Alnylam Will Seek Early Approval, But Givosiran Likely To Reach Market Later

Alnylam reported interim Phase III results that it believes support a filing for accelerated approval and a rapid market entry, but a US FDA decision may be delayed by up to six months to allow for a bigger dataset and complete safety assessment in acute hepatic porphyria.

Liver safety issues reported Sept. 27 in an interim analysis of the Phase III ENVISION study of Alnylam Pharmaceuticals Inc.'s RNAi therapeutic givosiran put a damper on hopes for a swift early approval and launch in acute hepatic porphyria based on a surrogate marker, but the company is pushing ahead with an accelerated attempt.

Quick Facts: Acute Hepatic Porphyria

Acute hepatic porphyrias are a family of rare, genetic diseases characterized by potentially life-threatening attacks and for many patients chronic debilitating symptoms that negatively impact daily functioning and quality of life.

Common symptoms of AHPs include severe, diffuse abdominal pain, weakness, nausea, and fatigue. Symptoms of AHPs can often resemble that of other more common conditions such as irritable bowel syndrome, appendicitis, fibromyalgia and endometriosis. Consequently, patients afflicted with an AHP are often misdiagnosed or remain undiagnosed for an average of 15 years.

Four types of AHP cause a deficiency in one of the enzymes of the heme biosynthesis pathway in the liver:

• Acute intermittent porphyria (AIP)

• Hereditary coproporphyria (HCP)

• Variegate porphyria (VP)

• ALAD-deficiency porphyria (ADP)

Source: Alnylam

The drug is an antisense therapeutic delivered via subcutaneous injection that targets aminolevulinic acid synthase 1 (ALAS1) in the liver to treat acute hepatic porphyria (AHP), a family of rare diseases (see box).

Treatment options are limited, but acute attacks of AHP may be treated intravenously with hemin, a preparation of heme, which also may be used prophylactically. However, chronic use of hemin has big drawbacks, notably a risk of developing renal insufficiency and iron overload, which in turn can cause liver cancer.

Givosiran – as an alternative to this problematic treatment – has breakthrough therapy status with the FDA, a PRIME designation in Europe, and orphan drug status for AHP in both regions.

Eye On Accelerated Approval

Alnylam plans to talk to the FDA about a new drug application (NDA) filing at the end of the year based on interim data with a surrogate marker in the ENVISION study.

There was an agreement that the company could pursue accelerated approval if efficacy for the surrogate met the stringent 0.001 p-value threshold in an interim analysis and if the safety profile was acceptable, with agency alignment on the overall package.

However, data from the Phase III study may not support the company's plan.

Givosiran is designed to lower levels of the liver enzyme ALAS1, with the goal of bringing aminolevulinic acid (ALA) and porphobilinogen (PBG) to near normal levels, preventing severe and life-threatening disease attacks and controlling chronic symptoms. Alnylam moved the drug into Phase III after a 2017 Phase I study showed that it was effective for reducing the number of attacks. (Also see "Alnylam's Overshadowed Givosiran Comes Into The Phase III Light" - Scrip, 28 Jun, 2017.)

ENVISION tests the drug against placebo in 94 patients, using the annualized attack rate requiring hospitalization, urgent health care visit or hemin administration at home over six months of treatment as the primary endpoint. Enrollment has been faster than expected, with all 94 on board, and top-line results for the primary endpoint are expected at the end of the first quarter.

Alnylam performed a pre-specified interim analysis using change in urinary aminolevulinic acid as a surrogate marker for clinical benefit.

The company released some data for the drug's effect on aminolevulinic acid in 43 patients, including 41 with acute intermittent porphyria (AIP), one with variegate porphyria and one with hereditary coproporphyria, who were on the study drug for at least three months, with data up to the cut-off date of Aug. 22.

The drug significantly reduced aminolevulinic acid in AIP patients; the p-value for this result was 0.001, but other details were not released.

"While we aren't able to currently disclose the magnitude of urinary ALA reduction, the very low p-value is indicative of a very robust treatment effect," CEO John Maraganore said during a Sept. 27 investor call.

"In light of the evidence for urinary ALA as a biomarker reasonably likely to predict clinical benefit, and the fact that we met the stringent interim analysis threshold of p less than 0.001, we view the positive interim results as very encouraging," said Akshay Vaishnaw, executive vice president of research and development.

Questioning Liver Safety

However, there are concerns on the safety front. Severe adverse events were reported for five patients (22% of 23) in the drug arm and two patients in the placebo group (10% of 20).

"One patient (4%) on givosiran discontinued treatment due to an increase in liver transaminase – which resolved – that was greater than eight times the upper limit of normal (ULN), a protocol-defined stopping rule," the company reported.

There were no deaths as of the data cut-off date.

Maraganore said the company believes the overall safety and efficacy profile is fully supportive of its efforts to bring givosiran to patients in the US as rapidly as possible through accelerated approval.

However, the exec also said the company previously advised the FDA that full attack rate data would be available in late 2019 or early 2020 versus the new early 2019 expectation. So with more rapid enrollment than expected, he noted, the FDA could decide it wants the company to hold off on a filing until it has the full package.

"If so, we believe the timing difference for a decision on our NDA in that event will be about four to six months compared with the NDA for an accelerated approval. As a reminder, we are waiting for full ENVISION Phase III trial results to file for marketing authorization in all other markets outside the US," Maraganore said.

Analysts Expect Delay

Biomedtracker analysts said there is a good possibility that the FDA will want the data for the primary endpoint, rather than approving the drug early based on the surrogate marker, in light of the safety issues and the short time to the final assessment.

"While patients with the disease can have liver involvement, the resolution with drug cessation suggests it may be drug-related, though more details are needed. The patient did not meet Hy's law criteria (a combined elevated transaminases and bilirubin that can portend more serious damage)," Biomedtracker analysts said.

There are mechanistic reasons why RNAi therapeutics can lead to hepatotoxicity and the FDA is likely to want to get a full picture of the risks, they said.

The nature of the severe adverse events relative to placebo (22% vs. 10%) is also unclear at this time, Biomedtracker noted.

"Overall, while the case of increased [liver function enzymes] is concerning, given the orphan indication and need for treatment, we tend to think the issue will not become large enough to preclude approval," Biomedtracker analysts said.

Similarly, in a Sept. 17 note, BMO Capital Markets analyst Do Kim said the agency is likely to opt to await full study results in early 2019 for a more complete assessment of the risk/benefit profile.

"While our Givosiran estimates could be pushed out 3-6 months, we expect final data to show significant clinical benefit, outweighing the higher safety risk," Kim said.

Kim also has faith in the relationship between ALA lowering and the reduction in the annualized attack rate and expects a significant result for the primary endpoint in early 2019, paving the way for approval.

BMO Capital Markets projects worldwide peak sales of $1bn.

Drug safety will be a key factor in the FDA's risk/benefit analysis, Morgan Stanley analyst David Lebowitz said in a Sept. 27 note, but he suspected that the FDA will allow an accelerated filing, since the primary endpoint data would be delivered soon after.

"While we understand the severity of the disease and the need for a therapy, given that final data including clinical endpoints is only 4-6 months down the line, we do not see a compelling reason that the FDA would allow the company to submit for accelerated approval," Lebowitz said.

Morgan Stanley pushed out modeling for first sales into 2020 and projects sales of $150m by 2025.

Alnylam President Barry Greene said during the call that the company is doing a significant amount of pre-commercial work ahead of approval, including raising disease awareness and communicating with patient advocates to ensure they understand that givosiran is coming.

"We imagined based upon the rare disease population, enrollment was going to take a lot longer, so the fact that patients were willing to come into a study so rapidly is a testament to the desire to seek treatment," Greene said.