In early June, Bristol Myers Squibb told regulators, researchers and patient advocacy groups that it had suspended a widely followed drug investigation due to potentially life-threatening side effects. It has taken the company three months to release this information to the general public.
Last month, Novartis also suspended research into a similar therapy. He did not confirm it until a Wall Street analyst noticed it while reviewing a database. It took a week for the company to reveal that three patients in the study had died.
Both Novartis and Bristol Myers are investigating their own innovative, faster-to-produce forms of CAR-T therapy for the treatment of autoimmune diseases, a promising new field of drug research that involves modifying a patient's own cells to attack disabling diseases such as lupus or rheumatoid arthritis.
In the Novartis trial, three people died from a rare complication in which the immune system overreacts. The suspension of Bristol Myers' zola-cel trial, announced this week, followed another complication called ICANS [immunoeffector cell-associated neurotoxicity syndrome], a form of brain inflammation. Both are known complications of CAR-T therapy, which is already marketed to treat some types of cancer.
"As part of routine safety monitoring, we have voluntarily suspended recruitment and treatment," a Bristol Myers spokesperson said in response to a query.
Pharmaceutical companies are not required to inform the public when an experimental treatment turns out to be dangerous. Federal regulations require companies to report cases like these to regulators very quickly, but there is no equivalent requirement to alert third parties, such as doctors, potential patients or investors, unless the company believes the information is relevant to its financial results. This gives pharmaceutical companies the freedom to decide when to communicate if they detect problems, even when there are hundreds of patients already enrolled in a study or about to decide whether to enroll.
"We suffer from a lack of information," said Sue Chrysogelos, who participated in a study of another pharmaceutical company's CAR-T therapy to treat her scleroderma.
Information about clinical trials can have great commercial value, so companies jealously protect it. However, when trials are suspended without this information being made public, patients may be forced to wait without being clear about the possible risks of participating.
“For patients who are waiting for this treatment, it is about finding the balance between continuing to wait in the hope of still being able to participate in the trial and considering whether it is worth taking the risk,” Chrysogelos said.
Novartis is studying its rap-cel treatment in eight clinical trials on autoimmune diseases, including multiple sclerosis and rheumatoid arthritis, a wide-ranging effort involving more than 500 patients. Bristol Myers' safety alert arose in a trial of zola-cel in patients with a type of lupus, but the company has suspended studies in other autoimmune diseases that cause inflammation and muscle weakness.
It took a Wall Street analyst to notice something strange in a database for the suspended investigation to come to light.
Sami Corwin, a biotechnology analyst at William Blair, was routinely monitoring clinical trials last week when she noticed that a number of studies evaluating therapies for autoimmune diseases had become unavailable. He started making some calls. A colleague noticed that Bristol Myers' rehearsals had also come to a standstill. At the end of the week his team had confirmed the suspension of trials at both companies.
Corwin published a research note that was picked up by a trade publication and, shortly after, Endpoints News reported on the deaths that occurred in the Novartis clinical trial.
Novartis had not told Corwin that the cases were fatal when she asked about suspending the trial, Corwin has said. "It was news to me."
The company has not responded to questions about whether the deaths reported in Novartis' studies occurred in a single clinical trial or in several. It is not clear whether the people died as a result of taking the drug or from underlying illnesses.
"The broader dissemination of information about incidents related to clinical trials is balanced with the need to preserve the integrity of ongoing trials," a Novartis spokesperson said, adding that the company was "analyzing all data to understand possible factors that have contributed to recent incidents."
A Bristol Myers spokesperson called these cases “transient and reversible” and said none had been fatal.
For decades, treating autoimmune diseases like lupus and rheumatoid arthritis has involved a lifetime of medications that suppress the immune system and wear down the body. CAR-T therapy has opened the possibility of a single treatment that restores the immune system for life.
In a preliminary Bristol Myers study involving just over 100 patients, more than 90% of patients with treatment-resistant autoimmune diseases went into remission without needing additional treatment, the company reported last year.
Those results supported their decision to move on to larger-scale trials that had been suspended.
Dr Anca Askanase, who is involved in the trial in which Bristol Myers detected the adverse effects, said she had received a letter from the company detailing the reasons for stopping the trial. He declined to provide further information, as he had signed a confidentiality agreement with the New Jersey-based pharmaceutical company.
"We're really looking forward to finding out more, because there's a lot of interest," said Askanase, chief of rheumatology at the Hospital for Special Surgery in New York. "Every piece of information is essential."
The lack of details has alarmed support and research groups that usually maintain regular contact with both companies.
Luke Evnin, president of the San Francisco-based Scleroderma Research Foundation, said he understood that potential legal and regulatory risks might make companies cautious about speaking out, but that he would "be surprised if they don't have to give an answer to everyone."
Doctors leading the trials are seeking their own answers, especially when it comes to what differentiates the suspended therapies from similar ones already widely used in oncology. In conventional CAR-T therapy, the patient's cells are grown in a laboratory for several weeks and then reinjected into the patient, a process that allows most of their growth to take place outside the body.
Novartis' manufacturing platform reduces that growth process to just one day, Oppenheimer analyst Kostas Biliouris said, by selecting genetically modified immune cells to multiply aggressively once inside the body, which could be what triggers a dangerous immune response.
Novartis did not respond to questions from The Wall Street Journal about the company's manufacturing platform.
Bristol Myers denies that her own therapy presents the same problems. The company has stated that it uses a different platform that takes about five days and is designed to allow the cells to stabilize before infusion.
