Judging by their performance on a conference call, the management team behind Synageva BioPharma was overjoyed by the phase III results generated by the lysosomal acid lipase replacement therapy sebelipase alfa. The project met the Arise trial’s primary endpoint and six of the 17 secondary targets, and submission of an NDA and a European application is on track for early 2015.
Despite this the company’s shares were down 12% in early trading today. Investors might be selling on the news – Synageva is unlikely to have anything else to report until the filing – but there is another possible explanation. The trial’s only serious adverse event, an infusion reaction that forced one of the patients to withdraw from the trial, occurred in the sebelipase arm.
Synageva would not give the exact figures for Arise’s primary outcome – attainment of normal levels of alanine aminotransferase – saying that this would be reserved for publication. ALT normalisation is a liver biomarker; the FDA is not always delighted with surrogates of this kind, but sebelipase has breakthrough status so the agency must have deemed this endpoint acceptable.
The trial was conducted in 66 patients with lysosomal acid lipase deficiency, a rare lysosomal storage disease that causes cirrhosis, fibrosis and atherosclerosis through buildup of fatty material in the liver and blood vessels. It can be fatal in the first six months of life. The patients in the Arise trial had a median age of 13 years.
In Arise, sebelipase was administered intravenously every other week at a dose of 1mg/kg for 20 weeks. In addition to the primary endpoint, the drug reduced LDL cholesterol, non-HDL-C and triglyceride levels and increased HDL-C levels from baseline to week 20 compared with placebo; all of which met statistical significance.
It also showed statistically significant improvements over placebo in aminotransaminase normalisation and in liver fat fraction as assessed using MRIs.
An invasive method was also used to give a more direct assessment of liver function, though for ethical reasons only in a subset of patients. Paired liver biopsies were available from 26 patients – 16 in the sebelipase arm and 10 in the control group – to indicate improvement in hepatic steatosis. Improvement was seen in 63% of the sebelipase patients and 40% of the placebo patients, but significance was not achieved.
Tony Quinn, Synageva’s chief medical officer, said that the sample size was too small for statistical significance, and added that all of the 32 patients who underwent biopsy at baseline had cirrhosis or fibrosis, causing variation in the samples.
Data on Arise’s other secondary endpoints was not released.
Building the market
The issue for orphan diseases such as lysosomal acid lipase deficiency is locating the few patients who have the disorder. Sanj Patel, Synageva chief executive, said the company was not slacking in its efforts to develop the market, and its assay for identifying patients would be a central plank of its approach.
This diagnostic, called the dry blood spot test, involves analysis of a drop of blood on filter paper. Calling it “a very robust test”, Mr Quinn said the test was “available at a number of important testing labs all over the world, including [those run by] LabCorp in the US”.
“We’ve begun to build a global commercial and medical infrastructure,” Mr Patel said on the call. “We have a strategy. The dry blood spot test is a very important piece of that but it’s not the only piece – there are a number of other things like publication of the study results that are very important for finding patients. It’s certainly a global approach.”
Analysts believe that this strategy could pay off; EvaluatePharma’s consensus forecasts have sebelipase achieving global revenues of $796m in 2020. But the patient withdrawal is still a worry. Management said that this patient was being evaluated with a view to moving forward with treatment. Perhaps if this can be achieved the company’s stock will arise once more.
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