Three deaths have forced Novartis to pause development of its CD19 CAR-T candidate in autoimmune diseases, just as Bristol Myers Squibb has halted a similar program due to immune-related adverse events, Fierce has learned.
The Swiss pharma has temporarily halted development of its autologous CD19 CAR-T therapy, rapcabtagene autoleucel (rap-cel; YTB323), for several autoimmune diseases in immunology and neuroscience, Novartis confirmed with Fierce on Monday.
The decision comes after the rap-cel program recorded three deaths from complications caused by serious immune effector cell-associated hemophagocytic syndrome (IEC-HS), according to Novartis.
IEC-HS is a severe systemic inflammatory side effect associated with immunotherapies like CAR-T cell therapy. The rogue immune response may be triggered when engineered T cells rapidly expand and activate inside the patient’s body.
Novartis confirmed the trials included phase 2 studies of rap-cel in systemic lupus erythematosus/lupus nephritis (CYTB323J12201), systemic sclerosis (CYTB323K12201), ANCA-associated vasculitis (CYTB323I12201) and idiopathic inflammatory myopathies (CYTB323L12201), as well as phase 1/2 studies evaluating safety, cellular kinetics and efficacy in rheumatoid arthritis and Sjogren’s disease, generalized myasthenia gravis, relapsing multiple sclerosis (MS), and non-active progressive MS (CYTB323M12101B, CYTB323O12101, CYTB323N12101 and CYTB323R12101, respectively). Screening, randomization and treatment administration across the studies have been put on hold, the spokesperson said.
“The temporary halt will allow for a more comprehensive review of the evolving clinical and safety data across the program, following three serious immune effector cell-associated hemophagocytic syndrome (IEC-HS) events,” Novartis told Fierce in an email. “Patient safety remains of [the] highest priority; patients who have been treated within the trials will continue to be monitored as per protocol.”
The company said the ongoing program in oncology, which is currently in phase 1/2 trial for chronic lymphocytic leukemia/small lymphocytic lymphoma, diffuse large B-cell lymphoma, adult acute lymphoblastic leukemia and high-risk large B-cell lymphoma, “is not affected by this halt.”
Rap-cel is an autologous CD19-targeted CAR-T aimed to reprogram patient’s own T cells to eliminate CD19-expressing B cells. This asset is manufactured using Novartis’ T-Charge platform, a rapid manufacturing platform that allows for fewer exhausted T cells and eliminates the need for extended culture time outside of the body, according to the website.
In a Monday note to clients, William Blair analysts also flagged that BMS paused enrollment in its autoimmune trials testing an autologous CD19-targeted CAR-T, zola-cel (BMS-986353). William Blair noted that in a follow-up, the company disclosed that the enrollment was paused due to “transient and reversible inflammatory events.”
“Out of an abundance of caution, we implemented a voluntary pause to review clinical data across our zola-cel program,” a BMS spokesperson told Fierce in an email. “We are focused on completing our evaluation and resuming enrollment as quickly as possible.”
Also targeting CD19, zola-cel acts through the same mechanism as BMS’ Breyanzi, an FDA -approved treatment for relapsed and refractory blood cancers.
Like rap-cel, zola-cel was also developed using a rapid manufacturing platform. BMS’ NEXT T platform is designed to encourage the growth of more uniform and potent T cells, which may prompt a deeper and more durable response in patients, according to its website.
Since both Novartis’ and BMS’ assets were developed using rapid manufacturing platforms, analysts from William Blair suggested “that rapid manufacturing could be driving increased cell expansion and the reported toxicities.”
The CD19 CAR-T development space is already quite saturated, as Cabaletta Bio, a Philadelphia-based biotech, is looking to submit its autologous candidate, resecabtagene autoleucel (rese-cel), for approval in the second half of next year to treat myositis, a condition characterized by inflammation of the muscles.Â
Back in April, Miltenyi Biomedicine showed that its asset, zorpocabtagene-autoleucel (zorpo-cel), drove three autoimmune diseases into remission in one patient.
Fate Therapeutics also recently reported improvements in patients with treatment-resistant systemic sclerosis who were dosed with its off-the-shelf candidate, FT819.
Editor's Note: The story was updated Aug. 31 at 10:10 p.m. ET to reflect that the three serious IEC-HS cases in Novartis' program were deaths.