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Four years to the month that it gained the first FDA approval for an RNA interference treatment, Alnylam Pharmaceuticals (ALNY) and its patisiran made biopharma history again—to the delight of shareholders and analysts—thanks to a successful Phase III trial that sent the company’s shares jumping 49% on Wednesday.

Patisiran—marketed as Onpattro® and approved in August 2018  for polyneuropathy (PN) of hereditary transthyretin-mediated amyloidosis (hATTR) in adults—aced the Phase III APOLLO-B study (NCT03997383), which assessed the RNAi drug as a treatment for transthyretin-mediated amyloidosis with cardiomyopathy (ATTR-CM). According to topline results, patisiran met the primary endpoint of change from baseline in the 6-Minute Walk Distance (6MWD) test at 12 months compared to placebo (p-value 0.0162).

“We see this result as a clean hit that should support a high probability of approval across geographies for patisiran in ATTR-CM,” Mani Foroohar, MD, Senior Managing Director, Genetic Medicines, and a senior research analyst with SVB Securities, wrote Wednesday in a research note.

The study also met the first secondary endpoint of change from baseline in quality of life compared to placebo, as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) (p-value 0.0397).

Full results from APOLLO-B are set to be reported on September 8 at the XVIII International Symposium on Amyloidosis (ISA 2022), set for September 4-8 in Heidelberg, Germany.

“We are thrilled that APOLLO-B successfully met all its major objectives, which we believe for the first time validates the hypothesis that TTR silencing by an RNAi therapeutic can be an effective approach for treating the cardiomyopathy of ATTR amyloidosis,” said Pushkal Garg, MD, Chief Medical Officer of Alnylam.

Also thrilled were Alnylam investors, who saw the company’s stock soar from $141.97 on Tuesday to $212.01—the biggest one-day gain for the company’s shares in five years. The share price had peaked at $220.92, a record high price that would have reflected a 56% leap.

This, despite Alnylam sharing some less positive top-line results from APOLLO-B as well. The company reported a non-significant result (p-value 0.0574) on the study’s secondary composite endpoint of all-cause mortality, frequency of cardiovascular events, and change from baseline in 6-MWT over 12 months compared to placebo. As a result, Alnylam said, it did not perform formal statistical testing on the final two composite endpoints, as they were not powered for statistical significance given the short duration of the study. Those two final endpoints were all-cause mortality and frequency of all-cause hospitalizations and urgent heart failure visits in patients not on tafamidis at baseline (nominal p-value 0.9888), and in the overall population (nominal p-value 0.5609).

Analyst projects $3.6B peak sales

Why then are investors so bullish on Alnylam, whose shares this year closed as low as $140.22 on May 11?

Because an additional approval for ATTR-CM could potentially more than double the peak-year sales potential of patisiran. Under the name Onpattro, the drug racked up $137.009 million in first-quarter net product revenues, up 34% from $101.951 million in Q1 2021, on top of $474.737 million for all of 2021, (up 55% from $306.081 million in 2020).

“ATTR-CM is the larger mkt oppty [market opportunity],” observed Maury Raycroft, PhD, equity analyst at Jefferies, in a Wednesday research note. “We est[imate] it will unlock $3.6B in peak sales” on top of $1.4 billion in combined peak year sales being estimated for Onpattro plus vutrisiran, a late-stage RNAi candidate that Alnylam is developing for a second indication, a treatment for ATTR, which encompasses both hATTR and wild-type ATTR (wtATTR) amyloidosis.

Alnylam is among companies developing ATTR treatments that they hope will someday outcompete Pfizer’s blockbusters of Vyndaqel® (tafamidis meglumine) and/ Vyndamax® (tafamidis), which contain different forms of the same active ingredient. The drugs generated a combined $612 million in revenue in the first quarter, up 35% from $453 million in Q1 2021, and $2.015 billion last year, up 56% from $1.288 billion in 2020.

Until last year, industry watchers expected Pfizer’s stiffest competition would emerge from BridgeBio Pharma, until the company acknowledged in December 2021 that its oral small molecule candidate acoramidis failed the Phase III ATTRibute-CM trial (NCT03860935) as placebo patients performed better than patients receiving the treatment in the 6MWD.

An expanded-label patisiran could start being marketed to patients as soon as next year. Alnylam plans to file a supplemental New Drug Application (sNDA) late this year and hopes to gain approval quickly enough to launch the new indication during 2023.

“For timeline, we note the [standard] review time for an sNDA or BLA is 10 mos (vs 12 mos for new NDA); so, west Onpattro expansion by 3Q/4Q ‘23,” Raycroft wrote. He added that it could be earlier, given the FDA’s familiarity w/ the drug and the regulatory review precedent for sNDAs.

Patisiran and vutrisiran—already marketed as Amvuttra® for treatment of PN of hATTR amyloidosis in adults—are building blocks of a franchise of ATTR treatments that Alnylam is intent on building. That franchise also includes ALN-TTRsc04, an RNAi candidate for which the company plans to submit an IND application to the FDA and launch a Phase I study in healthy volunteers, both later this year.

“Positive outcome is a major de-risking event for the larger cardiomyopathy (CM) oppty and an important event for the sector,” Raycroft added.

Ampio Pharmaceuticals (AMPE)

Ampio shares plummeted 34% on Wednesday, from $0.1562 to $0.1034, after the company disclosed in a regulatory filing that it eliminated the jobs of 10 of its 18 employees a day earlier. The company blamed the layoffs on its decision to halt development of anti-inflammation drug Ampion for all indications and end most other development activities pending the conclusion of its exploration of strategic alternatives.

“The reduction in force is a measure to manage costs and conserve cash resources with the goal of maximizing the opportunities available to Ampio during the Board’s review of strategic alternatives,” the company stated in the filing.

Ampio also disclosed that four of the employees it did not lay off were offered conditional retention and severance arrangements with the company through December 31, 2022—in exchange for retention and severance payments should their full term of service be completed. During that time, Ampio said, the company and its board will continue to “actively” evaluate and monitor its near-term personnel needs “based in part on the Company’s financial status and the Board’s review of strategic alternatives.”

Ampio said it expected to record a charge of up to $425,000 in the third quarter for employees being terminated by August 31 and a charge of up to $355,000 beginning in the third quarter and continuing through the fourth quarter of 2022—primarily reflecting one-time severance and termination benefits in cash.

In the filing, Ampio also revealed that it terminated the employment of two unnamed executives and restructured its board through resignations as well as by separating the roles of Chairman and CEO. Michael A. Martino, who had held both roles, remains as CEO, with former Cephalon President and CEO J. Kevin Buchi now serving as Chairman. Ampio also said that it re-constituted its Disclosure Committee with additional subject-matter experts; strengthened policies and procedures related to inventory management and distribution; and conducted company-wide training regarding appropriate use of Ampion while in the clinical trial stage.

Those changes all followed a Special Committee investigation that found that some unnamed former Ampio executive officers and senior staff knew that the AP-013 clinical trial had not shown efficacy for Ampion on its co-primary endpoints of pain and function, but had not fully reported the results and the timing of unblinding of data from the trial at the time of an interim analysis in March 2020. The investigation also found that some Ampio staffers, including a former executive officer and certain former directors, facilitated the provision of Ampion for unauthorized use. Current executive officers were not involved, according to the company.

Applied DNA Sciences (APDN)

Shares of Applied DNA Sciences multiplied in value after the diagnostics developer announced it had initiated analytical validation of a company-developed, PCR-based test that is specific for the genetic signature of the monkeypox virus through a subsidiary. Shares rocketed 412% on Tuesday, from 68 cents a share to $2.80, then soared another 46% on Wednesday to $4.10.

ADCL’s monkeypox test is designed to enable qualitative detection and differentiation of monkeypox from other non-variola orthopoxviruses using real-time PCR, by employing an A17L gene-target specific to the virus. If the test is validated by the company’s wholly owned clinical laboratory subsidiary, Applied DNA Clinical Labs (ADCL), a validation package will be submitted for approval to the Department of Health in New York state, where Gov. Kathy Hochul, a Democrat seeking re-election in November, declared the ongoing monkeypox outbreak a “State Disaster Emergency” via Executive Order No. 20. Executive Order No. 20.

If the test is validated and approved by the state, Applied DNA said, testing will be performed at the subsidiary’s CLEP/CLIA molecular diagnostics laboratory in Stony Brook, NY, where the company is based, using established and proven workflows intended to ensure accurate results and competitive turn-around-times.

“With a proven workflow and testing services born of COVID-19, upon test approval, ADCL stands ready to apply its testing capacity in service of New Yorkers’ health,” stated James A. Hayward, PhD, ScD, Chairman, President and CEO of Applied DNA Sciences.

Otonomy (OTIC)

Otonomy’s shares cratered 80% on Monday, from $1.43 to $0.2913, after the company said it would end development of its lead pipeline candidate OTO-313. Otonomy acknowledged that the tinnitus treatment failed its Phase II trial (NCT04829214) by demonstrating no clinically meaningful benefit versus placebo for primary and secondary endpoints across all timepoints.

The trial’s primary endpoint was a responder analysis based on the proportion of patients who reported a clinically meaningful improvement, defined as a reduction of 13 points or more in the Tinnitus Functional Index (TFI), from baseline to both Months 1 and 2 following treatment. The trial failed to meet that primary endpoint as well as secondary endpoints for the total study population.

“These results were unexpected with a much higher placebo response than observed in the prior Phase 1/2 study,” Otonomy President and CEO David A. Weber, PhD, said in a statement. “In addition to this trial, we have also reviewed preliminary top-line results for the one-month safety evaluation of higher and bilateral dosing of OTO-313 and did not observe a treatment benefit that is convincing in light of the Phase II results.”

OTO-313 was a sustained-exposure formulation of gacyclidine, a potent and selective NMDA receptor antagonist. OTO-313 showed a higher response rate than placebo in a prospectively defined patient subgroup with tinnitus duration of less than 6 months—the population studied in its successful Phase I/II trial (NCT03918109), whose results were announced in 2020. However, Otonomy concluded that the Phase II trial’s overall results did not support further development of the drug.

The Phase II trial was a randomized, double-blind, placebo-controlled study that enrolled 153 patients with persistent, unilateral tinnitus of at least moderate severity. Seventy-seven patients were randomized 1:1 to a single intratympanic injection of OTO-313; the other 76 patients, to placebo. Patients in both arms were followed for 4 months.

Otonomy said it will shift its clinical focus to OTO-413, sustained-exposure formulation of brain-derived neurotrophic factor (BDNF) being developed to treat hearing loss. In April, Otonomy announced positive Phase IIa results that corroborated findings from an earlier Phase I/II study. The company said it has completed enrollment for an evaluation of higher dosing of OTO-413, with top-line results expected in the fourth quarter.

Phathom Pharmaceuticals (PHAT)

Phathom’ shares tumbled 29% on Tuesday, from $9.07 to $6.46, after the company said it would delay the commercial launch two combination drugs designed to treat Helicobacter pylori (H. pylori) infection in adults to the first quarter of 2023.

Phathom said it is now planning for a combined commercial launch of Voquenza TriplePak (vonoprazan, amoxicillin and clarithromycin) and Voquenza DualPak (vonoprazan and amoxicillin), along with a product already anticipated to launch in Q1 next year, vonoprazan monotherapy for both treatment and maintenance if healing of all grades of erosive esophagitis (EE) and relief of heartburn in adults.

The monotherapy is under FDA review after the agency accepted Phathom’s New Drug Application and assigned the NDA a Prescription Drug User Fee Act (PDUFA) target action date of January 11, 2023.

The company blamed the launch delay on detecting trace levels of an unspecified nitrosamine in vonoprazan during post-approval testing. Phathom said it began the testing in order to heed FDA recommendations for all chemically synthesized drug compounds such as vonoprazan.

“We will be discussing with the FDA a new test method and controls, and confirming our assessment that our drug product is within acceptable intake levels. Our goal is to make our product available to H. pylori patients as soon as possible,” Phathom’s President and CEO Terrie Curran said in a statement. “We believe a combined launch will bring significant operational and financial benefits.”

Investors didn’t seem to agree—and may have also reacted to the company reporting GAAP earnings per share of $1.33, 30 cents below a consensus forecast.

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