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.

John Hood [file photo]

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On June 18, 2019, we initiated a confidential arbitration proceeding against Dr. Asa Abeliovich, our former consulting co-founder, related to alleged breaches of his consulting agreement and the improper use of our confidential information that he learned during the course of rendering services to us as our consulting Chief Scientific Officer/Chief Innovation Officer. We are in the early stage of this arbitration proceeding and are unable to assess or provide any assurances regarding its possible outcome.

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