Eli Lil­ly con­ducts an au­top­sy of an Alzheimer’s megaflop

For four years Eli Lil­ly $LLY com­mit­ted one of the biggest clin­i­cal ef­forts in the com­pa­ny’s his­to­ry to prov­ing that it could get solanezum­ab right on Alzheimer’s. Hav­ing nav­i­gat­ed through mul­ti­ple tri­al fail­ures al­ready, in­ves­ti­ga­tors were con­vinced that if they took what they had learned, changed the pa­tient pop­u­la­tion, stick­ing to on­ly pa­tients with a mild form of the dis­ease while us­ing bet­ter di­ag­nos­tics — even chang­ing the end­points in the lead up to the fi­nal read out — they could make a case that this drug could make a sig­nif­i­cant im­prove­ment for pa­tients.

In­stead, they came up with a set of mod­est fig­ures in­di­cat­ing that at best they had mere­ly tapped the brakes on the dis­ease. And to­day they spelled it all out in what will like­ly be the post mortem on what once fac­tored in as one of the biggest clin­i­cal gam­bles in the his­to­ry of bio­phar­ma.

Solanezum­ab was de­signed to flush amy­loid be­ta, a tox­ic pro­tein which of­ten clus­ters in the brains of Alzheimer’s vic­tims. The in­ves­ti­ga­tors of­fered some mixed mes­sages on just how ef­fec­tive so­la was in re­duc­ing a-be­ta de­posits. In­ves­ti­ga­tor tracked sig­nif­i­cant changes in plas­ma lev­els of the pro­tein, but check­ing amy­loid de­posits with PET imag­ing pro­duced no sig­nif­i­cant changes. Re­searchers in oth­er pro­grams will be fol­low­ing that close­ly as they make their own as­saults on amy­loid, which re­mains a key fo­cus. There is a grow­ing con­sen­sus in the field, though, that it will take com­bi­na­tion ther­a­pies to have a re­al im­pact on the mem­o­ry-wast­ing dis­ease that af­flicts mil­lions.

Look­ing for a dom­i­nant new block­buster, they had to set­tle for en­cour­ag­ing pa­tients to hope for some­thing bet­ter.

Lawrence S. Honig, MD, PhD, Co­lum­bia

“Alzheimer’s is a chal­leng­ing dis­ease that re­searchers have been com­mit­ted to study­ing for some years,” said Lawrence S. Honig, MD, PhD, pro­fes­sor of neu­rol­o­gy at Co­lum­bia Uni­ver­si­ty Med­ical Cen­ter and prin­ci­pal in­ves­ti­ga­tor of the EX­PE­DI­TION3 study, pre­sent­ed the da­ta at the meet­ing. “Now is not the time to give up. While the out­come of this study is not what we had hoped for, it is rea­son­able to be­lieve that dis­ease mod­i­fy­ing ther­a­pies to slow down the pro­gres­sion of Alzheimer’s dis­ease will be dis­cov­ered.”

The key fail­ure point was on ADAS-Cog14, which mea­sures a per­son’s cog­ni­tive func­tions, in­clud­ing mem­o­ry, at­ten­tion and lan­guage abil­i­ties. In­ves­ti­ga­tors tracked an 11% re­duc­tion in the rate of de­cline, a clear miss with a p-val­ue of .095.

The sec­ondary end­points weren’t that much dif­fer­ent.

  • There was the Mi­ni-Men­tal State Ex­am­i­na­tion, or MMSE, with a 13% slow­ing in cog­ni­tive de­cline.
  • The Clin­i­cal De­men­tia Rat­ing-Sum of Box­es (CDR-SB) scale showed a 15 per­cent slow­ing in de­cline (p=0.004) be­tween pa­tients treat­ed with solanezum­ab and pa­tients treat­ed with place­bo.
  • There was a 14 per­cent slow­ing of de­cline (p=.019) as mea­sured by the Alzheimer’s Dis­ease Co­op­er­a­tive Study- In­stru­men­tal Ac­tiv­i­ties of Dai­ly Liv­ing (AD­CS-iADL). The AD­CS-iADL scale mea­sures a per­son’s in­de­pen­dent per­for­mance in com­plex ac­tiv­i­ties of dai­ly liv­ing such as par­tic­i­pat­ing in a con­ver­sa­tion, prepar­ing a meal or shop­ping.
  • The Func­tion­al Ac­tiv­i­ties Ques­tion­naire did not show a sta­tis­ti­cal­ly sig­nif­i­cant dif­fer­ence be­tween pa­tients treat­ed with solanezum­ab and pa­tients treat­ed with place­bo (7 per­cent re­duc­tion in de­cline, p=0.140). The FAQ scale is a dif­fer­ent in­for­mant-based mea­sure of func­tion­al abil­i­ties. In­for­mants pro­vide per­for­mance rat­ings of the pa­tient on ten com­plex high­er-or­der ac­tiv­i­ties.

There was, though, a greater chance that the drug arm would suf­fer from spinal os­teoarthri­tis: 1.1 per­cent in the solanezum­ab group, 0.4 per­cent in the place­bo group. And there was a 0.9 per­cent rate of dy­suria in the solanezum­ab group.

In the mean­time, you can rack up an­oth­er set­back in a field that has known on­ly late-stage fail­ure in the past decade.

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 clinicaltrials.gov 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.