So close, yet so far: Zo­genix LGS tri­al suc­ceeds, but re­sults un­der­whelm

Mere­ly cross­ing the fin­ish line isn’t enough — the win must be de­ci­sive. Ask Zo­genix, whose ex­per­i­men­tal seizure drug met the main goal in a piv­otal study in pa­tients with Lennox-Gas­taut Syn­drome (LGS) on Thurs­day, but saw its shares plum­met af­ter the mag­ni­tude of the ther­a­py’s ef­fect fell short.

The drug, fen­flu­ramine (to be brand­ed Fin­tepla) — one-half of the no­to­ri­ous axed pre­scrip­tion weight-loss cock­tail fen-phen — was test­ed against a place­bo in 263 pa­tients with the rare, treat­ment-re­sis­tant form of child­hood epilep­sy. The da­ta comes months af­ter Zo­genix’s re­vamped ap­pli­ca­tion was ac­cept­ed for re­view in pa­tients with Dravet syn­drome, an­oth­er rare seizure dis­or­der.

Stephen Farr, CEO – Zo­genix

In the LGS study, pa­tients on the high­er dose (0.7 mg) of the drug saw a sta­tis­ti­cal­ly sig­nif­i­cant me­di­an re­duc­tion of 26.5% in seizure fre­quen­cy, ver­sus 7.8% in pa­tients tak­ing place­bo (p=0.0012). Oth­er sec­ondary end­points in­clud­ing pa­tients with ≥50% re­duc­tion in month­ly drop seizures; the pro­por­tion of pa­tients im­proved; and the pro­por­tion of pa­tients much im­proved or very much im­proved were all in fa­vor of the drug.

“The dif­fer­ence (18.7%) is sub­stan­tial­ly small­er than the ~60% re­duc­tion in seizures over place­bo seen for the high-dose co­hort in the Dravet fen­flu­ramine tri­al,” Stifel’s Paul Mat­teis wrote in a note.

Mat­teis raised his ap­proval prob­a­bil­i­ty in LGS to 80% but said that the poor mag­ni­tude of ef­fi­ca­cy prompt­ed a re­duc­tion in his mar­ket share es­ti­mate to 15% from 20%.

Last April, Zo­genix said the FDA had re­buffed re­view­ing Fin­tepla’s mar­ket­ing ap­pli­ca­tion for Dravet pa­tients, cit­ing the lack of cer­tain non-clin­i­cal stud­ies key for the as­sess­ment of chron­ic ad­min­is­tra­tion of the drug as well as an in­cor­rect ver­sion of a clin­i­cal dataset. In No­vem­ber, the FDA ac­cept­ed the com­pa­ny’s re­sub­mit­ted ap­pli­ca­tion, and the agency is ex­pect­ed to make its fi­nal de­ci­sion by March 25.

If ap­proved, fen­flu­ramine will com­pete with GW Phar­ma­ceu­ti­cals’ pi­o­neer­ing cannabis-de­rived Epid­i­olex — which is ap­proved for both Dravet and LGS — as well as Biocodex’s Di­a­comit.

“Epid­i­olex ab­solute seizure re­duc­tion in LGS was greater than seen here, how­ev­er, the place­bo ef­fect in GW’s stud­ies is con­sis­tent­ly much big­ger, which may be due to the ex­pec­ta­tion bias that con­sis­tent­ly hov­ers around CBD. This dy­nam­ic was first ob­served in Dravet, where the place­bo arm in GW’s study showed a 13% re­duc­tion in con­vul­sive seizures, vs 1.1% and 1.2% in ZGNX’s two Dravet ph3’s. Sim­i­lar­ly, in LGS, while Epid­i­olex showed 42% and 44% re­duc­tions in drop seizures, the place­bo arms in the two stud­ies showed re­duc­tions in seizure fre­quen­cy of 17% and 22%,” Mat­teis said.

“We’re there­fore un­sur­prised to see a sig­nif­i­cant­ly small­er place­bo ef­fect in fen­flu­ramine’s LGS study (just 7.8%), and any analy­sis of the ab­solute seizure re­duc­tion on Fin­tepla needs to be in­ter­pret­ed in the con­text of this dy­nam­ic. Pa­tients in both Zo­genix and GW’s LGS stud­ies look fair­ly se­vere, and Zo­genix made the case that the Fin­tepla im­prove­ment in seizure re­duc­tion, when looked at as a mul­ti­ple of place­bo, was ro­bust.”

Over­all, the ef­fi­ca­cy of Fin­tepla and Epid­i­olex is like­ly more sim­i­lar than dif­fer­ent in LGS (com­pared to the large dif­fer­ence in Dravet), Mat­teis con­clud­ed. “There­fore if one mod­els Fin­tepla as the more ex­pen­sive op­tion, which we do, it prob­a­bly makes sense to as­sume that it’s used lat­er in the LGS treat­ment par­a­digm.”

Zo­genix’s shares $ZGNX were down more than 32% at $35.65 in Fri­day pre­mar­ket trad­ing, while GW Phar­ma’s stock $GW­PH jumped about 9% to $129.

Secretary of health and human services Alex Azar speaking in the Rose Garden at the White House (Photo: AFP)

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In a new memorandum issued Tuesday last week, the HHS chief stripped health agencies under his purview — including the FDA — of their rulemaking ability, asserting all such power “is reserved to the Secretary.” Sheila Kaplan of the New York Times first obtained and reported the details of the September 15 bulletin.

Dan Skovronsky, Eli Lilly CSO

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Eli Lilly CSO Dan Skovronsky (file photo)

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Greg Friberg (File photo)

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Exelixis CEO Michael Morrissey (file photo)

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