Former FDA Commissioner Dr. Scott Gottlieb on finding cures for rare diseases

CNBC Cures Initiative: Advancing Rare Disease Research & Treatment

Key Concepts:

• Rare Diseases: Over 10,000 conditions affecting 30 million Americans, often lacking FDA-approved treatments (95% have no treatment).
• N-of-1 Diseases: Rare conditions with highly specific genetic mutations, requiring individualized treatment approaches.
• Sirna Oligonucleotide: A type of RNA molecule used to silence specific genes, offering potential for targeted therapies.
• AAV Vector: A viral vector used to deliver genetic material into cells for gene therapy, but with limitations like liver localization and immune response.
• Lipid Nanoparticles (LNPs): A delivery system encasing genetic material in lipid spheres for targeted tissue delivery.
• Synthetic Capsids: Engineered protein shells used to deliver genetic material, offering more direct targeting than viral vectors.
• Base Editing: A gene editing technique that modifies single DNA bases within a gene, rather than replacing the entire gene.
• Plausible Mechanism Pathway: A proposed FDA framework for approving treatments based on demonstrating biological effect rather than traditional clinical trials.
• Somatic Cells: Non-reproductive cells, meaning genetic alterations are not inherited.

I. Introduction: The Launch of CNBC Cures & Personal Story

The CNBC Cures initiative was announced, focusing on raising awareness and understanding of rare diseases. The initiative is personally motivated by the host’s experience with her nine-year-old daughter, Kaylee, who has SYNGAP1, a rare genetic condition causing autism, seizures, and developmental delays. Fewer than 2000 people worldwide share Kaylee’s condition. Despite the small patient populations for individual rare diseases, collectively they impact approximately 30 million Americans, with a significant proportion being children. A critical issue is the lack of FDA-approved treatments for 95% of these conditions. The host emphasizes that these diseases are often overlooked by the broader healthcare industry due to limited investment incentives and regulatory hurdles.

II. The FDA’s Evolving Approach to Rare Disease Treatment – Dr. Scott Gottlieb’s Insights

The conversation with former FDA Commissioner Dr. Scott Gottlieb centers on the agency’s evolving approach to rare disease treatment. Gottlieb recalls a pivotal case involving Julia Vitarello and Dr. Timothy Yu at Boston Children’s Hospital, whose daughter suffered from a specific mutation of Batten’s disease. They proposed a tailored Sirna oligonucleotide treatment, prompting the FDA to create a pathway for “N-of-1” diseases – treatments designed for a single patient’s unique genetic mutation.

Gottlieb explains that the initial focus shifted from approving individual products to regulating the process of creating these personalized therapies. He states, “Ultimately, what the agency is going to need to do is to start to think about new drug therapies for these ultra rare diseases, not as single products, but regulating the process that is used to drive the products rather than the product itself.” This means approval could be granted based on demonstrating the biological effect of a construct (like an oligonucleotide) – for example, reducing the production of an aberrant protein – rather than requiring extensive clinical trials with limited patient numbers. He highlights the “Plausible Mechanism Pathway” as a step towards operationalizing this approach, referencing a paper released by the FDA in November.

III. Advancements in Gene Therapy Technologies

Gottlieb details the significant advancements in gene therapy technologies since 2017. He identifies the development of the Adeno-Associated Virus (AAV) vector as a key breakthrough, enabling the delivery of genetic changes to patients. However, he acknowledges the AAV vector’s limitations, including systemic side effects (particularly liver localization) and the potential for patients to develop neutralizing antibodies, preventing re-dosing.

He then discusses newer technologies:

• Lipid Nanoparticles (LNPs): These encapsulate genetic material and deliver it directly to target tissues, improving specificity. LNPs were perfected with mRNA vaccine delivery.
• Synthetic Capsids: These engineered protein shells offer even more precise targeting of genetic alterations.
• Base Editing: This technique modifies single DNA bases within a gene, offering a more precise approach than delivering an entire gene.

IV. Challenges and Future Directions

The discussion addresses the durability of these treatments. While somatic cell alterations (affecting non-reproductive cells) can potentially last for years, the longevity of the effect and the need for re-dosing remain uncertain. Gottlieb notes that the development of neutralizing antibodies can limit re-dosing with AAV vectors, but newer constructs may overcome this issue.

He identifies regulation as the biggest roadblock, stating, “I think regulation is a roadblock here because it's still hard to do these so-called N of one trials.” He advocates for Congressional intervention to provide the FDA with targeted authorities and resources to facilitate the approval of these therapies. He also points out that the FDA initially predicted upwards of ten cell and gene therapy approvals per year, and is now approaching that rate, with seven approvals in the last two years.

V. Alternative Approaches & Long-Term Considerations

The conversation touches on alternative approaches like enzyme replacement therapy (e.g., for Gaucher’s disease) and the trade-offs between infusion-based treatments and potentially more durable genetic alterations. Gottlieb suggests that a genetic alteration offering safe and comparable efficacy could be preferable, even if it requires periodic re-dosing.

VI. Conclusion & Call to Action

The CNBC Cures initiative aims to accelerate research and treatment for rare diseases. The discussion highlights the significant progress in gene therapy technologies and the need for regulatory frameworks that can facilitate the development and approval of personalized treatments. The host encourages viewers to learn more at CNBC.com and to attend an in-person event on March 3rd in New York.

Notable Quote:

“Ultimately, what the agency is going to need to do is to start to think about new drug therapies for these ultra rare diseases, not as single products, but regulating the process that is used to drive the products rather than the product itself.” – Dr. Scott Gottlieb.