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.

How Pa­tients with Epilep­sy Ben­e­fit from Re­al-World Da­ta

Amanda Shields, Principal Data Scientist, Scientific Data Steward

Keith Wenzel, Senior Business Operations Director

Andy Wilson, Scientific Lead

Real-world data (RWD) has the potential to transform the drug development industry’s efforts to predict and treat seizures for patients with epilepsy. Anticipating or controlling an impending seizure can significantly increase quality of life for patients with epilepsy. However, because RWD is secondary data originally collected for other purposes, the challenge is selecting, harmonizing, and analyzing the data from multiple sources in a way that helps support patients.

Re­gen­eron's Evkeeza shows promise in curb­ing high triglyc­erides, but will ge­net­ic dis­par­i­ties lim­it use?

When Regeneron scored an early approval for lipid lowering antibody Evkeeza back in February, the drugmaker cracked open a new pathway to lower abnormally high cholesterol levels. Now, Regeneron is chasing high triglycerides as well with some promising mid-stage data — but will genetic restrictions limit the drug’s use?

Regeneron’s Evkeeza (evinacumab) cut median triglyceride levels by more than 800 mg/dL (57%) in patients with a rare disorder causing abnormally high triglyceride levels compared with an overall increase of 50 mg/dL (1.8%) in participants on placebo, according to Phase II data presented Sunday at the virtual American College of Cardiology meeting.

$DNA is once again on NYSE; FDA clears Soliris chal­lenger for the mar­ket; Flag­ship’s think­ing big again with eR­NA; and more

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I still remember the uncertainty in the air last year when nobody was sure whether ASCO would cancel their in-person meeting. But it’s now back again for the second virtual conference, and Endpoints News is here for it. Check out our 2-day event reviewing the landscape of cancer R&D and send news our way.

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As­traZeneca's Farx­i­ga missed big on Covid-19 study, but it's tak­ing SGLT2 safe­ty da­ta as a sil­ver lin­ing

AstraZeneca hasn’t seen many setbacks in recent months for SGLT2 inhibitor Farxiga, which broke ground in heart failure and kidney disease regardless of diabetes diagnosis. But the British drugmaker had to admit defeat in taking Farxiga into Covid-19, but follow-up results add a bit of a silver lining to that trial’s safety data.

Of hospitalized Covid-19 patients dosed with AstraZeneca’s Farxiga, 11.2% experienced an organ failure or died after 30 days of therapy compared with 13.8% of those given placebo, according to follow-up data from the DARE-19 study revealed Sunday at the virtual American College of Cardiology meeting.

Pfiz­er, Bris­tol My­er­s' Eliquis flops in post-heart surgery pa­tients, spurring an 'un­ex­plained sig­nal' in cer­tain deaths

Pfizer and Bristol Myers Squibb’s non-warfarin blood thinner Eliquis has raced out to become the most prescribed drug of its class on the market — even overtaking warfarin’s long-time lead. But in tricky-to-treat patients after a valve replacement, an investigator-sponsored study couldn’t turn up benefit and raised a troubling safety signal.

Eliquis failed to show benefit over standard of care in preventing serious clinical outcomes after a transaortic valve replacement (TAVR) and was linked to an “unexplained signal” in a subset of populations with a higher rate of non-CV deaths who did not need blood thinners apart from the surgery, according to data presented Saturday at the virtual American College of Cardiology meeting.

Vas Narasimhan (Photographer: Simon Dawson/Bloomberg via Getty Images)

No­var­tis whiffs on En­tresto study af­ter heart at­tacks — but that does­n't mean it's go­ing down qui­et­ly

If Novartis learned one thing from its interaction with the FDA over its latest heart failure approval for Entresto, it was that missing a primary endpoint may not be the nail in the coffin. Now, Entresto has missed again on a late-stage study in high-risk heart patients, and it’s already sowing the seeds for a path forward regardless.

Novartis’ Entresto couldn’t best standard-of-care ramipril in staving off a composite of deaths and heart failure events in patients with left ventricular systolic dysfunction and/or pulmonary congestion who have had a prior heart attack, according to topline data from the Phase III PARADISE-MI study revealed Saturday at the virtual American College of Cardiology meeting.

Michael Dell (Richard Drew, AP Images)

'Dude, you're get­ting a Del­l' — as a new deep-pock­et biotech in­vestor

What happens when you marry longtime insiders in the global biotech VC game with the family fund of tech billionaire Michael Dell, a synthetic biology legend out of MIT and Harvard and the former director of the NCI?

Today, the answer is a newly financed, $200 million biotech SPAC now cruising the industry for a top player interested in finding a short cut to Nasdaq.

Orion Biotech Opportunities priced their blank check company today, raising $200 million with Dell’s multibillion-dollar MSD group’s commitment on investing another $20 million in a forward-purchase agreement.

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Gene ther­a­py from Bio­gen's $800M buy­out flops in mid-stage study, deal­ing blow to new am­bi­tions

The #2 candidate from Biogen’s $800 million ocular gene therapy buyout has failed in a mid-stage trial, dealing an early blow to the big biotech’s plans to revitalize its pipeline with new technologies.

Biogen announced that the candidate, an experimental treatment for a rare and progressive form of blindness called X-linked retinitis pigmentosa (XLRP), failed to sufficiently improve vision in patients’ treated eye — patients only received an injection in one eye — after a year, on a standard scale, compared to their untreated eye. The company said they saw “positive trends” on several secondary endpoints, including visual acuity, but declined to say whether the trial actually hit any of those endpoints.

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In­cyte’s PD-(L)1 in­hibitor head­ed for an ODAC show­down next month

The FDA’s Oncologic Drugs Advisory Committee will spend a half day on June 24 reviewing Incyte’s PD-(L)1 inhibitor retifanlimab as a treatment for locally advanced or metastatic squamous carcinoma of the anal canal (SCAC) for those who have progressed on or who are intolerant of platinum-based chemotherapy.

The eighth PD-(L)1 entrant in January nabbed a priority review and an orphan designation from the FDA, which sets the agency’s final decision date as July 25.