FDA re­view rais­es some se­ri­ous ques­tions for Puma, but shares rock­et up on pos­i­tive notes

Puma Biotech­nol­o­gy will face some tough ques­tions from reg­u­la­tors dur­ing Wednes­day’s long-await­ed pan­el re­view for its ex­per­i­men­tal can­cer drug ner­a­tinib.

Not on­ly did the FDA re­view, out this morn­ing, raise point­ed ques­tions about the many changes that were made to Puma’s study for ear­ly-stage ERBB2-pos­i­tive breast can­cer, it al­so high­light­ed — as ex­pect­ed — the high rate of se­ri­ous di­ar­rhea ex­pe­ri­enced by pa­tients in the study.

One crit­i­cal is­sue: At one point, just four months be­fore Puma filed for an ap­proval, reg­u­la­tors al­so ad­vised Puma ex­ecs against fil­ing for an OK.

Pre-NDA meet­ing with Puma – FDA ad­vised they did not en­cour­age an NDA sub­mis­sion based on the ef­fi­ca­cy and safe­ty re­sults of Study 3004. This was due to sev­er­al study con­duct is­sues which would make in­ter­pre­ta­tion of the re­sults prob­lem­at­ic. The Ap­pli­cant was ad­vised that if an NDA was sub­mit­ted, an On­co­log­ic Drugs Ad­vi­so­ry Com­mit­tee dis­cus­sion would be re­quired.

At the same time, reg­u­la­tors did not con­demn the drug, not­ing that even with the ar­ray of changes to the study, there is da­ta sup­port­ing ef­fi­ca­cy. And the bulls ran with the win com­bined with an over­all neu­tral tone to the prob­lems Puma may face. Its shares $PBYI rock­et­ed up 80%, then quick­ly slid back down to a 50% gain on a sec­ond take of the re­view.

In its sum­ma­ry, the FDA not­ed that:

De­spite the un­planned amend­ments and po­ten­tial un­cer­tain­ty in­tro­duced with re­spect to the mag­ni­tude of ner­a­tinib ef­fect, based on the sen­si­tiv­i­ty analy­ses con­duct­ed, the re­sults ap­pear to be gen­er­al­ly sim­i­lar to the pri­ma­ry analy­sis re­sults, sup­port­ing an ef­fect of ner­a­tinib.

The FDA set up a rel­a­tive­ly short pan­el re­view for Wednes­day, which had trig­gered spec­u­la­tion from a host of short sell­ers who have dogged this biotech at every step that Puma was in line for a thump­ing. But as of now, that’s all it is.

Reg­u­la­tors not­ed, though, that they have con­cerns with the re­sults from the study.

There re­mains some un­cer­tain­ty re­gard­ing the true mag­ni­tude of the treat­ment ef­fect since the pri­ma­ry analy­sis (trun­cat­ed at 2-years fol­low-up) ob­served a haz­ard ra­tio of 0.66 (95% CI: 0.49, 0.90) which changed to 0.68 (95% CI: 0.51, 0.91) with the ex­plorato­ry up­dat­ed 2-year analy­sis and the ex­plorato­ry 5-year analy­sis ob­served a haz­ard ra­tio of 0.73 (95% CI: 0.57, 0.92).

Puma has been pil­lo­ried rou­tine­ly for the way it han­dled the se­vere in­stances of di­ar­rhea in its stud­ies. As the re­view notes, even with the ad­di­tion of an an­tidiar­rheal drug in Puma’s stud­ies there was still a high rate of dropouts.

While there were few­er dose re­duc­tions and dose holds in the Lop­eramide Co­hort of Study 6201 com­pared to pa­tients in Study 3004, there re­mained a sub­stan­tial rate of dis­con­tin­u­a­tion due to di­ar­rhea de­spite an­tidiar­rheal pro­phy­lax­is with Lop­eramide (16.8% in Study 3004 and 20.4% in Study 6201). In ad­di­tion, a high­er in­ci­dence of con­sti­pa­tion and nau­sea was re­port­ed in the Lop­eramide co­hort.

The FDA re­view should raise some ob­vi­ous ques­tions on Wednes­day. But the ju­ry still re­mains out on Puma’s fate. Matthew Eck­ler at RBC looked over the docs and saw much to be hap­py with.

In our ini­tial read, we didn’t come across any­thing that we view as over­ly sur­pris­ing. As ex­pect­ed, the FDA doc­u­ments read as harsh in some sec­tions (many FDA brief­ing books can), but ul­ti­mate­ly we see the points raised as hav­ing al­ready been wide­ly known in­clud­ing: 1) the clin­i­cal sig­nif­i­cance of iDFS ben­e­fit seen in Ex­teNET; 2) changes made to the de­sign of Ex­teNET; 3) Ner­a­tinib-as­so­ci­at­ed G3 di­ar­rhea; and 4) ben­e­fit of ner­a­tinib in the HR+ sub­group. We al­so note that we don’t see any men­tion of Aphin­i­ty in the FDA brief­ing book. The bot­tom line is that the FDA doc­u­ments read very bal­anced to us, and are frankly more pos­i­tive than we an­tic­i­pat­ed, set­ting the stage ODAC to make an un­am­bigu­ous rec­om­men­da­tion.

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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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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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?

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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UP­DAT­ED: J&J's Xarel­to, Amar­in's Vas­cepa are cost-ef­fec­tive, not bud­get friend­ly — ICER

ICER, an increasingly influential cost-effectiveness watchdog in the United States, has concluded in its review of treatments for cardiovascular disease that while the cost of J&J’s Xarelto and Amarin’s Vascepa meet its benchmark for value pricing — the two treatments will not likely treat as many patients as hoped without surpassing the annual budget threshold calculated by ICER for each therapy.

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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