According to an article published in Cold Agglutinin News, Dianthus Therapeutics (“Dianthus”) is planning on holding a proof-of-concept study in 2024. Within the study, the company would evaluate the safety and efficacy of DNTH103, an investigational long-acting classical complement pathway inhibitor administered via subcutaneous injections, for patients with cold agglutinin disease (CAD). 

The FDA has previously approved a therapy for CAD: Enjaymo (sutimlimab). Like DNTH103, Enjaymo suppresses the complement C1s protein. This protein is pro-inflammatory, so suppressing it can inhibit symptoms associated with this condition. Unlike DNTH103, Enjaymo binds to both active and inactive C1s protein, which means that patients must take more of the medication to receive symptom relief. 

Preclinical studies and an ongoing Phase 1 study have shown that DNTH103:

• Specifically targets the classical complement pathway while avoiding other pathways
• Stops red blood cell hemolysis in a more significant way that Enjaymo 
• Is safe and well-tolerated in heavy volunteers 

Within the upcoming Phase 2 open-label study, researchers will seek proof-of-concept that DNTH103 can cause similar clinical results to Enjaymo and other C1s inhibitors but at a lower dosage and more convenient dosing schedule. DNTH103 is also being explored for other conditions such as myasthenia gravis. If this trial goes forward as planned, data should be available in Q3/Q4 of 2024. 

What is Cold Agglutinin Disease (CAD)? 

Cold agglutinin disease is a rare autoimmune disorder characterized by red blood cell hemolysis (destruction). Normally, red blood cells carry oxygen throughout the body. In cold agglutinin disease, antibodies called cold agglutinins begin to attack red blood cells when exposed to cold temperatures (between 32-50F). It is most common in people between 40-80 years old and occurs slightly more frequently in females than males. CAD may be primary (occurring spontaneously with no known cause) or secondary (as the result of other conditions like mycoplasma pneumonia). 

Symptoms relating to CAD may include:

• Pallor (extremely pale skin)
• Hemolytic anemia (red blood cell destruction)
• Nausea and vomiting 
• Fatigue and general malaise
• Tinnitus (ringing in the ears)
• Headaches
• Dizziness 
• Skin discoloration
• Jaundice (yellowing of the skin, eyes, and mucous membranes)
• Leg, chest, and back pain
• Diarrhea
• Dark urine
• Heart palpitations
• Shortness of breath
• Blue-colored, cold, or painful hands and feet
• Enlarged heart

Plasmapheresis and certain medications designed to reduce symptoms may be used for treatment.