PD-1 agonist development progress inventory, which players on the agonist track?

"If blocking PD-1 on T cells can turn on the" brakes "of the immune system and revolutionize cancer therapy, then it could in turn suppress the immune response and be used in autoimmune diseases."

The idea was tested in a clinical trial at Eli Lilly. Eli Lilly now reports results of a phase 2a trial of its PD-1 agonist peresolimab in rheumatoid arthritis (RA) in the New England Journal of Medicine (NEJM). This is the first clinical evidence of a PD-1 agonist in a self-immune disease.

In the era of PD-1, PD-1 inhibitors have become more and more crowded, with serious product homogeneity and fierce price war, and the research and development of PD-1 inhibitors has retreated a lot. Could PD-1 agonists, in the opposite direction, write a new PD-1 future?
PD-1 agonists

The next big pharma blue ocean?

Under the pressure of large volume, Eli Lilly, Merck Sharp and Dohme, Bristol-Myers Squibb, Johnson & Johnson, Gilead and other MNCS have already started the PD-1 agonist distribution, aiming at the field of autoimmune therapy, and some are trying to replicate Eli Lilly's success.

These MNCS have invested time and money in the development of PD-1 agonists, but there has been no breakthrough.

Among them, the fastest progress is Eli Lilly's PD-1 agonist Peresolimab (LY3462817), which has entered phase II clinical studies in patients with rheumatoid arthritis.

Peresolimab is a humanized IgG1 monoclonal antibody that binds to and activates PD-1. Since PD-1 is primarily expressed on activated T cells, the binding of peresolimab to PD-1 has the potential to restore immune homeostasis without affecting the remaining cells in the immune repertoire.

In this phase 2a trial, Lilly assessed the efficacy and safety of peresolimab in adults with moderately to severely active rheumatoid arthritis who had an inadequate response, loss of response, or unacceptable side effects to conventional synthetic DMARDs or biologics.

Trial results showed that peresolimab showed efficacy in patients with rheumatoid arthritis. These results provide evidence of the potential efficacy of PD-1 receptor stimulation in the treatment of rheumatoid arthritis.

Lilly said future studies will continue to evaluate peresolimab in RA, including an ongoing phase 2b trial, called RESOLUTION-1, for the treatment of adults with moderate-to-severe RA. In addition, Eli Lilly is considering evaluating peresolimab in other autoimmune diseases.

Merck Sharp & Dohme's PD-1 agonist, MK-6194(PT101), was acquired.

In February 2021, Merck Sharp & Dohme acquired Pandion at a hefty price ($1.85 billion). The acquisition will give Merck, Sharp & Dohme access to a portfolio of experimental drugs targeting a variety of autoimmune diseases, including two PD-1 agonists.

One of these is the systemic PD-2 inhibitor PT627. The other is the topical PD-1 agonist PT101, which is the core asset of Pandion, an IL-2 mutant fusion protein, currently in ulcerative colitis stage 1, and the acquisition has become the industry's blockbuster deal of the year.

Last August, Gilead announced the acquisition of MiroBio for about $405 million in cash, gaining MB151 in a bet on the next generation of immune checkpoint agonist.

MB151 is a precision-engineered checkpoint agonist that offers transformative therapeutic potential for patients.

MiroBio is a UK-based private biotechnology company focused on restoring immune balance through agonists targeting immunosuppressive receptors. The acquisition will provide Gilead with MiroBio's proprietary discovery platform and entire portfolio of immunosuppressive receptor agonists. Gilead expects to advance additional agonists from MiroBio's I-ReSToRE platform over the next several years, including MB151 and other undisclosed early projects.

Biotech is also jumping on the track

A multiindication trial of rosnilimab is ongoing

In addition to the pharmaceutical giants, some small biotech companies are also getting in on the act. Anaptysbio is Lilly's biggest competitor in the PD-1 agonist field, and Anaptysbio's rosnilimab is arguably the most high-profile PD-1 agonist.

Rosnilimab has now entered clinical phase 2 for alopecia areata and will enter clinical phase 2 for RA in the third quarter. Anaptysbio initiated a phase 2 alopecia study of rosnilimab in 2021 after a phase 1 study showed sustained PD-1 occupancy and a favorable safety and tolerability profile.

However, clinical trials in alopecia failed, and Anaptysbio moved on to RA, arguing that PD-1-positive T cells are clinically validated drivers of RA disease. But Lilly's RA clinical trial data are more supportive on this point.

Anaptysbio has a separate PD-1 agonist asset, CC-90006, that was originally developed in partnership with Celgene, but that program was discontinued after Bristol-Myers Squibb acquired Celgene and completed its phase I clinical trial.

In addition, Ibio acquired RTX-002 with Rubryc for $1 million; It is currently in the preclinical stage.

Research progress of PD-1 agonists in China

Throughout the country, the market of PD-1 agonist is still in a relatively blank area, and there are few enterprises with research and development layout. At present, only Meiji Medicine has a corresponding pipeline.

Skyworld has a PD-L1 agonist pipeline, TJ-L1H3, for rheumatoid arthritis and lupus erythematosus.

Both drugs are currently in the preclinical stage.

Conclusion

Compared with the current fierce competition in the field of oncology, the market prospect of autoimmune diseases is equally broad. As a new therapy in the field of self-immunization, PD-1 agonist, which has not yet entered the hot competition, has a promising market prospect and has attracted the attention of multinational companies.

In contrast to the PD-1 inhibitor fire, the demand for PD-1 agonists for autoimmune treatment drugs has not been met so far, and it is still a blue ocean market, but the number of entrants has begun to increase. Domestic pharmaceutical enterprises are expected to keep pace and seize the opportunity to fill the gap in the PD-1 agonist market.