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.

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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