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Re­searchers in biotech, acad­e­mia and Big Phar­ma are of­fer­ing puz­zle pieces to crack CAR-T for sol­id tu­mors. Will they ever snap to­geth­er?

The idea seemed promising enough.

By the time a group of scientists reported an attempt to treat colon cancer with engineered T cells drawn from patients, expanded and armed with artificial surface proteins in 2010, the experimental therapy — known as CAR-T, short for chimeric antigen receptor transduced T cells — had turned from an eccentric therapeutic proposal to a somewhat viable approach being tested in the clinic. The target, HER2, was one of the most extensively studied targets in cancer, implicated in cancers of breast, bladder, ovary, pancreas, and more. A “next-generation” construct containing a fragment of a well-known antibody, deployed alongside additional tried and true tweaks, looked like a promising next step.

That’s not to mention the study was being conducted by Steve Rosenberg’s lab — the famed National Cancer Institute group that had produced some of the earliest data that convinced scientists of T cells’ ability to attack solid tumors.

Yet the trial took a shocking and tragic turn. Within 15 minutes of receiving the infusion, the first patient had serious trouble breathing. She was sent to the hospital, intubated, and died five days later.

“I think it shut every CAR-T cell therapy study down which targeted HER2 at the time,” recalled Stephen Gottschalk, who was working on a different HER2 program himself at Baylor College of Medicine. “We spent quite a lot of time with the FDA coming up with an approach that would allow us to do it safely.”

While CAR-Ts for hematological malignancies have largely sailed through those early safety scares — a group at Memorial Sloan Kettering had disclosed another death in a hematology trial that same year — and impressed the biopharma world with astonishing response rates, the same can’t be said about solid tumor efforts. Early clinical trials that didn’t turn up serious side effects also failed to demonstrate nearly the same level of efficacy seen in acute lymphoblastic leukemia and non-Hodgkin lymphoma.

Rather than giving up, both academic and industry researchers are doubling down, thanks in part to the big success in the hematologic space and the large market that awaits anyone who can finally unlock any kind of solid tumors with CAR-T.

The few skeptics haven’t stopped a torrent of venture dollars from propelling these efforts, most still preclinical, that promise to tear down the well-documented roadblocks now shielding many cancers from these potent killing cells. The question boils down to how you choose among them — and who will be the last ones standing.

Defining the challenge

Martin Pule remembers the early days when everything was harder in CAR-T.

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Un­pack­ing the Aduhelm de­ci­sion, Ver­tex's half full glass, a $525M J&J breakup, and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

By now you have surely read about the FDA’s controversial approval of Biogen’s Alzheimer’s drug and all its reverberations. But I’d still recommend checking out the meaty recap below to make sure you didn’t miss all the angles that the Endpoints team has covered. If you’d rather look ahead, look no further than our three-day virtual panels next week at BIO, where we will discuss what the new normal means for every part of the industry.

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What does a clear ma­jor­i­ty of the bio­phar­ma in­dus­try think of the FDA ap­proval of ad­u­canum­ab? 'Hor­ri­fy­ing' 'Dan­ger­ous' 'Con­fus­ing' 'Dis­as­ter'

Over the years, we’ve become used to seeing a consensus emerge early in our industry polls at Endpoints News. And when we took the pulse of drug hunters on the heels of a controversial FDA approval for aducanumab this week, it became immediately apparent that the vast majority of our readers — heavily concentrated among biopharma staffers and execs — were incensed by what they had just witnessed.

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Aaron Kesselheim (Scott Eisen/AP Images for AIDS Healthcare Foundation)

Har­vard’s Aaron Kessel­heim re­signs from ex­pert pan­el in wake of ad­u­canum­ab OK, blast­ing FDA for ‘worst drug ap­proval de­ci­sion in re­cent U.S. his­to­ry'

A third member of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee has resigned in the wake of Biogen’s controversial Aduhelm approval, slamming the agency as he left and further deepening the controversy surrounding the decision.

Harvard University professor Aaron Kesselheim quit in protest Thursday afternoon, calling the Aduhelm OK “probably the worst drug approval decision in recent U.S. history.” Kesselheim follows both Joel Perlmutter, a neurologist from Washington University in St. Louis, and David Knopman, a neurologist from the Mayo Clinic, out the door.

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David Knopman (Mayo Clinic via YouTube)

A sec­ond ad­comm mem­ber aban­dons his post in af­ter­math of con­tro­ver­sial ad­u­canum­ab de­ci­sion

As the fallout from the FDA’s approval of Alzheimer’s med aducanumab grows, a second member of the adcomm overseeing that drug’s review has walked away. But even with two experts now having resigned from that committee in protest, is there enough broad-level outrage to prevent another aducanumab from getting approved?

The FDA on Wednesday lost another member of its Peripheral and Central Nervous System Drugs Advisory Committee as Mayo Clinic neurologist David Knopman hit the exit over the agency’s decision to approve Biogen’s Alzheimer’s drug Aduhelm despite the committee’s near-unanimous vote against it.

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FDA plans new stud­ies on ac­cel­er­at­ed ap­proval dis­clo­sures in bio­phar­ma ads

When people read biopharma companies’ websites about new drugs approved via the FDA’s accelerated pathway, like Biogen’s new Alzheimer’s drug, do they understand that these drugs may only be reasonably likely to predict clinical benefit and still require confirmatory studies?

That’s what the FDA’s Office of Prescription Drug Promotion wants to firm up as an agency analysis of direct-to-consumer websites for accelerated approval drugs previously found that only 21% of the disclosures used language directly from the label.

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FDA au­tho­rizes about 10M J&J vac­cine dos­es, trash­es 60M more from trou­bled Emer­gent plant

The FDA on Friday released about 10 million doses of J&J’s vaccine for use, and disposed of another 60 million doses that were manufactured at the now-shuttered Emergent BioSolutions facility in Baltimore where cross-contamination occurred.

The agency said it’s not yet ready to allow the Emergent plant to be included in the J&J EUA, but that may occur soon. FDA came to the decision to authorize some of the doses after reviewing facility records and quality testing results.

Ver­tex and CRISPR Ther­a­peu­tics un­veil more pos­i­tive gene ther­a­py da­ta, but busul­fan again casts a shad­ow over the field

Less than 12 hours after revealing a flop on its second shot for alpha-1 antitrypsin deficiency, Vertex plowed ahead with another data drop from its partnership with CRISPR Therapeutics. And though the topline proved positive, concerns over conditioning agents continue to linger over the collaboration, as well as the entire gene therapy space.

Presenting data from two trials at the European Hematology Association annual meeting, the pair announced that follow-up data of at least three months for 22 patients with genetic blood disorders indicated a “consistent and sustained” response to the experimental drug CTX001. All 15 patients with transfusion-dependent beta thalassemia did not need further blood transfusions and all seven with severe sickle cell disease were pain free, the biotechs announced.

Janet Woodcock, acting FDA commissioner, at Thursday's Senate Appropriations hearing (Bill Clark/CQ Roll Call via AP Images)

Sen­a­tors lam­bast new Alzheimer’s drug’s price but give Janet Wood­cock a free pass on the ap­proval de­ci­sion

Senate Finance Democrats took aim at Biogen’s pricey new Alzheimer’s drug on Thursday, but members on both sides of the aisle at a separate appropriations hearing didn’t question acting FDA commissioner Janet Woodcock on the approval.

“I was appalled that Biogen priced their Alzheimer’s drug approved by the FDA at $56,000 per year — I’m not going to debate whether this is effective or not, but it’s double the household median income for Michiganders over the age of 65,” Sen. Debbie Stabenow (D-MI) said at the finance hearing.

Reshma Kewalramani, Vertex CEO (BIO via YouTube)

UP­DAT­ED: Ver­tex strikes out on its lat­est big shot at a rare ge­net­ic dis­ease. But they're go­ing to keep on swing­ing

It’s been several months since Vertex culled one of its small molecules for alpha-1 antitrypsin deficiency (AATD), taking a big hit after evidence of liver damage surfaced in a key Phase II trial. Now we learned that the company has whiffed on its second shot, and there’s nothing left in the clinic to treat the rare genetic disease — but that won’t stop it from trying.

Despite avoiding the safety issues that plagued the last candidate, Vertex $VRTX is taking the axe to VX-864 after Phase II results revealed the magnitude of the drug’s response is “unlikely to translate into substantial clinical benefit.” As a result of the news, the company’s stock fell 12.5% after hours.

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