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.

UP­DAT­ED: In a fresh dis­ap­point­ment, Am­gen spot­lights a ma­jor safe­ty is­sue with KRAS com­bo

Amgen had hoped that its latest study matching its landmark KRAS G12C drug Lumakras with checkpoint inhibitors would open up its treatment horizons and expand its commercial potential. Instead, the combo spurred safety issues that blunted efficacy and forced the pharma giant to alter course on its treatment strategy, once again disappointing analysts who have been tracking the drug’s faltering sales and limited therapeutic reach.

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Ad­dress­ing the ‘Ca­pac­i­ty Crunch’ with a Scal­able Plat­form Process Ap­proach

The field of gene therapy has been diligently moving forward over the past several decades to bring potentially life-saving treatments to patients with genetic diseases. In addition to two approved adeno-associated viral (AAV) gene therapies, there are more than 250 AAV gene therapies in various clinical trial stages.1 AAV vectors remain the most frequently used vector for delivering therapeutic transgenes to target tissues due to their demonstrated and lasting clinical efficacy and extensive safety track record. As AAV therapies advance through clinical trials and into commercialization, many biotech companies are turning to contract development and manufacturing organizations (CDMOs) to prepare their programs for late-stage clinical and commercial scale manufacturing. Given the scope and scale of the manufacturing needs that will accompany regulatory approvals for these assets, CDMOs continue to expand their capacity to meet the needs of increasing prevalent patient populations. However, despite rapid growth, projected gene therapy manufacturing demands still outpace the collective capacity of the CDMO industry.

A $5B Pfiz­er buy­out? Am­gen, Gilead head­line M&A Thurs­day; Al­ny­lam's AT­TR sweep; An­drew Lo's rare dis­ease quest; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

One of the cool things about adding EndpointsPharma to the daily roster is that my colleagues can now dedicate time to tracking quarterly updates and tuning into calls with Big Pharma companies. Check out their dispatch from the Q2 earnings below.

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Bob Bradway, Amgen CEO (Justin Kase Conder/AP Images for Amgen)

UP­DAT­ED: Am­gen chief Brad­way nabs a rare dis­ease play­er in $4B buy­out as the M&A tem­po ac­cel­er­ates

Amgen CEO Bob Bradway is bellying up to the M&A table today, scooping up the newly anointed commercial biotech ChemoCentryx $CCXI and its recently approved rare disease drug for $3.7 billion out of the cash stockpile. The deal comes in at $52 a share — a hefty increase over the $24.11 close yesterday.

Bradway and the Amgen team get a drug called Tavneos (avacopan) in the deal, a complement factor C5a inhibitor OK’d to treat anti-neutrophil cytoplasmic autoantibody (ANCA)-vasculitis, an autoimmune disease which can be lethal.

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Albert Bourla, Pfizer CEO (Laurent Gillieron/Keystone via AP)

Break­ing: Pfiz­er in hot pur­suit of a $5B buy­out of Glob­al Blood Ther­a­peu­tics — re­port

Pfizer CEO Albert Bourla has vowed to leave no stone unturned in the search for new biotech deals, and the BD team is not letting him down.

The Wall Street Journal reported today that Pfizer is in the final stages of acquiring Global Blood Therapeutics for $5 billion. According to the Journal report, though, Pfizer is not the only buyer at the deal table and while the pharma giant may be close to clinching it, there are no guarantees it will continue.

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George Yancopoulos, Regeneron president and CSO (Brendan McDermid/Reuters/Alamy)

George Yan­copou­los says he's on the trail of the holy grail: ‘This could rep­re­sent the next break­through for im­munother­a­py’

Two of the most outspoken — and successful — drug developers in biotech say they’ve collected early-stage clinical data that are pointing them down the trail to the holy grail in cancer immunotherapy R&D.

While analysts largely busied themselves today with chronicling the ongoing success of Regeneron’s two big cash cows — Dupixent and Eylea — chief scientist George Yancopoulos and CEO Len Schleifer used the Q2 call to spotlight their early success with a combination of the “homegrown” PSMAxCD28 costimulatory bispecific antibody REGN5678 in combination with their PD-1 checkpoint Libtayo. The presentation comes just weeks after Regeneron completed a deal to gather all rights to the PD-1 that had been in Sanofi’s hands. And the two top execs are unstinting in their praise of the potential of a whole set of costimulatory pipeline projects which they say may finally deliver the long-awaited next-level approach to broadening the immunotherapy field of drugs.

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(AP Photo/Richard Vogel, File)

US de­clares mon­key­pox a na­tion­al health emer­gency, as new drug­mak­ers con­sid­er en­ter­ing vac­cine race

Rising monkeypox cases have put the US on high alert as it announces a national health emergency, which grants the government more power in its response.

The news comes as Bavarian Nordic continues to fill orders for its Jynneos vaccine and other companies – including Moderna – consider jumping into the vaccine race. Meanwhile, the New York Times reports that the US has allowed around 20 million doses of smallpox vaccine in its stockpile to expire.

Al Sandrock, Voyager Therapeutics CEO

Al San­drock prunes his post-Bio­gen voy­age with sim­i­lar fo­cus on ALS

Al Sandrock is narrowing the focus of Voyager Therapeutics, concentrating on CNS diseases that were the hallmark of his time leading R&D at Biogen, including an emphasis on a familial form of ALS for which his former employer is getting a speedy review at the FDA.

Less than six months into his journey as CEO at Voyager, Sandrock is focusing the preclinical pipeline on Alzheimer’s disease, GBA1 Parkinson’s disease and SOD1 amyotrophic lateral sclerosis, the rare form of ALS for which the FDA will decide whether to approve Biogen’s tofersen by Jan. 25, 2023.

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Pfiz­er ter­mi­nates PhI­II study of rare car­dio­vas­cu­lar drug picked up in $11.4B Ar­ray ac­qui­si­tion

While Pfizer’s $11.4 billion acquisition of Array BioPharma in the summer of 2019 was mainly focused on oncology, namely Braftovi and Mektovi, there were a few non-cancer assets, including a Phase III drug being tested in a rare cardiovascular disease.

The late-stage trial is now being axed, alongside any further development of the oral small molecule, the pharma giant disclosed after the closing bell on Wednesday. Based on an interim futility analysis of the global Phase III REALM-DCM trial, Pfizer determined a path forward was not in its best interest. Pfizer no longer expected the study would meet its primary goal.

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