The termination means the company has regained the worldwide rights to APVO414, which it will continue evaluating in an ongoing Phase 1 clinical trial of the therapy’s safety and effectiveness, and patients’ ability to tolerate it.
Aptevo said switching participants’ treatment regimen in the ongoing trial has led to better results than in the initial Phase 1 trial. Participants are producing fewer anti-drug antibodies — which neutralize the therapy’s effectiveness — under the new regimen than the old one.
“We’re encouraged by the latest preliminary data from the ongoing Phase 1 clinical study of APVO414,” Dr. Scott Stromatt, senior vice president of Aptevo, said in a press release. “The data suggest that administration of APVO414 by continuous infusion, rather than weekly intravenous (IV) dosing, is effective at reducing the titer [amount] of anti-drug antibodies (ADA) previously observed in the initial weekly IV dosing cohorts.”
The ongoing trial (NCT02262910) is still recruiting participants. Researchers are trying to identify the maximum dose of APVO414 that patients can tolerate. In the second stage, they will be evaluating APVO414’s ability to trigger an immune response, its effect on the body, and the body’s effect on it.
The first group of 12 patients in the initial Phase 1 trial received escalating doses of intravenous APVO414 weekly. Seven patients, or 58 percent, developed anti-drug antibodies that neutralized the treatment’s effectiveness. None of the 12 had adverse effects, and patients with high levels of the antibodies were able to clear the drug out of their blood.
At that point, researchers decided to start administering APVO414 through continuous intravenous infusion rather than in weekly doses.
Two groups of patients have completed the new regimens. Half developed anti-drug antibodies, but their levels were significantly lower than the levels in the initial patient group. An encouraging finding was that researchers were able to continue detecting the drug in the second and third groups’ blood samples.
“These results clearly demonstrate that the [new] administration regimen markedly reduced the generation of [anti-drug antibodies],” Stromatt said. “Additionally, we have seen early pharmacodynamic effects of the drug, such as redistribution of T cells. We are encouraged and plan to continue dose escalation in order to determine the maximum tolerated dose and to examine the clinical activity of APVO414.”
APVO414 binds to two proteins at the same time. One is a protein known as prostate-specific membrane antigen (PSMA), which is in prostate cancer cells. The other, CD3, is in immune system T-cells. The drug acts by redirecting the T-cells so they can kill tumor cells containing PSMA.
Preclinical-trial studies showed that APVO414 can prompt T-cells to multiply and kill tumor cells.
Researchers published the results of those studies in Molecular Cancer Therapeutics and presented them at the 2016 American Association for Cancer Research Meeting. The title of the journal article was “MOR209/ES414, a Novel Bispecific Antibody Targeting PSMA for the Treatment of Metastatic Castration-Resistant Prostate Cancer.”
“Aptevo has made a number of significant improvements to our ADAPTIR [therapy creation] platform since the development of our first-generation” treatments, such as APVO414, said Dr. Jane Gross, the company’s senior vice president.
“Our next-generation ADAPTIR technology platform has been optimized to enable the development of bispecific antibody candidates [those with two targets] with highly desirable drug-like properties, including enhanced potency and stability, prolonged half-life, and excellent manufacturing attributes – similar to traditional antibodies.” Half life is the amount of time it takes for a drug to lose half its strength in the body.
Gross said the company is using “state-of-the-art technologies to examine our next-generation bispecific candidates.” The new technology may be able to address the problem of APVO414 triggering the anti-drug autobodies, she said.
“We look forward to obtaining additional information from the ongoing APVO414 clinical trial and advancing next-generation ADAPTIR bispecific molecules into clinical development,” Gross added.