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Xencor’s Novartis-partnered bispecific on hold after patient deaths

The two death’s included one case of CRS

FDA

Xencor has had a clinical hold placed on its phase 1 trial of a bispecific antibody for acute myeloid leukaemia (AML) after two deaths that the company says may be related to the drug.

The partial clinical hold imposed by the FDA means that no new subjects can be enrolled into the study of XmAb14045, a bispecific antibody targeting CD123 and CD3, but those already on treatment can continue on protocol.

The two deaths included one case of cytokine release syndrome (CRS), the side effect that caused so many problems in early CAR-T studies and is also a known problem with Amgen’s already-approved Blincyto (blinatumomab) for acute lymphoblastic leukaemia (ALL) drug. Blincyto is a bispecific that targets CD3 and CD19 and lists CRS in a boxed warning on the label.

The CRS case in Xencor’s trial occurred after a single dose of XmAb14045, says the biotech, and treatment was “complicated by the patient's decision to withdraw care.” The other death was a result of acute pulmonary oedema that developed after several doses of the drug.

Shares in Xencor fell 6.5% after the news as investors worried about the prospects for the bispecific, which was one of the main assets in a $2.5bn alliance with Novartis agreed in 2016 along with XmAb13676, another bispecific in development for B-cell malignancies.

CD3 is a popular domain target for bispecific antibodies as it activates T-cells to kill malignant cells. It is coupled with a second tumour-associated domain designed to bring T cells into contact with the cancer cells – CD123 in the case of XmAb14045 and CD20 for XmAb13676.

Novartis handed back rights XmAb13676 last month due to a “strategic pipeline reprioritisation”, so if side effects scupper the remaining bispecific the collaboration with Xencor could effectively be defunct.

Bassil Dahiyat (pictured below), chief executive officer at Xencor, said the company is “working with the investigators and the FDA and will provide an update when more information about resuming enrolment can be shared.”

Bassil Dahiyat

He added that ongoing phase 1 studies of other CD3 bispecific antibodies, XmAb13676 and XmAb18087, are not affected.

It’s not the first CD3-targeting bispecific to run into safety concerns. In December, MacroGenics had two trials of its MGD009 CD3/B7-H3 drug for solid tumours placed on partial clinical hold by the FDA, once again on safety grounds. In this case however the concerns were about liver toxicity.

A few weeks earlier a trial of Affimed’s CD3- and CD19-targeting bispecific AFM11 in non-Hodgkin’s lymphoma was also placed on full clinical hold after a death and two life-threatening events, while in July 2018 Genmab/Johnson & Johnson’s CD3/CD123 bispecific JNJ-63709178 was placed under clinical hold for the second time by the FDA due to a “grade 3 adverse event.”

Article by
Phil Taylor

21st February 2019

From: Research, Regulatory

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