Anil Kumar, Retrotope president

An ul­tra-rare dis­ease drug missed on func­tion but hit on sur­vival and mor­tal­i­ty. Is it enough for the FDA?

A Cal­i­for­nia com­pa­ny de­vel­op­ing a drug for an ul­tra-rare, uni­ver­sal­ly fa­tal neu­ro­log­i­cal dis­ease man­i­fest­ing in in­fan­cy re­port­ed Wednes­day that its ther­a­py missed the pri­ma­ry end­point in a Phase II/III study, but showed good enough sur­vival and mor­tal­i­ty da­ta to po­ten­tial­ly per­suade the FDA.

Retro­tope re­vealed its can­di­date for in­fan­tile neu­roax­on­al dy­s­tro­phy, or IN­AD, did not achieve sta­tis­ti­cal sig­nif­i­cance in a neu­ro­log­i­cal as­sess­ment, show­ing no dif­fer­ences be­tween pa­tients who re­ceived treat­ment and those in a nat­ur­al his­to­ry study. Re­searchers did, how­ev­er, see im­prove­ment in pro­gres­sion-free sur­vival and a de­crease in mor­tal­i­ty, both of which mus­tered sta­tis­ti­cal sig­nif­i­cance in sec­ondary end­points.

The bio­phar­ma’s da­ta come in the wake of Bio­gen’s con­tro­ver­sial ap­proval for its new Alzheimer’s drug, Aduhelm, and the po­ten­tial­ly chang­ing reg­u­la­to­ry land­scape in neu­ro­log­i­cal dis­eases. Bil­ly Dunn’s neu­ro crew showed a par­tic­u­lar le­nien­cy in shep­herd­ing the drug across the fin­ish line, ac­cord­ing to STAT News re­ports, and phar­ma com­pa­nies big and small are os­ten­si­bly tak­ing ad­van­tage.

No­tably, Eli Lil­ly is seek­ing an ac­cel­er­at­ed ap­proval for its ex­per­i­men­tal Alzheimer’s drug do­nanemab us­ing the same path­way af­ford­ed to Aduhelm. The Big Phar­ma al­so an­nounced plans for a makeover, build­ing a new neu­ro­science unit to al­lot more re­sources to­wards its Alzheimer’s ef­forts.

Roche is al­so en­gag­ing in dis­cus­sions with the FDA about its own Alzheimer’s pro­gram in gan­tenerum­ab, an ex­per­i­men­tal ther­a­py that failed to show ef­fi­ca­cy in three clin­i­cal tri­als.

Giv­en IN­AD’s clas­si­fi­ca­tion as ul­tra-rare and the lack of any avail­able treat­ment, the FDA asked Retro­tope to re­quest a feed­back meet­ing so the pair can chart a path for­ward, Retro­tope pres­i­dent Anil Ku­mar told End­points News.

“They asked us to re­quest that when they saw the sum­ma­ry da­ta,” Ku­mar said of the agency. “We’re go­ing to say, ‘Here’s the da­ta, it shows the best bio­mark­er in this dis­ease is sur­vival.’”

Retro­tope plans to in­clude the neu­ro­log­i­cal test as part of the da­ta pack­age, but the as­sess­ment, known as the Mod­i­fied Ash­worth Spas­tic­i­ty Scale, is like “try­ing to fit a square peg in­to a round hole,” Ku­mar added. The pres­i­dent said it shows a bet­ter cor­re­la­tion for pa­tients lat­er in their dis­ease while Retro­tope en­rolled chil­dren at all IN­AD stages.

IN­AD re­sults from the body’s in­abil­i­ty to clear buildups of tox­ic byprod­ucts of lipid per­ox­i­da­tion, a process that caus­es dam­age to cell mem­branes. The dis­ease can emerge in in­fants as young as six months when mus­cle tone de­vel­op­ment fal­ters, tri­al in­ves­ti­ga­tor Alex Fay told End­points, and from then on dis­ease mile­stones that had been gained are soon lost.

“Kids lose the abil­i­ty to sit up on their own, and so­cial in­ter­ac­tive­ness al­so starts to be af­fect­ed over time,” Fay said. “So while they may re­tain abil­i­ty to smile, they lose ex­pres­sive speech and lan­guage out­put.”

To con­duct its study, Retro­tope re­cruit­ed 19 pa­tients for ac­tive treat­ment and 36 for the nat­ur­al his­to­ry study, which ran con­cur­rent­ly. Chil­dren tak­ing the drug, dubbed RT001, were treat­ed for a min­i­mum of one year and up to two years, while the nat­ur­al his­to­ry group has on­ly been ob­served for a year, Ku­mar said.

On the pri­ma­ry end­point, RT001 in­duced an im­prove­ment of 6.42 points on the scale com­pared to the con­trol, miss­ing sta­tis­ti­cal sig­nif­i­cance with a p-val­ue of p=0.14. The scale mea­sures spas­tic­i­ty, or a spe­cif­ic type of mus­cle stiff­ness that de­vel­ops with in­juries to the brain and spinal cord, Fay said.

Mean­while, the pro­gres­sion-free sur­vival mark of an 82.5% im­prove­ment clinched a p-val­ue of p=0.021 and the de­creased mor­tal­i­ty risk came in at a 88.8% re­duc­tion, good for a p-val­ue of p=0.014. Be­cause of these fig­ures, Ku­mar said the drug al­so proved re­mark­ably safe, giv­ing what Retro­tope hopes is a ben­e­fit in dis­cus­sions with the FDA.

It’s not yet clear what kind of ap­proval Retro­tope will seek, with more in­for­ma­tion ex­pect­ed to come dur­ing the FDA feed­back meet­ing. Even though it would be “im­pos­si­ble” to do a place­bo-con­trolled tri­al in IN­AD be­cause it’s so rare, Ku­mar said the bio­phar­ma could uti­lize fol­low-up da­ta from the nat­ur­al his­to­ry study in place of a con­fir­ma­to­ry study.

Where­as the ac­tive tri­al has da­ta for up to two years, the nat­ur­al his­to­ry group is on­ly up to a year of ob­ser­va­tion. Ku­mar said he hopes the ex­tra da­ta could get the pro­gram to sta­tis­ti­cal sig­nif­i­cance and con­tin­ue to show sur­vival ben­e­fits.

De­spite the FDA’s flex­i­bil­i­ty in Alzheimer’s dis­ease, Retro­tope’s pitch could end up clos­er to that of ALS ad­vo­cates, who have ar­gued pa­tients are left with so few op­tions for treat­ment they have noth­ing to lose from try­ing ex­per­i­men­tal ther­a­pies. In that field, a pro­gram from Amy­lyx Phar­ma­ceu­ti­cals achieved sta­tis­ti­cal sig­nif­i­cance on func­tion, and the biotech will be sub­mit­ting for ap­proval in the US af­ter the FDA changed its mind on re­quir­ing an­oth­er study.

A new era of treat­ment: How bio­mark­ers are chang­ing the way we think about can­cer

AJ Patel was recovering from a complicated brain surgery when his oncologist burst into the hospital room yelling, “I’ve got some really great news for you!”

For two years, Patel had been going from doctor to doctor trying to diagnose his wheezing, only to be dealt the devastating news that he had stage IV lung cancer and only six months to live. And then they found the brain tumors.

“What are you talking about?” Patel asked. He had never seen an oncologist so happy.

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Michael Corbo, Pfizer CDO of inflammation & immunology

UP­DAT­ED: Plan­ning ahead for crowd­ed ul­cer­a­tive col­i­tis mar­ket, Pfiz­er spells out PhI­II da­ta on $6.7B Are­na drug

Pfizer has laid out the detailed results behind its boast that etrasimod — the S1P receptor modulator at the center of its $6.7 billion buyout of Arena Pharma — is the winner of the class, potentially leapfrogging an earlier entrant from Bristol Myers Squibb.

Pivotal data from the ELEVATE program in ulcerative colitis — which consists of two Phase III trials, one lasting 52 weeks and the other just 12 weeks — illustrate an “encouraging balance of efficacy and safety,” according to Michael Corbo, chief development officer of inflammation & immunology at Pfizer. The company is presenting the results as a late breaker at Digestive Disease Week.

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Mihael Polymeropoulos, Vanda Pharmaceuticals CEO

Phar­ma com­pa­ny con­tin­ues its FDA law­suit spree, this time af­ter agency de­nies fast-track des­ig­na­tion

Vanda Pharmaceuticals is making a name for itself, at least in terms of suing the FDA.

The DC-headquartered firm on Monday filed its latest suit against the agency, with the company raising concerns over the FDA’s failure to grant a fast track designation for Vanda’s potential chronic digestive disorder drug tradipitant, which is a neurokinin 1 receptor antagonist.

Specifically, Vanda said FDA’s “essential point” in its one-page denial letter on the designation pointed to “the lack of necessary safety data,” which was “inconsistent with the criteria for … Fast Track designation.”

An NYU surgeon transplants an engineered pig kidney into the outside of a brain-dead patient (Joe Carrotta/NYU Langone Health)

'Xeno­trans­plan­ta­tion is com­ing': New NE­JM pa­per gives de­tailed look in­to 2 pig-to-hu­man kid­ney trans­plant cas­es

The thymokidney is a curious organ, if you could call it that. It’s a sort of Frankensteinian creation — a system of pig thymus embedded underneath the outer layer of a pig’s kidney, made for human transplantation.

In the first case of pig-to-human xenotransplantation of a kidney into a brain-dead patient, the thymokidney quietly featured front and center.

In that experiment, which took place in September of last year, NYU researchers led by Robert Montgomery sutured a pig thymokidney onto the leg of a brain-dead 66-year-old woman. That case was widely reported on by a horde of major media outlets, including the New York Times, the BBC, and an in-depth feature by USA Today.

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Vlad Coric, Biohaven CEO

UP­DAT­ED: Fresh off $11.6B sale to Pfiz­er, New Bio­haven hits Phase III set­back just weeks af­ter Vlad Coric chalked up promise

When Pfizer bought up Biohaven’s migraine portfolio in the largest M&A deal of the year earlier this month, Biohaven CEO Vlad Coric promised the rest of the pipeline, which will live on under the umbrella of New Biohaven, still has a lot to offer. But that vision took a dent Monday as the drugmaker revealed it’s once again flopped on troriluzole.

The glutamate regulator failed to meet the primary endpoint on a Phase III study in patients with spinocerebellar ataxia, an inherited disorder that impairs a person’s ability to walk, speak and swallow. SCA can also lead to premature death.

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Mod­er­na seeks to dis­miss Al­ny­lam suit over Covid-19 vac­cine com­po­nent, claim­ing wrong venue

RNAi therapeutics juggernaut Alnylam Pharmaceuticals made a splash in March when it sued and sought money from both Pfizer and Moderna regarding their use of Alnylam’s biodegradable lipids, which Alnylam claims have been integral to the way both companies’ mRNA-based Covid-19 vaccines work.

But now, Moderna lawyers are firing back, telling the same Delaware district court that Alnylam’s claims can only proceed against the US government in the Court of Federal Claims because of the way the company’s contract is set up with the US government. The US has spent almost $10 billion on Moderna’s Covid-19 vaccine so far.

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Cracks in the fa­cade: Is phar­ma's pan­dem­ic ‘feel good fac­tor’ wan­ing?

The discordant effects of the Covid-19 pandemic on pharma reputation continues. While the overall industry still retains a respectable halo from its Covid-19 quick response and leadership, a new patient group study reveals a different story emerging in the details.

On one hand, US patient advocacy groups rated the industry higher-than-ever overall. More than two-thirds (67%) of groups gave the industry a thumbs up for 2021, a whopping 10 percentage point increase over the year before, according to the PatientView annual study, now in its 9th year.

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Saqib Islam, SpringWorks CEO

Pfiz­er spin­out Spring­Works will ship its first drug to the FDA be­fore year’s end with PhI­II win

SpringWorks Therapeutics thinks it has cemented the backbone for its first “pipeline-in-a-product” oncology treatment and will send it to the FDA before the clock strikes 2023 with a Phase III win on Tuesday.

The oral gamma secretase inhibitor, dubbed nirogacestat, beat placebo on the primary goal of progression-free survival in adults with progressing desmoid tumors.

The soft-tissue tumors can lead to long-lasting pain, disfigurement and amputation, and there are currently no approved meds for the rare oncology indication. The tumors typically impact patients aged 20 to 44 years old and disproportionately affect women at rates 2 to 3 times higher, with up to a total of 1,650 new cases diagnosed in the US annually, according to SpringWorks.

Robert Califf (Michael Brochstein/Sipa USA via AP Images)

House Re­pub­li­cans at­tack Chi­na-on­ly da­ta in FDA sub­mis­sions, seek new in­ves­ti­ga­tion in­to re­search in­spec­tions

Three Republican representatives are calling on the FDA to take a closer look at the applications including only clinical data from China.

The letter to FDA commissioner Rob Califf late last week comes as the agency recently rejected Eli Lilly’s anti-PD-1 antibody, which attempted to bring China-only data but ran into a bruising adcomm that may crush the hopes of any other companies looking to bring cheaper follow-ons based only on Chinese data.

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