Bispecific: It might sound to some like a self-contained contradiction, as in “doubly singular” or “twice particular.” But if the word “specific” is taken in its primary meaning as “clearly defined or identified,” then the matter becomes clear – and, in the case of bispecific antibodies, it’s becoming clearer by the year.
“While much debate remains around where exactly bispecifics will fit into the therapeutic landscape (e.g., CAR T killers?), what is not up for debate is the importance of getting up to speed on where bispecifics are today and where they might be going in the future,” J.P. Morgan analyst Cory Kasimov pointed out in a recent report.
The approval of the CD19-directed bispecific T-cell engager Blincyto (blinatumomab), from Thousand Oaks, Calif.-based Amgen Inc. in 2014 piqued investor interest in the oncology space. Amgen gained accelerated approval from the FDA to treat patients with relapsed or refractory Philadelphia chromosome-negative precursor B-cell acute lymphoblastic leukemia, or B-cell ALL, and the clearance heralded the arrival officially of bispecific antibodies.
Blincyto, however, wasn’t the first approved bispecific. That title belongs to Removab (catumaxomab), developed by Trion Pharma GmbH and Fresenius Biotech GmbH. The molecule gained European approval in 2009 to treat malignant ascites (abdominal fluid) in cancer patients by targeting the T-cell antigen CD3 and epithelial cell adhesion molecule (EpCAM; CD326). Removab didn’t make much progress in the market.
In the hemophilia A space, company backers and patients were heartened by the FDA’s go-ahead, and the ensuing commercial success of Hemlibra (emicizumab-kxwh) from Basel, Switzerland-based Roche Holding AG’s Genentech unit. The product brings together factors IXa and X to mimic the role of factor VIII (FVIII) to restore blood clotting, and was green-lighted by the FDA to prevent or reduce the frequency of bleeding episodes in adults and children with hemophilia A who develop FVIII inhibitors. It was advanced by Genentech in collaboration with Chugai Pharmaceutical Co. Ltd., of Tokyo, which discovered the asset. Nearly one in three people with severe hemophilia A can develop inhibitors to FVIII replacement therapies.
News in the bispecific space continues to churn. Akeso Biopharma Inc., from China’s Guangdong province, not long ago closed a $150 million series D financing round to advance its pipeline, especially two PD-1-based bispecific antibodies, AK-104 and AK-112. Pascal Biosciences Inc., headquartered in Vancouver, British Columbia, and South Korean biotech Y-biologics Inc., based in Daejeon, inked a research collaboration agreement for the discovery and development of bispecific antibodies for the treatment of leukemia. Research marches on, as Memorial Sloan-Kettering Cancer Center investigators in late October presented encouraging, albeit early, data on Utrecht, the Netherlands-based Merus NV’s bispecific antibody, MCLA-128, for the treatment of patients with NRG-1 gene fusions at the AACR-NCI-EORTC Molecular Targets meeting. Two of three patients that received MCLA-128 under an expanded access protocol had a partial response to the drug, while the third patient also showed tumor shrinkage, though not enough to meet the 30% cutoff necessary for qualifying as a partial response under RECIST criteria. Two of the patients had metastatic pancreatic cancer, while the third had metastatic non-small-cell lung cancer. And more is coming. Tarrytown, N.Y.-based Regeneron Pharmaceuticals Inc. said it will report results from experiments with CD20xCD3 and BCMAxCD3 bispecifics (as well as its C5 antibody programs) at the American Society of Hematology annual meeting in December in Orlando, Fla.
Bispecific molecules’ promise comes from their “off-the-shelf” nature and ability to target multiple entities in a way that affects or mimics biological processes, such as redirecting T cells and modulating cell surface receptors. J.P. Morgan’s Kasimov in his deep dive pointed to “many types of bispecifics in development looking to address a whole host of indications. Perhaps not surprisingly, a large focus is in cancer (and more specifically on blood cancers) where there are more than 100 bispecifics being pursued.” Also underway is “a pervasive, ongoing R&D effort exploring ways to improve upon current approaches and expand the field into even more diseases and patient populations,” he said.
Not to be overlooked is the tie-up between Cambridge, Mass.-based Pandion Therapeutics Inc. and Astellas Pharma Inc., of Tokyo, which brings as much as $45 million in up-front money and payments related to research and preclinical activities, with potentially more than $750 million in development and commercial milestone rewards to come, plus royalties if products reach the market. The duo will work on locally acting immunomodulators for autoimmune diseases of the pancreas, first focusing on type 1 diabetes. The effort combines Pandion’s modular biologics and functional immunology expertise with Astellas’ pharmaceutical strength. Pandion will be responsible for design and discovery of bispecific drug candidates based on the firm’s modular immune effector and tissue tether platform, and Astellas will handle preclinical, clinical and commercialization activities for selected prospects.
The march forward remains encouraging, but not all news has been good. New York-based Pfizer Inc. lately pulled the plug on early stage bispecific PF-06671008 in solid tumors, which was part of the big pharma firm’s deal with Macrogenics Inc., of Rockville, Md. In 2010, the pair signed a global research collaboration and license agreement to discover, develop and commercialize Dual-Affinity Re-Targeting (DART) products directed at two undisclosed cancer targets. Macrogenics’ DART approach makes proteins amenable to various applications and can potentially be used to redirect the body’s cell-destroying, immune effector cells against tumor cells.
Research early and late continues to roll out. Cambridge, Mass.-based Compass Therapeutics Inc. had poster presentations at the Society for Immunotherapy of Cancer meeting in National Harbor, Md. One showed data on CTX-8371, a bispecific antibody targeting the inhibitory receptor PD-1 as well as ligand PD-L1. CTX-8371 was discovered in an unbiased screen of checkpoint bispecifics using Compass’ StitchMabs technology. CTX-8371 showed significantly increased potency in vitro and in vivo compared to combinations of monoclonals blocking PD-1 and PD-L1. Mechanistic studies of CTX-8371 suggest that the enhanced potency is associated with its unique ability to drive PD-1 down-regulation from the surface of effector T cells, the company said.
In Kasimov’s view, the advent of Blincyto “reinvigorated the bispecific platform and demonstrated proof-of-concept results for the broader field,” and other targets in this space (mainly CD20 and BCMA), though early in the clinic, “have demonstrated encouraging results. Within oncology, durability of these treatments will be key (especially in the context of how this stacks up to other modalities [such as] CAR T). In our opinion, it is too early to know how this will play out.” He called the data with Hemlibra in hemophilia A “remarkable” and noted that other indications are being pursued in ophthalmology, immunology and pain.