'Surrogate Of A Surrogate' Not Good Enough For Raxone Accelerated Approval

FDA’s decision to require second pre-approval trial for Santhera’s DMD candidate is just latest example of the inability of rare disease treatments with surrogate endpoints to qualify for pathway.

Rare disease candidates with surrogate endpoints are struggling to gain accelerated approval from FDA, most recently highlighted by the agency declining to grant Santhera Pharmaceuticals accelerated approval for its Duchene muscular dystrophy candidate Raxone (idebenone).

The decision will force the Swiss drugmaker to conduct another Phase III study of the drug, for which it expects results by 2019. Santhera had hoped to win accelerated approval based on the results for a previously completed Phase III trial, but announced the delay July 14 (see related story in Scrip).

RBC Capital Markets analyst Simos Simeonidis said in a note he believes FDA’s decision was based on its discomfort with the use of peak expiratory flow as a primary endpoint. Simeonidis – who spoke with Santhera CEO Thomas Meier – says FDA described the peak expiratory flow end point as “a surrogate of a surrogate.”

Instead, FDA is calling for a confirmatory Phase III study with forced vital capacity as an endpoint, which the agency believes is “linked to better outcomes,” Simeonidis said.

Peak expiratory flow is frequently used as an endpoint used in asthma control trials. Respiratory failure is a common complication of DMD.

Raxone previously picked up Fast Track designation in April 2015 following positive results from the Phase III study with the peak expiratory flow endpoint, which found the drug delayed the loss of respiratory function.

The failure of the drug to gain accelerated approval, however, appears to be part of a larger trend. Stephanie Fischer, a spokeswoman for the EveryLife Foundation for Rare Diseases, says FDA rarely allows accelerated approval via a surrogate endpoint for rare diseases.

Sarepta Therapeutics Inc.'s DMD candidate eteplirsen, for example, recently failed to garner accelerated approval, after the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee voted 7-6 that there was not substantial evidence that the treatment induces dystrophin production to a level that is reasonably likely to predict clinical benefit. (Also see "Patients Can't Rescue Sarepta's Eteplirsen" - Pink Sheet, 25 Apr, 2016.)

Current accelerated approval regulations allow FDA to grant marketing approval to candidates for treating serious or life-threatening illnesses based on whether they are “reasonably likely” to have an effect on a surrogate endpoint. They do not spell out specific criteria for what constitutes a reasonable likelihood.

The pathway challenges for orphan drugs recently prompted Emil Kakkis, president and founder of the EveryLife Foundation, to call for clearer guidance from the FDA to enable innovative rare disease therapies to more easily access the accelerated approval mechanism.

“Although FDA issued new guidances for expedited programs, including accelerated approval, and the Qualification Process for Drug Development Tools, the qualification process for novel biomarkers as primary endpoints in the accelerated approval pathway remains insufficiently defined,” Kakkis wrote in commentary published in the journal Nature America. Progress is needed in establishing a more predictable pathway, including a set of reasonable scientific criteria to provide greater access to accelerated approval for rare genetic disease treatments with novel biomarker endpoints, he said.