FDA approval of patisiran, branded Onpattro, to treat hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) represents several firsts for Alnylam Pharmaceuticals Inc., not least of which is the distinction of bringing the initial RNA interference (RNAi) drug to market. Although the Cambridge, Mass.-based company also beat competitor Akcea Therapeutics Inc., which is developing Tegsedi (inotersen), to first approval in the hATTR indication, Alnylam now faces the challenge of wooing physicians and patients to a drug in a class without precedent.

Onpattro is designed to interfere with RNA production of an abnormal form of the protein TTR and, by preventing its production, to help reduce accumulation of amyloid deposits in peripheral nerves. The FDA had granted the application fast track, priority review and breakthrough therapy designations, along with orphan drug designation.

The agency's decision came down to the wire. Yvonne Greenstreet, Alnylam's executive vice president and chief operating officer, acknowledged this month on the second-quarter earnings call that the company was continuing to "work collaboratively with our colleagues at the FDA" to win a nod by the Aug. 11 PDUFA date.

Despite that hand-holding, Alnylam didn't exactly get the label it was expecting. The summary of product characteristics, or SmPC, posted last month following a positive recommendation for Onpattro from the EMA's Committee on Human Medicinal Products, or CHMP, to treat hATTR amyloidosis in adults with stage 1 or 2 polyneuropathy encompassed secondary and exploratory endpoint data, including results reflecting exploratory cardiac parameters. Such was not the case for the U.S. label.

"Our NDA and MAA filing packages included the request for an indication for the treatment of hATTR amyloidosis based on the fact that this is a single disease with multisymptom involvement, patisiran's mechanism of action as a targeted therapy and a consistent improvement seen vs. placebo across all primary, secondary and key exploratory endpoints from the APOLLO phase III study," CEO John Maraganore explained on the company's call to discuss the approval. "As is often the case, where we ended up on the label materialized very late in the review process. While the indication of the U.S. label is for patients with polyneuropathy, and the label does not include cardiac data, we do look forward to working with the FDA to expand the Onpattro label more broadly in the future."

President Barry Greene did not rule out the prospect that the FDA might require additional trials to incorporate cardiac data into the label but, he added, the agency expressed its willingness to engage in additional dialogue with the company.

"Over the course of discussions, as the FDA looked at the data, they certainly acknowledged that this was a monogenic, multisymptom disease," Greene said. "They appreciated the consistency of the data. But as they looked at the endpoints, they felt that the primary and secondary endpoints characterized the benefits of Onpattro on the neuropathic manifestation of the disease. The cardiac endpoints that we had, while very interesting, were exploratory and didn't firmly establish the benefits of Onpattro on the cardiac manifestations of the disease."

At this point, it's unclear "what that will take" to show those cardiac benefits, he acknowledged.

Greenstreet was quick to observe that FDA and EMA officials "looked at exactly the same datasets and have come to different decisions" regarding Onpattro's approved indication.

And in any event, the company's sales effort will encompass all specialists who treat hATTR amyloidosis, officials emphasized.

"This is a multisymptom disease," Greene pointed out. "We will be targeting cardiologists, neurologists, gastroenterologists and other physicians that touch these patients."

The narrower-than-expected indication represented a smudge on an otherwise clean label, which included no black box warning, laboratory monitoring or contraindications. Precautions against infusion-related reactions and reduced serum vitamin A levels both were deemed easily manageable.

Analyst: 'Rapid patient uptake' expected

Alnylam has been prepping for Onpattro's commercialization for months, most recently by adding head count and expanding its footprint in Kendall Square. On the company's earnings call, Maraganore had pronounced Onpattro "launch-ready" in the U.S. and Germany, expected to be the first commercial effort in the EU. Following FDA approval, the company said product would available for shipment to U.S. health care providers within 48 hours through two specialty pharmacies and one specialty distributor.

Onpattro is priced at $9,500 per vial based on an average of 2.7 vials administered every three weeks, or an average of 17.5 times per year, for an average annual list price of $450,000, though officials maintained that the average effective net price will be $345,000. Alnylam determined the price, Greene said, with patient access top of mind, based on the urgent unmet need in hATTR amyloidosis; clinical outcomes that showed the treatment improved polyneuropathy and reversed neuropathy impairment in most patients; the indication's rare disease status, with fewer than 3,000 diagnosed patients in the U.S.; and the fact that the drug, in development for 16 years, represented the first entry in a new drug class.

Alnylam, he added, is "deeply committed" to the patient community and to continued development in the amyloidosis therapeutic space. In fact, the company's next-generation ALN-TTRsc02 candidate is expected to move quickly into phase III development following accord with the FDA on design of a pivotal trial.

In conjunction with the approval, Alnylam also disclosed that it agreed on the structure and key terms of value-based agreements for Onpattro with certain payers, including Harvard Pilgrim Health Care, contractually committing to provide real-world benefits that align with predetermined clinical criteria and to pay a rebate to insurers when these criteria are not met. Although the company did not name other insurers, officials said the "engaged payers" cover approximately 76 percent of commercially insured U.S. lives.

Alnylam also expects Onpattro to be covered under Medicare part B.

In the EU, reimbursement will be negotiated on a country-by-country basis following the EU's decision on the drug, expected next month.

To address disease awareness and diagnosis, which Greene called the biggest challenges for hATTR amyloidosis, the company also rolled out Alnylam Act, a third-party genetic testing service in the U.S. and Canada that's free to patients. As of July 31, Alnylam Act already had enabled testing of approximately 6,700 individuals who may carry gene mutations associated with hATTR amyloidosis and identified 460 patients with pathogenic TTR mutations.

"We are also pleased to have an active expanded access program in the U.S. and Europe, providing early access to patisiran in response to requests from treating physicians for eligible patients," Greene said, noting that the company already has fulfilled physician requests for more than 200 individuals in the U.S. and Europe who are receiving treatment with patisiran.

Last week, the U.K.'s Medicines and Healthcare Products Regulatory Agency, or MHRA, also rendered a positive scientific opinion through its early access to medicines scheme, enabling eligible adults to gain access to the therapy prior to EU marketing authorization.

Alnylam plans to file a new drug application for Onpattro with Japan's PMDA by the end of the third quarter.

Other players in the RNAi field welcomed the approval.

"This year is a turning point for people living with hereditary transthyretin amyloidosis," Paula Soteropoulos, Akcea's CEO, told BioWorld. As the Cambridge, Mass.-based company awaits its Oct. 6 PDUFA date for Tegsedi in hATTR, "we are excited to be a part of bringing new therapies to patients who previously had limited options to safely and effectively manage this fatal disease," she added, pointing to the potential for multiple approvals within the year.

"I am really excited to see this first siRNA approval," added Geert Cauwenbergh, president and CEO of Marlborough, Mass.-based Rxi Pharmaceuticals Corp., which "will help the entire RNAi category of drug companies to attract additional financial resources to accelerate development and approval of other drugs in this class."

Shares (NASDAQ:ALNY) of Alnylam were up about 3 percent Friday, topping the day at $97.49, before trading was halted prior to the FDA announcement. After hours, shares were off 4 percent, a development anticipated by Piper Jaffray's Edward Tenthoff. In a hot comment following Onpattro's approval, he pointed to the restriction to patients with polyneuropathy and predicted shares "may open lower on this label."

Still, Tenthoff added, "We expect clean safety, overwhelming efficacy and first mover advantage to result in rapid patient uptake, even if inotersen is approved by the October 6th PDUFA."

Patisiran was No. 6 on Drugs to Watch 2018, the annual report on blockbuster drugs issued by Clarivate Analytics, parent company of BioWorld, with 2022 projected sales of $1.21 billion.

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