De­sert­ed by Astel­las and Mer­ck, lit­tle Cor­re­vio still can't win over FDA pan­el con­cerned with its AFib drug's safe­ty

When the FDA spurned Astel­las’ pitch for atri­al fib­ril­la­tion drug ver­nakalant in 2008, reg­u­la­tors made it abun­dant­ly clear that it wasn’t the ef­fi­ca­cy they had a prob­lem with — two Phase III tri­als had shown the drug suc­cess­ful­ly re­stored 52% of pa­tients’ heart­beat from ir­reg­u­lar to nor­mal — but the car­dio safe­ty is­sues for a drug that was to com­pete with well es­tab­lished, low-risk op­tions. One li­cens­ing deal, one clin­i­cal hold and sev­er­al stud­ies lat­er, the chances of ap­proval aren’t look­ing any bet­ter.

Ex­perts on the agency’s Car­dio­vas­cu­lar and Re­nal Drugs Ad­vi­so­ry Com­mit­tee vot­ed 11-2 against ap­prov­ing the drug, deal­ing a fresh blow to its mak­er, Cor­re­vio Phar­ma. The pan­el large­ly agreed with the FDA in­ter­nal re­view that con­clud­ed the ben­e­fits didn’t out­weigh the risks, rais­ing is­sues such as low blood pres­sure, ar­rhyth­mias in the ven­tri­cles and even death.

Mark Cor­ri­g­an

Cor­re­vio, which mar­kets ver­nakalant as Brinavess in its na­tive Cana­da, Eu­rope and sev­er­al oth­er coun­tries, saw its stock $CORV sink be­low the $1 mark af­ter plum­met­ing 55%.

“We are dis­ap­point­ed with to­day’s out­come be­cause we be­lieve in the strength of the da­ta we pre­sent­ed to­day for Brinavess,” CEO Mark Cor­ri­g­an said in a state­ment. “The treat­ment land­scape is cur­rent­ly miss­ing a rapid, ef­fi­ca­cious and well tol­er­at­ed op­tion to treat pa­tients with re­cent on­set atri­al fib­ril­la­tion and we be­lieve Brinavess has the po­ten­tial to fill that un­met med­ical need.”

It had tak­en Cor­re­vio a decade to get here. In re­sponse to the FDA’s re­jec­tion in 2008 — which ac­tu­al­ly fol­lowed a refuse-to-file let­ter two years pri­or — the biotech, then known as Car­diome, planned and start­ed a new Phase III tri­al, ACT V. But in 2010, a case of car­dio­vas­cu­lar col­lapse with pulse­less elec­tri­cal ac­tiv­i­ty even­tu­al­ly lead­ing to death trig­gered a full clin­i­cal hold on that study.

Mer­ck, which had li­censed rights to the oral ver­sion of ver­nakalant ear­li­er, took over the IV side too for a short while, on­ly to have its ap­pli­ca­tion to re­move the hold and pro­posed mod­i­fi­ca­tions slammed by reg­u­la­tors. The FDA’s con­clu­sion:

We do not be­lieve that you have iden­ti­fied ei­ther a de­fin­i­tive mech­a­nism or root cause of these episodes of ver­nakalant-in­duced se­vere hy­poten­sion and/or clin­i­cal shock and do not be­lieve that your pro­posed mod­i­fi­ca­tions to the el­i­gi­bil­i­ty cri­te­ria are ad­e­quate to as­sure that such events will not re­cur in an­oth­er tri­al.

The team that is now Cor­re­vio has since con­duct­ed mul­ti­ple an­i­mal stud­ies in at­tempts to un­der­stand what’s go­ing on and find a sat­is­fy­ing mit­i­ga­tion strat­e­gy — in vain.

“(T)he hold re­mains in place at this time,” the FDA re­view­ers not­ed in their dossier ahead of the ad­comm.

Al­so pack­aged in the NDA were da­ta from post­mar­ket­ing stud­ies done out­side the US, par­tic­u­lar­ly an EU tri­al dubbed SPEC­TRUM, in which the treat­ment con­vert­ed 70.2% of AFib pa­tients in­to nor­mal si­nus rhythm, with a me­di­an to con­ver­sion time of 12 min­utes.

But the FDA still not­ed a to­tal of 174 se­ri­ous ad­verse drug re­ac­tions and five deaths. And some mem­bers of the pan­el point­ed out that giv­en the pa­tients in the tri­als were at low risk of de­vel­op­ing com­pli­ca­tions, there didn’t seem to be a con­vinc­ing way to pre­dict who needs spe­cial mon­i­tor­ing for safe­ty is­sues.

“It clear­ly has ben­e­fit but it does have risk,” said Bar­ry Davis of the Uni­ver­si­ty of Texas School of Pub­lic Health, who vot­ed against the drug, per Reuters. “If this were the on­ly drug or treat­ment around, yes, but there are oth­er op­tions.”

In ad­di­tion to med­ica­tion such as fle­cainide, dofetilide, propafenone and ibu­tilide, physi­cians may al­so pre­scribe elec­tri­cal car­diover­sion — if they de­cide an in­ter­ven­tion is need­ed at all.

There is still a pos­si­bil­i­ty — no mat­ter how slim — that the FDA will over­ride the ad­comm’s rec­om­men­da­tion and OK the drug. The fi­nal de­ci­sion will be hand­ed down by De­cem­ber 24.

2019 Trin­i­ty Drug In­dex Eval­u­ates Ac­tu­al Com­mer­cial Per­for­mance of Nov­el Drugs Ap­proved in 2016

Fewer Approvals, but Neurology Rivals Oncology and Sees Major Innovations

This report, the fourth in our Trinity Drug Index series, outlines key themes and emerging trends in the industry as we progress towards a new world of targeted and innovative products. It provides a comprehensive evaluation of the performance of novel drugs approved by the FDA in 2016, scoring each on its commercial performance, therapeutic value, and R&D investment (Table 1: Drug ranking – Ratings on a 1-5 scale).

How to cap­i­talise on a lean launch

For start-up biotechnology companies and resource stretched pharmaceutical organisations, launching a novel product can be challenging. Lean teams can make setting a launch strategy and achieving your commercial goals seem like a colossal undertaking, but can these barriers be transformed into opportunities that work to your brand’s advantage?
We spoke to Managing Consultant Frances Hendry to find out how Blue Latitude Health partnered with a fledgling subsidiary of a pharmaceutical organisation to launch an innovative product in a
complex market.
What does the launch environment look like for this product?
FH: We started working on the product at Phase II and now we’re going into Phase III trials. There is a significant unmet need in this disease area, and everyone is excited about the launch. However, the organisation is still evolving and the team is quite small – naturally this causes a little turbulence.

UP­DAT­ED: Eli Lil­ly’s $1.6B can­cer drug failed to spark even the slight­est pos­i­tive gain for pa­tients in its 1st PhI­II

Eli Lilly had high hopes for its pegylated IL-10 drug pegilodecakin when it bought Armo last year for $1.6 billion in cash. But after reporting a few months ago that it had failed a Phase III in pancreatic cancer, without the data, its likely value has plunged. And now we’re getting some exact data that underscore just how little positive effect it had.

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Aymeric Le Chatelier, Ipsen

A $1B-plus drug stum­bles in­to an­oth­er big PhI­II set­back -- this time flunk­ing fu­til­i­ty test -- as FDA hold re­mains in ef­fect for Ipsen

David Meek

At the time Ipsen stepped up last year with more than a billion dollars in cash to buy Clementia and a late-stage program for a rare bone disease that afflicts children, then CEO David Meek was confident that he had put the French biotech on a short path to a mid-2020 launch.

Instead of prepping a launch, though, the company was hit with a hold on the FDA’s concerns that a therapy designed to prevent overgrowth of bone for cases of fibrodysplasia ossificans progressiva might actually stunt children’s growth. So they ordered a halt to any treatments for kids 14 and under. Meek left soon after to run a startup in Boston. And today the Paris-based biotech is grappling with the independent monitoring committee’s decision that their Phase III had failed a futility test.

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Roche's check­point play­er Tecen­triq flops in an­oth­er blad­der can­cer sub­set

Just weeks after Merck’s star checkpoint inhibitor Keytruda secured FDA approval for a subset of bladder cancer patients, Swiss competitor Roche’s Tecentriq has failed in a pivotal bladder cancer study.

The 809-patient trial — IMvigor010 — tested the PD-L1 drug in patients with muscle-invasive urothelial cancer (MIUC) who had undergone surgery, and were at high risk for recurrence.

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UP­DAT­ED: FDA’s golodirsen CRL: Sarep­ta’s Duchenne drugs are dan­ger­ous to pa­tients, of­fer­ing on­ly a small ben­e­fit. And where's that con­fir­ma­to­ry tri­al?

Back last summer, Sarepta CEO Doug Ingram told Duchenne MD families and investors that the FDA’s shock rejection of their second Duchenne MD drug golodirsen was due to some concerns regulators raised about the risk of infection and the possibility of kidney toxicity. But when pressed to release the letter for all to see, he declined, according to a report from BioPharmaDive, saying that kind of move “might not look like we’re being as respectful as we’d like to be.”

He went on to assure everyone that he hadn’t misrepresented the CRL.

But Ingram’s public remarks didn’t include everything in the letter, which — following the FDA’s surprise about-face and unexplained approval — has now been posted on the FDA’s website and broadly circulated on Twitter early Wednesday.

The CRL raises plenty of fresh questions about why the FDA abruptly decided to reverse itself and hand out an OK for a drug a senior regulator at the FDA believed — 5 months ago, when he wrote the letter — is dangerous to patients. It also puts the spotlight back on Sarepta $SRPT, which failed to launch a confirmatory study of eteplirsen, which was only approved after a heated internal controversy at the FDA. Ellis Unger, director of CDER’s Office of Drug Evaluation I, notes that study could have clarified quite a lot about the benefit and risks associated with their drugs — which can cost as much as a million dollars per patient per year, depending on weight.

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Gilead claims Tru­va­da patents in HHS’ com­plaint are in­valid

Back in November, the Department of Health and Human Services took the rare step of filing a complaint against Gilead for infringing on government-owned patents related to the HIV drug Truvada (emtricitabine/tenofovir disoproxil fumarate) for pre-exposure prophylaxis (PrEP).

But on Thursday, Gilead filed its own retort, making clear that it does not believe it has infringed on the Centers for Disease Control and Prevention’s (CDC) Truvada patents because they are invalid.

Stephen Hahn, AP

The FDA has de­val­ued the gold stan­dard on R&D. And that threat­ens every­one in drug de­vel­op­ment

Bioregnum Opinion Column by John Carroll

A few weeks ago, when Stephen Hahn was being lightly queried by Senators in his confirmation hearing as the new commissioner of the FDA, he made the usual vow to maintain the gold standard in drug development.

Neatly summarized, that standard requires the agency to sign off on clinical data — usually from two, well-controlled human studies — that prove a drug’s benefit outweighs any risks.

Over the last few years, biopharma has enjoyed an unprecedented loosening over just what it takes to clear that bar. Regulators are more willing to drop the second trial requirement ahead of an accelerated approval — particularly if they have an unmet medical need where patients are clamoring for a therapy.

That confirmatory trial the FDA demands can wait a few years. And most everyone in biopharma would tell you that’s the right thing for patients. They know its a tonic for everyone in the industry faced with pushing a drug through clinical development. And it’s helped inspire a global biotech boom.

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UP­DAT­ED: New play­ers are jump­ing in­to the scram­ble to de­vel­op a vac­cine as pan­dem­ic pan­ic spreads fast

When the CNN news crew in Wuhan caught wind of the Chinese government’s plan to quarantine the city of 11 million people, they made a run for one of the last trains out — their Atlanta colleagues urging them on. On the way to the train station, they were forced to skirt the local seafood market, where the coronavirus at the heart of a brewing outbreak may have taken root.

And they breathlessly reported every moment of the early morning dash.

In shuttering the city, triggering an exodus of masked residents who caught wind of the quarantine ahead of time, China signaled that they were prepared to take extreme actions to stop the spread of a virus that has claimed 17 lives, sickened many more and panicked people around the globe.

CNN helped illustrate how hard all that can be.

The early reaction in the biotech industry has been classic, with small-cap companies scrambling to headline efforts to step in fast. But there are also new players in the field with new tech that has been introduced since the last of a series of pandemic panics that could change the usual storylines. And they’re volunteering for a crash course in speeding up vaccine development — a field where overnight solutions have been impossible to prove.

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