The FDA has issued a complete response letter (CRL) to Chiesi Global Rare Diseases in regards to its new drug application (NDA) for oral idebenone to treat Leber hereditary optic neuropathy (LHON).
The news was announced earlier this month after the previous Prescription Drug User Fee Act (PDUFA) target date passed on Feb. 28.
First: a refresh on Chiesi.
As the business unit of the Italian Chiesi Group, Chiesi is a research-based international biopharmaceutical group with six research and development centers across the globe—including North Carolina in the United States.
Its focus: Developing and marketing therapeutic solutions in respiratory health, rare diseases, and speciality care—see here for specifics on these areas (including ophthalmology).
Next up: idebenone.
Before we talk about this: Keep in mind that LHON is caused by mutations in mitochondrial DNA that impair Complex I of the electron transport chain (ETC), leading to acute central vision loss.
Idebenone is a synthetic analogue of coenzyme Q10 (CoQ10)—a critical electron carrier in the mitochondrial respiratory chain that can bypass defective Complex I—designed to:
- Support mitochondrial energy production
- Reduce oxidative stress
- Contribute to adenosine triphosphate (ATP) production
More specifically: The orally-administered asset is used to restore energy production and protect retinal ganglion cells (RGCs) from damage caused by mitochondrial dysfunction (also known as the underlying cause of LHON).
What else should we know?
While not yet approved in the U.S., idebenone is already approved by the European Medicines Agency (EMA) in several ex-European Union countries (see here).
- Its brand name: Raxone.
Noted. Now, let’s talk about its pathway towards US approval.
Chiesi is seeking regulatory approval (and eventual commercial market access) for idebenone to treat adolescents and adults with LHON.
But while the FDA granted priority review for its NDA in September 2025, it has since determined that the LHON candidate’s package is unable to move forward in its current form.
… why, exactly?
It boils down to the clinical data included in idebenone’s NDA package—or rather, the lack of key data, according to the FDA.
As Chiesi shared: “The agency requested additional clinical data from adequate and well-controlled studies to further demonstrate the safety and effectiveness of idebenone in LHON,” as well as “clarification and updates to certain chemistry, manufacturing, and non-clinical information.”
So what clinical data was included in this package?
Two data sets encompassing both phase 3 and 4 trials:
- Phase 3: pivotal randomized, double-blind, placebo-controlled study (RHODES; NCT00747487)
- Primary endpoint: Best recovery of visual acuity (VA)
- Phase 4: open-label interventional study (LEROS; NCT02774005)
- Primary endpoint: Clinically relevant benefit of visual recovery or stabilization
These studies evaluated the safety and efficacy of idebenone among patients (adolescents and adults) with LHON across primary mitochondrial DNA mutations.
… and the findings?
In the RHODES trial: Overall VA improved slightly with idebenone (6 Early Treatment Diabetic Retinopathy Scale [ETDRS] letters) but worsened in patients receiving a placebo (~1 letter)
- To note, the primary goal fell short and did not achieve statistical significance
And in the LEROS trial: 12-month and 24-month data found 42.3% and 52.9%, respectively, of idebenone-treated eyes showed visual benefits versus 20.7% and 36% of untreated eyes, respectively.
- To note, the primary goal was met
Click here for more on the RHODES trial data. And see here for more on the LEROS trial data.
Got it. Were there any other issues needing to be resolved?
The FDA also indicated that “issues relating to a referenced Drug Master File (DMF)” must be addressed before it can consider a potential approval.
- Take note: A DMF is a confidential, detailed submission to the FDA with proprietary information on the manufacturing, processing, packaging or storage of human drug products—and are reviewed in connection with such applications as an NDA.
The company added that “no clinical safety concerns were identified in the CRL.”
Well then .. what’s next for this NDA?
Chiesi Executive Vice President, Giacomo Chiesi, stated that, though the FDA’s decision wasn’t the outcome they hoped for, “We remain committed to championing the needs of the LHON community and to supporting ongoing research efforts that may one day lead to new treatment options and improved care pathways.”
In other words: It’s not immediately clear whether Chiesi will resubmit its idebenone NDA with the requested additional clinical data.
If they do move toward a resuvmission, what’s the potential for ibenone?
As we’ve previously reported, idebenone could be the first and only clinically proven therapeutic in the U.S. designed to target the underlying cause of LHON.
Stay tuned in the near future for developments on this front …