Rare Disease Day 2024, which falls on February 29 this year, is an opportunity to unite under a common cause: to bring attention to the challenges faced by those living with rare diseases and to push for advancements in research, treatment and policy.

There have been significant advancements in new rare disease drugs, particularly for genetic disorders that can be treated by correcting, replacing or silencing defective genes. Technologies like CRISPR-Cas9 have revolutionized the potential for gene editing, offering hope for curative treatments for conditions like Duchenne muscular dystrophy (DMD) and certain types of inherited blindness.

The US Food and Drug Administration (FDA) has approved a number of new rare disease drugs in recent years, including gene therapies. In 2020, 31 out of 53 novel drug approvals were for rare or orphan diseases​​. This focus continues, with 20 out of 37 novel drug approvals targeted towards rare diseases​ in 2022 and around 24 out of 55 in 2023.

Recent FDA Approvals of New Rare Disease Drugs

• Filspari (sparsentan) for primary immunoglobulin A nephropathy (IgAN), a rare kidney disease, marking it as the first non-immunosuppressive therapy for the condition. Approved in February 2023, Filspari is distinguished by its mechanism of action, which involves blocking both endothelin and angiotensin receptors, offering a new treatment option beyond angiotensin-targeting angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) commonly repurposed for IgAN​​.

• Skyclarys (omobaloxone) was approved in 2023 for the treatment of adults and pediatric patients 16 years of age and older with Friedreich’s ataxia, a rare, neurological disease​​. Developed by Reata Pharmaceuticals, which Biogen acquired later that year, it is the first and only treatment for the condition, which is classified as an ultra-rare neuromuscular condition that damages the nervous system to affect movement.

• Casgevy (exa-cel) and Lyfgenia (lovo-cel) were the first gene therapies to be approved by the FDA for the treatment of sickle cell disease (SCD). Both therapies were awarded their approvals on the same day in December 2023. With the approval, Vertex Pharmaceuticals and CRISPR Therapeutics’ jointly developed Casgevy also became the first CRISPR/Cas9-based therapy approved in the US. bluebird bio’s Lyfgenia is a lentiviral-based gene therapy, which, like Casgevy, is designed to increase levels of functional hemoglobin in red blood cells, which are compromised in SCD.

• bluebird won approvals for two other gene therapies in 2022 — Skysona (elivaldogene autotemcel, eli-cel) for the treatment of the rare neurological disorder cerebral adrenoleukodystrophy (CALD) and Zynteglo (betibeglogene autotemcel, beti-cel) for beta-thalassemia.

• Elvidys (delandistrogene moxeparvovec-rokl) was the first gene therapy approved for DMD and remains the only one for the disease. Developed by Sarepta Therapeutics, the therapy is approved for ambulatory children four to five years of age with DMD who have a confirmed mutation in the dystrophin gene. Sarepta hopes to clarify Elvidys’ effectiveness in older children in a confirmatory trial.

Despite high price tags of a couple of million dollars, gene therapy makers say they are working to ensure patients are able to access the treatments through patient assistance programs developed in conjunction with the support of governments.

XTALKS WEBINAR: A Collaborative Approach to Advancing Access and Equity in Rare Disease Clinical Trials

Live and On-Demand: Thursday, February 29, 2024, at 11am EST (4pm GMT/UK)

Register for this free webinar to join the discussion with clinical trial experts on a collaborative approach to patient-friendly trials in rare disease.

Advances in Rare Disease Clinical Research

Orphan Drug Legislation

Many countries have implemented orphan drug acts to incentivize the development of treatments for rare diseases. These regulations offer benefits such as tax credits, grant funding and extended market exclusivity for approved drugs. The FDA introduced its Orphan Drug Act in 1983.

Innovative Trial Designs

To address the challenges of conducting clinical trials in small populations, researchers are using innovative designs such as basket trials, n-of-1 trials and adaptive designs. These approaches allow for more flexible and efficient studies across multiple rare diseases or subtypes within a single trial, which can accelerate the development process and reduce costs.

Patient-Centric Approaches

There’s a growing emphasis on patient-centric approaches, including patient-reported outcomes (PRO) and engagement with patient advocacy groups in trial design and execution. These approaches help ensure that trials address the needs and concerns of the rare disease community. Tools like PRO measures (PROMs) are being used more frequently to assess the impact of treatments from the patient’s perspective.

Advanced Technologies

The use of genomics, biomarkers, digital health technologies and technologies like AI and machine learning are improving the identification of potential participants and enabling more precise and personalized treatment approaches.

International Collaboration

Collaboration between pharmaceutical companies, academic institutions and patient advocacy groups has become an essential driver in rare disease research in recent years. Global networks and consortia are facilitating collaboration across countries and disciplines, pooling resources and sharing data to overcome the challenges of rare disease research. Public-private partnerships are also playing a crucial role in advancing research and development.

An example is the International Rare Diseases Research Consortium (IRDiRC), which is dedicated to addressing rare diseases through research and achieving the “vision of all people living with a rare disease to receive an accurate diagnosis, care and available therapy within one year of coming to medical attention.” Launched in 2011, the IRDiRC has working task forces and working groups that aim to identify and find solutions in areas including primary care, integration of new technologies in rare disease diagnosis, drug repurposing, telehealth, newborn screening as well as frameworks for assessing impacts associated with diagnosis, treatment and support on the patient journey.

Regulatory Innovations

Regulatory agencies like the FDA and European Medicines Agency (EMA) are increasingly offering guidance and support for rare Disease Drug Development, including fast-track and breakthrough therapy designations, which can expedite the review and approval process. They also offer guidance on clinical trial design and regulatory pathways to accelerate the approval of orphan drugs.

There are also government programs dedicated to rare disease research, such as the Accelerating Medicines Partnership Bespoke Gene Therapy Consortium (AMP BGTC), part of the Foundation for the National Institutes of Health (FNIH), which recently announced eight rare diseases that the consortium selected for its clinical trial portfolio.

Governments and regulatory bodies worldwide have also introduced various incentives to stimulate rare disease drug development, including orphan drug designation, which provides benefits like tax credits, grant funding and extended market exclusivity.

Digital Health and Real-World Evidence

Digital health technologies, including wearable devices and mobile health apps, are being used to monitor patients in real time, providing valuable data on disease progression and treatment effects. Additionally, the use of real-world evidence (RWE) is expanding, offering insights into the safety and effectiveness of therapies outside the controlled environment of clinical trials.

Despite these advances, there continue to be many challenges in rare disease research. Some of the challenges include small patient populations that make it difficult to conduct large-scale trials; limited understanding of the disease; limited data; regulatory complexities and hurdles; funding and resource limitations; and ethical and logistical considerations, including those around placebo use in small populations with serious or life-threatening conditions.

The landscape of rare disease drug development is evolving rapidly, with a focus on precision medicine, patient-centric approaches and innovative regulatory and research strategies. These developments promise to bring new treatments to patients more quickly and efficiently than ever before, offering hope to those with conditions once considered untreatable.