Pfizer, in a rare COVID-19 setback, dumps Paxlovid's intravenous sibling to leave ACTIV-3 future in doubt

 Add Pfizer to the long list of victims of ACTIV-3. While the Big Pharma has enjoyed unparalleled success in COVID-19, it was unable to buck the trend in the National Institutes of Health (NIH) study of hospitalized patients and has stopped development of Paxlovid’s intravenous sibling PF-07304814.

The NIH set up ACTIV-3 to test anti-SARS-CoV-2 monoclonal antibodies and other therapies in patients hospitalized with COVID-19. Brii Biosciences, Eli Lilly, GlaxoSmithKline and Novartis are among the drug developers to contribute candidates to the study. All those candidates failed to move the needle in hospitalized patients with severe COVID-19, resulting in a persistent unmet need even as the broader pandemic armory has gone from strength to strength.

PF-07304814 represented a different answer to the question of how to treat severe COVID-19. Like one of the components of Pfizer’s oral COVID-19 drug Paxlovid, PF-07304814 is a SARS-CoV-2 main protease inhibitor. The idea was to expand into patients with severe COVID-19 through intravenous delivery.

That plan, like others tested by Pfizer’s peers, came unstuck in NIH’s ACTIV-3 trial. Dosing of the intravenous antiviral in the trial has stopped, and Pfizer has discontinued the global clinical development. Pfizer said the decision “was made based on a totality of information, including a careful review of early data and a thorough assessment of the candidate’s potential to successfully fulfill patient needs.”

The discontinuation means ACTIV-3 is no longer enrolling patients. In a recent update to the listing on ClinicalTrials.gov, the sponsor changed the status from “recruiting” to “active, not recruiting” and added “Suspended: Participants are not currently being randomized to this intervention” to the description of the PF-07304814 arm. Patients aren’t being randomized into any of the other arms, either.

If that marks the end of ACTIV-3, the study will go down as a rare graveyard for COVID-19 programs. The global vaccine race and push to create therapies for mild to moderate COVID-19 each featured multiple successes. But efforts to improve on Gilead Sciences' Veklury in hospitalized COVID-19 patients have floundered, potentially because by that point in the disease pathway elements other than the virus are at play.

Pfizer disclosed the discontinuation of PF-07304814 in its quarterly pipeline update. The Big Pharma also used the update to reveal the end of work on PRMT5 inhibitor PF-06939999 in solid tumor patients and PF-07059013 in sickle cell disease. Both programs were in phase 1.

https://www.fiercebiotech.com/biotech/pfizer-a-rare-covid-19-setback-dumps-paxlovid-s-intravenous-sibling-to-leave-activ-3-future

Axsome’s migraine drug finally set for FDA inspection, but investors want to know about depression therapy

 The FDA will in fact be able to inspect Axsome’s manufacturing facility for its migraine drug by the decision date as the agency gets these crucial inspections back on track following COVID disruptions. 

The regulatory update for the migraine treatment, called AXS-07, was welcome news for investors, according to a note from Mizuho Securities. But what investors had really been hoping for was an update on a key depression drug, which has been delayed as the agency identified deficiencies in the application.  

Axsome disclosed the news in a Securities and Exchange Commission filing after market close on Monday. The FDA paused domestic surveillance inspections in late December amid a nationwide rise in COVID infections, but they resumed on Monday with cases now declining. 

It’s a welcome update for the New York City-based biopharma, which has been in a state of limbo as it awaits regulatory actions from the FDA on AXS-07. The agency is expected to rule on the med by April 30.

Migraine is a packed field and has seen a rush of Big Pharma entrants in recent years, including Eli Lilly’s Reyvow and Amgen’s Aimovig, which target receptors in the brain associated with migraines. Axsome touts its drug as being “multi-mechanistic” to work beyond just targeting receptors. 

Mizuho warned that Axsome may struggle to find a foothold in the market should AXS-07 be granted approval. The biotech's competitors "have greater financial resources and expertise in manufacturing, preclinical testing and marketing approved products than Axsome currently does." While Axsome currently has a cash runway up to at least 2024, risks to additional financing remain, according to Mizuho. 

While the progression of AXS-07 through the regulatory process is a positive step, Mizuho said investors are likely more focused on AXS-05, the treatment for major depressive disorder. The company announced last August that the FDA would not complete a review of that drug by the PDUFA date, which was originally Aug. 22, 2021.

Since the delay, the company has responded to two deficiencies in its new drug application that were highlighted by the regulatory agency. The company said in January the deficiencies stem from the "analytical methods in the chemistry, manufacturing and controls section" of the new drug application. Mizuho said even amid the delay, it still expects AXS-05 to be approved as early as late 2022. 

Prior to the FDA’s delay, Axsome reported that the drug met both the primary and key secondary endpoints in a phase 2 trial, significantly delaying the time to relapse of depressive symptoms. The company said that no relapses were observed with the drug over six months of double-blind treatment.

https://www.fiercebiotech.com/biotech/axsome-s-migraine-drug-slated-for-fda-inspection-but-questions-remain-halted-depression

Pfizer CEO doesn't see virus going away for 'foreseeable future'

 Among all biopharma companies, Pfizer has had the most successful response to COVID-19 by bringing to market a hugely lucrative vaccine and a new antiviral pill. Despite its pandemic wins, Pfizer scientists think it’s “unlikely that [SARS-CoV-2] will be fully eradicated in the foreseeable future,” the company's CEO said Tuesday.

That’s because the virus’ global distribution makes it difficult to contain, Pfizer CEO Albert Bourla told analysts on the company's fourth-quarter conference call. The virus also has the ability to “mutate often,” which makes it tough for companies to “stay ahead,” he said. Meanwhile, natural infections don’t confer the sort of durable protection needed stop mutations and spread, Bourla said.

Pfizer's pandemic countermeasures have no doubt been good for its top-line. Last year, Pfizer's full-year sales came in at a whopping $81.3 billion, buoyed by nearly $37 billion in COVID-19 vaccine sales. Looking forward, the company expects $54 billion in total sales from the Comirnaty vaccine and its new antiviral pill Paxlovid this year. Of that total, the company expects Comirnaty to account for $32 billion in 2022 sales.

As for Paxlovid, Pfizer expects to produce 6 million treatment courses during 2022’s first quarter, Bourla said. Overall, the company plans to crank out 30 million Paxlovid courses in the first half of 2022 and 120 million courses for the full year.

Excluding COVID-19 sales, Pfizer's full-year revenues grew 6% last year to $44.4 billion.

Meanwhile, despite the megablockbuster haul from its COVID-19 vaccine, other parts of Pfizer’s prophylactic business are struggling. Look no further than the Prevnar family of pneumococcal shots—once Pfizer’s best-selling product—which endured a 25% global sales slump for the last three months of the year.

Pfizer blamed the fourth-quarter downturn in Prevnar 13 and Prevnar 20 sales on a 27% revenue decline in the U.S. Like many drugmakers in the vaccine game, Pfizer felt the squeeze last fall as the U.S. government prioritized COVID-19 vaccines and boosters over other shots. 

Looking ahead, thanks to COVID sales and a beefy M&A war chest, Bourla is optimistic about Pfizer’s ability to continue charting growth through the end of the decade—even in spite of some heavy losses of exclusivity (LOE) on the horizon.

Consensus estimates currently predict Pfizer’s top line will shrink between 2025 and 2030, but that’s “inconsistent” with Pfizer’s own vision for the future, Bourla said.

“Our goal is to continue to be a growth company from ’25 to 2030, despite the impact of LOEs expected during that period," the CEO said.

Starting in 2025, Pfizer faces U.S. patent expirations on Inlyta and Xeljanz, followed by potential LOEs on Eliquis, Ibrance and Xtandi through the second half of the decade. And it'll counter those—at least in part—through external business development.

“The strength of our balance sheet and cash flows allows us to pursue new business development opportunities going forward that could add at least $25 billion of risk-adjusted revenue to our 2030 topline expectation, Bourla said. 

“I see this pace of business development accelerating going forward,” he added. The CEO said he's “confident it will be an important driver in ensuring Pfizer is a growth company in the back half of this decade.”

Still, it wasn’t all good news for Pfizer Tuesday. Quietly, the company culled a quartet of potential new indications for its approved cancer meds Bavencio and Talzenna. Pfizer has pulled the plug on Talzenna solo in second-line metastatic castration-resistant prostate cancer, plus Bavencio alone in first-line non-small cell lung cancer. The company also axed development on combination therapies of Bavencio and Talzenna in solid tumors with a BRCA or ATM defect, as well as locally advanced, primary or recurrent metastatic solid tumors.

https://www.fiercepharma.com/pharma/pfizer-eyes-pandemic-long-haul-as-prevnar-sales-lag

Amgen hold-up gives Mirati a vital lifeline

Six months might not seem like much, but for Mirati every second of it will count. Readout of Amgen’s confirmatory lung cancer trial of Lumakras, yesterday delayed from the first to the second half of this year, buys vital breathing space for Mirati as it scrambles to get its rival adagrasib onto the market.

Since Mirati is a year behind Amgen, the possibility of Lumakras being formally approved, based on the confirmatory data, jeopardised adagrasib’s chances of gaining an accelerated label. Mirati earlier rejected the suggestion that there was a risk, but recent precedent shows the threat to be real; the group must now execute quickly.

When Evaluate Vantage two weeks asked Mirati’s chief executive, David Meek, whether Lumakras confirmatory data and full approval threatened adagrasib he stated: “No, we don’t think so. The FDA is well aware of the timelines of both programmes. We have breakthrough therapy designation [and] we were granted real-time oncology review, so we fully expect our approval.”

Still, investors need look no further than last October for an example of a very similar timing crunch. Then Agenus had to pull an accelerated filing under priority review for balstilimab in cervical cancer after the FDA granted Merck & Co’s Keytruda full approval, making a conditional green light for a similarly acting rival in the same setting unsustainable.

The timeline

For Mirati the timeline is crucial. Until yesterday’s delay Amgen had been due to reveal results of Lumakras’s confirmatory Codebreak-200 trial before the mid-year point, which is when Mirati expects adagrasib to be approved.

But even this Mirati expectation is extremely bullish: though the adagrasib NDA has been submitted it has yet to be reviewed and accepted, something Mirati expects imminently. If the FDA raises no questions, grants the filing priority review and accepts it now, a six-month cycle would put August as the action date for approval.

Thus Mirati is banking not only on flawless execution and priority review but also on a super-fast turnaround, as had happened for Lumakras, which was greenlit in the space of just three and a half months. However, a standard 10-month review is a possibility, and would put the adagrasib action date into November.

This bear case could see the FDA reviewing Lumakras's confirmatory dataset before adagrasib's Pdufa date, even with Amgen’s delay.

Timeline of the duelling Kras G12C inhibitors in lung cancer
	Lumakras (Amgen)	Adagrasib (Mirati)
Accelerated filing for 2L Kras G12C+ve NSCLC accepted	Feb 2021	Feb 2022*
Goal action date	Aug 2021	Aug/Nov 2022*^
Accelerated US approval	May 2021	Jul-Nov 2022*
Confirmatory study readout	Delayed from H1 to H2 2022 (Codebreak-200)*	H2 2023 (Krystal-12)*
Full US approval	2022/23*	2023/24*
Note: *expected; ^Aug if priority review is granted, Nov if it is not. Source: company statements.

While Mirati has gained a valuable lifeline its investors will recall the crucial months it has already lost; adagrasib and Lumakras had been on similar timelines, with the former sometimes showing superior efficacy on a cross-trial basis, but while Amgen moved fast to get its asset before the regulator Mirati became embroiled in a C-suite overhaul.

How does Mirati now catch up? “We are coming in later, we are well aware of that,” said Mr Meek. But adagrasib is “a different agent, with a 24-hour half life, which enables near complete inhibition of mutant Kras G12C. Response rates across the board are higher with adagrasib relative to other G12C inhibitors.”

He also cited adagrasib’s CNS activity, and the project’s activity in colorectal cancer shows another point of departure from Lumakras. Still, the first filing is in NSCLC, while Mirati continues to “finetune” the colorectal cancer approval pathway with the FDA.

Interestingly, while Mr Meek denied the threat Amgen’s confirmatory data pose to adagrasib, he said they would “present challenges to follow-on Kras G12C inhibitors; they’re not going to be able to pursue the conditional marketing authorisation accelerated pathway, at least in second-line lung cancer.”

For Amgen a delay to Codebreak-200 matters much less than Lumakras’s 2021 sales, which some analysts yesterday saw as light. For Mirati to take advantage of the bullet it might just have dodged it cannot afford any further delays.

https://www.evaluate.com/vantage/articles/news/trial-results/amgen-hold-gives-mirati-vital-lifeline 

Transcript : Idorsia Ltd, 2021 Earnings Call, Feb 08, 2022

 https://www.marketscreener.com/quote/stock/IDORSIA-LTD-35837944/news/Transcript-Idorsia-Ltd-2021-Earnings-Call-Feb-08-2022-37818127/

Transcript : Centene Corporation, 2021 Earnings Call, Feb 08, 2022

 https://www.marketscreener.com/quote/stock/CENTENE-CORPORATION-55763517/news/Transcript-Centene-Corporation-2021-Earnings-Call-Feb-08-2022-37815478/

Transcript : Pfizer Inc., Q4 2021 Earnings Call, Feb 08, 2022

 https://www.marketscreener.com/quote/stock/PFIZER-INC-23365019/news/Transcript-Pfizer-Inc-Q4-2021-Earnings-Call-Feb-08-2022-37819915/