DUBLIN – Shares in Santhera Pharmaceuticals Holding AG dropped 37 percent Thursday after the FDA blocked the company's bid to win accelerated approval for Raxone (idebenone) in Duchenne muscular dystrophy (DMD) patients not taking glucocorticoids.

Liestal, Switzerland-based Santhera had hoped, with the FDA's agreement, to file this year under the subpart H approval pathway, which could have triggered a possible approval by around the second quarter of 2017. "That's off the table now," CEO Thomas Meier told BioWorld Today.

Instead, it must first complete a planned phase III trial in patients taking glucocorticoids, which will not read out until the second half of 2019, pushing back a potential approval, in all patients, by about three years. "It's disappointing," said Meier. "The reason – they didn't say it, this is speculation – is they could be afraid of off-label use."

Santhera had hoped that the FDA would accept a dossier based on several completed trials, foremost among them being the phase III DELOS (DuchEnne Muscular Dystrophy Long-term IdebenOne Study) trial, which found that Raxone significantly slowed the rate of decline of respiratory function in patients who were not on concomitant glucocorticoid therapy. (See BioWorld Today, May 14, 2014.)

It had been buoyed by a recent analysis, which found that those effects led to improved clinical outcomes, including a reduction in the frequency and severity of bronchopulmonary problems, a cut in antibiotic usage and a reduction (albeit one that was not statistically significant) in hospitalization rates. (See BioWorld Today, June 2, 2016.)

Steroid administration has been a mainstay of therapy for several decades, as it maintains muscle strength and function and delays decline by two to three years. As DMD children age, however, the benefit wears off, while the accompanying weight gain can be a factor in the loss of ambulation. About 40 percent of patients stop taking glucocorticoids. "They have no other treatment option. This is a high unmet need," Meier said.

The FDA appears reluctant, however, to recognize that distinction, preferring to see data from both sets of patients – those on concomitant glucocorticoids and those not – at the same time.

The EMA, on the other hand, has shown more flexibility on the issue. Santhera's marketing authorization application was accepted for regulatory review last month – the file was submitted as a type II variation of its existing approval for treating visual impairment in Leber's hereditary optic neuropathy, a mitochondrially inherited condition that leads to abrupt loss of central vision. In DMD, Raxone does not tackle the root cause of the disease – the absence of the muscle protein dystrophin – but it slows the decline in respiratory function by reducing the production of reactive oxygen species in the mitochondria, which is caused by excess calcium influx.

The double-blinded SIDEROS trial will recruit about 260 DMD patients on concomitant glucocorticoids. They will be randomized to a drug treatment arm – 900 mg per day – or a placebo arm for 78 weeks. The primary endpoint will be the change in lung function, as measured by change from baseline to week 78 in forced vital capacity percent predicted.

Given its mechanism, Raxone is genotype-independent and is an ideal candidate, therefore, for combination trials involving exon-skipping drugs. The present impasse will delay that possibility for several years – in the U.S. at least. Although there is no direct link between the FDA decision on Raxone and the bid for early approval of Exondys (eteplirsen) by Sarepta Therapeutics Inc., RBC Capital Markets analyst Simos Simeonidis believes it does not bode well. "Even though there are multiple differences between the Santhera and Sarepta drugs and datasets, (most of which favor Santhera, by the way), we do see a direct negative read-through to the expected Sarepta decision from today's news. We believe today's news makes a positive decision on eteplirsen even more unlikely," he wrote in an investor note.

"The bull thesis on Sarepta has been that the FDA would be 'lenient' and 'forgiving' with weaker datasets in DMD, because of the devastating nature of the disease and the lack of available drugs for this patient community," he added. However, the Santhera rebuff, coupled with the rejection of Biomarin Pharmaceutical Inc.'s Kyndrisa (drisapersen), a refuse-to-file letter for PTC Therapeutics Inc.'s Translarna (ataluren) and a negative advisory committee vote for eteplirsen, is yet further evidence that this is not the case, he added. The FDA has yet to communicate a new PDUFA date for eteplirsen, having postponed a decision due on May 26. (See BioWorld Today, Jan. 15, 2016, Feb. 24, 2016, and June 8, 2016.)

Santhera's stock (ZURICH:SANN) hit a 12-month low of CHF49 (US$49.93) during trading Thursday but edged back to close at CHF52.65, down CHF30.85.