WASHINGTON, D.C. — The Food and Drug Administration has released draft guidance outlining a new pathway to approve highly individualized treatments for ultra-rare diseases and has granted expedited approval to a lung cancer drug under a fast-track voucher program.
What This Means for You
- Drug developers may rely on a new “Plausible Mechanism Framework” when traditional large clinical trials are not feasible.
- The FDA approved the lung cancer drug Hernexeos 44 days after its application was filed.
- Public comments on the draft ultra-rare disease guidance are open for 60 days after publication in the Federal Register.
New Framework for Ultra-Rare Diseases
The FDA on February 23 issued draft guidance describing how sponsors can generate substantial evidence of safety and effectiveness for targeted individualized therapies when randomized controlled trials are not practical due to extremely small patient populations.
Randomized controlled trials typically compare a new treatment to a placebo or standard therapy in large groups of patients. In ultra-rare diseases, the number of patients may be too small to conduct such trials.
The draft guidance, issued by the Center for Biologics Evaluation and Research and the Center for Drug Evaluation and Research, focuses on genome editing and RNA-based therapies such as antisense oligonucleotides — short strands of synthetic genetic material designed to alter how genes are expressed. The agency said the framework could apply to other tailored therapies that directly address a disease’s known biological cause.
The guidance introduces what FDA officials describe as a “Plausible Mechanism Framework,” under which approval could be supported by strong scientific evidence that a therapy corrects or modifies the underlying genetic, cellular or molecular abnormality causing the disease.
Key elements outlined in the draft include identifying the disease-causing abnormality, demonstrating the therapy targets the root cause or biological pathway, relying on well-characterized data from untreated patients, and confirming successful gene editing or molecular targeting. For traditional approval, the therapy should show improvement in clinical outcomes, disease progression, or biomarkers that are known to predict benefit.
“President Trump promised to accelerate cures for American families — and we are delivering, especially for children with ultra-rare diseases who cannot afford to wait,” Health and Human Services Secretary Robert F. Kennedy Jr. said.
FDA Commissioner Marty Makary said the guidance is intended to tailor regulatory requirements to small patient populations and “remove barriers and exercise regulatory flexibility to encourage scientific advances.”
The draft guidance, titled Considerations for the Use of the Plausible Mechanism Framework to Develop Individualized Therapies that Target Specific Genetic Conditions with Known Biological Cause, is available for public comment at Regulations.gov.
Lung Cancer Drug Approved Under Voucher Pilot
On February 26, the FDA granted approval to the lung cancer drug Hernexeos (zongertinib) under the Commissioner’s National Priority Voucher pilot program.
The application for Hernexeos was filed January 13, 2026. According to the FDA, the agency rendered a final decision 44 days after the filing date.
Hernexeos is approved for adults with unresectable — meaning tumors that cannot be removed surgically — or metastatic non-squamous non-small cell lung cancer whose tumors have specific HER2 (ERBB2) tyrosine kinase domain activating mutations detected by an FDA-authorized test.
In clinical trial data submitted to the agency, 76 percent of previously untreated patients experienced a substantial decrease in tumor size. The FDA said that response rate compares with a typical 30 to 45 percent response under the current standard of care.
“As a part of the national priority voucher program, the FDA is on the hunt for game-changing therapies that can qualify for a priority review,” Makary said. “Patients and sponsors deserve an efficient FDA process that cuts out idle time and delivers powerful treatments safely and quickly for the American people.”
Hernexeos previously received accelerated approval in August 2025 for patients who had received prior systemic therapy. The new approval extends that treatment option to patients who have not received prior therapy.
The Commissioner’s National Priority Voucher pilot program is designed to expedite review of applications that address national health priorities, including unmet medical needs and innovative therapies. Companies selected for the program receive enhanced communications and rolling review, allowing portions of an application to be reviewed as they are completed.
The FDA granted Hernexeos Breakthrough Therapy and Priority Review designations. Serious side effects associated with the drug include liver toxicity, heart dysfunction, interstitial lung disease, and embryofetal toxicity. The most common side effects reported include diarrhea, rash, fatigue, nausea, muscle and joint pain, and upper respiratory tract infection.
The accelerated approval was granted to Boehringer Ingelheim Pharmaceuticals Inc.
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