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Minerva Neurosciences (NERV) shares rocketed 86% to $8.37 early on Wednesday afternoon before ending the day with a 67% gain, from $4.51 to $7.51, a day after the company disclosed that Point72—the global asset management firm founded and led by New York Mets owner Steven A. Cohen—had taken an 8.8% stake in the central nervous system disease drug developer by acquiring 470,000 shares.

The stock purchase, was disclosed in a regulatory filing by Cohen and two Point72 entities on Tuesday after the close of trading. Point72 Capital Advisors is the general partner of Point72 Asset Management. Both are controlled by Cohen, whose Mets have led the National League East for most of this baseball season.

Point72 bought the shares on Monday, the same day that Minerva announced that it had submitted a New Drug Application (NDA) to the FDA for roluperidone as a treatment for negative symptoms in patients with schizophrenia. The NDA includes results from two late-stage clinical trials (MIN-101C03 and MIN-101C07) in patients with moderate to severe negative symptoms and stable positive symptoms of schizophrenia (NCT03397134 and Eudra-CT 2017-003333-29)

“We believe that roluperidone may represent a new therapeutic option to treat patients with negative symptoms of schizophrenia for which there are currently no approved therapies in the United States,” Remy Luthringer, Minerva’s Executive Chairman and CEO, said in a statement. “While positive symptoms of schizophrenia are generally well managed with antipsychotics, negative symptoms are often the main burden of illness and can impact the patients’ quality of life as a result of disabilities caused by impaired vocational and social skills.”

According to its website, Point72 has approximately $26.1 billion in assets under management as of July 1, more than 2,000 employees globally, and more than 150 investing teams.

As clinical hold hits Pharvaris shares, rivals take aim at HAE

Some of Wall Street’s leaders and laggards in recent days are a handful of drug developers with one thing in common: A desire to make HAE—as in a therapy for hereditary angioedema—out of a Swiss company’s clinical setback in its development of an oral treatment for the rare inherited disorder.

Shares of Swiss-based Pharvaris (PHVS) tumbled 34% on Monday, from $18.49 to $12.15, after the company announced that the FDA placed a clinical hold on two U.S. Phase II trials of PHVS416, a softgel capsule whose active pharmaceutical ingredient is the company’s lead asset PHA121. Pharvaris’ slide continued into Tuesday, when shares fell another nearly 10%, to $10.99.

The clinical holds put a stop to the RAPIDe-1 trial (NCT04618211), designed to assess PHVS416 as an on-demand treatment for HAE attacks, and the HAE CHAPTER-1 proof of concept study (NCT05047185), designed to evaluate PHVS416 as a prophylactic treatment. Until the clinical hold, Pharvaris had been expected to read out data from RAPIDe-1 in the fourth quarter of this year, and from HAE CHAPTER-1 in Q1 2023.

Pharvaris did not reveal what led to the clinical holds, but did say that the FDA’s decision was based on nonclinical data–and that it planned to provide additional updates following “interactions” with the FDA. The agency is expected to send the company a formal clinical hold letter in approximately 30 days.

“We are fully committed to working closely with the FDA to address the agency’s concerns,” Pharvaris CEO Berndt Modig said in a statement. “Pharvaris remains dedicated to providing new therapeutic choices for the treatment of HAE and is working diligently to bring PHA121 to people living with HAE.”

PHA121 is designed to work by inhibiting bradykinin signaling through the bradykinin B2 receptor, a mechanism of action similar to that of Takeda Pharmaceutical’s marketed acute HAE attack treatment Firazyr® (icatibant), which has generated signals of long-term toxicity.

However, Joseph P. Schwartz, senior Managing Director, Rare Diseases and a senior research analyst with SVB Securities, reported in a research note that management told him and colleagues they had not seen any Firazyr-related toxicities in their candidates, had not heard any concerns about the mechanism itself, and submitted six- and nine-month toxicity studies “some time ago.”

Schwartz and SVB on Tuesday lowered its share price target for Pharvaris from $45 to $25 a share. Also cutting its price target was Oppenheimer (from $48 to $22), while Pharvaris was downgraded by both Bank of America (from Neutral to Underperform) and Morgan Stanley (from Overweight to Equal Weight).

Maury Raycroft, PhD, an analyst with Jefferies, wrote in a research note that Pharvaris’ clinical holds could benefit another HAE drug developer—KalVista Pharmaceuticals (KALV), which has two oral therapies for the disease in its pipeline that are expected to read out data next year. KalVista is enrolling patients in both the Phase III KONFIDENT trial (NCT05259917) for its on-demand HAE candidate Sebetralstat, and the Phase II KOMPLETE trial (NCT05055258) for its HAE prophylaxis candidate KVD824.

Last year, KVD824 endured a four-month FDA clinical hold after the agency sought additional data and analysis of preclinical studies.

“We see oppty for KALV to capture substantial mkt share in both prophy and on-demand HAE settings,” Raycroft observed.

The opportunities, he estimated, could lead to potential worldwide sales in 2026 of more than $2 billion for KVD824 and more than $1 billion in sales for Sebetralstat.

In his note to investors, Schwartz declared KalVistaPHVS’ main competitor in the HAE space, as the company is also building an oral franchise.”

“It has been a close race between the two up until this point; however, the clinical hold may allow KALV to retake the lead,” Schwartz observed. “We look forward to the KALV readouts next year, which we believe should help make the competitive landscape clearer.”

Some investors apparently saw opportunity as well, as KalVista shares jumped nearly 10%, from $15.01 to $16.48, following news of Pharvaris’ clinical hold.

KalVista is among several drug developers developing HAE treatments. Notable among them: CSL recently said it will seek FDA approval during its current financial year (which ends June 30, 2023) for its once-monthly garadacimab (CSL312), a first-in-class monoclonal antibody inhibiting Factor XIIa. CSL announced August 17 that garadacimab met the primary endpoint in its Phase III GUARDIAN trial (NCT04739059), but did not release full results pending presentation at an upcoming scientific congress and publication in a peer-reviewed journal. The following day, shares of Australian-based CSL (CSL.AX) rose 3% from A$292.50 to A$299.20 ($202.11 to $206.74).

Patient demand exists for oral HAE drugs, Raycroft wrote, judging from growing net sales for BioCryst Pharmaceuticals (BCRX)’ Orladeyo® (berotralstat), which has generated $114.9 million in net revenue during the first half of this year, nearly double the $122.6 million racked up all of last year. BioCryst has since raised its investor guidance on full-year Orladeyo net revenue from “no less than $250 million” to between $255 million and $265 million for 2022, projected to climb to $1 billion during the drug’s peak year.

“We view the BCRX launch as another positive for KALV, demonstrating appeal for oral HAE tx option to naive pts and ability to switch pts off current prophy options,” Raycroft added.

Aerie Pharmaceuticals (AERI)

Aerie shares soared 36% on Tuesday, a day after the Durham, NC, ophthalmic therapy developer said it had agreed to be acquired by Alcon (ALC), the Swiss eye disease drug giant spun out of Novartis in 2019, for $770 million, to be funded via short- and long-term debt.

The acquisition deal will expand Alcon’s portfolio of marketed drugs with Rocklatan® (netarsudil and latanoprost ophthalmic solution) 0.02%/0.005% and Rhopressa® (netarsudil ophthalmic solution) 0.02%, both indicated for reduction of elevated intraocular pressure (IOP) in open-angle glaucoma or ocular hypertension—and add to Alcon’s pipeline the Phase III dry eye disease candidate AR-15512, as well as several clinical and preclinical ophthalmic candidates.

Alcon said the deal will complement its recent expansion into the pharmaceutical eye drop space, which entailed acquiring exclusive U.S. commercialization rights to Simbrinza® from Novartis in April 2021 and of Eysuvis® and Inveltys® from Kala Pharmaceuticals in May.

“Aerie is a natural fit with on-market and pipeline products, and R&D capabilities that offer the infrastructure needed to expand our ophthalmic pharmaceutical presence,” Alcon CEO David Endicott said in a statement.

At $15.25 per share, the deal represents a 37% premium above Aerie’s closing price on Monday, the last trading day before the acquisition deal was announced. That apparently sat well with investors, who sent shares surging on Tuesday from $11.15 to $15.16. Shares of Alcon stayed flat, dipping 0.3% from $67.94 to $67.75.

Aerie most recently guided investors to a total glaucoma franchise net product revenue range of $130 million to $140 million for 2022, up 16% to 25% from 2021. However, Needham analyst Serge Belanger downgraded Aerie from “Buy” to “Hold,” asserting that the launch of Rocklatan and Rhopressa failed to meet expectations of billion-dollar-plus “blockbuster” sales, while the downturn in the market made it harder for Aerie to finance commercialization efforts.

Belanger said Aerie had sought a buyer since its original management left. That was touched off by then-Chairman and CEO Vicente Anido, PhD, leaving the company in September 2021, days after the dry eye disease candidate AR-15512 missed its co-primary endpoints in a Phase IIb trial—but met secondary endpoints, prompting Aerie to advance into Phase III studies the small-molecule selective agonist of the transient receptor potential melastatin 8 (TRPM8) cold thermoreceptor.

The acquisition is expected to close in the fourth quarter, subject to approval by Aerie stockholders and customary closing conditions, including clearance under the Hart-Scott Rodino Antitrust Improvements Act.

Foghorn Therapeutics (FHTX)

Foghorn shares fell 25% on Tuesday, from $14.69 to an even $11.00, after the company acknowledged that day that the FDA had placed a full clinical hold on a Phase I dose escalation study (NCT04891757) evaluating its blood cancer candidate FHD-286 in relapsed and/or refractory acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS).

The FDA slapped the full clinical hold more than three months after placing a partial hold on the AML study following the reported death of a patient with potential differentiation syndrome. Afterward, Foghorn submitted data disclosing additional suspected cases of fatal differentiation syndrome that are believed to be associated with FHD-286. Differentiation syndrome is associated with AML/MDS therapeutics that induce differentiation, an effect that has been seen with, and is believed to be on-target for, the proposed mechanism of action for FHD-286.

Foghorn said the FDA had additional questions and required further analyses before the clinical hold may be lifted. “We are committed to patient safety and will work with the FDA to address the agency’s questions and provide further analyses to resolve the clinical hold as soon as possible,” CEO Adrian Gottschalk stated.

The clinical hold did not affect Foghorn’s dose escalation Phase I study of FHD-286 in metastatic uveal melanoma (mUM; NCT04879017), which according to the company is continuing per protocol, with data to be reported in the first half of 2023.

FHD-286 is a selective, allosteric and orally available, small-molecule, enzymatic inhibitor of BRG1 and BRM, two highly similar proteins that are ATPases across all forms of the BAF complex, a key regulator of the chromatin regulatory system.

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