Seattle Genetics has called a halt to all clinical testing of vadastuximab talirine (SGN-CD33A) after seeing a higher rate of patient deaths with the drug in a phase 3 trial.
Several earlier-stage trials of the CD33-targeting antibody-drug conjugate were halted by the FDA last December on safety concerns, mainly relating to possible liver toxicity. Now, the CASCADE registration study in acute myeloid leukemia (AML) and another phase 1/2 study in myelodysplastic syndrome have also been stopped, leaving the program looking decidedly shaky and driving the company's shares down more than 11% premarket.
There was no evidence of liver damage in CASCADE, but a higher rate of deaths—including fatal infections—were seen with vadastuximab talirine compared to placebo in the study. It's a big blow to the company as well as AML patients and their carers, particularly as data reported at the American Society of Hematology meeting last December showed a complete remission rate of 70% with the drug.
Seattle CEO Clay Siegall, Ph.D., said in a statement that the finding was "disappointing and unexpected," adding that the biotech would be discussing the data with the FDA to determine future plans for the program. He was quick to highlight the other candidates in Seattle's pipeline, however, including enfortumab vedotin—heading for phase 2 in bladder cancer—and SGN-LIV1A, a candidate for triple-negative breast cancer in early-stage testing.
"AML is a devastating disease with a poor prognosis in most patients, and there is a great need for therapeutics against this disease," said Siegall in the statement. "We thank the patients, caregivers and investigators for their support of this trial."
Thankfully for Seattle, its first product, Adcetris (brentuximab vedotin) for relapsed Hodgkin lymphoma and anaplastic large cell lymphoma, remains in the growth phase after six years on the market. The Takeda-partnered product grew 20% in the first quarter of the year in the U.S. and Canada, where the biotech retains marketing rights, bringing in $70 million.
Seattle expects sales of Adcetris to approach $300 million this year and is banking on plenty of upside from three phase 3 trials in new indications, namely cutaneous T-cell lymphoma (ALCANZA), newly diagnosed Hodgkin lymphoma (ECHELON-1) and front-line peripheral T-cell lymphoma (ECHELON-2). Seattle is planning to file for approval of Adcetris in CTCL later this year on the strength of the ALCANZA data and is also expecting top-line data from ECHELON-1 before year-end.
But for an aborted deal with Immunomedics, Seattle could also have had a highly regarded potential blockbuster in its portfolio—sacituzumab govitecan (IMMU-132) for breast and lung cancer—but that deal fell apart after an Immunomedics shareholder revolt that claimed the scalps of its CEO and founder.
Analysts at Barclays said: "Following the news that Seattle is discontinuing its phase 3 CASCADE vadastuximab talirine (SGN-CD33A) trial in frontline older acute myeloid leukemia (AML) and suspending patient enrollment and treatment in all of the other 33A trials, we're removing it from our model and reducing our price target to $55/share from our prior $64/share.
"We spoke with Seattle management, which emphasized that the primary issue in CASCADE was serious infections in an immune compromised, elderly population and was not related to the hepatoxocity or veno-occlusive disease (VOD) that caused a clinical hold of 33A last fall. Given 33A's mixed safety record, we believe that its clinical and regulatory prospects have meaningfully diminished due to its risk/benefit profile and we suspect that further developmental efforts are not likely to be fruitful, including the ongoing phase 1/2 clinical trial in frontline high risk myelodysplastic syndrome (MDS)."