SAN DIEGO — Legend Biotech was a barely known Chinese drugmaker until last summer, when it shot to stardom on early data that showed its CAR-T therapy was achieving a perfect overall response rate and few cases of serious side effects in a small group of multiple myeloma patients. The outcomes were impressive — and for some, too much so.
Critics, including one prominent shortseller of Legend's parent company, grew concerned the results were much like the biotech's name: awe-inspiring yet unrealistic. Craig Hofmeister, an acting associate professor at the Emory University School of Medicine, described them as "outlandish," telling BioPharma Dive "it's unheard of to have everyone respond without a side effect."
According to Hofmeister, the expectation was that Legend's data would become more grounded as it matured. That proved to be the case Monday at the American Society of Hematology's annual meeting, where Legend and big pharma partner Johnson & Johnson provided updates which affirmed the therapy's strong efficacy yet brought it down to a less lofty position.
Across the 57 advanced multiple myeloma patients included in the update, the overall response rate to Legend's therapy (called LCAR-B38M) was 88%. The complete response rate was 74%, with almost everyone in that category showing no minimal residual disease in their bone marrow — a marker of a particularly deep response.
Complete responders also went a median of two years before their cancers progressed. Taking all patients into account, median progression free survival was 15 months.
Legend's numbers remain very much competitive and, on some measures, ahead of Celgene and Bluebrid bio's. Those partner companies are developing rival CAR-T therapies for multiple myeloma and are widely seen as front-runners in the space. A pivotal study of their lead candidate has already enrolled, and data presented at ASH suggests a successor candidate is proceeding apace.
As for safety, many patients treated with LCAR-B38M developed a common but still closely watched side effect of CAR-T infusion known as cytokine release syndrome, or CRS.
Though few cases were deemed serious, nine in 10 patients experienced some degree of CRS — a higher proportion than observed in other, albeit smaller, groups of multiple myeloma patients receiving experimental CAR-T treatment. One patient, who was recovering from Grade 2 CRS, developed difficulty breathing and died soon after from a potential pulmonary embolism and acute coronary syndrome, according to a presentation at ASH by study investigator Wan-Hong Zhao.
Conversely, instances of neurotoxicity were very low, with just one patient showing mild aphasia, agitation and seizure-like activity.
The results paint a fuller picture of LCAR-B38M than what was presented at the American Society of Clinical Oncology's annual meeting in June 2017.
There, Legend reported that within two months after infusing the study's first 35 enrolled patients, the objective response rate was 100% and the rate of either complete response or very good partial response was 94%. At the time, the five patients who had been followed for a year or more were all still meeting stringent complete response criteria and showed no detectable cancer cells in their bone marrow.
Those initial outcomes proved attractive to J&J, as did LCAR-B38M's differentiated structure. The CAR-T therapy binds to two epitopes of BCMA, an all-important protein found on the surface of multiple myeloma cancer cells. Before 2017 closed out, the drug giant's subsidiary Janssen agreed to pay $350 million to license the therapy.
"This unique design with a high affinity binding to different epitopes theoretically could have a good potential for the clinical profile, but of course you have to see the results in the clinic," said Sen Zhuang, vice president of oncology clinical research at Janssen, during an interview with BioPharma Dive.
Zhuang said the updates presented at ASH give Janssen more confidence in the therapy's efficacy and durability. To that end, Janssen and Legend recently kicked off a Phase 2 study based in the U.S. So far, the available LCAR-B3M data have come from a single clinical site in China. Three other Chinese sites have enrolled 17 patients, but Legend anticipates submitting data from them separately.
Positive findings in the U.S. would be an important milestone for LCAR-B38M. In an Oct. 25 note, Jefferies analyst Michael Yee pointed out that "there has been significant increased controversy around the validity of this data in Asia, and might have broader read-through to other Asia products."
The Phase 2 U.S. trial has an estimated enrollment of 60 participants and a primary completion scheduled for July 2020.
Even if the trial succeeds, J&J and Legend will still have to contend with substantial competition. Celgene's acquisition of Juno gives it another candidate in testing, while companies like Amgen and Poseida Therapeutics are developing BMCA-targeting therapies of their own. Legend's data, though, indicates the Chinese biotech's therapy is not just a myth.