Prob­lems, prob­lems, prob­lems: But Alk­er­mes will fight it out this week over the FDA’s ob­jec­tions to its big de­pres­sion drug ALKS 5461

Alk­er­mes tried sev­er­al new things when their re­searchers test­ed ALKS 5461 for ma­jor de­pres­sion in clin­i­cal tri­als. Now they have to see if they can con­vince the FDA and a group of out­side ex­perts that the drug is ac­tu­al­ly as ef­fec­tive — and as safe — as they in­sist it is.

Alk­er­mes $ALKS is at­tempt­ing to gain an ap­proval for this drug — which is seen as a lynch pin to its fu­ture rev­enue — de­spite key tri­al fail­ures and an ar­guably thin lay­er of con­tro­ver­sial da­ta back­ing the drug.

In the agency’s in­ter­nal re­view of the drug, ini­tial­ly re­ject­ed by the FDA and then tak­en in for a re­view af­ter a sud­den about-face on its de­mand for new tri­als ahead of a mar­ket­ing de­ci­sion, reg­u­la­tors make it clear that Alk­er­mes pushed ahead with a study de­sign they clear­ly in­sist­ed was in­ad­e­quate to pro­vide the in­sight on ef­fi­ca­cy they need to ap­prove a drug for ma­jor de­pres­sion.

Those ob­jec­tions helped dri­ve down the stock price to­day, which slid 6.5% on the frosty — though not for­bid­ding — re­cep­tion.

Most im­por­tant­ly, the reg­u­la­tors high­light Alk­er­mes’ move to use an ab­bre­vi­at­ed scor­ing sys­tem, cut­ting out es­sen­tial points that have scut­tled oth­er de­pres­sion drugs — in­clud­ing track­ing sui­ci­dal think­ing on the part of pa­tients.

From the re­view:

The Mont­gomery Ås­berg De­pres­sion Rat­ing Scale is a 10-item di­ag­nos­tic ques­tion­naire used to mea­sure the sever­i­ty of de­pres­sive episodes in pa­tients with mood dis­or­ders (MADRS-10). The Ap­pli­cant used an abridged 6-item ver­sion of the MADRS-10 for the pri­ma­ry end­point of one of the prin­ci­pal stud­ies (Study 207). The Di­vi­sion had ren­dered ad­vice ex­plic­it­ly against this plan, based on analy­ses of the MADRS-10 and MADRS-6 by both the Di­vi­sion and the Agency’s Clin­i­cal Out­comes As­sess­ment (COA) Staff. The COA Staff had con­clud­ed that the MADRS-6 could not re­place the MADRS-10 for use as a pri­ma­ry end­point be­cause the abridged ques­tion­naire ex­cludes con­cepts that are rel­e­vant and im­por­tant in MDD, specif­i­cal­ly “re­duced sleep,” “re­duced ap­petite,” “con­cen­tra­tion dif­fi­cul­ties,” and “sui­ci­dal thoughts.”

Not on­ly that, but the agency takes ex­cep­tion to Alk­er­mes’ view that the drug is a non-opi­oid.

(B)up­renor­phine is an opi­oid. Al­though the Ap­pli­cant has made sev­er­al ar­gu­ments that the oth­er com­po­nent of their drug, sami­dor­phan, negates the μ-opi­oid prop­er­ties of buprenor­phine, this has not been con­clu­sive­ly proven. Al­though we agree with the Ap­pli­cant that there are few­er opi­oid prop­er­ties for this com­bi­na­tion prod­uct than there like­ly would have been from the opi­oid alone, there re­mains some ev­i­dence of a mild opi­ate ef­fect (in­clud­ing mild with­draw­al ef­fects) from the tri­als.

In sev­er­al cas­es, the FDA spot­lights messy da­ta that they clear­ly have tak­en is­sue with. That in­cludes drop­ping the clas­sic ap­proach of as­sess­ing pa­tients at par­tic­u­lar time points in a study and in­stead shoot­ing for av­er­age scores over a pe­ri­od of time. That may not fly with the FDA, but the reg­u­la­tors do want to hear the ex­perts’ opin­ions on that sub­ject.

Alk­er­mes al­so used a nov­el tri­al de­sign to se­lect pa­tients for the study, and now reg­u­la­tors want the out­side ex­perts to dis­cuss their opin­ions on how this worked. Ex­plain­ing the move, reg­u­la­tors not­ed:

In Stage 1, pa­tients who meet study en­trance cri­te­ria are ran­dom­ized to drug vs. place­bo, with a skewed ran­dom­iza­tion ra­tio that places far more pa­tients in the place­bo group. Stage 2 in­cludes on­ly non-re­spon­ders from the Stage 1 place­bo group, and these pa­tients are re-ran­dom­ized to drug vs. place­bo. Re­sults from the two stages are merged to pro­vide a sin­gle over­all test of hy­poth­e­sis. There are a num­ber of un­re­solved sta­tis­ti­cal ques­tions re­gard­ing the most ap­pro­pri­ate method for an­a­lyz­ing the re­sults of an SPCD study.

The ex­pert pan­el will gath­er on Thurs­day to hash it all out and of­fer their opin­ion to the FDA over­lords. In the mean­time, Paul Mat­teis at Stifel says Alk­er­mes is fac­ing some se­vere head­winds go­ing in­to the pan­el re­view Thurs­day.

Over­all, the docs are def­i­nite­ly neg­a­tive and sug­gest that FDA is lean­ing to­wards a CRL, but they al­so don’t seem to com­plete­ly close the door on ap­proval (for ex­am­ple they dis­cuss, hy­po­thet­i­cal­ly, what a REMS would look like – on­ly rel­e­vant if the drug were ap­proved). We con­tin­ue to be­lieve that the prob­a­bil­i­ty of ap­proval is well be­low 50%, and we don’t think the docs to­day are like­ly to ma­jor­ly change in­vestors’ views on the is­sue.

Mer­ck is tak­ing the ax to its US op­er­a­tions, cut­ting 500 jobs in its lat­est re­or­ga­ni­za­tion

Merck is cutting 500 jobs in its US sales and headquarters commercial teams in its latest effort to find new ways to streamline the operation.

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Alice Shaw, Lung Cancer Foundation of America

Top ALK ex­pert and can­cer drug re­searcher Al­ice Shaw bids adieu to acad­e­mia, hel­lo to No­var­tis

Jay Bradner has recruited a marquee oncology drug researcher into the ranks of the Novartis Institutes for BioMedical Research. Alice Shaw is jumping from prestigious posts intertwined through Mass General, Harvard and Dana-Farber to take the lead of NIBR’s translational clinical oncology group.

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Mi­rati preps its first look at their KRAS G12C con­tender, and they have to clear a high bar for suc­cess

If you’re a big KRAS G12C fan, mark your calendars for October 28 at 4:20 pm EDT.

That’s when Mirati $MRTX will unveil its first peek at the early clinical data available on MRTX849 in presentations at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in Boston.

Mirati has been experiencing the full effect of a rival’s initial success at targeting the G12C pocket found on KRAS, offering the biotech some support on the concept they’re after — and biotech fans a race to the top. Amgen made a big splash with its first positive snapshot on lung cancer, but deflated sky-high expectations as it proved harder to find similar benefits in other types of cancers.

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The FDA will hus­tle up an ex­pe­dit­ed re­view for As­traZeneca’s next shot at a block­buster can­cer drug fran­chise

AstraZeneca paid a hefty price to partner with Daiichi Sankyo on their experimental antibody drug conjugate for HER2 positive breast cancer. And they’ve been rewarded with a fast ride through the FDA, with a straight shot at creating another blockbuster oncology franchise.

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Hal Barron, GSK's president of R&D and CSO, speaks to Endpoints News founder and editor John Carroll in London at Endpoints' #UKBIO19 summit on October 8, 2019

[Video] Cel­e­brat­ing tri­al fail­ures, chang­ing the cul­ture and al­ly­ing with Cal­i­for­nia dream­ers: R&D chief Hal Bar­ron talks about a new era at GSK

Last week I had a chance to sit down with Hal Barron at Endpoints’ #UKBIO19 summit to discuss his views on R&D at GSK, a topic that has been central to his life since he took the top research post close to 2 years ago. During the conversation, Barron talked about changing the culture at GSK, a move that involves several new approaches — one of which involves celebrating their setbacks as they shift resources to the most promising programs in the pipeline. Barron also discussed his new alliances in the Bay Area — including his collaboration pact with Lyell, which we covered here — frankly assesses the pluses and minuses of the UK drug development scene, and talks about his plans for making GSK a much more effective drug developer.

This is one discussion you won’t want to miss. Insider and Enterprise subscribers can log-in to watch the video.

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Flu Virus (Source: CDC)

FDA ex­pands Xofluza ap­proval as Roche strug­gles to catch loom­ing flu mar­ket

As a potentially powerful flu season looms, so does a big test for Roche and its new flu drug, Xofluza. The Swiss giant just got a small boost in advance of that test as the FDA expanded Xofluza’s indication to include patients at high risk of developing flu-related complications.

Xofluza (baloxavir marboxil) was approved last October in the US, the first landmark flu drug approval in 20 years and a much-needed green light for a company that had watched its leading flu drug Tamiflu get eaten alive by generics. Like its predecessor, the pill offered a reduction in flu symptoms but not a cure.

EMA backs sev­en ther­a­pies, in­clud­ing Mer­ck­'s Ebo­la vac­cine

The first-ever Ebola vaccine is on the precipice of approval after the European Medicine’s Agency (EMA) backed the Merck product in this week’s roster of recommendations.

The drugmaker $MRK began developing the vaccine, christened Ervebo, during the West African outbreak that occurred between 2014 and 2016, killing more than 11,000.

The current outbreak in the Democratic Republic of Congo (DRC) has shown case fatality rates of approximately 67%, the agency estimated. Earlier this year, the WHO declared the outbreak — which so far has infected more than 3,000 people — a public health emergency of international concern.

Ronald Herb­st fol­lows Med­Im­mune ex­o­dus to Pyx­is CSO post; Jeff God­dard to suc­ceed CEO of AIT Bio­science

→ The outflow of top execs from MedImmune continues to fill the leadership ranks of smaller biotechs. The latest to take off is Ronald Herbst, the head of oncology research, who’s assuming the CSO post at Pyxis Oncology.  

Herbst was part of the old MedImmune organization AstraZeneca CEO Pascal Soriot restructured earlier this year, reorganizing the company and eliminating the storied subsidiary as a separate organization.

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Med­ical an­i­ma­tion: Mak­ing it eas­i­er for the site and the pa­tient to un­der­stand

Medical animation has in recent years become an increasingly important tool for conveying niche information to a varied audience, particularly to those audiences without expertise in the specialist area. Science programmes today, for example, have moved from the piece-to-camera of the university professor explaining how a complex disease mechanism works, to actually showing the viewer first-hand what it might look like to shrink ourselves down to the size of an ant’s foot, and travel inside the human body to witness these processes in action. Effectively communicating a complex disease pathophysiology, or the novel mechanism of action of a new drug, can be complex. This is especially difficult when the audience domain knowledge is limited or non-existent. Medical animation can help with this communication challenge in several ways.
Improved accessibility to visualisation
Visualisation is a core component of our ability to understand a concept. Ask 10 people to visualise an apple, and each will come up with a slightly different image, some apples smaller than others, some more round, some with bites taken. Acceptable, you say, we can move on to the next part of the story. Now ask 10 people to visualise how HIV’s capsid protein gets arranged into the hexamers and pentamers that form the viral capsid that holds HIV’s genetic material. This request may pose a challenge even to someone with some virology knowledge, and it is that inability to effectively visualise what is going on that holds us back from fully understanding the rest of the story. So how does medical animation help us to overcome this visualisation challenge?