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.

Biotech Half­time Re­port: Af­ter a bumpy year, is biotech ready to re­bound?

The biotech sector has come down firmly from the highs of February as negative sentiment takes hold. The sector had a major boost of optimism from the success of the COVID-19 vaccines, making investors keenly aware of the potential of biopharma R&D engines. But from early this year, clinical trial, regulatory and access setbacks have reminded investors of the sector’s inherent risks.

RBC Capital Markets recently surveyed investors to take the temperature of the market, a mix of specialists/generalists and long-only/ long-short investment strategies. Heading into the second half of the year, investors mostly see the sector as undervalued (49%), a large change from the first half of the year when only 20% rated it as undervalued. Around 41% of investors now believe that biotech will underperform the S&P500 in the second half of 2021. Despite that view, 54% plan to maintain their position in the market and 41% still plan to increase their holdings.

How to col­lect and sub­mit RWD to win ap­proval for a new drug in­di­ca­tion: FDA spells it out in a long-await­ed guid­ance

Real-world data is messy. There can be differences in the standards used to collect different types of data, differences in terminologies and curation strategies, and even in the way data is exchanged.

While acknowledging this somewhat controlled chaos, the FDA is now explaining how biopharma companies can submit study data derived from real-world data (RWD) sources in applicable regulatory submissions, including new drug indications.

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David Lockhart, ReCode Therapeutics CEO

Pfiz­er throws its weight be­hind LNP play­er eye­ing mR­NA treat­ments for CF, PCD

David Lockhart did not see the meteoric rise of messenger RNA and lipid nanoparticles coming.

Thanks to the worldwide fight against Covid-19, mRNA — the genetic code that can be engineered to turn the body into a mini protein factory — and LNPs, those tiny bubbles of fat carrying those instructions, have found their way into hundreds of millions of people. Within the biotech world, pioneers like Alnylam and Intellia have demonstrated just how versatile LNPs can be as a delivery vehicle for anything from siRNA to CRISPR/Cas9.

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No­vo CEO Lars Fruer­gaard Jør­gensen on R&D risk, the deal strat­e­gy and tar­gets for gen­der di­ver­si­ty


I kicked off our European R&D summit last week with a conversation involving Novo Nordisk CEO Lars Fruergaard Jørgensen. Novo is aiming to launch a new era of obesity management with a new approval for semaglutide. And Jørgensen had a lot to say about what comes next in R&D, how they manage risk and gender diversity targets at the trendsetting European pharma giant.

John Carroll: I’m here with Lars Jørgensen, the CEO of Novo Nordisk. Lars, it’s been a really interesting year so far with Novo Nordisk, right? You’ve projected a new era of growing sales. You’ve been able to expand on the GLP-1 franchise that was already well established in diabetes now going into obesity. And I think a tremendous number of people are really interested in how that’s working out. You have forecast a growing amount of sales. We don’t know specifically how that might play out. I know a lot of the analysts have different ideas, how those numbers might play out, but that we are in fact embarking on a new era for Novo Nordisk in terms of what the company’s capable of doing and what it’s able to do and what it wants to do. And I wanted to start off by asking you about obesity in particular. Semaglutide has been approved in the United States for obesity. It’s an area of R&D that’s been very troubled for decades. There have been weight loss drugs that have come along. They’ve attracted a lot of attention, but they haven’t actually ever gained traction in the market. My first question is what’s different this time about obesity? What is different about this drug and why do you expect it to work now whereas previous drugs haven’t?

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Pascal Soriot, AstraZeneca CEO (via Getty images)

UP­DAT­ED: FDA slaps As­traZeneca's MCL-1 can­cer drug with a hold af­ter safe­ty is­sue — 2 years af­ter Am­gen axed a trou­bled ri­val

There are new questions being posed about a class of cancer drugs in the wake of the second FDA-enforced clinical hold in the field.

Two years after the FDA hit Amgen with a clinical hold on its MCL-1 inhibitor AMG 397 following signs of cardiac toxicity, AstraZeneca says that regulators hit them with a hold on their rival therapy of the same class.

The pharma giant noted on that its Phase I/II study for the MCL-1 drug AZD5991 “has been put on hold to allow further evaluation of safety related information.”

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Sur­geons suc­cess­ful­ly at­tach pig kid­ney to a hu­man for the first time, us­ing tech from Unit­ed's Re­vivi­cor

In a first, researchers reportedly successfully transplanted a pig kidney into a human without triggering an immediate immune response this week. And the technology came from the biotech United Therapeutics.

Surgeons spent three days attaching the kidney to the patient’s blood vessels, but when all was said and done, the kidney appeared to be functioning normally in early testing, Reuters and the New York Times were among those to report. The kidney came from a genetically altered pig developed through United’s Revivicor unit.

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Leen Kawas (L) has resigned as CEO of Athira and will be replaced by COO Mark Litton

Ex­clu­sive: Athi­ra CEO Leen Kawas re­signs af­ter in­ves­ti­ga­tion finds she ma­nip­u­lat­ed da­ta

Leen Kawas, CEO and founder of the Alzheimer’s upstart Athira Pharma, has resigned after an internal investigation found she altered images in her doctoral thesis and four other papers that were foundational to establishing the company.

Mark Litton, the company’s COO since June 2019 and a longtime biotech executive, has been named full-time CEO. Kawas, meanwhile, will no longer have ties to the company except for owning a few hundred thousand shares.

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Sen. Richard Durbin (D-IL, foreground) and Sen. Richard Blumenthal (D-CT) (Patrick Semansky/AP Images)

Sen­a­tors back FDA's plan to re­quire manda­to­ry pre­scriber ed­u­ca­tion for opi­oids

Three Senate Democrats are backing an FDA plan to require mandatory prescriber education for opioids as overdose deaths have risen sharply over the past decade, with almost 97,000 American opioid-related overdose deaths in the past year alone.

While acknowledging a decline in overall opioid analgesic dispensing in recent years, the FDA said it’s reconsidering the need for mandatory prescriber training through a REMS given the current situation with overdoses, and is seeking input on the aspects of the opioid crisis that mandatory training could potentially mitigate.

Bris­tol My­ers pledges to sell its Ac­celeron shares as ac­tivist in­vestors cir­cle Mer­ck­'s $11.5B buy­out — re­port

Just as Avoro Capital’s campaign to derail Merck’s proposed $11.5 billion buyout of Acceleron gains steam, Bristol Myers Squibb is leaning in with some hefty counterweight.

The pharma giant is planning to tender its Acceleron shares, Bloomberg reported, which add up to a sizable 11.5% stake. Based on the offer price, the sale would net Bristol Myers around $1.3 billion.

To complete its deal, Merck needs a majority of shareholders to agree to sell their shares.