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By year-end 2022, the number of biologic approvals narrowly outpaced that of small-molecule new molecular entities (NMEs), a landmark in biologics’ steady rise since the end of the twentieth century. Like small molecules, they’re being combined and finding new indications: AstraZeneca’s CTLA-4 inhibitor Imjudo (tremelimumab-actl) was approved in October 2022 for unresectable liver cancer and, the following month, in combination with Imfinzi (durvalumab) and chemotherapy in patients with metastatic non-small-cell lung cancer (NSCLC) not harboring epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations. Merck’s anti-PD-1 (programmed cell death protein-1) behemoth Keytruda (pembrolizumab) in 2022 added advanced endometrial cancer to its 30+ tally of approved indications, with another lined up for 2023 after an overall survival hit in a phase 3 trial in patients with human epidermal growth factor receptor 2 (HER2)-negative gastroesophageal junction adenocarcinoma. The company is running over a dozen trials of Keytruda in early-stage disease.

Another force driving biologics’ growth is their evolution beyond simple antibodies, peptides or enzymes. Newer modalities including bispecific proteins, antibody–drug conjugates, and cell or gene therapies accounted for about half of biologic approvals through the end of November 2022, up from less than a third in 2021.

Oxford, UK-based ImmunoCore’s Kimmtrak (tebentafusp-tebn), a bispecific T cell engager protein approved for unresectable or metastatic uveal melanoma, was first out of the gate in January 2022. It comprises a soluble T cell receptor fused to an anti-CD3 immune effector that redirects T cells to target glycoprotein 100 (gp100)-expressing melanoma cells. Kimmtrak, the first therapy for metastatic uveal melanoma, benefited from Breakthrough designation and Real Time Oncology Review and was assessed concurrently by other health authorities, including European Medicines Agency, under Project Orbis. (It was approved in Europe in April 2022.)

Kimmtrak paved the way for other bispecifics designed to bind specific cancer and immune system targets to generate a more powerful anticancer response. Johnson & Johnson’s Tecvayli (teclistamab-cqyv), approved in October for advanced multiple myeloma, is a bispecific T cell engager antibody that latches onto T cells, via the surface CD3 receptor, and to B cell maturation antigen (BCMA) expressed on myeloma cells. The big pharma on 9 December submitted another bispecific, talquetamab, which targets CD3 and GPRC5D, a new multiple myeloma target.

In the closing weeks of 2022, the FDA approved Roche’s bispecific antibody Lunsumio (mosunetuzumab) for follicular lymphoma that has failed least two previous therapies. It targets CD20 on B cells and CD3 on T cells, redirecting the latter to engage and destroy the B cells. Lunsumio received conditional approval in Europe in June. Another Roche bispecific, Vabysmo (faricimab-svoa) was approved in 2022 for wet age-related macular degeneration and diabetic macular edema. Vabysmo targets the angiopoietin-2 and vascular endothelial growth factor-A pathways that contribute to vision loss in these conditions.

Bispecifics may provide a more convenient alternative to CAR-T cell therapies, whose complex, expensive manufacture and administration have limited their reach and commercial fortunes. Earlier in 2022, Johnson & Johnson and partner Legend Biotech won approval for Carvykti (ciltacabtagene autoleucel), a BCMA-directed CAR-T cell therapy, in the same indication as Tecvayli: adults having received at least four lines of previous therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody.

Carvykti became the sixth CAR-T cell therapy in the United States (Table 3). The CAR-T cell R&D pipeline is huge, including sponsors seeking more convenient allogeneic (off the shelf) varieties and ‘point of care’ manufacturing facilities to expand access, as well as those seeking to address solid tumors. In October, Europe’s Committee for Medicinal Products for Human Use recommended approval of what could be the first ever allogeneic T cell therapy, Atara Biotherapeutics’ tabelecleucel (Tab-cel) for Epstein–Barr virus (EBV)-positive post-transplant lymphoproliferative disease. Tab-cel uses EBV-directed T cells from healthy donors. A US biologic license application has been delayed owing to comparability issues between commercial and pivotal clinical trial product.

Table 3 FDA-approved CAR-T therapies

Another new modality arrived 30 November, when the FDA approved the first fecal microbiome product, Rebyota (fecal microbiota, live-jslm), for people with recurrent Clostridioides difficile infections following antibiotic treatment. The product is prepared from stool donated by healthy individuals, screened for pathogens, and administered as a one-time enema to restore a healthy balance of bacteria in the colon. The approval, granted to Saint-Prex, Switzerland-based Ferring Pharmaceuticals, follows several setbacks across the field and could open the gates for other similar treatments. Seres Therapeutics completed a rolling submission of its orally administered microbiome therapeutic, also for C. difficile, in September 2022. Fecal microbiota transplants — doses of untampered stool — have been used to manage this condition, but regulation and quality control are difficult.


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