Rare but Not Forgotten | Strategies to Maximize Impact for Rare Disease Patients

Session Focus

Musolino framed the panel around leaders who have worked through multiple rounds of evolution in rare disease and defeated expectations in environments others found unfavorable, while putting patients at the forefront of drug development. Patient-centered development became clear many years ago, marking a different era.

The discussion covered what has changed over the past decade, the persistent challenge of finding patients, and how the business model for very small populations holds together.

What Changed in a Decade

Carole Ben-Maimon MD, whose company is developing a protein replacement approach for Friedreich’s ataxia, identified a regulatory shift. There is now real understanding that traditional drug development techniques and well-controlled trial design cannot simply be applied to these populations. In the US the FDA is becoming increasingly sensitive to this, particularly the neurology division, and CBER is more aware on gene therapy. Her assessment: the field is on the fringe of making progress.

The second change she named has nothing to do with regulation. Incentives improved. The Orphan Drug Act was a major advance, followed by Fast Track and pediatric review vouchers, mechanisms agencies and legislators had been hesitant to allow. She also pointed to the voice of the patient and patient-focused drug development meetings, where developers learn what actually bothers patients.

Charlie Gayer pointed to new modalities arriving from outside the space, including RNA silencing and gene editing, as companies recognize the business potential in rare disease.

His concern is where that attention goes. Companies entering tend to move toward the bigger rare, leaving a need for those focused on ultra-rare or smaller rare populations. Pressed for numbers, he defined smaller rare as roughly five to tens of thousands of patients, as opposed to hundreds of thousands, a distinction that substantially affects a company’s business model and its investability.

Kasper Roet PhD identified two breakthroughs. Genetic medicines including oligonucleotides, siRNA, ASOs, gene therapies and CRISPR provided new ways to treat diseases of DNA and RNA.

The second is the genesis of his own company. In the nervous system, neurons could never be cultured from people, and most of these diseases are human-specific, meaning animal models do not translate to the clinic. Stem cell models changed that: skin or blood cells from patients become stem cells and then neurons, allowing the disease to be studied in a dish.

The Business Model Behind Rare Disease

David Meeker MD gave the panel’s most consequential historical account, describing his time at Genzyme beginning in 1991.

The company’s first genetic rare disease approval came on the basis of 13 patients. That was the phase three trial.

He argued the Orphan Drug Act was incredibly important, but something else mattered equally. CEO Henri Termeer priced that drug at a very high level, understanding that a high price per patient was necessary. That meant $400,000 per patient in 1991, which created an enormous reaction from the community.

The industry conclusion was the part that reshaped the field. If you could charge that much per patient, the patient could not afford it, but the system probably could. A small number of patients at a high price is a business model, and Meeker credited that realization with driving enormous subsequent innovation.

He illustrated the arithmetic with his own company’s programs, which target impaired signaling through the melanocortin 4 pathway, the mechanism telling the body it is full and raising metabolic rate after eating. Patients with impaired signaling experience uncontrolled hunger and consequent obesity.

The first genetic approval in that group has tens of patients on treatment five years after approval, probably fewer than 100 to 200 in the US. His verdict: not a business. The most recent approval covers 10,000 patients, which is very significant in rare disease and incredibly small otherwise.

Finding Patients

Gayer described the practical problem using Netherton syndrome, a serious rare skin condition his company is pursuing. There is no ICD-10 code. The phenotypic spectrum is broad, so patients get lost elsewhere. And there is no therapy on the market, which matters because physicians tend not to look for things they cannot treat.

With the target well understood, the question was whether enough patients existed. Published epidemiology consisted largely of case studies.

The company used AI and natural language models to examine EMR systems, which he cited as another change of the last decade. That gave confidence this was not a disease of tens or a hundred patients but roughly 3,000 in the US, and combined with the patient community’s urgency, justified proceeding.

His experience in hereditary angioedema and lysosomal storage diseases supports the pattern that once a treatment exists, patients come out of the woodwork.

Meeker reinforced that availability of treatment is an enormous catalyst. Absent one, a physician may never see the condition, and even on diagnosis there is no consequence to missing it.

What has not changed despite all the technology is the diagnostic odyssey. Patients still see five or six specialists before finding one who connects the dots, even where a therapy exists. His example was Gaucher disease, a classic monogenetic presentation that is unmistakable once seen, where for decades patients continued to be found with advanced disease in sophisticated healthcare systems including the US.

Roet said ALS fits the pattern exactly. Life expectancy is about three years while average time to diagnosis is one year, meaning patients are already well progressed when identified. Two genetic drugs now work on ultra-rare forms of ALS, and it is becoming clear that earlier treatment produces better effect.

He raised a policy concern directly. Newborn genetic screening has moved from a standard national activity to being state dependent, which means patients with genetic underpinnings of rare disease will not be identified. In his opinion this is something everyone should be very worried about.

Ben-Maimon added the confirmation problem. Some diseases resemble others, and the tools to confirm a suspected diagnosis matter particularly in drug development, especially where a therapy carries side effects or is a gene therapy that must not be given to the wrong person.

Key Takeaways

1. Regulators have grown more flexible on trial design for rare disease, particularly FDA neurology and CBER.

2. New modalities are drawing companies toward the bigger rare, leaving ultra-rare populations underserved.

3. Stem cell models solved the translation problem for human-specific neurological disease.

4. A 1991 approval on 13 patients priced at $400,000 established the rare disease business model.

5. Population size determines viability. Fewer than 200 patients is not a business; 10,000 is significant in rare disease.

6. AI applied to EMR data resolved an epidemiology question that published case studies could not.

7. The diagnostic odyssey persists despite technology, and the shift of newborn screening to state discretion threatens identification.