As Cullinan Therapeutics launches the first U.S. clinical trial of a CD19 bispecific in an autoimmune disease, CEO Nadim Ahmed wants to shape expectations around efficacy.\n Breakthrough research and investor enthusiasm prompted Cullinan Therapeutics to redirect one of its cancer programs toward autoimmune diseases in 2024. Now, CEO Nadim Ahmed wants to reset expectations, hoping that speed and a “thriller or killer” approach will be his friends as the company navigates both competitive fields in parallel.Cullinan’s stock price surged last April after the company unveiled plans to switch the focus of its CD19xCD3 T-cell engager, CLN-978, from blood cancer to lupus and other autoimmune diseases.The pivot was inspired by a 2022 paper describing using anti-CD19 CAR-T therapy in patients with refractory systemic lupus erythematosus (SLE). The results were so impressive that when Ahmed floated the idea of taking CLN-978 into autoimmune diseases with analysts and investors at the 2024 J.P. Morgan Healthcare Conference, he received overwhelmingly positive feedback.Having previously held hematology leadership roles at Celgene and then Bristol Myers Squibb, Ahmed knew how transformative CAR-T therapies can be, but he also understood that the risk-benefit equation is different in autoimmune diseases. “It felt to me that if you have an off-the-shelf regimen that can be potent, with less of the logistics, the manufacturing, potentially better safety profile—because of the risk of secondary cancers—all of those things, that this could really be a very strong idea,” Ahmed recalled.Within a few weeks, Cullinan Oncology became Cullinan Therapeutics, even though a big chunk of the company’s pipeline—including its lead program, which just read out in a phase 2 study for non-small cell lung cancer—remains in oncology. Since then, the company has built an immunology unit, hired in-house rheumatologists to run clinical development on that side, and in October, won FDA clearance to evaluate CLN-978 in humans with moderate to severe SLE. Resetting expectations At this year’s JPM, Ahmed wanted to set the tone for the new Cullinan. The company aims to provide initial SLE data in the fourth quarter “on a meaningful number of patients that can be interpretable,” Ahmed told Fierce on the sidelines of the conference this January.But Cullinan is only one of many that are swept up by this seismic shift in the autoimmune cell therapy world. And investor enthusiasm in Cullinan was not as high as it was a year ago, as the company’s stock price has fallen below its pre-pivot level.Part of the stock fluctuations can be attributed to the macroenvironment, Ahmed said. And another part reflects what he called a disconnect between investor expectations and clinicians’ real-world desire for adoption, a gap that Ahmed is trying to close.To Ahmed, some investors have unfairly upheld CLN-978, an off-the-shelf bispecific, to the same efficacy standard as an autologous CAR-T. Early results from Kyverna Therapeutics’ CAR-T candidate, KYV-101, showed that the one-time therapy could eliminate disease activity, including the need for immunosuppressants and steroids in all patients when given at the desired dose to refractory lupus patients. Although Kyverna investor enthusiasm dropped after a patient receiving a lower dose relapsed, that 100% disease control rate has become a benchmark for all T-cell therapies that want a spot in lupus. However, after speaking with rheumatologists, Ahmed found the bar is “very different” for an off-the-shelf regimen.“What they tell us is, if today, my patients are not getting into a DORIS remission—at least not with taking them off background therapy as well—if you can get me a minimum of 20% to 30% of my patients, with a safety profile that’s no greater than grade 1 or 2 [cytokine release syndrome], you’re going to get very widespread systematic adoption of this therapy,” Ahmed said.“That doesn’t mean we’re not going to aspire for the highest,” he added. “Of course we are.” An increasingly crowded field If Cullinan investors got excited about a burgeoning opportunity at the beginning of 2024, then they have good reason to be less enthused this year. In the short amount of time, the autoimmune cell therapy field became inundated by players. For CAR-T therapies alone, an article published in October in the journal Bone Marrow Transplantation counted 17 trials globally in autoimmune diseases, including 11 in SLE or lupus nephritis.And that doesn’t even count the many more T-cell engagers like CLN-978 that are itching to have a go at lupus. In October, Benlysta-maker GSK put down $300 million upfront to test Chimagen Biosciences’ CD19/CD20 dual-targeted T-cell engager in lupus and potentially other B-cell-driven autoimmune disorders. New startups such as Candid Therapeutics and Ouro Medicines have recently launched with mega financing rounds with the same goal of developing T-cell engagers for autoimmune diseases.More companies such as Takeda, Nkarta, Sana Biotechnology and IGM Biosciences are also shifting the focus of their oncology CAR or T-cell engager programs to autoimmune diseases.With lupus taking up most of the industry’s interest, Kyverna has instead designated stiff person syndrome, a rare autoimmune neurological disorder, as its CAR-T’s lead indication. But Ahmed argued that the reasons for picking SLE as CLN-978’s initial indication still hold true.“There was a benchmark that, in a way, we kind of had to go to,” Ahmed said, referencing Kyverna’s initial clinical lupus data. Ahmed argued that CAR-T therapies, because of their complicated manufacturing and delivery processes, will likely be limited to a “more narrowly defined patient population” in lupus, whereas bispecifics “could be a solution for the large masses of patients.”Within the T-cell engager class, Ahmed suggested that CLN-978’s high binding affinity for CD19 might differentiate it from competitors.“As you start getting into the short-lived plasma cells, you start to see dimming a little bit of the CD19 expression,” the Cullinan CEO explained. “So, having very high affinity is going to be really important to kind of continue to give that breadth of coverage across the B cell compartment.”Because CLN-978’s binding affinity for CD3 on T cells is in a different range from that for CD19 on disease-causing B cells, it may afford Cullinan a wide window to optimize efficacy while limiting potential immune side effects, Ahmed continued. In addition, CLN-978’s relatively small weight compared with other IgG-based molecules might facilitate better tissue penetration for B cell depletion, he added.These mechanistic theories still need clinical validation, Ahmed acknowledged. The autoimmune cell therapy field remains very young and requires a deeper understanding of the biology. Researchers and drug developers still don’t have clear answers to many key questions, such as the depth of B cell depletion needed to achieve a remission, the duration of response and the possibility of retreatment.Last year, a study published in The New England Journal of Medicine described a case of aggressive refractory SLE that achieved a drug-free complete remission after receiving Johnson & Johnson’s BCMAxCD3 bispecific Tecvayli. The findings add to the unknowns because the B cell subtypes covered by anti-BCMA and anti-CD19 therapies are different. Ahmed noted that BCMA bispecifics have shown a higher risk of infection in its currently FDA-approved multiple myeloma indication, so “you have to go into it eyes wide open.”The Cullinan helmsman didn’t directly answer whether the biotech will work on a BCMA candidate to complement CLN-978, but said “we’re thinking about continued opportunities in the autoimmune disease space.”CLN-978 has one more advantage—it\'s the first and so far the only CD19 T-cell engager cleared to enter a lupus clinical trial in the U.S. Cullinan is also plotting a rheumatoid arthritis study for the asset in the second quarter. ‘Let’s generate data as quickly as possible’ Meanwhile, Cullinan\'s four other clinical programs are all in oncology. The biotech and its partner Taiho are preparing to pursue accelerated approval in lung cancer for their EGFR exon20 inhibitor zipalertinib later this year after the program met its primary endpoint of overall response rate in a pivotal phase 2b in January. If the drug is approved, Cullinan is on tap for 50-50 profit sharing and has a co-commercialization option which Ahmed said could be cost-efficient if the company’s pipeline continues to advance.The company also has an anti-MICA/B antibody, called CLN-619, that’s in phase 1 testing in both multiple myeloma and solid tumors.Hematology, solid tumors and autoimmune disease, plus a “modality-agonist” approach—that looks like quite a lot for a biotech that’s less than 10 years old. “At the beginning, you have to start off with multiple molecules, because you don’t know which one’s going to make it,” Ahmed said.“The way we approach this is, let’s generate data as quickly as possible,” he continued. “If we generate clinical data as quickly as possible, that’s going to drive value, and that gives us optionality.”Ahmed is pairing fast data generation with a “thriller or killer experimentation approach.” That means maintaining a very high bar for moving assets forward and nixing program quickly if it fails to meet the bar. Cullinan recently returned a B7H4x4-1BB bispecific candidate to Harbour BioMed after seeing phase 1 data. The termination was due to the lack of clear single-agent activity of the molecule rather than freeing up resources for CLN-978, Ahmed explained.As to whether the firm will raise the bar further to give CLN-978 more oxygen, Ahmed pointed to the $280 million oversubscribed private placement it announced alongside the autoimmune pivot in 2024, noting that the $640 million in cash the company had as of the end of September was enough to support operations into 2028.“Now, can you do 20 randomized phase 3 studies? That’s very different,” Ahmed said. “But I don’t have to worry about that right now. We got to generate the data that’s going to drive value first.”
