KPG-818’s Novel Mechanism of Action
Elsewhere at EULAR 2024, positive results of another phase 2 study involving a drug with an entirely different mechanism of action, KPG-818, were reported in a poster presentation. KPG-818 modulates CRBN, which results in the degradation of two transcription factors (Aiolos and Ikaros) that are involved in the development, maturation, and proliferation of innate and adaptive immune cells and have been linked to genetic risk in SLE, according to the poster’s authors. It is currently in development for the treatment of SLE, Behçet disease, inflammatory bowel disease, multiple myeloma, and non-Hodgkin lymphoma.
Yao Wang, MD, chief medical officer of KPG-818’s developer Kangpu Biopharmaceuticals, Hefei, China, and associates found that oral doses of 0.15 or 0.6 mg KPG-818 were “generally well-tolerated” and produced immunomodulatory changes that could be beneficial in people with SLE over a 12-week treatment period.
“Only two new agents have been approved for the treatment of SLE in the past five decades in USA and Europe,” Dr. Wang and team wrote, which highlights “a significant unmet need for more effective and safe treatment options.”
They believe that KPG-818 might well fit the bill based on the results of their study, in which 35 of 37 recruited patients completed the treatment. Compared with placebo, they observed reduced numbers of total B cells, Aiolos+ T and B cells, and increased Treg cells.
SLEDAI-2K and Cutaneous Lupus Erythematosus Disease Area and Severity Index activity scores in the 0.15-mg group were improved relative to baseline and placebo.
“The proof-of-concept findings suggest a favorable benefit/risk ratio in SLE for KPG-818,” Dr. Wang and coauthors said, supporting its further development in SLE.
Need for Treatments
Dr. Isenberg told this news organization that both daratumumab and KPG-818 would be welcome additions as treatment options if further trials proved their worth.
“The great frustration about lupus is that, compared to patients with rheumatoid arthritis, the choice has been so limited,” Dr. Isenberg said. Aside from rituximab (Rituxan) and belimumab (Benlysta), which are used with certain restrictions, there are no other biologic targeted treatments available in the United Kingdom. Anifrolumab (Saphnelo) has a license in the United States and some European countries but is not yet available for him to use in his practice.
Daratumumab and KPG-818 are “different types of molecules, and if they work that will be great. It would be nice to have the choice,” Dr. Isenberg said. “Whether they will be as effective as I think rituximab is, I don’t know, but these are some very encouraging results.”
Of course, these are all phase 2 trials, and the “big problem” is that such positive results do not always translate when it comes to phase 3, as Dr. D’Cruz told this news organization.
“Until a few years ago, there had been about 25 or 30 industry-led trails, and they’d all failed, except for belimumab and anifrolumab,” Dr. D’Cruz said. These drugs were found to work and be generally safe in phase 1 and 2 trials, but “when they come to phase 3, they all seem to fail, and we don’t know why.”
These are large global studies, D’Cruz added, observing that problems with patient selection, steroid use, and choice of outcome measures were possible factors for why the EXPLORER and LUNAR studies had shown no benefit for rituximab despite the drug being widely used to treat SLE.
Dr. Isenberg, who has coauthored an article on the topic of why drugs seem to fail at the final hurdle, noted: “I think it has a lot to do with the nature of the disease. It’s a complicated disease.” From having “savvy physicians doing the trials for you” to the placebo response, there are “a whole bunch or reasons why these things haven’t worked in lupus.”
Dr. Morand commented: “We’ve got many programs in phase 2 and 3, and because there’s so many, they’re all facing recruitment challenges, and as a consequence of so much activity, every program is going a little slower than hoped for.”
As for other drugs on the horizon, Dr. Morand noted: “We’re very optimistic about things like litifilimab and deucravacitinib; that’s two examples that are in phase 3. Earlier in the program of development, [there are] a huge range of targets being addressed. The future looks bright. But we might have to wait a while.”
Dr. Arnaud has consulted for AstraZeneca, AbbVie, Alpine Immune Sciences, Biogen, Bristol Myers Squibb, Boehringer Ingelheim, Chugai Pharmaceutical, GlaxoSmithKline, Grifols, Janssen, Kezar Life Sciences, LFB, Lilly, Medac, Merck, Novartis, Pfizer, Roche, and UCB. Dr. Isenberg has served as an adviser to Merck Serono, AstraZeneca, Eli Lilly, Servier, and ImmuPharma. Any honoraria received is passed on to a local arthritis charity connected to his hospital. Dr. D’Cruz has served as a consultant and advisory board member for GlaxoSmithKline and CSL Vifor. Dr. Morand has received research support, consultancy fees, or both from multiple pharmaceutical companies paid to his institution including AbbVie, Amgen, AstraZeneca, Biogen, Bristol Myers Squibb, Eli Lilly, EMD Serono, Dragonfly, Genentech, GlaxoSmithKline, Janssen, Novartis, RemeGen, Takeda, UCB, and Zenas. The ianalumab trial presented by Dr. Agmon-Levin was sponsored by Novartis Pharma; however, she reported having no conflicts of interest. The DARALUP study was an investigator-initiated trial supported by Janssen. Dr. Alexander has received consulting fees, study support, honoraria, and travel grants from various pharmaceutical companies including AbbVie, Amgen, AstraZeneca, Bayer, GlaxoSmithKline, Janssen, and Lilly. Dr. Nash has consulted for The Rheumatology Education Group Consultants. The KPG-818 study reported by Dr. Wang was sponsored by Kangpu Biopharmaceuticals.
A version of this article first appeared on Medscape.com.