Alnylam heads for phase 3 with acute porphyria program

RNA interference (RNAi) specialist Alnylam has hit the accelerator on its candidate drug for ultrarare porphyria diseases, prepping for phase 3 trials later this year after unveiling initial results in 12 patients.

Alnylam's givosiran achieved a dramatic reduction in annual attack rates in the phase 1 trial reported at the International Congress on Porphyrins and Porphyrias in Bordeaux, France, and could become the first drug to be approved for preventing attacks, according to the biotech.

It's a needed boon for Alnylam, which was hit hard last year after it was forced to drop its hereditary ATTR amyloidosis drug revusiran. More patient deaths were seen on that drug versus placebo in the late-stage ENDEAVOUR trial, forcing a switch to new lead drug patisiran.

Porphyrias are a group of disorders that result from a build-up of substances—called porphyrins—that can damage organs and the nervous system. As the name suggests, acute hepatic porphyrias damage the liver, and are among the most common forms of the disease, but are still very uncommon. Taken together, all forms of porphyria afflict fewer than 200,000 people in the U.S., according to the American Porphyria Foundation (APP).

The most common symptom is intense abdominal pain, but some people also suffer muscular weakness, sensory disturbances or convulsions, and as a group the diseases are "devastating for patients" with attacks lasting for days and often requiring admission to hospital, according to Akshay Vaishnaw M.D., Ph.D., Alnylam's head of R&D, who discussed the data on a conference call this morning.

At the moment, the only drug approved for use in porphyria is hemin, which is labeled as a treatment for attacks but is given off-label to some patients for prevention. Intravenous glucose therapy is also used, but both treatments have limited activity in preventing or hastening recovery from attacks, according to the APP.

Enter givosiran, a gene-silencing drug designed to switch off the aminolevulinic acid synthase 1 (ALAS1) gene. The drug reduces levels of two porphyrin precursors (ALA and PBG), which researchers hope will prevent attacks.

The RNAi switched off ALAS1 in the trial and achieved a 73% reduction (PDF) in annualized attack rate compared to placebo in the 12-patient phase 1 trial, with a 73% reduction in annualized hemin doses. Clinicians have suggested a 30% reduction in attacks would be clinically meaningful, according to Barry Greene, president of Alnylam.

Importantly, the reduction in attacks appeared to be dose-dependent and matched reductions in ALA/PBG levels, suggesting these could be used as biomarkers for the drug's activity in future studies, said Vaishnaw.  There was one death among patients in the treatment group (due to hemorrhagic pancreatitis) as well as three other serious adverse events that the investigators concluded were not linked to the study drug.

Data from an eight-patient open-label extension study found a further reduction in attacks and suggested control could be better with longer-term dosing, said Vaishnaw, although he stressed the results are still preliminary with such a small patient cohort. That said, there is no evidence for this with hemin, but some data suggest that control gets worse in hemin-treated patients over time, he added.

Either way, "there is no question these annualized attack rate reductions have a big impact on the lives of patients," said Vaishnaw on the conference call.

"We are very encouraged by the data … and the potential for the givosiran program," said Greene, noting that the drug could offer a once-monthly, low-volume subcutaneous injection therapy for patients with porphyrias.

On the thorny topic of pricing, Alnylam is thinking ahead and already reckons it can make a big impact on the costs of acute hepatic porphyrias. Treatment currently costs between $400,000 and $650,000 per patient per year, according to a natural history study (EXPLORE) due for presentation at the ICPP meeting on Wednesday

The phase 3 program will get underway in the fourth quarter and focus on attack rates—the most devastating element of the disease—said Alnylam. It will, however, also include a pharmacoeconomic analysis to take into account direct healthcare costs as well as indirect factors such as loss of work days, etc.

Alnylam—which said it plans to self-develop and commercialize the drug—has already secured breakthrough registration for the drug in the U.S. and PRIME (priority medicine) status in the E.U., so if the phase 3 program goes well, givosiran is in line for speedy review by regulators.