Xencor acknowledged today that the FDA has placed the company’s Phase I trial of its CD123 x CD3 bispecific antibody XmAb®14045 on a partial clinical hold following the deaths of two patients linked to the blood cancer candidate.

Xencor said one patient experienced cytokine release syndrome (CRS) after their first dose, “the treatment of which was complicated by the patient’s decision to withdraw care.”

The other patient developed acute pulmonary edema following “several” doses of XmAb14045, the company said.

As a result, according to Xencor, the FDA has placed the trial on partial clinical hold pending review of additional details regarding these events, safety and efficacy information across the study, and satisfactory review of amendments to the study protocol and related documents.

Xencor said it will be “working closely with the FDA to review these events and resolve the partial clinical hold.”

“We are working with the investigators and the FDA and will provide an update when more information about resuming enrollment can be shared,” Xencor president and CEO Bassil Dahiyat, PhD, said in a statement. “Patient safety is Xencor’s highest concern.”

XmAb14045 is a tumor-targeted antibody that contains both a CD123 binding domain and the cytotoxic T-cell binding domain CD3. A Xencor-developed XmAb® Bispecific Fc domain serves as the scaffold for the two antigen binding domains, and is intended to confer long circulating half-life, stability, and ease of manufacture on XmAb14045.

Xencor has reasoned that engagement of CD3 via XmAb14045 will activate T cells for highly potent and targeted killing of tumor cells that express CD123—which is highly expressed on AML cells and leukemic stem cells, and is associated with poorer prognosis in AML patients.

XmAb14045 has been under study in the Phase I trial (NCT02730312), designed to assess the safety and tolerability of weekly intravenous administration of the bispecific antibody candidate in patients with relapsed or refractory acute myeloid leukemia and other CD123-expressing hematologic malignancies. Those malignancies include B-cell acute lymphoblastic leukemia; blastic plasmacytoid dendritic cell neoplasm; and the blast phase or “blast crisis” of chronic myeloid leukemia.

The trial is also designed to determine the maximally tolerated dose (MTD) after the first dose, and the MTD after second and subsequent infusions.

Dahiyat said that the partial clinical hold will have no effect on Xencor’s ongoing Phase I studies evaluating its other CD3 bispecific antibodies. Those trials include NCT03411915, which is intended to assess XmAb®18087 in neuroendocrine tumor and gastrointestinal neoplasm patients; and NCT02924402, designed to evaluate XmAb®13676 in B-cell Non-Hodgkins Lymphoma and other blood cancers.

Novartis collaboration

XmAb13676 and XmAb14045 are the two Xencor CD3 bispecific antibodies which Novartis agreed to co-develop and commercialize outside the U.S. in 2016, as part of a collaboration that generated $150 million upfront. The collaboration was also designed to generate an eventual up-to-$2.4 billion in development, regulatory, and sales milestone payments for Xencor, a Monrovia, CA, biopharma focused on developing antibodies for treating cancer as well as autoimmune diseases, asthma, and allergic diseases.

Through the collaboration, Novartis also gained rights to use Xencor’s XmAb antibody engineering platform to develop and commercialize four additional bispecific antibodies for targets to be selected by Novartis, with Xencor eligible to “opt in” to one of these programs in the U.S. The agreement also gave Novartis a worldwide nonexclusive license to use Xencor’s XmAb Fc technologies in up to 10 molecules.

Xencor also stands to gain tiered, low double-digit royalties tied to sales of XmAb14045 outside of the U.S., and mid-single-digit tiered royalties for worldwide sales of the four Novartis bispecific molecules.

Last month, Xencor said it will regain rights to XmAb13676 effective June 20. Xencor attributed Novartis’ decision as being “due to strategic pipeline reprioritization.”

In the January 7 statement announcing Novartis’ decision, Dahiyat insisted: “Both companies are eager to advance XmAb14045 in clinical development.”

He cited the company’s presentation of positive early data from the Phase I in patients with relapsed/refractory AML, which he said included observed multiple complete remissions on a weekly dosing schedule. Xencor announced on November 1, 2018, that as of the date of data cutoff on June 27, 2018, three of 13 evaluable patients with AML (23%) achieved either complete remission (CR) or CR with incomplete hematologic recovery (CRi) at the two highest dose levels studied to date, 1.3 and 2.3 mcg/kg weekly.

The 13 were among 63 patients with relapsed/refractory AML and one patient with B cell acute lymphoblastic leukemia who had received XmAb14045.

In addition to Novartis, biopharma giants partnering with Xencor include Amgen, MorphoSys, CSL, Alexion Pharmaceuticals, and Boehringer Ingelheim.

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