FDA Approves First Treatment for Ultra-Rare Genetic Disease Alkaptonuria

The U.S. Food and Drug Administration (FDA) has granted approval to Cycle Pharmaceuticals' Harliku (nitisinone), marking a significant milestone as the first FDA-approved treatment for alkaptonuria (AKU), an ultra-rare genetic disorder. This approval represents a breakthrough for patients suffering from this debilitating condition, which affects approximately one in 100,000 to 250,000 people worldwide.

A New Hope for AKU Patients

Alkaptonuria, caused by a deficiency in the HGD enzyme, leads to a pathological buildup of acid in the skin, resulting in ochronosis—a bluish or reddish discoloration of skin patches. Beyond skin discoloration, AKU can severely impact bones and joints, causing arthritis, reduced mobility, and increased fracture risk. The disease may also impair lung function and elevate risks of heart failure, coronary artery disease, and stroke.

Harliku, an oral small-molecule drug, works by inhibiting a key enzyme in the HGD cascade, effectively reducing urine HGA levels. This mechanism of action addresses the root cause of AKU, offering patients a targeted treatment option for the first time.

Clinical Efficacy and Safety Profile

The FDA's decision was supported by data from a 40-patient randomized clinical trial, published in October 2024 in Molecular Genetics and Metabolism. The study demonstrated that after three years of treatment, Harliku improved pain, physical function, and energy levels in AKU patients.

While Harliku does not carry a boxed warning, healthcare providers should be aware of potential side effects, including lowered white blood and platelet counts, ocular symptoms, and hyperkeratotic plaques—an abnormal thickening of the skin.

Implications for Rare Disease Drug Development

Harliku's approval comes at a time when the rare disease space is experiencing increased regulatory support. FDA Commissioner Marty Makary recently announced the consideration of a "new pathway" for rare disease therapies, potentially allowing approvals based on a "plausible mechanism." This shift in approach could accelerate the development and approval of treatments for other ultra-rare conditions.

Health Secretary Robert F. Kennedy Jr. has also voiced support for this initiative, stating, "We are going to continue to figure out new ways... of accelerating approvals for drugs and treatments that treat rare diseases." This commitment from top health officials signals a promising future for rare disease research and drug development.