Rallybio Reports Complete C5 Blockade in RLYB116 Phase 1 Study, Setting Up Move Into Rare Disease
Rallybio Corporation announced positive results from a Phase I confirmatory pharmacokinetic/pharmacodynamic study of RLYB116, a subcutaneously administered complement inhibitor targeting C5, in healthy volunteers. The once-weekly injection, built on the Affibody platform licensed from Sweden-based Affibody AB, achieved complete and sustained inhibition of terminal complement activity at the 300 mg dose, with no gastrointestinal adverse events and no discontinuations. Rallybio, a Connecticut-based biotech focused on complement-mediated diseases, is developing the molecule for immune platelet transfusion refractoriness (PTR) and refractory antiphospholipid syndrome (APS) — two conditions that currently lack approved complement-targeted therapies.
Trial Specifics: RLYB116 Phase 1 Confirmatory PK/PD Study Design and Results
The single-blind, multiple ascending dose study (NCT06797375) enrolled two cohorts of eight healthy volunteers each, randomized 3-to-1 to receive RLYB116 or placebo administered subcutaneously once weekly for four weeks. Cohort 1 received 150 mg and Cohort 2 received 300 mg, with a 10-week follow-up period after the final dose. The study's objective was to confirm that RLYB116 could produce complete and sustained terminal complement inhibition with an acceptable tolerability profile. At the 300 mg dose, the company reported complete and sustained inhibition of ex-vivo hemolytic activity, the functional pharmacodynamic readout used to assess blockade of the terminal complement cascade. No numerical PK/PD data, confidence intervals, or formal statistical analyses were disclosed; the results were described qualitatively as demonstrating clinically effective blockade.
Both dose levels were well tolerated. The most common adverse events were mild-to-moderate injection site reactions, consistent with other subcutaneously administered biologics. No gastrointestinal side effects were reported in either cohort — a finding the company highlighted as validating manufacturing process enhancements designed to improve tolerability. No severe adverse events occurred and no participant discontinued treatment. The company did not disclose whether the 10-week follow-up period has concluded or whether additional pharmacodynamic durability data will be reported separately.
Rallybio said it is planning to initiate a Phase II study of RLYB116 in immune PTR during H2 2026, with topline data anticipated in 2027. David Bejker, CEO of Affibody, said the results "further illustrate the potential of the Affibody platform to deliver best-in-class therapies." The molecule was initially discovered by Affibody under a collaboration with Swedish Orphan Biovitrum AB (Sobi) before being licensed to Rallybio for clinical development in complement-mediated diseases. No US FDA designations such as Fast Track, Orphan Drug, or Breakthrough Therapy have been publicly confirmed for RLYB116, and the molecule remains unapproved in all jurisdictions.
Research Context: C5 Inhibition and the Complement-Mediated Disease Landscape
RLYB116 is a long-acting inhibitor of complement factor C5, a protein that sits at a terminal bottleneck in the complement cascade. Cleavage of C5 generates two effector fragments: C5a, a potent inflammatory mediator, and C5b, which initiates assembly of the membrane attack complex (MAC/C5b-9) responsible for cell lysis. By blocking C5, RLYB116 prevents both downstream pathways simultaneously. The Affibody platform produces small therapeutic proteins of approximately 6 kDa — substantially smaller than monoclonal antibodies — which the company says enables formulation as a low-volume subcutaneous injection suitable for once-weekly self-administration.
The two indications Rallybio has prioritized occupy distinct positions in the complement disease space. Immune PTR occurs when patients develop alloantibodies, primarily against HLA antigens on transfused platelets, leading to complement-mediated destruction of the transfused cells and failure to achieve adequate platelet count increments. Current management relies on HLA-matched or crossmatch-compatible platelet products, a logistically constrained approach with no pharmacological alternatives. RLYB116 appears to be the first complement inhibitor C5 molecule to enter clinical development specifically for this indication.
Refractory APS involves pathological thrombosis and pregnancy morbidity driven in part by antiphospholipid antibody-mediated complement activation. Preclinical work has established that C5 and C5a receptor signaling contribute to thrombotic and inflammatory injury in APS models, and clinical experience with off-label eculizumab use in catastrophic APS has provided proof-of-concept for C5 blockade in this setting.
The C5 inhibitor landscape is well populated, though no approved agent targets either PTR or refractory APS as a labeled indication. Key competitors include: