms or real-world data analysis, for example.

Catherine Pickering (CP): AI has already demonstrated its potential in improving the efficiency of diagnosis and treatment. The use of AI can bypass some conventional limitations associated with rare diseases. Namely, it can optimise traditional randomised control trials, and may eventually reduce costs for drug research and development. Recent advancements have enabled researchers to train models based on large datasets and then fine-tune these models on smaller datasets typically associated with rare diseases.

JS: AI has significantly contributed to rare disease research by analysing vast datasets, identifying patterns, and accelerating the discovery of potential treatments. Machine learning algorithms aid in the interpretation of genetic data, facilitating the identification of disease-related mutations. In the future, AI is expected to enhance drug repurposing, streamline clinical trials, and enable more personalised treatment strategies, ultimately improving outcomes for individuals with rare diseases. AI has also contributed to finding eligible patients for approved therapies by mining large claims datasets.

MVP: One thing that is yet to be understood is if AI can significantly improve the odds of identifying drugs that eventually make it across the finish line. In principle, any technology that allows us to do more and much faster will have an impact in the understanding and treatment of diseases. However, a fundamental challenge in the drug development industry is that this hypothesis can only be tested in the clinic, and I think it will take more time to see if AI can deliver on its promise.

Jörg Thomas Dierks (JTD): It is notoriously difficult to understand rare diseases, even within the medical and scientific community, and misdiagnosis is common. AI can be a valuable tool in reducing the time taken to reach an accurate diagnosis and can help with gaining a greater understanding of rare diseases.

How are collaborations between researchers, pharmaceutical companies, and patient advocacy groups shaping the landscape of rare disease research and treatment?

CP: Collaborations are supporting earlier, faster, and more accurate diagnosis of rare diseases. This, in turn, facilitates more efficient rare disease research, clinical trials, and treatment. Ultimately, rare disease communities are very important in supporting patients, advocating for better research, care and treatment, connecting patients and doctors with resources, and influencing regulatory policy.

MVP: Collaborations between biopharmaceutical companies and patient advocacy groups (PAGs) play a crucial role in the development of novel drugs for rare diseases. PAGs, with their close connections to patient communities, can help facilitate patient identification and recruitment for clinical trials, and can even conduct Natural History Studies that are fundamental to understanding the progression of the disease and associated relevant endpoints – such as the Foundation Fighting Blindness did with the ProgStar study in Stargardt disease. More importantly, foundations help us understand what is really important for the patients, and what we need to achieve to improve their quality of life.

JS: Collaborations among researchers, pharmaceutical companies, and patient advocacy groups are vital in advancing rare disease research and treatment. These partnerships facilitate information sharing, accelerate drug development, and address the unique challenges of rare diseases. Patient advocacy groups provide valuable insights, ensuring that research aligns with patient needs. Collaborative efforts enhance data sharing, streamline clinical trials, and promote a more comprehensive understanding of rare diseases, ultimately improving the development and accessibility of treatments.

JTD: Collaborations and support from stakeholders are of great benefit to finding treatments for rare diseases, including receiving help from patient advocacy groups to gain valuable insights on the patient experience from the patients/sufferers themselves.

What are the challenges for clinical trial recruitment for rare diseases?

MVP: Recruiting patients for clinical trials for rare diseases is, by definition, challenging due to the small number of individuals affected by these conditions, which makes it difficult to reach, identify, and enrol enough participants to ensure statistically significant results. These patients are also dispersed around the globe, which complicates their access to trial sites. Finally, many rare diseases are not well-known and have not been deeply studied and characterised, resulting in a lack of awareness or information about available trials for both patients and healthcare providers, further limiting recruitment possibilities.

JPC: Patient education is important because choosing a gene therapy is like choosing an entirely new destination.

It’s important patients understand the risks and benefits throughout the treatment journey. This starts as early as the decision to be screened, being screened, deciding to be injected, to being injected with a co-medication. This awareness must continue throughout the follow-up period, which will be vital as we learn more about long-term durability and safety.

JS: Clinical trial recruitment for rare diseases faces challenges such as limited patient populations, geographical dispersion, and often a lack of awareness about these conditions. Identifying eligible participants becomes challenging due to the rarity of the diseases, potentially leading to prolonged trial durations. Additionally, logistical and financial barriers can hinder patient engagement. Collaboration between researchers, patient advocacy groups, and healthcare professionals is crucial to overcoming these challenges and improving the efficiency of clinical trial recruitment for rare diseases.

CP: Because of the low numbers of patients with rare diseases, it can be challenging to recruit into clinical trials. Further, under legislation passed in 2023, the FDA will require diversity plans for Phase 3 clinical trials conducted in the US. This will enable historically underrepresented patients a stronger opportunity to have investigational access to treatments, but it also places extra challenges on clinical trial recruitment. Drug developers can seek exemptions for the required diversity plan if certain conditions are met.

JTD: The patient population in rare diseases is much smaller by definition than in more prevalent diseases. The pool of potential trial participants is therefore proportionally smaller and can be geographically spread out. Due to the complexities of rare diseases and factors such as slow diagnosis or misdiagnosis, trial recruitment is challenging, and it can often take longer for regulators to consider and approve trials and treatments. Sufferers also have a very complex patient journey, as they typically have to visit several specialists to receive a proper diagnosis. Consequently, patient associations are often very active and supportive, due to the need to give rare disease patients a ‘voice’, and so these channels can help support clinical trial recruitment.

Do you think it will be easier or harder for rare disease biotechs to secure financing in 2024? What advice can you give your peers?

CP: Coming off one of the most challenging periods for IPOs in recent history, 2024 has gotten off to a promising start. Projects with sound scientific rationale, and convincing preclinical and clinical data are a necessity in a funding environment that has become much more risk averse. Investors are showing a preference for mid-to-late-stage data, so, many biotechs will stay private for longer, instead favouring other strategies to raise capital alongside equity financing, including venture debt and non-dilutive funding, such as grants, partnerships, and mergers.

JS: 2024 is expected to be easier than 2023, which was a tough year, but likely more challenging than pre-pandemic years. There is plenty of capital available that has not been deployed and investor confidence appears to be recovering, albeit slowly. While interest in innovative treatments persists, securing financing remains competitive. Peers should emphasise robust and compelling data, engage in strategic partnerships, and effectively communicate the societal and medical impact of their work to attract investors. Staying informed about funding trends, leveraging collaborative networks, and showcasing the clinical and commercial potential of their initiatives will be key for rare disease biotechs seeking financing.

MVP: Judging by the optimism earlier this year at the JP Morgan Healthcare Conference in San Francisco, 2024 will provide more opportunities to secure financing. The best advice I have received and tested to be true is that you need to be determined and giving up is not an option: there are patients waiting for us to bring much needed treatments across the finish line.

JPC: Being cautiously optimistic, it could be easier if inflation is reduced and data is supportive – otherwise, it will remain hard.

About the interviewees

Jean-Philippe Combal has 26 years of experience in the pharma & biotech industries. He is a highly skilled senior executive with a broad range of experience leading global development and a successful track record of innovation and development in the area of orphan drugs. While chief operating officer of GenSight Biologics, he successfully contributed and participated to an investment round of more than $80m, including a successful IPO, and piloted the advancement of two major gene therapy programmes from non-clinical to phase 3 pivotal trials, as well as regulatory and launch readiness strategies. Combal earned his PhD in Toxicology and PharmD from Paris XI University and holds a Master’s in Strategic Marketing from ESCP Paris, as well as a General Management Programme from the centre of executive development at INSEAD.

Dr Jörg Thomas Dierks has 30 years of healthcare experience and has held several senior executive positions in the pharmaceutical industry. He joined Neuraxpharm in 2018 from his previous post as CEO of Meda, a Swedish specialty pharmaceutical company, which he held from 2013. Dierks had been the chief operating officer for Meda from 2005 and also assumed the role of chief scientific officer for a period of time. He was instrumental in growing the business over many years and led its sale to Mylan in 2016 for $10bn. Before joining Meda, Dierks was chief operating officer at Viatris, a pharmaceutical company based in Germany. He graduated from Johannes-Gutenberg-Universität zu Mainz with a degree in Human Medicine. This included working for a year in a hospital in Koblenz in 1986, earning him the title of Medical Doctor. One year later, Dierks was awarded the title of Doctor of Medicine. He also studied business administration for scientists at the Fernuniversität Gesamthochschule in Hagen.

Catherine Pickering holds a PhD in Medicinal Chemistry and an MBA. During her career, she has held various licensing and business development positions in pharma and biotech. Before founding and building iOnctura, she led the global oncology and immuno-oncology licensing and business development function at Merck. During her time at Merck, she was also an integral member of the oncology franchise leadership team, a cross functional team responsible for creating the strategy and managing the oncology business.

Jeremy Skillington began his biotechnology career in the Business Development group of Genentech, Inc in California in 2002. At Genentech, he was responsible for executing over 40 licensing, investment, and collaboration transactions. Returning to Ireland in 2009, Skillington led Business Development and was a member of the Senior Management team at Opsona Therapeutics Ltd, before becoming a founder and CEO of mmune-oncology company TriMod Therapeutics Ltd. In 2014, he joined German investment fund HS Lifesciences GmbH to provide start-up and business development support to portfolio companies ImmunoQure AG and Ethris GmbH. Skillington joined Inflazome at its founding in 2016 and was instrumental in their acquisition by Roche in September 2020 for €380m (£325m) upfront and significant downstream milestones. He studied Biochemistry at the National University of Ireland, Galway where he was awarded his PhD. He performed his post-doctoral research at the University of California, San Francisco in the lab of Professor Rik Derynck.

Miquel Vila-Perelló co-founded SpliceBio and serves as CEO. He has broad experience in biotechnology, chemical biology, and protein chemistry, as well as in the managing of research teams and projects. After obtaining his PhD at the University of Barcelona, Vila- Perelló carried out postdoctoral studies at The Rockefeller University. He later became a Research Scholar at Princeton University, where he managed the Protein Center at the Department of Chemistry. Over the last ten years, he has contributed to the discovery and development of novel protein ligation technologies. He has authored more than 23 publications, including patent applications, and has a proven track record for the leadership of scientific teams and non-dilutive fundraising.