This story is part one in a four-part series about cell therapy created by the Fierce Biotech team. Gabrielle Masson, Helen Floersh, James Waldron and Max Bayer contributed reporting to this series. Part 2 is here, part 3 is here and the final installment is here.
Cell therapy has been slashed by a thousand cuts over the past few years, from the failure of autologous CAR-T to live up to expectations, to market challenges to manufacturing woes. And now, the focus has shifted to autoimmune conditions.
The biopharma industry is now facing a reckoning; Will the market ever fully accept these treatments?
“We've lost our luster in cell therapies,” said Eric Schmidt, Ph.D., biotech analyst for Cantor Fitzgerald, in an interview. “It's honestly been a pretty depressing last 12 months or so.”
Sami Corwin, Ph.D., a research analyst at William Blair, calls this moment in time for cell therapy “a pivot.”
Big Pharmas like Sanofi and Bristol Myers Squibb have begun streamlining work in the earlier cell therapy space, confronted with manufacturing challenges and the reality of marketing a personalized therapy. BMS shut down a California research center that was focused on the tumor microenvironment in April as part of a major restructuring.
“The changes in our Cell Therapy Organization will streamline and focus efforts on the most promising areas, enabling us to maximize our inline assets, while building the foundation necessary to deliver on our best-in-class pipeline,” a spokesperson for BMS said at the time. The company markets the cell therapy Breyanzi in certain types of lymphoma and leukemia, and Abecma for multiple myeloma.
Days later, BMS signed a $65 million upfront deal with Repertoire to work on tolerizing vaccines for autoimmune diseases, underscoring the pharma's interest in autoimmune.
Also undergoing a pipeline reorganization, Sanofi shuttered legacy business Kiadis, which had been working on developing next-gen, ‘off-the-shelf,’ natural killer cell therapies.
All of this has led to a muddled present, in which biotechs are walking away from oncology with uncertain partnership opportunities for the near future.
“I guess in part, you can blame capacity and in part you can probably blame the complexity of the therapy. Or maybe you blame the competition as well,” Schmidt said.
Even as cell therapies have put out strong data in oncology, the modality has been overshadowed by bispecifics, which have grown quickly in cancer care and surpassed sales for approved cell therapies in the myeloma space, specifically.
“From a commercial standpoint, the autologous products … just haven't really knocked the cover off the ball the way that people might have been hopeful, given how strong the clinical data were,” Schmidt said, speaking specifically to CD19 cell therapies, which include Gilead’s Tecartus, Yescarta and Kymriah and BMS’s Breyanzi.
Gilead has achieved the greatest success with Yescarta, which generated $380 million in net sales for the first quarter. Schmidt calls this the one “shining, positive example” in the field of approved therapies. The remaining approved cell therapies are all at or below $157 million.
But these products have not lived up to the hype elsewhere. “And that’s a real problem,” Schmidt said. “I don't know why. And I’m kind of hard-pressed to think it's just about supply and complexity and delivery.”
Companies have also made slow progress in moving cell therapies into solid tumors, although some progress has been made including the approval of Iovance Biotherapeutics' Amtagvi in melanoma. Mustang Bio and City of Hope also recently showed in an early-stage trial that CAR-T therapy may have a future in the difficult brain cancer glioblastoma.
For Allogene’s Zachary Roberts, M.D., Ph.D., the problems that have dogged cell therapy are simply because the tech wasn’t quite ready when all of these treatments rushed into the clinic.
“I'm fond of saying that autologous products probably would not have been the first cell therapies approved, had we had the advanced gene editing tools that we have today,” said Roberts, EVP of R&D and chief medical officer. “So autologous products, as transformational as they have been, I believe, are essentially a stepping stone to the more cutting-edge allogeneic products like ours, and I'm excited by the in vivo CAR field, although they're still years away, and watching those data develop.”
Cindy Perettie, global head of Gilead’s Kite Pharma unit, said that preclinical data does not translate as well into humans, so there is a huge amount of risk moving things into the clinic.
“Having that phase one bake-off or horse race is really critical in these,” she said.
Nevertheless, biotechs remain committed to cell therapy. Companies in the space are now going to have to find a way to justify the continued push and bring investors back around.
“We have no idea as an investment community where the bar will be drawn,” Schmidt said. “As you go forward over the next 12 months, there will be a ton of cards to turn over, a ton of learnings.”
Finding the spotlight
The definition of cell therapy is vast and each specific technology has its challenges. Gene-edited cell therapies, for instance, are about to get a huge market test with the recent approval of sickle cell treatments Casgevy (Vertex Pharma and CRISPR Therapeutics) and Lyfgenia (bluebird bio). Both had huge price tags slapped on them and will need to confront the realities of a payer environment that might not be ready for them. That’s another story, however.
Other types of cell therapy include CAR natural killer (NK) cells or T cell receptor (TCR) modified T cells. According to Schmidt, the biotechs working on NK cells have all “pretty much given up,” turning as well to autoimmune and “hoping that the bar is lower.”
“Everyone who's got a platform has repositioned itself to autoimmune disease, more on hope than on any data,” he said.
It’s CAR-T cell therapy that has made the greatest splash in the clinic, only to be sucked back out to sea with reports of relapse among patients.
One of the first major corrections in CAR-T, which is sometimes referred to as cell-based gene therapy, was when autologous candidates were swapped out for so-called “off the shelf” allogeneic therapies that used donated cells rather than a patient’s own. This was said to ease the manufacturing and patient burden and speed turnaround time.
Many first-gen allogenic biotechs emerged around 2018 with great promise, only to stutter, according to Corwin and Schmidt.
“Outside the autologous products there’s been nothing to cheer about from a clinical standpoint,” Schmidt said. “The allogeneic therapies have, for the most part, taken a step backward.”
Allogene stopped two trials of a CAR-T candidate in advanced lymphoma to focus on minimal residual disease in January. The move will slide cemacabtagene ansegedleucel (cema-cel) to the seventh slot in frontline treatment after six cycles of chemotherapy, where a potential market could exist as doctors tend to simply watch for the 30% of patients who relapse.
Caribou Biosciences, after being dogged by relapses among patients, repositioned itself with a partially matched allogeneic product—not the same as an off-the-shelf option, according to Schmidt. He said the company, which was co-founded by Nobel laureate Jennifer Doudna, Ph.D., is “on thin ice.”
While the bulk of Caribou's pipeline remains focused on cancer, the company was just approved to test CB-010 in autoimmune, too. The trial will cover two types of lupus, lupus nephritis and extra renal lupus.
"We're very encouraged by the initial safety and efficacy data that we've seen with CB-010 in oncology and that really motivated us to choose to also invest in developing it in parallel in lupus," Caribou CEO Rachel Haurwitz told investors at the BofA Securities 2024 Healthcare Conference earlier this month. The chief executive remains confident in the oncology side of CB-010's development program as well, with the company poised to unveil data at the upcoming American Society of Clinical Oncology meeting this week.
Not ready to give up on its CAR NK technology, Nkarta was cleared by the FDA last fall to test a candidate called NKX019 in lupus, a move that investors cheered. The allogeneic, CD19-directed CAR NK cell therapy was already in clinical testing for B-cell malignancies. Data from the oncology trial revealed in March showed sharply falling response rates, compared to an earlier cohort.
Even CRISPR Tx, which is one of few companies to have a cell therapy approved with the Vertex-partnered Casgevy, pivoted its pipeline in December 2023 toward autoimmune.
Some companies are continuing to try and prove autologous therapies can thrive, bolstered by the regulatory approvals that have come.
BioNTech has been working on its manufacturing process to prepare the CAR-T BNT211 for pivotal trials. The German biotech signed a $250 million upfront deal with Autolus Therapeutics in February to use the company’s manufacturing technology. In return, BioNTech is supporting Autolus’ autologous CD19 CAR-T called obe-cel, which is currently awaiting an FDA decision for B-cell acute lymphoblastic leukemia.
“I am a huge believer in cell therapy. And I think that we are still very much in the first chapter ... And I think what we're doing right now as a field is looking for ways to accelerate and simplify what we have to do with cell therapy to bring approvals in quicker and in interesting ways,” Allogene’s Roberts said.
But now, thanks to some key studies out of Germany, the science on cell therapy has improved and the ability to address larger markets could be within reach. Corwin believes companies that are onto next-gen allogenic may “come back into the spotlight now.”
Editor's note: This story is part of a series on cell therapy. The second part will be published May 30. This story was updated May 29 at 3:23 p.m. ET, to include comments from Caribou CEO Rachel Haurwitz. this story was updated at 9:47 a.m. ET on May 30 to clarify that Allogene's treatment is being tested as the seventh step in front-line chemotherapy.