UPDATED: Novartis washes its hands of another bispecific at the center of $2.5B Xencor deal

09 Nov 2021
endpts.com
Antibody
A centerpiece of Novartis’ $2.5 billion bispecifics deal with Xencor has been sidelined, the California biotech said in its third quarter earnings report Monday. Novartis terminated its ex-US rights to the program dubbed vibecotamab, a bispecific targeting CD123 and CD3 for acute myeloid leukemia. The move will take effect next February, Xencor said Monday. Xencor will drop development of the drug altogether as well, saying it has no future plans for in-house research. The Swiss biopharma previously handed back rights to the other Xencor drug involved in the partnership in January 2019. That program, a CD20 and CD3 bispecific called plamotamab, is now one of Xencor’s lead candidates, with updated Phase I data coming at ASH next month and a new partner signed in J&J’s Janssen. In Monday’s earnings call with analysts, Xencor CEO Bassil Dahiyat alluded to a tougher competitive landscape shrinking new opportunities in AML — following AbbVie and Roche’s 2019 approval of Venclexta — in response to a question about why Novartis backed out. He also noted CD123’s difficulty as a target, saying its “narrow therapeutic window” brings challenges in dosing frequency. “In spite of the very encouraging early complete remissions that we’ve had and continuing additional activity we’ve seen, all those pieces make the product profile and the competitive landscape tough, really frankly tough for us to want to pursue and our partner, Novartis, agree,” Dahiyat said. In an email to Endpoints News , a Xencor spokesperson said the deal remains ongoing, with the pair working on “a bispecific antibody and a non-bispecific antibody that incorporates another of our XmAb Fc domains.” Novartis and Xencor originally agreed to develop vibecotamab, previously known as XmAb14045, back in 2016 when the companies signed a deal giving Xencor $150 million upfront and promising another $2.4 billion in milestones. At the time, it had been the latest in a string of high-profile biopharmas to partner with Xencor, following Amgen, Merck and J&J, among others. But while vibecotamab was still a preclinical program in 2016, it soon ran into trouble in the clinic. The FDA slapped a hold on a Phase I study in February 2019 after two patients in the trial died, one from cytokine release syndrome and another from acute pulmonary edema following several doses. Regulators lifted the hold the following April, after Xencor amended study protocols to update how CRS is monitored and managed. It’s not clear if investigators ever determined whether the deaths were linked to the drug. Additional studies for vibecotamab had previously been scheduled for 2020, but Xencor said previously that plans had been affected by the Covid-19 pandemic. Now, though, those plans have been shelved. CD123 has given other drugmakers trouble in the past, as well as bispecifics with CD3. In 2016, the FDA put a full hold on a J&J program for the target combo, and Cellectis saw a patient death in 2017 for a CD123-targeting CAR-T candidate. Novartis, meanwhile, has its own in-house CD123 called JEZ567, being studied for AML. This article was updated to include comment from Xencor.
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