ADCT says decision to pull HER2 drug doesn’t affect other candidates

Lausanne, Switzerland, near to ADC Therapeutics' headquarters (Courtesy of GFDL [CC BY-SA 3.0])

Swiss biotech ADC Therapeutics has abandoned one of its midpipeline candidates for HER2-positive cancers because of toxicity issues in a phase 1 trial in solid tumors.

The company has stressed however that the decision to pull ADCT-502 from development doesn’t have an impact on its other antibody-drug conjugate (ADC) candidates, which are in early clinical development for a range of solid and hematological cancers.

ADCT Chief Medical Officer Jay Feingold, M.D., Ph.D., explains that the pyrrolobenzodiazepine dimer technology used in its ADCs has recognized side effects, including fluid retention and pulmonary edema, that in trials so far have been manageable through careful dose selection.

He notes however that in the ADCT-502 trial—which enrolled patients with HER2-expressing breast, gastric, esophageal, bladder and lung tumors—“we did not achieve the necessary efficacy at tolerated doses required for patient benefit.” The results are still being assessed, but early indications are that high levels of HER2 expression in the lungs might have shifted the benefit:risk ratio for the drug.

ADCT is already using a new, site-specific conjugation technology to link the antibody and drug components in its ADCs that it hopes will improve tolerability, and this will be deployed in two of three new candidates that the company’s CEO, Chris Martin, Ph.D., says will start clinical trials in the next nine months.

A spokesman for the company tells us that the three new ADCs are ADCT-601, which targets AXL, a transmembrane receptor overexpressed in a range of solid tumors; ADCT-602, which targets CD22, found in blood cancers like acute lymphocytic leukemia; and ADCT-701, a DLK-1-targeting drug that will also be tested in solid tumors.

ADCT-601 and ADCT-701 use the new site-specific conjugation technology, dubbed GlycoConnect and licensed from Synaffix, he said. Poster presentations on the two candidates were made at the AACR meeting in Chicago earlier this month.

While the results are disappointing, Martin said that “patients with HER2 expressing tumors have multiple therapeutic options including novel therapies in clinical development that are producing encouraging data.”

He also points to the progress being made with ADCT’s two lead candidates that are still firmly on course to start later-stage testing before the end of the year. Those are anti-CD19 drug ADCT-402 for diffuse large B-cell lymphoma, mantle cell lymphoma and follicular lymphoma, and ADCT-301, a CD25-targeting drug for Hodgkin lymphoma and other T-cell lymphomas.

That will take its total number of clinical-stage ADC candidates to six in early 2019. To help fund that effort, the company raised $200 million in an AstraZeneca-backed financing last year, taking the total raised to date to $455 million.