For World Duchenne Awareness Day, I’m Looking At The Next 7,300 Days

Last year, for World Duchenne Awareness Day, I wrote about my son’s diagnosis with Duchenne muscular dystrophy (DMD), and how I was “ready.” For this year, I want to look at the next 20 years (or 7,300 days) and outline what we can do to transform drug development – not only for Duchenne – but for the entire rare disease community.??

More than 7,000 rare diseases have been identified, affecting an estimated 350 million people worldwide. To put that into perspective, cancer affects an estimated 250 million people worldwide. Despite being one of the largest patient populations collectively, more than 90% of rare diseases are still without an approved treatment or option to improve odds for better long-term outcomes, leaving patients and healthcare providers with few therapeutic options beyond those that manage symptoms.

One might think that extraordinary unmet need would translate into a robust research environment. Yet, that is far from the case. The reality is that there are shockingly few clinical trials investigating potentially novel therapies for most rare diseases, especially for patients with an ultra-rare diagnosis.??

However, we can’t continue using the current drug development approach of single disease with single medicine. It would take centuries of time, not to mention unapproachable costs, to make a drug for each of the genetically defined rare diseases, which represent 80% of the ~7,000 diseases.?

My experience as a member of the rare disease community is that we're a group of extraordinarily motivated people doing everything we can to figure out the next advancements and what we need to do to push the science well beyond where we are today.?

But to develop new therapies at a pace that these patients deserve, we need to scale.

Gene therapies and gene editing are on the horizon, and many are considering how to accelerate these medical innovations to more patients. I’ve also previously written about our goal at Alltrna to develop genetic medicines that could unify the treatment of diseases caused by premature termination codons. This is an approach underpinned by the uniqueness of tRNA biology (read more about Defining Stop Codon Disease here).?

To be ready and able to scale, we need to make meaningful changes to address the deficiencies in our systems for rare disease patients. I’ve outlined three approaches that could make a meaningful difference:

1. Universal newborn screening to enable access to comprehensive multidisciplinary care (September is also Newborn Screening Month)

Since approximately 80% of rare diseases are genetic in nature, those affected are born with these conditions and more than half of these diseases manifest in childhood. Screening for these conditions before patients are symptomatic can play a crucial role in ensuring individuals can access specialized care and intervention that could lead to more favorable outcomes.

In the United States and elsewhere, newborn screening initiatives are growing, but remain limited in nature and differ vastly across states and geographies. Currently only about 35 rare diseases are screened based on those which have treatments available. An early diagnosis can be greatly beneficial, even if there are no approved medicines. Optimized supportive care as well as access to clinical trials, many of which have narrow age ranges for inclusion, are often the standards of care for these diseases. Patients and their families need information to seek these out in time to have a positive impact.

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2. Additional incentives for researching and developing novel modalities

One of the main reasons why there are so few clinical trials dedicated to most rare diseases is because of the challenge crafting a compelling commercial case that offsets research and development costs. Market opportunities are naturally constrained by the relatively small patient populations, making it cumbersome to justify an attractive return on investment, especially outside the most prevalent rare diagnoses.

Programs have been put in place to try to overcome this barrier. The United States’ Orphan Drug Act (ODA) of 1983 introduced financial incentives such as tax credits, waivers to FDA user fees, and a longer exclusivity period before competition is permitted. These measures have helped mitigate some of the financial risks to a rare disease drug developer, resulting in a significant increase in new therapeutics. In 2022, the FDA approved 25 new medicines for rare diseases, which is in stark contrast to just 10 approved in the entire decade prior to the passage of the ODA.[i]

We need to identify more measures like these to further incentivize innovation, especially for ultra-rare diseases. For example, the permanent establishment of voucher programs for priority reviews, not just for pediatrics but broader rare disease populations. Such vouchers can expedite the review for future development programs have been successful in spurring research in other areas of great unmet need, such as neglected tropical diseases.[ii]

Furthermore, we need greater support for novel reimbursement mechanisms for rare diseases across all payer systems, and especially for Health Technology Assessment (HTA) markets. Projecting the future impact on health utilization costs needed for reimbursement in these markets is greatly hampered due to the lack of existing treatments for rare diseases. Easing the path for global reimbursement upon regulatory approval, despite some of these unique challenges, would increase manufacturers’ confidence that a favorable return on investment can be reliably realized in rare diseases.

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3. Support for novel approaches that unify and expedite new therapeutic development

In recent years, there has been growing support for nontraditional development methods, such as basket and umbrella trials, which could be game-changing for expediting innovation for rare diseases. Basket trials are used across diseases for patients that share a genetic alteration, whereas umbrella trials are used to evaluate multiple targeted therapies in a single disease with patients grouped by genetic alteration.

One major benefit of these models is that they expand the target populations without limiting the disease subtype being studied, allowing for potentially faster indication expansion and broader labels encompassing multiple diseases. Another major advantage is the opportunity to include patients with a rare or even ultra-rare diagnosis with lower prevalence numbers, allowing these populations to have access to research where otherwise they might be overlooked. Despite the prevalence of these types of trials increasing, especially in the oncology field, basket and umbrella trials are still grossly underutilized in the rare disease setting, with only about 1% of new trials embracing this format.

I've been in the industry for well over 20 years, and I've had the privilege to work on a number of different products, mostly in the oncology space. When I look back on my career, I've been able to play a small role in the advancement of oncology that we've seen over the last two decades. In the next 20 years, I want to look back and feel like I have had a similar impact in the rare disease setting, and that is what I am focusing on, every single day.

[i] https://phrma.org/Scientific-Innovation/Progress-in-Fighting-Rare-Diseases

[ii] https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0006695

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