As Duchenne winds change, PTC and Santhera score surprise wins

The travails of Prosensa and Sarepta notwithstanding, enthusiasm for Duchenne muscular dystrophy remains undiminished. Just ask PTC Therapeutics, up 65% this morning on an unexpected EU approval for ataluren, and Santhera Pharmaceuticals, whose stock has surged threefold on the back of a phase III success with idebenone.

PTC has benefited from a shock U-turn by the CHMP, which had turned down ataluren, now called Translarna, in January. Santhera, unlike PTC, Prosensa and Sarepta, treated relatively advanced DMD patients and got striking results, but faces a problem: idebenone is purported to be a dietary supplement, available cheaply and easily online.

The CHMP’s earlier negative opinion on PTC’s ataluren, a small molecule designed to correct a nonsense DNA mutation that leads to DMD, was based on a phase IIb study in which it failed to show a statistically significant six-minute walk test (6MWT) benefit.

However, the agency now says a re-examination of the data suggests “some evidence of success” with ataluren at 40mg/kg/day, and that “the way the medicine works is plausible”. It has granted conditional EU approval, which will be renewable yearly based on further studies.

PTC highlighted a “clinically meaningful” 31.3-metre 6MWT benefit over placebo after 48 weeks’ treatment in patients five years old and above, and a 68-metre benefit in those able to walk 350 metres or less at baseline given 40mg/kg/day. The group had specifically requested a re-examination of the CHMP’s January rejection.

Delayed reaction

For Santhera, a positive primary endpoint result from the idebenone trial, Delos, was revealed 10 days ago, but caused barely a ripple in the stock. After yesterday's presentation at the Bioequity Europe conference, however, the shares surged 163%, and were up another 25% in trading today, valuing the group at CHF110m ($123m).

Sarepta and Prosensa had recruited relatively young DMD boys into studies of their respective exon-skipping projects, eteplirsen and drisapersen, and indeed the equivocal data they had obtained suggested that catching the disease as early as possible, in ambulant patients, was the key to successful treatment.

Santhera, however, chose a different strategy, recruiting into Delos 64 patients between 10 and 18 years of age – 59 of whom were unable to walk. Accordingly using the 6MWT was pointless, and instead Delos focused on measures of respiratory function over the trial’s year-long duration.

Peak expiratory flow – the primary endpoint – declined less in idebenone-treated patients (3.1 percentage points) than in placebo recipients (9.0 points), hitting statistical significance with p=0.04. Decline in forced expiratory volume, a key secondary measure relating to respiratory muscle strength, also favoured idebenone, by 8.3 points (p=0.03).

“DMD patients die because of respiratory failure. We’re not just treating a complication [of the disease],” Thomas Meier, Santhera’s chief executive, told EP Vantage. He added that the FDA had encouraged the company to enrol older, wheelchair-bound patients with loss of respiratory function into Delos.

He said the plan was to seek a DMD indication on idebenone’s label, and a variation to the project’s current EU filing for a rare eye disorder was now possible.

Dietary supplement?

The problem, at least in the eyes of potential partners, is that idebenone appears to be sold as a dietary supplement. Santhera says peak annual sales of CHF580m are possible at a price of €30,000-35,000 a year, but numerous websites offer the product cheaply, with one selling 60 150mg pills – a 10-day supply at the Delos dosing – for just $50.

Mr Meier calls this a misstatement. “Regulators have shut down companies trying to sell [idebenone as a dietary supplement],” he stated, adding that he was confident of protection afforded by idebenone’s EU and US orphan drug designation; a similar situation existed in Canada, where the product was sold for Friedreich’s ataxia.

Whatever potential Santhera now has for partnering or fund-raising, it is undeniable that the mood in DMD is shifting. On a call today PTC management said it had persuaded the CHMP by educating the regulator to help it understand the data, but what the group did not mention is the considerable pressure that DMD patient groups have brought to bear on regulators of late.

In PTC’s slipstream, shares in Prosensa and Sarepta, which also have considerable patient group followings, climbed 30% and 8% respectively today on renewed hopes for their DMD projects.

PTC’s biggest risk now is a recently begun phase III ataluren study. But, given the patient group pressure, for the regulator to pull ataluren’s conditional approval – even on the basis of a subsequent study fail – would be public relations suicide.

Study Design Trial ID
Delos (phase III) 64 non-steroid DMD pts (240 planned initially), idebenone 900mg/day NCT01027884
Act DMD (phase III) 220 ambulant DMD pts, nonsense mutation, ataluren 10-20mg/kg NCT01826487

(This story was amended to correct a mistake in Santhera's reporting of percentage point changes.)

To contact the writer of this story email Jacob Plieth in London at [email protected] or follow @JacobEPVantage on Twitter

EP Vantage will not publish on Monday 26 May owing to a public holiday in the UK. We will return on May 27, 2014.

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