BioWorld International Correspondent

Newron Pharmaceuticals S.p.A. missed the primary efficacy endpoint in a Phase III clinical trial of safinamide as an add-on to dopamine agonist therapy in early stage Parkinson's disease, but for reasons that appear to be more related to the limitations of the trial design rather than to the innate efficacy of the drug.

The 18-month trial attained its other main objective, demonstrating long term safety. Safinamide also demonstrated, with statistical significance, efficacy on secondary endpoints based on motor symptom assessments and quality of life measures.

The primary efficacy endpoint was defined as time from baseline to intervention, in the form of an increased dose of dopamine agonist, addition of another dopamine agonist, administration of levodopa or another Parkinson's drug, or discontinuation of therapy due to lack of efficacy. Although safinamide appeared to delay the need for intervention by 93 days - the median time to intervention of patients receiving placebo was 466 days versus 559 for patients receiving the drug - the result was not statistically significant (p=0.334).

The study took the form of a 12-month extension to a six-month efficacy trial that originally enrolled 270 patients. Of these, 227 enrolled in the extension study, ostensibly to assess long term safety.

"We also kept the trial double blinded because we also wanted a chance to assess efficacy long term. At the time of submission of most Parkinson's drugs, long term efficacy has never been assessed," Ravi Anand, chief medical officer at Milan, Italy-based Newron, said on a conference call last week.

"What we wanted to do in this trial was to start looking into efficacy measures that would provide additional support to the label, potentially, or to the marketing of the product," Newron CEO Luca Benatti told BioWorld International. The efficacy of dopamine agonists tends to drop after about two and half or three years. Newron is positioning safinamide as an add-on therapy that would extend this period, without causing additional side effects.

Ravi Anand, said several factors contributed to the miss on the time to intervention endpoint. Both the size and duration of the trial were limited. "Usually when you do time to intervention studies you need a very long follow-up period," Anand told BioWorld International.

To compensate for the lack of numbers, the company pooled data from high-dose (150 mg to 200 mg once daily) and low-dose (50 mg to 100 mg once daily) arms of the study, before learning that the higher doses were less effective. The study was also undone by unexpectedly low event rates in both the drug and placebo arms, particularly during the first six to eight months.

An alternative analysis that looked at the data from Day 240 onward did pick up a positive signal from the low-dose arm. In the placebo group, 51 percent of patients required an intervention after that point, whereas just 25 percent in the low dose arm did, and the result was statistically significant (p=0.049).

"From my point of view this is actually very good news," Anand said. It confirms the product's long term efficacy, he said, and provides additional information that will feed into the design of other Phase III studies that Newron and its development partner, the Merck Serono division of Darmstadt, Germany-based Merck KgaA, are conducting.

Florian Gaiser, analyst at Zurich, Switzerland-based Kepler Equities was also unconcerned about the miss. "I'm not so worried because they can address that endpoint in a Phase III later," he told BioWorld International. "It's the first time they've had a go at this kind of endpoint."

Although the company's share price dropped slightly on the news, "the market isn't exactly negative about it either," Gaiser said. His position on the stock was unchanged by the news. He retains a buy recommendation on the stock, with a target price of CHF95 (US$79.23). Newron shares (NWRN.SW) were changing hands at CHF60.65 in late afternoon trading Tuesday on the Swiss Stock Exchange in Zurich, down almost 2 percent from the previous day's close of CHF61.80.

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