VIENNA – One year after reporting a 75% decrease in acute intermittent porphyria (AIP) attacks from a phase I trial of its RNAi drug, givosiran, Alnylam Pharmaceuticals Inc. returned to the International Liver Congress once again, this time announcing a 74% decrease in its much larger phase III Envision trial.

The drug, based on the N-acetylgalactosamine (GalNAc) conjugation technology, is slated for regulatory filings in both the U.S. and Europe later this year, and with breakthrough therapy and PRIME designations, it could reach the market in early 2020 as the first approved preventive therapy for acute hepatic porphyria (AHP).

The Envision results were part of the press program Friday and were scheduled for presentation Saturday at ILC 2019, the 54th annual meeting of the European Association for the Study of the Liver (EASL).

"That 74% reduction in mean attack rate was corresponding to a 90% median reduction, which then means that half of the patients actually on givosiran had no attacks during the six-month, double-blind period," Akin Akinc, Alnylam's vice president and general manager of the givosiran program, told BioWorld. "And just to put that in perspective, on average, the median rate coming in was four attacks in the prior six months."

Top-line data of givosiran, which targets aminolevulinic acid synthase (ALAS1), was announced in March, showing the drug hit its primary endpoint, but the details were saved for ILC 2019, and include some concerning safety data on liver enzymes. Liver transaminase increases of greater than three times the upper limit of normal or baseline were seen in seven patients on givosiran and one on placebo. (See BioWorld, March 7, 2019.)

Patient perspectives, however, showed that 89% of givosiran-treated patients vs. 37% of placebo-treated patients reported that their overall health status was improved, according to the Patient Global Impression of Change Questionnaire, and 93 of 94 patients that participated in Envision enrolled in the open-label extension (OLE) period of the study.

"Clearly, there's no safety issue which is precluding continuation in the study," said Manisha Balwani, associate professor of the Department of Genetics and Genomic Sciences and Department of Medicine at the Icahn School of Medicine at Mount Sinai, and the principal investor of the Envision study. "Yes, there were some events of elevated liver enzymes and chronic renal insufficiency ... but I personally don't think there's any safety signal, which has precluded patients from continuing."

In addition to a 74% mean and 90% median reductions over placebo in the annualized rate of composite porphyria attacks during the six-month, double-blind period – the primary endpoint of the trial (p=6.04x10-9) – givosiran hit five of nine hierarchically tested secondary endpoints, showing mean reductions of 91% in urinary aminolevulinic acid (ALA) in AIP patients at three months, 83% in urinary ALA in AIP patients at six months, 73% in urinary levels of porphobilinogen in AIP patients at six months, 77% in the number of annualized days on hemin in AIP patients, and 73% in composite annualized attack rate for patients with any AHP.

Four secondary endpoints – pain, fatigue, nausea and a health-related quality of life measure – failed to hit significance.

"All of these become quite disabling for these patients and are much harder to tackle," Balwani said. "With the current standard of care, there's no effective treatment for these, so I think at least with the results of the phase I/II study, we did see improvements across all of these symptoms with these patients, and as we get long-term data on this study, I'm hoping we'll see a treatment response as well."

Annualized rate of composite porphyria attacks, the primary endpoint, was defined as those requiring hospitalization, urgent health care or hemin administration. Approved in 1983, hemin is the only current therapy available to treat AHP patients when an attack occurs.

"It's not been very effective in preventing attacks, although it has been used prophylactically off-label," Balwani said.

Higher level of treatment satisfaction

In terms of safety, adverse events were reported in 89.6% of givosiran patients and 80.4% of placebo patients, with serious adverse events (SAEs) in 20.8% of drug patients vs. 8.7% of placebo patients. SAEs consisted of two cases of chronic kidney disease, which resulted in elective hospitalization for diagnostic evaluation, and one case each of asthma, device-related infection, gastroenteritis, hypoglycemia, abnormal liver function test, major depression, pain management and pyrexia. Three were attributed to givosiran. No patients died, but one patient discontinued treatment due to an SAE.

Adverse events, which occurred more frequently with givosiran than with placebo, were nausea (27.1% vs. 10.9%), injection site reactions (16.7% vs. 0%), chronic kidney disease (10.4% vs. 0%) and fatigue (10.4% vs. 4.3%). Four of the five patients with chronic kidney disease had a prior history of the disease or a lower baseline estimated glomerular filtration rate.

Of the patients experiencing liver transaminase increases, all had evidence of iron overload or liver disease at baseline. One patient discontinued treatment due to an increase in alanine aminotransferase (ALT) level greater than eight times the upper limit of normal, which was a protocol-defined stopping rule, but the elevation subsequently resolved itself. In six other drug-treated patients, peak ALT levels ranged from three to more than five times the upper limit of normal, but the elevations were asymptomatic and were resolved with continued dosing in five patients or after a brief pause in dosing in one patient.

Overall, patients receiving givosiran reported a higher level of treatment satisfaction (72%) than placebo patients (14%) and an increased ability to perform daily living activities, according to the Porphyria Patient Experience Questionnaire. Specifically, they reported improvements in traveling for work or pleasure (35.1% vs. 13.2% placebo), participating in social activities (35.1% vs. 7.9% placebo) and exercising moderately (32.4% vs. 5.3% placebo).

AIP is one of four subtypes of AHP, a rare and serious genetic condition caused by problems with the normal liver production of heme. The defects cause the accumulation of neurotoxic heme intermediates aminolevulinic acid, thought to be primarily responsible for causing attacks and symptoms in patients. Common symptoms are severe abdominal pain, weakness, nausea and fatigue. The disease can lead to long-term complications, such as chronic neuropathic pain, hypertension, chronic kidney disease and liver disease.

"Cardinal among those is really an excruciating abdominal pain," Akinc said.

Alnylam is currently submitting its rolling new drug application to the FDA, soon to be followed by a marketing authorization application in Europe. Although only 94 patients participated in Envision, the trial was a global pivotal study encompassing 36 sites in 18 countries, and it followed a phase I trial and phase I/II open-label extension conducted in only 17 patients. (See BioWorld, April 16, 2018.)

"It's a very rare disease," Akinc said. "This was the largest pivotal trial that's been done in this population."

Alnylam gained FDA approval of its first RNAi therapeutic through a priority and orphan pathway in August of last year. Onpattro (patisiran) is indicated for hereditary transthyretin-mediated amyloidosis. (See BioWorld, Aug. 13, 2018.)

As Alnylam prepares for a potential approval of givosiran, "we're going to be leveraging a lot of the commercial build put in place" for Onpattro, Akinc said.

Alnylam's stock (NASDAQ:ALNY) closed at $89.81 on Friday.

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