Safe­ty qualms in MyoKar­dia mid-stage study cause in­vestors to pause

Ahead of the piv­otal da­ta read­out of MyoKar­dia’s lead drug, mava­camten, in pa­tients with ob­struc­tive hy­per­trophic car­diomy­opa­thy (HCM), in­vestors took is­sue with the drug’s safe­ty pro­file in a sep­a­rate Phase II non-ob­struc­tive HCM study.

Mava­camten is ex­pect­ed to break new ground in heart dis­ease — a field mo­nop­o­lized by large phar­ma­ceu­ti­cal com­pa­nies large­ly due to the long, ar­du­ous and ex­pen­sive tri­als that are com­mon­place in heart drug de­vel­op­ment. Un­like oth­er de­vel­op­ers fo­cus­ing on com­mon heart dis­or­ders, MyoKar­dia’s treat­ment is al­so tar­get­ing a so-far un­tapped dis­ease — hy­per­trophic car­diomy­opa­thy — a ge­net­ic con­di­tion in which heart mus­cle thick­ens, mak­ing it hard­er for the or­gan to pump blood to the rest of the body.

On Mon­day, MyoKar­dia dis­closed da­ta from the 59-pa­tient, place­bo-con­trolled MAV­ER­ICK-HCM study, which was in pa­tients with non-ob­struc­tive HCM. In this pop­u­la­tion of pa­tients, which ac­counts for a third of all HCM pa­tients, the heart con­tracts ex­trav­a­gant­ly and the left ven­tri­cle thick­ens, lim­it­ing the or­gan’s abil­i­ty to pump blood to meet the body’s needs, al­though there is no phys­i­cal ob­struc­tion present in the out­flow tract of the left ven­tri­cle.

The drug’s im­pact on ejec­tion frac­tion — the per­cent­age of blood that’s pumped out of a filled ven­tri­cle (typ­i­cal­ly the left ven­tri­cle, the heart’s main pump­ing cham­ber) with each heart­beat — trig­gered safe­ty con­cerns, af­ter MyoKar­dia said five pa­tients on the drug arm saw tran­sient ejec­tion frac­tion re­duc­tions be­low the pro­to­col-de­fined thresh­old of 45%. A left ven­tri­cle ejec­tion frac­tion of 55% or high­er is con­sid­ered nor­mal, ac­cord­ing to the Mayo Clin­ic.

Shares of the South San Fran­cis­co drug de­vel­op­er $MYOK slipped 7.6% to $55.45 in Tues­day pre­mar­ket trad­ing.

Study da­ta al­so showed the rate of side-ef­fects in the mava­camten-treat­ed pa­tients al­so ex­ceed­ed those in the placeb0 group, al­though se­ri­ous ad­verse events oc­curred twice as fre­quent­ly in the place­bo arm as com­pared to pa­tients re­ceiv­ing mava­camten.

Over­all, the tri­al achieved the main goal of es­tab­lish­ing safe­ty and tol­er­a­bil­i­ty of mava­camten in non-ob­struc­tive HCM in the 16 week treat­ment pe­ri­od, the com­pa­ny said, adding that “mean­ing­ful re­duc­tions” in bio­mark­ers of car­diac stress were ob­served across the mava­camten co­horts and “clear sig­nals of clin­i­cal ben­e­fit” were ob­served in a sub­group with el­e­vat­ed car­diac fill­ing pres­sures and in a pre-spec­i­fied group of pa­tients at high­er risk for mor­bid­i­ty and mor­tal­i­ty.

In ad­di­tion, pa­tients giv­en mava­camten al­so ex­pe­ri­enced marked­ly low­er lev­els of the bio­mark­er NT-proB­NP (p=0.004). NT-proB­NP is a val­i­dat­ed mark­er of car­diac wall stress that is cor­re­lat­ed with in­creased rates of heart fail­ure-re­lat­ed hos­pi­tal­iza­tions and pro­gres­sion to end-stage dis­ease and stroke.

“The MAV­ER­ICK study more than dou­bles mava­camten’s safe­ty data­base and the drug ap­pears rea­son­ably well tol­er­at­ed, al­though we ex­pect in­vestors will look for ad­di­tion­al clar­i­ty on rates of ar­rhyth­mia and the 5 cas­es of tran­sient LVEF de­clines un­der 45% to fur­ther ex­plore the over­all safe­ty of ma­va,” Cred­it Su­isse an­a­lyst Mar­tin Auster wrote in a note.

MyoKar­dia chief Tas­sos Gi­anakakos ex­pressed his sat­is­fac­tion with the MAV­ER­ICK da­ta, sug­gest­ing that ev­i­dence of mava­camten’s ben­e­fi­cial im­pact on pa­ra­me­ters of di­as­tolic func­tion, and place­bo re­sponse ob­ser­va­tions have en­hanced his con­fi­dence in mava­camten’s per­for­mance in the ob­struc­tive HCM piv­otal study.

De­tailed MAV­ER­ICK da­ta will be pre­sent­ed at a sci­en­tif­ic con­fer­ence. Based on these re­sults, how­ev­er, MyoKar­dia plans to con­sult with the FDA and sort out the steps it needs to take the drug to mar­ket — for which a reg­u­la­to­ry up­date will be pro­vid­ed in 2020. Mean­while, the com­pa­ny al­so plans to test mava­camten in de­fined groups of pa­tients with non-ob­struc­tive HCM and heart fail­ure with pre­served ejec­tion frac­tion (HF­pEF).

“While this news is en­cour­ag­ing, it’s not ful­ly clear to us how dos­ing in this set­ting will be de­ter­mined. Full MAV­ER­ICK da­ta pre­sen­ta­tion could be a mean­ing­ful cat­a­lyst next year, as we think lack of specifics may lead in­vestors to heav­i­ly dis­count po­ten­tial la­bel ex­pan­sion strate­gies for now,” Auster said.

MyoKar­dia’s ap­proach to re­search is to de­vel­op drugs for ge­net­i­cal­ly de­fined pa­tient groups, which is al­so re­flect­ed in its sec­ond pro­gram, MYK-491, un­der de­vel­op­ment for di­lat­ed car­diomy­opa­thy.

In Jan­u­ary, MyoKar­dia dis­closed that Sanofi was walk­ing away from their heart drug part­ner­ship forged in 2014. The part­ner­ship in­volved the de­vel­op­ment of up to three pro­grams through dis­cov­ery and in­to clin­i­cal de­vel­op­ment for the treat­ment of hy­per­trophic car­diomy­opa­thy and di­lat­ed car­diomy­opa­thy. In Ju­ly, MyoKar­dia said it had re­gained the US roy­al­ty rights to two prod­ucts from the French drug­mak­er for $50 mil­lion up­front.

Regeneron CEO Leonard Schleifer speaks at a meeting with President Donald Trump, members of the Coronavirus Task Force, and pharmaceutical executives in the Cabinet Room of the White House (AP Photo/Andrew Harnik)

OWS shifts spot­light to drugs to fight Covid-19, hand­ing Re­gen­eron $450M to be­gin large scale man­u­fac­tur­ing in the US

The US government is on a spending spree. And after committing billions to vaccines defense operations are now doling out more of the big bucks through Operation Warp Speed to back a rapid flip of a drug into the market to stop Covid-19 from ravaging patients — possibly inside of 2 months.

The beneficiary this morning is Regeneron, the big biotech engaged in a frenzied race to develop an antibody cocktail called REGN-COV2 that just started a late-stage program to prove its worth in fighting the virus. BARDA and the Department of Defense are awarding Regeneron a $450 million contract to cover bulk delivery of the cocktail starting as early as late summer, with money added for fill/finish and storage activities.

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UP­DAT­ED: Bio­gen shares spike as ex­ecs com­plete a de­layed pitch for their con­tro­ver­sial Alzheimer's drug — the next move be­longs to the FDA

Biogen is stepping out onto the high wire today, reporting that the team working on the controversial Alzheimer’s drug aducanumab has now completed their submission to the FDA. And they want the agency to bless it with a priority review that would cut the agency’s decision-making time to a mere 6 months.

The news drove a 10% spike in Biogen’s stock $BIIB ahead of the bell.

Part of that spike can be attributed to a relief rally. Biogen execs rattled backers and a host of analysts earlier in the year when they unexpectedly delayed their filing to the third quarter. That delay provoked all manner of speculation after CEO Michel Vounatsos and R&D chief Al Sandrock failed to persuade influential observers that the pandemic and other factors had slowed the timeline for filing. Actually making the pitch at least satisfies skeptics that the FDA was not likely pushing back as Biogen was pushing in. From the start, Biogen execs claimed that they were doing everything in cooperation with the FDA, saying that regulators had signaled their interest in reviewing the submission.

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Daniel O'Day, Gilead CEO (Kevin Dietsch/UPI/Bloomberg via Getty Images)

A new study points to $6.5B in pub­lic sup­port build­ing the sci­en­tif­ic foun­da­tion of Gilead­'s remde­sivir. Should that be re­flect­ed in the price?

By drug R&D standards, Gilead’s move to repurpose remdesivir for Covid-19 and grab an emergency use authorization was a remarkably easy, low-cost layup that required modest efficacy and a clean safety profile from just a small group of patients.

The drug OK also arrived after Gilead had paid much of the freight on getting it positioned to move fast.

In a study by Fred Ledley, director of the Center for Integration of Science and Industry at Bentley University in Waltham, MA, researchers concluded that the NIH had invested only $46.5 million in the research devoted to the drug ahead of the pandemic, a small sum compared to the more than $1 billion Gilead expected to spend getting it out this year, all on top of what it had already cost in R&D expenses.

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FDA bars the door — for now — against Mer­ck’s star can­cer drug af­ter Roche beat them to the punch

Merck has been handed a rare setback at the FDA.

After filing for the accelerated approval of a combination of their star PD-1 drug Keytruda with Eisai’s Lenvima as a first-line treatment for unresectable hepatocellular carcinoma, the FDA nixed the move, handing out a CRL because Roche beat them to the punch on the same indication by a matter of weeks.

According to Merck:

Ahead of the Prescription Drug User Fee Act action dates of Merck’s and Eisai’s applications, another combination therapy was approved based on a randomized, controlled trial that demonstrated overall survival. Consequently, the CRL stated that Merck’s and Eisai’s applications do not provide evidence that Keytruda in combination with Lenvima represents a meaningful advantage over available therapies for the treatment of unresectable or metastatic HCC with no prior systemic therapy for advanced disease. Since the applications for KEYNOTE-524/Study 116 no longer meet the criteria for accelerated approval, both companies plan to work with the FDA to take appropriate next steps, which include conducting a well-controlled clinical trial that demonstrates substantial evidence of effectiveness and the clinical benefit of the combination.

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Covid-19 roundup: Mod­er­na sticks to Ju­ly for its Phase III as ru­mors swirl; Fol­low­ing US lead, EU buys up Covid-19 treat­ments

The Phase III might be delayed from its original early July goal, but Moderna says it will still kick off the pivotal study for what could ultimately be the first Covid-19 vaccine before the end of the month.

A day after Reuters reported that squabbling between the Cambridge biotech and government regulators had held up the trial by about two weeks, Moderna released a statement saying that they had completed enrollment of their 650-person Phase II trial and were on track to begin Phase III by the end of the month. The protocol for that study, which is meant to prove whether or not the vaccine can prevent people from becoming sick, has been finalized, they said.

GSK sets the stage for a toe-to-toe mar­ket show­down with Gilead­'s HIV cham­pi­on Tru­va­da

ViiV Healthcare and majority owner GlaxoSmithKline have cleared another important hurdle on a long-running quest to challenge Gilead’s dominance in preventative HIV treatments.

The final analysis of a new study shows the GSK subsidiary’s long-lasting injection, cabotegravir, proved 66% more effective in HIV prevention than Gilead’s breakthrough Truvada pill. And they now intend to carve away some of the blockbuster revenue that Gilead has enjoyed for years.

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Trump and Navar­ro press again for hy­drox­y­chloro­quine. Can the FDA stay in­de­pen­dent?

Tuesday morning, economist and Trump advisor Peter Navarro walked onto the White House driveway and promptly brought a political cloud back onto the FDA.

Speaking to a White House pool reporter, Navarro said that four Detroit doctors were, based on a single disputed study, filing for the FDA to again issue an emergency authorization for hydroxychloroquine, the anti-malarial pill that President Trump hyped for months as a Covid-19 treatment over the objections of his own scientists. Then, while avoiding directly calling for the FDA to OK the drug, blasted the agency. He said its decision to pull an earlier authorization “was based on bad science” and “had a tremendously negative effect” on doctors and patients.

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Donald and Melania Trump watch the smoke of fireworks from the South Lawn of the White House on July 4, 2020 (via Getty)

Which drug de­vel­op­ers of­fer Trump a quick, game-chang­ing ‘so­lu­tion’ as the pan­dem­ic roars back? Eli Lil­ly and Ab­Cellera look to break out of the pack

We are unleashing our nation’s scientific brilliance and will likely have a therapeutic and/or vaccine solution long before the end of the year.

— Donald Trump, July 4

Next week administration officials plan to promote a new study they say shows promising results on therapeutics, the officials said. They wouldn’t describe the study in any further detail because, they said, its disclosure would be “market-moving.”

— NBC News, July 3

Something’s cooking. And it’s not just July 4 leftovers involving stale buns and uneaten hot dogs.

Over the long weekend observers picked up signs that the focus in the Trump administration may swiftly shift from the bright spotlight on vaccines being promised this fall, around the time of the election, to include drugs that could possibly keep patients out of the hospital and take the political sting out of the soaring Covid-19 numbers causing embarrassment in states that swiftly reopened — as Trump cheered along.

So far, Gilead has been the chief beneficiary of the drive on drugs, swiftly offering enough early data to get remdesivir an emergency authorization and into the hands of the US government. But their drug, while helpful in cutting stays, is known for a limited, modest effect. And that won’t tamp down on the hurricane of criticism that’s been tearing at the White House, and buffeting the president’s most stalwart core defenders as the economy suffers.

We’ve had positive early-stage vaccine data, most recently from Pfizer and BioNTech, playing catchup on an mRNA race led by Moderna — where every little sign of potential trouble is magnified into a lethal threat, just as every advance excites a frenzy of support. But that race still has months to play out, with more Phase I data due ahead of the mid-stage numbers looming ahead. A vaccine may not be available in large enough quantities until well into 2021, which is still wildly ambitious.

So what about a drug solution?

Trump’s initial support for a panacea focused on hydroxychloroquine. But that fizzled in the face of data underscoring its ineffectiveness — killing trials that aren’t likely to be restarted because of a recent population-based study offering some support. And there are a number of existing drugs being repurposed to see how they help hospitalized patients.

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Zai Lab inks Chi­na deal with Turn­ing Point with $25M up­front; Xen­cor, Atre­ca team up on bis­pecifics

Zai Lab is paying out a $25 million upfront for the rights to sell Turning Point Therapeutics’ lead drug repotrectinib in Greater China. The San Diego-based biotech is also in line for up to $151 million in milestones, along with mid-to-high teen royalties. Zai plans to add sites to the Phase II trial of the drug, which is designed to treat ROS1-positive advanced NSCLC in patients who were not previously treated with a TKI.