Dianthus Therapeutics’ (DNTH) primary asset is DNTH103, a selective monoclonal antibody targeting the active form of complement C1s. The main focus is a me-better version of Sanofi’s already-marketed C1s monoclonal antibody, Sutimlimab. DNTH103 completed a Phase I study showing favorable safety and PK. DNTH plans to initiate multiple Phase II trials for autoimmune neuromuscular disorder indications in 2024.
Classical Complement Pathway – An Introduction to C1s Targets
Fig. 1 Complement signaling pathways.1
Many autoimmune diseases, especially those associated with pathogenic autoantibodies, have been shown to be connected with abnormal activation of the complement pathway. The complement C1 complex (C1q, C1r, C1s) is the most upstream component of the classical pathway of complement. Upon binding to immune complexes formed by autoantigen-antibody, it prompts sequential cleavage of C3 and C5 through a series of reactions. This, in turn, triggers subsequent reactions such as the generation of C3a and C5a for recruiting and activating effector cells, the deposition of C3-conditioning hormones that mediate phagocytosis and lymphocyte activation, and the eventual formation of the membrane attack complex.
Alexion’s Soliris and Ultomiris, developed based on the C5 target, were great successes, and have been approved for several self-immunization indications such as PNH, NMO, and gMG. However, because C5 is located furthest downstream of the classical pathway of complement, antagonizing C5 does not ameliorate C3-mediated pathological changes. Many drug companies have attempted to target the C1 complex upstream of the classical pathway to address this issue.
Unlike complement therapies such as Soliris, Ultomiris, and Pegcetacoplan, targeting the C1 complex inhibits only the complement classical pathway and has no blocking effect on the lectin pathway or the alternative pathway. This could potentially lead to a safety advantage. Interestingly, congenital defects in C1q in the C1 complex are the predominant genetic risk factor for lupus. 85%-90% of individuals deficient in C1q develop symptoms of SLE, possibly because the complement classical pathway is responsible for the regulatory effects of antibody complexes, cellular debris, and apoptotic cells. Unlike C1q, inhibition of C1s has a minimal effect on phagocytosis to uptake apoptotic cells. Thus, inhibiting C1s to control the overactivated complement pathway became a new option.
Creative Biolabs offers a wide range of products for C1s research.
Sanofi Lays Out Two Targeted Drugs for C1s Targets
(1) Sutimlimab
Sutimlimab, a humanized C1s monoclonal antibody of the IgG4 subtype, is the first and only marketed C1s monoclonal antibody approved by the FDA in 2022 for the treatment of Cold Agglutinin Disease (CAD). It is the first approved therapy for CAD.
CAD is a rare autoimmune hemolytic anemia, a disease in which an excessive immune response is triggered by the binding of cold agglutinins (cold-reactive anti-red blood cell antibodies) to the surface of red blood cells, and affects approximately 5,000 patients in the United States.
There are still some problems with Sutimlimab. Complement is mostly present in the body in an inactive form, and Sutimlimab targets both active and inactive forms of C1s. The concentration of inactive forms of C1s in the body is much higher than that of active forms, resulting in higher dosages of the drug in patients. Sanofi has responded to these problems with the launch of its second-generation monoclonal antibody to C1s, SAR445088.
(2) SAR445088
SAR445088 is Sanofi’s second-generation C1s monoclonal antibody. Compared to Sutimlimab, which targets both active and inactive C1s, SAR445088 is highly selective for the active form of C1s and has a longer half-life for intravenous/subcutaneous administration in humans. This supports a longer dosing cycle and a more convenient mode of subcutaneous administration.
According to public disclosure, SAR44588 is in clinical phase II for the indications of antibody-mediated rejection and chronic inflammatory demyelinating polyneuropathy (CIDP), a rare autoantibody-mediated polyneurological disorder with key features including nerve demyelination and inflammation of the peripheral nervous system leading to impaired motor and sensory function, with approximately 15,000 patients in the United States. Existing standard therapies have significant side effects and high costs, and there are no new mechanism drugs on the market. Thus, there is a large unmet need for CIDP. SAR44588 has shown promising preliminary clinical results in an ongoing Phase II clinical trial for CIDP.
DNTH103
DNTH103 Phase I clinical trials have been completed and demonstrated good PK properties and safety with a half-life of 60 days, supporting a biweekly subcutaneous dosing regimen with a favorable safety profile and no SAE events. DNTH103 is expected to undergo a generalized myasthenia gravis (gMG) trial in the 1st quarter of 2024, followed by a multifocal motor neuropathy (MMN) trial in the second half of 2024 and a CIDP clinical trial in the second half of 2024.
Conventional therapies for gMG (including acetylcholinesterase inhibitors, corticosteroids, non-steroidal immunotherapies, IVIg, and PLEX) are effective in controlling symptoms, but are slow-acting and have serious side effects. Complement inhibitors and anti-FcRn therapies have greatly improved the treatment of gMG, and targeting the complement pathway or IgG has been shown to be effective in gMG.
C1s antibodies promise a breakthrough in gMG indications, particularly in AchR+ MG, where the classical pathway is initiated when IgG1 or IgG3 (and less frequently IgG2) autoantibodies attached to the AChR bind to C1q. This is the primary pathogenetic mechanism of AChR+ MG. DNTH103 has also been shown in the preclinical setting using sera from patients with AChR+ MG, demonstrating that DNTH103 may have better efficacy compared to C5 antibodies.
DNTH103 has the potential to offer greater advantages in terms of avoiding the risk of serious infections, low dosage, and less frequent dosing.
Summary and Prospects
C1s, as an upstream component of the classical complement pathway, is a very promising target in autoimmune IgG-mediated self-immune diseases. The current safety data are excellent. Both the C1s target and DNTH as a company have multiple challenges ahead:
1) According to statistical analysis of epidemiology, inhibition of targets in the C1 complex still carries a theoretical risk of increasing the probability of developing lupus.
2) Theoretically, targeting the classical pathway can treat autoimmune diseases mediated by autoantibodies of IgG1/IgG3 subtypes, but there is not enough clinical evidence to prove the effectiveness of merely inhibiting the classical pathway in autoimmune diseases other than CAD. Admittedly, as C3 and C5 act as downstream components of the complement pathway, and inhibition of C3/C5 can inhibit all three pathways simultaneously to play a role.
3) It is difficult to demonstrate the efficacy of anti-C1s antibodies in gMG with preclinical evidence on animal models due to the lack of a better animal model, in contrast to the higher clinical risk of gMG.
Reference:
1. Kolev, Martin, Gaelle Le Friec, and Claudia Kemper. “Complement—tapping into new sites and effector systems.” Nature Reviews Immunology 14.12 (2014): 811-820.