This story is part 2 in a four-part series about cell therapy created by the Fierce Biotech team. Part 1 is available here, part 3 is here and the final installment is here. Gabrielle Masson, Helen Floersh, James Waldron and Max Bayer contributed reporting to this series.
It’s not often that a clinical trial of just five patients can spark a gold rush. That’s exactly what happened when a German lab released studies last year indicating that cell therapy could help patients with severe autoimmune diseases.
The data sent a shock wave through the biotech ecosystem, sending companies sling-shotting from oncology to autoimmune.
“The field has been quite struck, with good reason, with the preliminary data that we've now seen across a few different autoimmune disorders,” said Zachary Roberts, M.D., VP of R&D and chief medical officer at cell therapy biotech Allogene. “The healthiest interpretation of the field’s reaction to those early data is looking for an opportunity to meet unmet medical need.”
More on the data behind the autoimmune gold rush: How 'remarkable' results in lupus carried CAR-T to immunology
Sami Corwin, Ph.D., a research analyst at William Blair, said the human data showed that CAR-T therapy could produce an immune reset in patients with stubborn autoimmune diseases that weren’t reacting to common treatments. This opened up a whole new world of indications, particularly in lupus where there’s long been an unmet demand.
“We saw so many allogeneic players pivot over to autoimmune disease and it was kind of using what had been a disadvantage in the oncology space to their advantage,” Corwin said. “Because as of right now, it appears that you don't need long-term CAR-T persistence to induce this immunological reset.”
Moving between oncology and autoimmune is not a novel idea. Companies have been doing it for years.
Cindy Perettie, global head of Kite Pharma, a Gilead unit, points to attempts by Roche’s Genentech unit to bring Rituxan, which is approved for various blood cancers, into multiple sclerosis. Ultimately, it didn’t quite work, so the Genentech team got to work on what has now become the approved medicine Ocrevus. Both drugs target the protein CD20 and Rituxan has gone on to be approved in rheumatoid arthritis, pemphigus vulgaris and other autoimmune conditions.
Now, the lupus space is looking crowded, Corwin wrote in a May 9 note. But biotechs have a whole catalog of potential autoimmune indications that could be treatable by CAR-T, meaning a much larger market opportunity than the hematologic malignancy space, she added.
Allogene is retaining multiple assets in the field of oncology, as Roberts believes there is still potential and substantial unmet demand.
“What Allogene has done that's quite different from what some competitors of ours have done, is we've left at least one of our two feet, if not one and a half of our feet, firmly in the world of oncology,” he said. “The reason that we did that was very intentional. And that's because the work is still not done in oncology. There's still hundreds of thousands of people dying every year from malignancy.”
He continued: “And I think this pivot … away from oncology by some of these companies and fully into autoimmune, frankly, kind of abandons work that has not yet been completed.”
Poseida Therapeutics is also keeping an egg in the oncology basket, despite opening up an autoimmune offshoot to its pipeline. Caribou Biotherapeutics is doing both after getting clearance to start a phase 1 lupus trial for the anti-CD19 CAR-T cell therapy CCB-010.
mRNA cell therapy biotech Cartesian Therapeutics has always had its eyes on immunology, according to Chief Medical Officer Miloš Miljković, M.D. The biotech’s lead product is Descartes-08, an autologous BCMA-directed mRNA CAR-T, currently in phase 2b testing for myasthenia gravis and phase 2 for lupus. However, the therapy started in multiple myeloma to achieve proof-of-concept and safety.
“You have to start with what everybody is comfortable with the most,” Miljković said in an interview at the American Society of Gene & Cell Therapy in Baltimore earlier this month. Cartesian's goal has been to broaden the scope of CAR-T to an outpatient setting, compared to the current treatment regimen that requires patients to stay close to a treatment center for weeks. “As you gather the safety data you peel away the inpatient monitoring, you peel away lymphodepletion and you end up where we are now.”
So far, data has shown in both oncology and immunology that no lymphodepletion regimen is required and the therapy can be administered on an outpatient basis. There has been no cytokine release syndrome reported and no dose-limiting toxicities.
Analysts seem to think that Cartesian is on to something, with Mizuho predicting a $1 billion opportunity for Descartes-08 in myasthenia gravis and more than $1 billion in lupus, according to a May 24 note. That's before the CAR-T is considered for other autoimmune diseases that could come into play down the road. Mizuho said Cartesian's approach to CAR-T is safer as it does not involve DNA integration into the T-cell's genome like others. A readout for the myasthenia gravis trial is due mid-year.
Nkarta's NKX019, which was previously tested in non-Hodgkin lymphoma and has now moved into lupus, requires single-agent lymphodepletion of cyclophosphamide, a common chemotherapy agent that is used in the autoimmune disease already. Caribou's GALLOP trial is also using cyclophosphamide, plus fludarabine.
Big Pharma watches and waits
Kite Pharma is the global leader on the oncology side of cell therapy—“there’s no doubt about that”—said Perettie. But as biotechs have tipped into autoimmune, Kite has been comfortable watching from the sidelines.
“There's something great about being first. There's also something really good about watching and waiting. We're learning a lot,” Perettie said.
The Kite team has “three or four bets” in autoimmune, some early external programs and one in-house. Perettie also thinks that Kite may have some phase 1 assets in oncology that could translate into autoimmune.
Regeneron, which just bought out 2seventy bio’s cell therapy portfolio, has also been watching smaller companies hustle toward autoimmune. While Phil Gregory, head of Regeneron Cell Medicines, agrees the data that sparked the rush are exciting, his team wants to play the long game. Using a baseball analogy, he said: “You're going to try and convince people you will win the game because you just hit a home run really early.”
Regeneron has a huge legacy in immunology as one-half of the Dupixent dynasty with Sanofi, so a pivot into autoimmune seems right up its alley. Gregory acknowledged this, noting that 2seventy did bring over at least one early-stage autoimmune asset.
With that said, he added: “Regeneron’s strategy is to win the game. So you don't have to swing and miss early, you can play for the base hits, you can play for the doubles that create the knowledge, the learnings that are gonna get you to the best product ever."
That means Regeneron plans to spend a lot of time on early-stage research, working on early biology and genetics cell research to underpin the clinical strategy. This approach is something that a Big Pharma can pull off with ease, whereas a biotech has to pick a horse and go with it, convincing investors to hang on and support the work in the meantime.
No matter what, Cartesian has benefited from the renewed interest, Miljković said. But many of the new entrants are starting from scratch, whereas Cartesian already has that key lymphodepletion and safety data and two ongoing mid-stage trials.
“What’s interesting is that people are trying to get into the autoimmune space with drugs that are built for oncology. And the kind of tradeoffs you take when you build a drug to treat cancer is not the set of tradeoffs you take when you build a drug for most of the autoimmune space,” Miljković said.
While there may be a subset of autoimmune patients with very severe disease, that’s a minority, compared to cancer where patients with more aggressive disease eventually have to look for last-resort options. They are more willing to accept safety tradeoffs in that circumstance.
“For most of these patients, it's something they live with and they want the treatment to be worked around their daily lives. They can’t stop everything and go on a journey of months or years like many patients, unfortunately, still with cancer have to do,” Miljković said.
Corwin said in her May 9 note that Nkarta’s lupus offering NKX019 has previously shown a safety profile in oncology that would be attractive to patients with less severe autoimmune disease.
The experience in cancer has certainly built up a number of lessons learned for biotech. Miljković said safety is the key learning, knowing that the treatment is going to have the same profile as it did in cancer. If there was no cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome (ICANS) then the therapy could be a good candidate for autoimmune.
Cartesian’s early data suggests that not all patients are one and done, however the treatment is less intense than what a patient with cancer would undergo. Out of seven patients with myasthenia gravis in an open-label study who received Descartes-08, five still had deep responses at 12 months. One of the two remaining patients who lost their response was re-dosed and had another deep response, Miljković explained.
Most importantly, that data is familiar to regulators. Corwin said that companies with oncology data can easily take the safety package to the FDA to support a flip to autoimmune for clinical testing.
“Whether the product that was developed for the oncology setting is the right product to be brought into the autoimmune setting, I think is a different story though,” Corwin said in an interview.
Some programs may have used genetic edits focused specifically at cancer, which won’t translate well to autoimmune. But most of the time, Corwin has watched companies make the switch with their existing meds. Some are altering the dosing or changing up the lymphodepletion regimen.
So far, early data is suggesting that cell therapy dosing needs to be more variable in autoimmune, whereas in cancer, one dose is typically discovered and cleared for safety and then moves across the different types of hematological malignancies, Perettie said.
Ultimately, companies have to remember that autoimmune is not cancer, where patients at the end of the line of treatment are willing to accept some difficult side effects in exchange for a few extra months of life or improved quality of life. The goal with autoimmune is typically to return to normal life and live with the disease without flare-ups.
“The risk-benefit is different for a patient with autoimmune disease because the duration they're going to live with that disease is obviously very different to an end-stage cancer patient,” Gregory said.
If the treatment burden proves too much for everyday patients, Schmidt believes there will always be those with severe disease who are willing to give it a shot for relief.
“I think if you had a severe refractory autoimmune disease, you'd still reach for the best and biggest gun,” he said.
Editor's note: This story is part of a series on cell therapy. The fourth and final part will be published May 31.