Alnylam presents positive results for givosiran RNAi therapeutic to treat acute hepatic porphyria

Alnylam Pharmaceuticals presented full results from the Phase III ENVISION trial at the European Association for the Study of the Liver (EASL) annual meeting showing that its investigational RNAi therapeutic givosiran was associated with a significant 74-percent mean reduction in composite annualised attack rate (AAR) versus placebo in patients with acute hepatic porphyria (AHP). "Givosiran substantially reduced the frequency of attacks, providing strong support for a treatment benefit, with a consistent effect across all components of the primary endpoint and all subgroups analysed," remarked Akshay Vaishnaw, head of R&D at the company. 

In the trial, 94 patients with AHP, including 89 with genetically-confirmed acute intermittent porphyria (AIP), the most common form of the disease, were randomly assigned givosiran, which targets aminolevulinic acid synthase 1, or placebo. The primary endpoint was reduction relative to placebo in the annualised rate of composite porphyria attacks, defined as those requiring hospitalisation, urgent healthcare visit, or hemin administration, in patients with AIP over six months. 

Results showed that the 46 givosiran-treated patients with AIP were on track for an expected average of 3.2 porphyria attacks per year after six months, versus an anticipated average of 12.5 attacks per year for the 43 patients with AIP in the placebo arm, translating to a difference of 74 percent. There was also a corresponding median reduction of 90 percent in composite AAR, with median AARs of 1.0 versus 10.7 in the givosiran and placebo groups, respectively. Further, Alnylam reported that 50 percent of givosiran-treated patients were attack-free during the six-month treatment period as compared to 16.3 percent for placebo. 

The company said givosiran also demonstrated significant differences in five of nine hierarchically tested secondary endpoints relative to placebo, including mean reductions of 91 percent and 83 percent in urinary aminolevulinic acid in patients with AIP at three months and six months, respectively. In addition, the RNAi therapeutic was associated with a 73-percent mean decrease in urinary levels of porphobilinogen at six months in patients with AIP, as well as an average reduction of 77 percent in the number of annualised days on hemin in AIP patients, and a 73-percent decline in composite AAR for patients with any AHP. Alnylam missed on other secondary goals, like measures of pain and fatigue, although company president Barry Greene expects better results over time. 

Serious adverse events (SAEs) were reported in 20.8 percent of givosiran-treated patients and 8.7 percent of those on placebo. Alnylam stated that three SAEs in the givosiran group were reported as being related to the study drug, including pyrexia, abnormal liver function test, and one case of chronic kidney disease. There were no deaths in the study. Lead investigator Manisha Balwani suggested the safety findings may be more indicative of the unknowns of AHP and how it impacts patients, rather than givosiran. "I do think it's something we need to explore a little more and see the long-term effects, but when I look at the severity of the disorder, the drug, and my own personal experience [treating AHP patients], I have no reservations using it." 

Alnylam did not disclose any potential pricing information, but the company estimates that each AHP patient already costs the healthcare system between $480 000 and $650 000 per year, Greene said. If approved, givosiran could become the first therapy specifically indicated for AHP, and only the second marketed drug that harnesses RNA interference, following the  approval last year of Alnylam's other RNAi drug Onpattro (patisiran) in the US and Europe for polyneuropathy due to hereditary transthyretin-mediated amyloidosis.

The drugmaker has already submitted parts of its approval applications for givosiran in the US and Europe, and intends to wrap them up by mid-2019. Last year, it decided against pursuing accelerated FDA approval for the treatment following discussions with the US regulator. 

 

To read more Top Story articles, click here.