Affimed disclosed that it has placed the two-trial Phase I clinical program for its cancer immunotherapy candidate AFM11 (CD19/CD3-targeting T-cell engager) on clinical hold following the death of one patient, and life-threatening events in two others.

The death occurred in a Phase I trial (NCT02106091) designed to assess AFM11 in patients with relapsed or refractory CD19 positive B-cell non-Hodgkin lymphoma (NHL).

The two life-threatening events both occurred in the program’s other Phase I trial (NCT02848911), designed to determine the maximum tolerated dose in patients with acute lymphoblastic leukemia (ALL), as well as assess safety and tolerability of increasing doses and different infusion times of AFM11 infusion in patients with adult B-precursor ALL.

“Affimed will be working closely with the global health authorities, the Safety Monitoring Committees, and the studies' clinical investigators to review the events, carefully assess all of the data, and determine next steps for the AFM11 program,” Affimed said yesterday in a statement. “Affimed intends to provide an update on AFM11 upon completion of the evaluation.”

A combined 33 patients have been treated in both trials, with preliminary signs of clinical activity observed in several patients, Affimed said.

All three patients who suffered the serious adverse events were enrolled in the highest dose cohorts of each study.

‘Very Potent’ Cytotoxicity

AFM11 is a novel CD19/CD3-directed tandem diabody (TandAb®) consisting of two binding sites for CD19, a B-cell epitope found on malignant cells that cause leukemia or lymphoma, and two binding sites for CD3, a component of the T-cell receptor.

According to Affimed, the resulting cross-linking event forms an immunological synapse, which generates a strong activating signal that induces the transport of cytotoxic granules to the cell surface where they release perforin and granzyme in the vicinity of the tumor cell. Perforin facilitates the diffusion of granzyme into the target cell, where it initiates the apoptotic pathway leading to the destruction of the cancer cell. 

In preclinical studies cited by Affimed, AFM11 showed “very potent” cytotoxicity, even at very low T-cell counts, an outcome that the company said differentiated AFM11 from Amgen’s marketed bispecific CD19-directed CD3 T-cell engager Blincyto® (blinatumomab).

That differentiation, according to Affimed, makes AFM11 clinically relevant for patients whose immune system is compromised, such as from myelosuppressive chemotherapies, or for patients with tumors where perfusion is restricted.

News of the clinical hold and serious adverse events touched off a stock selloff that sent Affimed’s shares tumbling 25% from Friday’s close of $4.63 in trading on the NASDAQ Global Market, to $3.47 as of 10:13 a.m.

The clinical hold does not affect Affimed’s program to develop and commercialize novel NK cell engager-based immunotherapies targeting the CD16A receptor, also known as FcγRIIIA—the subject of an up-to-$5 billion collaboration announced by Affimed in August with Genentech, a member of the Roche Group.

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