With eye on win­ning over FDA in the wake of RTF, Zo­genix pub­lish­es new Fin­tepla da­ta

Bat­tered by a refuse-to-file let­ter from the FDA in April, Zo­genix has made strides to con­vince the FDA that its Dravet syn­drome drug is worth ap­proval. Last month, the reg­u­la­tor ac­cept­ed its re­sub­mit­ted ap­pli­ca­tion to mar­ket Fin­tepla, one half of the no­to­ri­ous axed pre­scrip­tion weight-loss cock­tail fenphen, for pa­tients with the rare, se­vere form of child­hood epilep­sy.

Ear­li­er this week, da­ta from a Zo­genix-fund­ed 119-pa­tient study led by re­searchers from UCSF, Uni­ver­si­ty of Leu­ven and oth­er treat­ment cen­ters showed that Fin­tepla, known chem­i­cal­ly as fen­flu­ramine, helped cut con­vul­sive seizures by 62% ver­sus place­bo in pa­tients with Dravet syn­drome.

In the tri­al, two dos­es of Fin­tepla were test­ed. The high­er dose in­duced the 62% re­duc­tion, while the small­er dose in­duced a 32% cut in seizures ver­sus place­bo. The longest seizure-free in­ter­val, on av­er­age, was 25 days for the high­er-dose group, 15 for the low­er-dose group, and 9 days for place­bo.

Pa­tients en­rolled in the tri­al had an av­er­age of 40 con­vul­sive seizures in the month be­fore the tri­al, de­spite their ex­ist­ing treat­ment reg­i­men. Rough­ly 10% to 15% of Dravet syn­drome pa­tients die by the age of 25 due to seizure-trig­gered ir­reg­u­lar heart rhythm or suf­fo­ca­tion.

On the safe­ty side, most side-ef­fects were mild-to-mod­er­ate and oc­curred across the three arms of the tri­al and no cas­es of pul­monary ar­te­r­i­al hy­per­ten­sion or “clin­i­cal­ly sig­nif­i­cant” signs or symp­toms of car­dio­vas­cu­lar dis­ease were ob­served in the 14-week tri­al, nor in the on­go­ing open-la­bel ex­ten­sion tri­al, in which some pa­tients have been tak­ing the drug for more than one year.

How­ev­er, weight-loss was a side ef­fect of note in both the Fin­tepla arms. In the high­er dose group, 8/40 pa­tients lost 7.2% to 11.4% of their body weight, while in the small­er dose group, 5/39 pa­tients ex­pe­ri­enced weight loss that ranged from 8.4% to 21.9% of their body weight. Oth­er ad­verse events as­so­ci­at­ed with the drug were de­creased ap­petite, di­ar­rhea, lethar­gy, and som­no­lence.

“Our con­clu­sions about the car­dio­vas­cu­lar safe­ty of fen­flu­ramine are lim­it­ed by the short treat­ment and ob­ser­va­tion pe­ri­od of 14 weeks in this tri­al,” the au­thors wrote in the jour­nal Lancet. “These find­ings are con­sis­tent with those re­port­ed with long-term use of fen­flu­ramine at dos­es be­tween 0·13–0·69 mg/kg per day in Dravet syn­drome in Bel­gium, where no cas­es of valve dys­func­tion or pul­monary hy­per­ten­sion have been re­port­ed with up to 30 years of fen­flu­ramine treat­ment with on­go­ing echocar­dio­graph­ic ex­am­i­na­tions.”

The di­et drug fen-phen — a for­mu­la­tion of an ap­petite de­pres­sant and a type of am­phet­a­mine — was once deemed a sil­ver bul­let for the bur­geon­ing obe­si­ty cri­sis. But it was tak­en off US shelves in 1997 af­ter fresh da­ta showed it could cause heart valve de­fects in as many as a third of pa­tients.  In Bel­gium, fen­flu­ramine has been ap­proved for com­pas­sion­ate use since 2002.

In April, Zo­genix said the FDA had re­buffed re­view­ing Fin­tepla’s mar­ket­ing ap­pli­ca­tion, 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. Last month, the FDA ac­cept­ed Zo­genix’s re­vamped ap­pli­ca­tion. The agency is ex­pect­ed to make its fi­nal de­ci­sion by March 25.

If ap­proved, Fin­tepla will com­pete with GW Phar­ma­ceu­ti­cals’ pi­o­neer­ing cannabis-de­rived Epid­i­olex, which is pit­ted as a block­buster, as well as Biocodex’s Di­a­comit.

Mean­while, Fin­tepla is al­so un­der in­ves­ti­ga­tion for use in Lennox-Gas­taut syn­drome. Late-stage da­ta from a Phase III study is ex­pect­ed in ear­ly 2020.

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

Trump’s HHS claims ab­solute au­thor­i­ty over the FDA, clear­ing path to a vac­cine EUA

The top career staff at the FDA have vowed not to let politics get in the way of science when looking at vaccine data this fall. But Alex Azar, who happens to be their boss’s boss, apparently won’t even give them a chance to stand in the way.

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.

Eli Lilly CSO Dan Skovronsky (file photo)

#ES­MO20: Eli Lil­ly shows off the da­ta for its Verzenio suc­cess. Was it worth $18 bil­lion?

The press release alone, devoid of any number except for the size of the trial, added nearly $20 billion to Eli Lilly’s market cap back in June. Now investors and oncologists will get to see if the data live up to the hype.

On Sunday at ESMO, Eli Lilly announced the full results for its Phase III MonarchE trial of Verzenio, showing that across over 5,000 women who had had HR+, HER2- breast cancer, the drug reduced the odds of recurrence by 25%. That meant 7.8% of the patients on the drug arm saw their cancers return within 2 years, compared with 11.3% on the placebo arm.

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Greg Friberg (File photo)

#ES­MO20: Am­gen team nails down sol­id ear­ly ev­i­dence of AMG 510’s po­ten­tial for NSCLC, un­lock­ing the door to a wave of KRAS pro­grams

The first time I sat down with Amgen’s Greg Friberg to talk about the pharma giant’s KRAS G12C program for sotorasib (AMG 510) at ASCO a little more than a year ago, there was high excitement about the first glimpse of efficacy from their Phase I study, with 5 of 10 evaluable non-small cell lung cancer patients demonstrating a response to the drug.

After decades of failure targeting KRAS, sotorasib offered the first positive look at a new approach that promised to open a door to a whole new approach by targeting a particular mutation to a big target that had remained “undruggable” for decades.

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#ES­MO20: Out to beat Tagris­so, J&J touts 100% ORR for EGFR bis­pe­cif­ic/TKI com­bo — fu­el­ing a quick leap to PhI­II

J&J’s one-two punch on EGFR-mutant non-small cell lung cancer has turned up some promising — although decidedly early — results, fueling the idea that there’s yet room to one up on third-generation tyrosine kinase inhibitors.

Twenty out of 20 advanced NSCLC patients had a response after taking a combination of an in-house TKI dubbed lazertinib and amivantamab, a bispecific antibody targeting both EGFR and cMET engineered on partner Genmab’s platform, J&J reported at ESMO. All were treatment-naïve, and none has seen their cancer progress at a median follow-up of seven months.

#ES­MO20: As­traZeneca aims to spur PRO­found shift in prostate can­cer treat­ment with Lyn­parza OS da­ta

AstraZeneca has unveiled the final, mature overall survival data that cemented Lynparza’s first approval in prostate cancer approval — touting its lead against rivals with the only PARP inhibitor to have demonstrated such benefit.

But getting the Merck-partnered drug to the right patients remains a challenge, something the companies are hoping to change with the new data cut.

The OS numbers on the subgroup with BRCA1/2 or ATM-mutated metastatic castration-resistant prostate cancer are similar to the first look on offer when the FDA expanded the label in May: Lynparza reduced the risk of death by 31% versus Xtandi and Zytiga. Patients on Lynparza lived a median of 19.1 months, compared to 14.7 months for the anti-androgen therapies (p = 0.0175).

Exelixis CEO Michael Morrissey (file photo)

#ES­MO20: Look out Mer­ck. Bris­tol My­ers and Ex­elix­is stake out their com­bo’s claim to best-in-class sta­tus for front­line kid­ney can­cer

Now that the PD-(L)1 checkpoints are deeply entrenched in the oncology market, it’s time to welcome a wave of combination therapies — beyond chemo — looking to extend their benefit to larger numbers of patients. Bristol Myers Squibb ($BMY} and Exelixis {EXEL} are close to the front of that line.

Today at ESMO the collaborators pulled the curtain back on some stellar data for their combination of Opdivo (the PD-1) and Cabometyx (the TKI), marking a significant advance for the blockbuster Bristol Myers franchise while offering a big leg up for the team at Exelixis.

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Dan Skovronsky, Eli Lilly CSO

An­a­lysts are quick to pan Eli Lil­ly's puz­zling first cut of pos­i­tive clin­i­cal da­ta for its Covid-19 an­ti­body

Eli Lilly spotlighted a success for one of 3 doses of their closely-watched Covid-19 antibody drug Wednesday morning. But analysts quickly highlighted some obvious anomalies that could come back to haunt the pharma giant as it looks for an emergency use authorization to launch marketing efforts.

The pharma giant reported that LY-CoV555, developed in collaboration with AbCellera, significantly reduced the rate of hospitalization among patients who were treated with the antibody. The drug arm of the study had a 1.7% hospitalization rate, compared to 6% in the control group, marking a 72% drop in risk.

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#ES­MO20: It’s not just Keytru­da any­more — Mer­ck spot­lights 3 top ear­ly-stage can­cer drugs

Any $12 billion megablockbuster in the portfolio tends to overshadow everything else in the pipeline. Which is something Merck can tell you a little bit about.

Keytruda not only dominates the PD-(L)1 field, it looms over everything Merck does, to the point some analysts wonder if Merck is a one-trick pony.

There’s no shortage of Keytruda data on display at ESMO this weekend, but now the focus is shifting to the future role of new drugs and combos in maintaining that lead position for years to come. And the pharma giant has a special focus for 3 early-stage efforts where Roger Perlmutter’s oncology team is placing some big bets.

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#ES­MO20: Trodelvy da­ta show that Gilead­'s $21B buy­out may have been worth the big pre­mi­um

Gilead CEO Dan O’Day has been on a shopping spree. And while some analysts gawked at the biotech’s recent $21 billion Immunomedics buyout, new data released at virtual ESMO 2020 suggest the acquisition may have been worth the hefty price.

The deal, announced last weekend, will give California-based Gilead $GILD Trodelvy, which was recently approved for metastatic triple-negative breast cancer (mTNBC).

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