FDA Rejects Ultra-Rare Disease Therapy, Dealing Blow to Saol Therapeutics

The U.S. Food and Drug Administration (FDA) has rejected Saol Therapeutics' application for SL1009, a potential treatment for pyruvate dehydrogenase complex deficiency (PDCD), an ultra-rare mitochondrial disease affecting children. This decision marks a significant setback in the development of therapies for rare pediatric conditions and highlights the challenges faced by pharmaceutical companies in navigating the regulatory landscape for ultra-rare diseases.

Complete Response Letter Raises Concerns

Saol Therapeutics received a Complete Response Letter (CRL) from the FDA detailing specific observations that need to be addressed. While the company has not disclosed the exact reasons for the rejection, it anticipates that addressing the FDA's concerns will require "several years" and "significant financial resources." The privately held biotech is currently in discussions with the FDA to find a path forward that does not necessitate an additional clinical trial.

SL1009, an oral formulation of sodium dichloroacetate, had previously secured orphan drug, rare pediatric disease, and priority review designations from the FDA for PDCD. The treatment is designed to be used in conjunction with a proprietary genetic test, highlighting the personalized approach often required for ultra-rare conditions.

Impact on PDCD Patients and Advocacy Response

PDCD is an extremely rare condition, affecting fewer than 1,000 patients in the United States and occurring in approximately 90 births per year. The disease is characterized by the toxic buildup of lactic acid in the body, leading to severe health complications including nausea, vomiting, breathing problems, neurological impairments, and abnormal heartbeat. Most patients with PDCD do not survive beyond early childhood, and currently, there are no approved treatments for the disease.

The FDA's decision has sparked concern among patient advocacy groups. The United Mitochondrial Disease Foundation, along with other organizations such as MitoAction, Cure Mito Foundation, Hope for PDCD, and the Elizabeth Watt PDCD Research Fund, expressed "deep disappointment" with the rejection. In an open letter, these groups emphasized that the decision could delay access to potentially life-saving therapies, potentially leading to "irreversible damage – or even death" for patients.

Contrast with Recent Rare Disease Successes

The rejection of SL1009 comes in stark contrast to recent successes in the rare disease space. August 2025 saw four regulatory firsts for rare conditions:

1. Jazz Pharmaceuticals' Modeyso became the first approved drug for diffuse midline glioma with an H3 K27M mutation.
2. Insmed's Brinsupri secured the first FDA approval for non-cystic fibrosis bronchiectasis and became the first therapy to block the DPP1 enzyme.
3. Precigen's Papzimeos was approved as the first non-replicating immunotherapy for recurrent respiratory papillomatosis.
4. Ionis' Dawnzera received the industry's first RNA-targeting prophylactic approval for hereditary angioedema.

These approvals underscore the potential for innovation in rare disease treatment, making the setback for PDCD patients particularly poignant. As Saol Therapeutics works to address the FDA's concerns, the case of SL1009 highlights the delicate balance between maintaining rigorous scientific standards and providing regulatory flexibility for ultra-rare disease populations.