Another IO Target in Jeopardy? J&J Returns All Rights to CD40 Agonist ADC-1013

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Recently, Eli Lilly’s announcement that it was abandoning the clinical development of its PD-L1/TIM-3 bispecific antibody sparked concerns in the immuno-oncology community regarding the TIM-3 target. Yesterday (July 31), Johnson & Johnson returned all rights to the monoclonal antibody drug ADC-1013 (JNJ-64457107) to its partner Alligator Bioscience, drawing industry attention to another immuno-oncology target, CD40.

Some analysts are even concerned whether CD40 is destined to follow in the footsteps of OX40 and IDO. The latter two targets were previously held in high regard by the industry but encountered significant setbacks in clinical development. Other analysts believe that such outcomes may be an inevitable norm in new drug development and should be viewed with composure; even behind the thriving landscape of PD-(L)1 inhibitors, failures persist.

Johnson & Johnson and Alligator entered into a strategic collaboration in 2015 to jointly develop ADC-1013, which is currently in Phase I clinical trials for the treatment of metastatic cancer. According to a statement released by Alligator, Johnson & Johnson’s decision to terminate the collaboration was driven by strategic portfolio considerations prioritizing other assets.

The real reason may stem from last month’s American Society of Clinical Oncology (ASCO) Annual Meeting, where disappointing early data on ADC-1013 were presented. Johnson & Johnson’s withdrawal may bring bad news to Alligator Bioscience and raise questions about the CD40 target. Following the announcement of the termination of their collaboration, Alligator’s stock price plunged 40% in early trading.

ADC-1013 is a CD40 agonist antibody and Alligator’s lead asset. The company now needs to seek new partners or funding to develop the drug. However, as of the end of June, Alligator had only $37 million in cash reserves. Some analysts believe that without redesigning ADC-1013, it may be difficult for the company to secure new partnerships.

Per Norlén, CEO of Alligator Bioscience, stated in a press release: “Our ambition for ADC-1013 was to develop a CD40 antibody capable of stimulating the immune system without causing adverse systemic side effects, and the current data package indicates that we have succeeded. The observed mild side effects, along with early signs of clinical benefit, have strengthened our confidence. We are highly satisfied with the progress made in collaboration with Johnson & Johnson on the development of ADC-1013, while also understanding Johnson & Johnson’s need to prioritize its R&D portfolio.”

Further investigation of the facts reveals that Alligator has little reason for optimism. Results from a Phase I study in 95 patients with solid tumors showed partial response in only one patient with renal cell carcinoma. Leerink analysts compared Apexigen’s CD40 agonist monoclonal antibody APX005M with ADC-1013. In a Phase Ib study presented at the American Association for Cancer Research (AACR) Annual Meeting, two APX005M regimens (APX005M plus standard chemotherapy [gemcitabine and nab-paclitaxel], and APX005M plus standard chemotherapy plus Opdivo) demonstrated very robust data as first-line treatment for metastatic pancreatic cancer, achieving an overall response rate of 54%. In another clinical trial in melanoma, the combination of APX005M and Opdivo yielded an overall response rate of 17%.

CD40 plays a central role in tumor immune responses (Image source: Apexigen)

CD40 is a key immune co-stimulatory receptor in the immune system, present on the surface of antigen-presenting cells (APCs) within the immune system. It plays a pivotal role in activating mechanisms of both the innate and adaptive immune systems. Pharmacological activation of CD40 can mimic endogenous immune activation processes, thereby stimulating the endogenous immune system and reversing immunosuppression in cancer patients.

Currently, multiple pharmaceutical companies have entered the field of CD40-targeted therapies, including Roche and Seattle Genetics. In addition to the early-stage data disclosed by Apexigen and Alligator Bioscience, no other clinical results appear to be available for other CD40 agonists. According to information from the clinical trials database ClinicalTrials.gov, the clinical studies of Roche’s selicrelumab and AbbVie’s ABBV-428 are scheduled to conclude this year.

Leerink analysts believe that the superior early efficacy of APX005M compared to ADC-1013 may be attributed to its tight binding to the FcγRIIb receptor, resulting in enhanced cross-linking and augmented CD40 agonism. While CD40 agonists hold promise in combination regimens, some pharmaceutical companies argue that a simple combination of two monoclonal antibodies is insufficient. BioNTech is currently developing HERA-CD40L, a hexavalent CD40 agonist, which remains in the preclinical stage.

Reference source: Another immuno-oncology mechanism threatens to disappoint