After previously delaying its decision date, the FDA has outright rejected Saol Therapeutics’ investigational treatment for an ultrarare pediatric mitochondrial disease.
The CNS-focused biotech is planning on pushing back against the rejection for its pyruvate dehydrogenase complex deficiency (PDCD) candidate—known as SL1009 or DCA—and the FDA’s request for a new trial.
While Saol’s experimental asset failed to meet the primary efficacy goal in a phase 3 trial, the biotech has underscored statistically significant improvements in motor function during an extension phase and a secondary endpoint showing.
“While we fully support rigorous scientific standards, regulatory flexibility is essential for rare disease populations like PDCD, where delays in access to potentially life-saving therapies can lead to irreversible damage—or even death,” six patient advocacy groups wrote in a joint community statement.
“Make no mistake, that is the risk when it comes to DCA not being available for PDCD patients,” reads the statement, which was delivered late last week.
In the complete response letter (CRL), the FDA provided “specific observations” that Saol must address to understand the path forward for DCA, according to a Sept. 8 release from the company.
Saol is now requesting a Type A meeting with the FDA in hopes of determining a path forward that doesn’t require another phase 3 trial, Saol CEO Dave Penake told Fierce Biotech in an emailed statement. The meeting is designed to help an otherwise stalled candidate move forward.
The FDA’s observations listed in the CRL were not related to manufacturing, Saol said in its release. To address the undisclosed deficiencies the agency has requested would take numerous years, the biotech said.
“The estimated cost, timing and feasibility are prohibitive for us to proceed,” CEO Penake said.
The biotech’s investigational product is an oral solution with sodium dichloroacetate as the active ingredient that is designed to treat PDCD, an extraordinarily rare genetic metabolic disorder. Many children diagnosed with the condition do not live beyond early childhood.
In January, the FDA gave Saol a Prescription Drug User Fee Act (PDUFA) date of May 27 under the priority review pathway.
The federal agency then requested a 90-day extension, extending a decision to Aug. 27, Penake said. The company received the CRL on the afternoon of Aug. 27, with the FDA’s last information request coming in April, according to Saol’s CEO.
The biotech has run two phase 3 studies: a double-blind placebo-controlled trial that continues via an open-label extension (OLE) and a survival analysis compared to a natural history cohort.
The biotech’s asset failed to meet the primary efficacy endpoint in the placebo-controlled phase 3 trial, which was based on observer-reported outcomes. But the company said the treatment was well-tolerated and significantly improved survival compared to controls.
DCA also significantly decreased plasma lactate concentrations—a secondary endpoint—compared to placebo. Elevated plasma lactate levels are a key diagnostic indicator for PDCD.
The biotech also said that the phase 3 extension demonstrated a statistically significant improvement in motor function, and that families have reported an increased quality of life related to the investigational treatment.
The private biotech’s candidate has received orphan drug, priority review and rare pediatric disease designations from the FDA.
Currently, no treatment for PDCD exists. The disease impacts about 90 newborns in the U.S. each year, affecting fewer than 1,000 Americans overall.
While Saol waits to meet with the FDA, the Ireland- and Bermuda-based biotech has said that it will continue to provide DCA without interruption through the OLE and an expanded access program.
Saol’s product is designed specially for PDCD patients, including individuals who need feeding tubes. Proper administration of the investigational treatment includes a companion, genetic diagnostic that identifies personalized safe dosing, according to the CEO.
In partnership with Medosome Biotec, Saol also filed a Humanitarian Device Exemption application for the dose-determining test, which is a medical device approval pathway based on “probable benefit.”
“The FDA has statutory authority, and a moral and ethical obligation, to apply flexibility when evaluating therapies for life-threatening rare diseases like PDCD,” six advocacy groups wrote in their community statement and call to action letter.
“When this authority is not exercised, it raises serious questions about whether the rare disease drug approval pathway is truly serving the patients it was intended to help,” the organizations wrote.
“We are asking the FDA to continue to work with Saol Therapeutics to find an expedited path forward for DCA,” the organizations continued. “There is simply too much on the line for any other option.”
In the meantime, the organizations urge the PDCD community to contact members of Congress to help inform them about the condition and the importance of regulatory flexibility for rare disease therapies.
The rejection came right as the agency proposed a new pathway for ultrarare diseases designed to boost regulatory flexibility. The proposal would allow a single-arm trial, plus other supportive data, to serve as pivotal evidence for drug reviews.
However, several stipulations apply. The investigational medicines must take aim at correcting or replacing a specific genetic defect underlying a disease and the drugs must be for conditions that impact fewer than 1,000 Americans.
“We are encouraged by recent FDA actions and commentary that recognize the importance of regulatory flexibility and speed for treating rare diseases,” CEO Penake said in the release. “Traditional clinical trials often take many years; time that children with PDCD simply do not have.”
The latest iteration of the FDA—led by President Donald Trump’s commissioner pick Marty Makary, M.D.—has faced scrutiny over its decisions tied to rare disease prospects. This includes the agency’s rejection of Replimune’s melanoma candidate, with the editorial board at The Wall Street Journal even responding to the decision with a scathing opinion piece that claimed “therapies for rare and deadly disease are dying in Marty Makary’s shop.”
Meanwhile, Stealth BioTherapeutics has pushed the agency to reconsider its recent rejection of elamipretide, another ultrarare disease candidate that was hit by several FDA delays before receiving a rebuff.
Just last month, the agency accelerated a decision for a new drug application that the biotech submitted, with a verdict expected by Sept. 26.
The timeline is surprising since the agency has given Stealth a PDUFA date of Feb. 15, 2026.
The fast-approaching September date may reflect a renewed urgency at the agency after it faced a wide-ranging public outcry.
In a June 30 letter, 14 members of Congress urged Makary to provide clarity about the approval process for elamipretide. Less than a month later, seven Congress members wrote to him again, voicing concern about the regulatory path for the experimental drug.
Editor's note: The headline was updated at 11:15 a.m. ET.