Now that Ionis Pharmaceuticals Inc. and affiliate Akcea Therapeutics Inc. have gained FDA clearance – albeit delayed and with a black box warning – of antisense oligonucleotide Tegsedi (inotersen) for polyneuropathy of hereditary transthyretin (ATTR)-mediated amyloidosis in adults, speculation has begun about the drug's chances in the marketplace given the double-stranded small interfering RNA drug Onpattro (patisiran) from Alnylam Pharmaceuticals Inc., which won the FDA's go-ahead in August for the same indication.

Many are unconvinced, but they were so before the approval. The products are priced similarly, and Tegsedi has a dosing edge: self-administered by subcutaneous injection vs. Onpattro's intravenous route every three weeks with steroids. But the black box warning due to the risk of thrombocytopenia and kidney trouble stands as a significant blot on Tegsedi's escutcheon.

Akcea will market Tegsedi with a risk evaluation and mitigation strategy. Before patients start using the drug, blood and urine will be tested to determine platelet counts and kidney and liver function. While patients are on therapy, platelet counts will be measured every week (or more frequently as needed), kidney function will be gauged every two weeks, and liver function will be checked every four months. If a patient is directed to stop taking Tegsedi, blood and urine samples will be examined for eight more weeks after quitting.

"We see potential for this warning to impact uptake of the product but acknowledge consensus already reflects minority share for Tegsedi," J.P. Morgan analyst Jessica Fye wrote in a report, noting that Ionis "expects annual pricing of about $450,000, consistent with the average annual list price of $450,000 for Onpattro (net price of $345,000)." Overall, she said, "we see this approval as a clear positive in light of the skepticism by the Street."

That skepticism was fed by the FDA's delay of three months in approving Tegsedi, and by the complete response letter in August for Ionis' familial chylomicronemia syndrome candidate, Waylivra (volanesorsen). Concerns over the drug's safety, clinical benefit and trial population had surfaced in an adcom meeting. (See BioWorld, Aug. 29, 2018.)

Laidlaw analyst Yale Jen sounded somewhat more optimistic than Fye regarding uptake. "Tegsedi adoption could accelerate once patients and physicians feel more comfortable about the thrombocytopenia concern and [they may] like to take advantage of the subcutaneous, self-administrated, at-home delivery benefits," he wrote in a report, adding that he does "not view the efficacy of the two drugs [as] meaningfully different once in real-world practice."

For what it's worth, Alnylam didn't get its hoped-for U.S. label, either. In the EU, where Onpattro was given the go-ahead in July, the summary of product characteristics – posted after a positive opinion came down in Europe a month earlier – encompassed secondary and exploratory endpoint data, including results reflecting cardiac parameters. In the U.S., Onpattro's label is not so expansive. But that's small potatoes compared to a black box warning, and FDA officials proved leery enough of Tegsedi that, unlike regulators in the EU, they didn't leave open the possibility of reducing the dose if problems arise during treatment.

During a conference call last Friday with investors, Ionis CEO Paula Soteropoulos addressed the matter, saying that the agency and the company agreed that, "given the fact that we have so few events," practices followed in an open-label extension study and early access program should be maintained until more data are in hand, at which point the subject will be revisited. Meanwhile, Ionis President Sarah Boyce said the company has a sales team "fully in place ready to go out as of Monday morning."

Spinraza in SMA crosshairs?

Also in play in the space is New York-based Pfizer Inc.'s tafamidis, a small-molecule drug in phase III testing. In April, top-line data from the ATTR-Act trial in TTR amyloid cardiomyopathy (ATTR-CM) found that tafamidis provided a statistically significant reduction in the combination of all-cause mortality and frequency of cardiovascular (CV)-related hospitalizations vs. placebo at 30 months. It was the first pivotal trial to test a pharmacological treatment for the condition. Tafamidis, a TTR stabilizer, is approved as Vyndaqel in Europe and several other ex-U.S. markets to treat TTR amyloid polyneuropathy. The drug was the primary driver for Pfizer's 2010 acquisition of Foldrx Pharmaceuticals Inc., of Cambridge, Mass. It's also approved in Japan solely for the hereditary form of that condition. (See BioWorld, April 2, 2018.)

In late August, Pfizer reported the long-awaited full results of the ATTR-Act study along with a simultaneous publication in The New England Journal of Medicine. "Overall, the top-line results are strong, with a 30 percent reduction in mortality (driven by death) and 32 percent reduction in the rate of CV-related hospitalizations," Evercore ISI analyst Joshua Schimmer said in an email alert to investors. "For now, we believe Alnylam's patisiran (and to a lesser extent Ionis/Akcea's inotersen) will generally be safe in the neuropathy population" and could gain some share in the mixed-phenotype population, "while we expect tafamidis to do well in the larger, wild-type population if approved," he wrote.

In September, Pfizer reported more sensitivity and post-hoc analyses from ATTR-Act, providing further detail on the effect of tafamidis across wild-type, hereditary and New York Heart Association class subgroups of patients with ATTR-CM.

Another gladiator in the arena is Intellia Therapeutics Inc., of Cambridge, Mass., a genome-editing firm with late-stage preclinical work underway. "[The] setup for lead indication, ATTR, is tough, which keeps us cautious over near to midterm," Raymond James analyst Steven Seedhouse wrote as he initiated coverage in September with a "market perform" rating. Recent data with the Alnylam, Pfizer and Ionis therapies "establish high hurdles for any presumptive 'next gen' ATTR therapeutic," he said. "The 'one-and-done' benefit argument for gene editing won't work if data are inferior, in our view. Possible data for other less competitive indications (like alpha-1 antitrypsin deficiency) are even farther away still, which is another reason to simply remain on the sidelines in 2019," he said.

For Ionis, Spinraza (nusinersen) for spinal muscular atrophy (SMA) – partnered with Cambridge, Mass.-based Biogen Inc. – "represents a key valuation backstop in [the] stock price," in the view of J.P. Morgan's Fye.

The survival motor neuron-2 (SM2)-directed antisense oligonucleotide was approved in late 2016. But earlier this month, Roche Holding AG, of Basel, Switzerland, and South Plainfield, N.J.-based PTC Therapeutics Inc. made public pivotal data with SM2 gene splicing modifier risdiplam (RG-7916) in SMA. "While there are always challenges comparing data across clinical trials, we come away from the update impressed by the emerging clinical profile for risdiplam," she said in a report. "Indeed, we see increasing competitive intensity in the SMA space longer term." While the data did not represent "an overwhelming surprise (we believe positive results were expected), we view these updates supporting potentially a broad benefit in all patients with SMA, including type 2 and type 3." The results "bear watching, particularly in the context of a convenient oral administration, and we would not be surprised to see this become a greater focus in Ionis' stock," she said.

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