Phase III data: ACCESS-1 trial of pozelimab + cemdisiran vs. ravulizumab in paroxysmal nocturnal hemoglobinuria

Poze-Cemdi is a first-in-class combination of an antibody and an siRNA targeting C5: pozelimab is a fully human monoclonal antibody designed to block the activity of C5, while cemdisiran is an investigational siRNA therapeutic that reduces circulating levels of C5.

PNH is an ultra-rare, chronic, life-threatening complement-mediated blood disorder. People with PNH have an acquired genetic mutation in which red blood cells are destroyed (known as hemolysis) by the complement system, which is part of the innate immune system. The lysed red blood cells release lactate dehydrogenase (LDH), which is a biomarker used to measure the degree of hemolysis. Hemolysis causes a range of symptoms including fatigue, shortness of breath, and life-threatening blood clots. Inhibition of C5, a protein involved in complement system activation, is an established treatment approach to prevent intravascular hemolysis, which occurs inside blood vessels; LDH can be used to determine the effectiveness of C5 inhibition. Addressing intravascular hemolysis is a critical treatment approach to reducing the symptoms and risk of life-threatening complications of PNH.

“C5 inhibitors are widely considered the mainstay of PNH treatment, but a proportion of patients still do not achieve adequate control of intravascular hemolysis, may experience residual anemia, and may feel significant treatment burden, as many of these therapies require clinic or home visits for intravenous delivery,” said Christopher Patriquin, M.D., MSc, Assistant Professor of Medicine, Hematology, at the University of Toronto, hematologist at University Health Network and a trial investigator. “In this Phase III exploratory cohort, the complementary mechanisms of pozelimab and cemdisiran enabled complete, rapid, uninterrupted and durable inhibition of terminal complement throughout the dosing interval. The combination helped more patients achieve target LDH levels compared to the current standard-of-care C5 inhibitor, with the added benefit of infrequent four-week subcutaneous delivery that has potential for self-administration. These data validate this novel combination approach, and we look forward to results from the registrational cohort, which if repeated, could help transform what may be possible for many people with PNH.”

Updated results from an exploratory arm (Cohort A) of the ACCESS-1 trial, as well as interim results from a follow-on, open label extension (OLE) were presented at ASH. Patients were naïve to complement inhibition, with the primary endpoint of Cohort A being percent change in LDH at 26 weeks. LDH is a well-accepted biomarker of intravascular hemolysis that measures how effective a treatment is at inhibiting the destruction of red blood cells and has also demonstrated a correlation to clinical outcomes.  Adequate control of hemolysis is defined as LDH levels of ≤1.5 times upper limit of normal (ULN), while normalization is defined as ≤1 times ULN, respectively.

In Cohort A, patients were randomized to receive either poze-cemdi or ravulizumab. The ravulizumab arm generally responded as would be expected based on historical clinical trial data, which indicate that 44% of treated patients did not achieve LDH normalization (≤1 x ULN).  Results for those treated with poze-cemdi (n=25), compared to ravulizumab (n=23), were as follows:

• 96% achieved adequate LDH control (≤1.5 x ULN) across study visits (weeks 8-26) on average with poze-cemdi, compared to 80% with ravulizumab. At 26 weeks, 5 patients receiving ravulizumab, compared with 1 patient receiving poze-cemdi, did not achieve meaningful LDH control.
• 93% achieved LDH normalization (≤1 x ULN) across study visits (week 8-26) on average with poze-cemdi, compared to 65% with ravulizumab.
• 84% decrease in LDH from baseline at week 26 with poze-cemdi compared to 74% with ravulizumab.
• The CH50 profile observed with poze-cemdi demonstrated complete and uninterrupted inhibition of terminal complement, compared to the profile for ravulizumab showing loss of inhibition at the end of the dosing interval.

After week 26, all patients who completed ACCESS-1 could enroll in a follow-on OLE trial and receive poze-cemdi, including those who initially received ravulizumab (n=19). At the start of the OLE, 68% (n=13) of patients treated with ravulizumab had adequate LDH control. After switching to poze-cemdi, 95% of patients (n=18) achieved LDH control. This included 4 of 5 patients who had failed to achieve LDH control while on ravulizumab.

The safety profile of poze-cemdi was generally consistent with approved C5 inhibitors. During ACCESS-1, treatment-emergent adverse events (TEAEs) occurred in 84% of patients treated with poze-cemdi, compared to 87% treated with ravulizumab. The most common TEAEs (≥10%) for poze-cemdi compared to ravulizumab were headache (28% vs. 17%), upper respiratory tract infection (12% vs. 9%), nausea (12% vs. 4%), anemia (12% vs. 9%), fatigue (8% vs. 13%) and cough (4% vs. 13%). Serious adverse events (SAEs) occurred in two patients receiving poze-cemdi that were considered unrelated to treatment by the investigator. This included one patient who had post-traumatic cellulitis that resolved with treatment while continuing poze-cemdi. The second patient experienced a fever, seizure and hemolytic crisis within one week of the first dose of the combination that also resolved while continuing poze-cemdi; the patient later had a fatal SAE of sepsis and disseminated intravascular coagulation on day 130.

In the OLE, among patients who switched to poze-cemdi from ravulizumab, 68% experienced TEAEs, with the most common being non-serious, mild to moderate injection-site reactions. There were no TEAEs consistent with type 3 hypersensitivity reactions due to large drug-target-drug immune complexes after switching from ravulizumab to poze-cemdi, which have been observed when switching between other C5 inhibitors. There were also no fatal TEAEs, and no patients discontinued therapy due to an adverse event.

The potential use of pozelimab and cemdisiran for the treatment of PNH is investigational and has not been approved by any regulatory authority.

About the Pozelimab and Cemdisiran Clinical Trial Program; Pozelimab and cemdisiran are being evaluated in separate Phase III trials for several complement-mediated disorders, including PNH, myasthenia gravis (MG) and geographic atrophy (GA). PNH: ACCESS-1 is a randomized, active-controlled study comprised of two cohorts, evaluating poze-cemdi in patients with PNH who are naïve to, or have not recently received, complement inhibitor therapy. The first cohort (Cohort A) is an exploratory cohort examining the combination administered subcutaneously as a maintenance regimen every four weeks compared to ravulizumab delivered as a maintenance regimen every eight weeks by intravenous infusion. Cohort B is a registrational cohort examining poze-cemdi against eculizumab. Patients in both cohorts may participate in a follow-on OLE study (ACCESS-EXTENSION) assessing the long-term safety and efficacy of the combination, including in patients who switch from ravulizumab or eculizumab.

MG: NIMBLE is a randomized, double-blind placebo controlled trial evaluating poze-cemdi as well as cemdisiran monotherapy in patients with generalized MG.

GA: SIENNA is a randomized, double-blind, placebo controlled trial evaluating poze-cemdi as well as cemdisiran monotherapy in patients with GA secondary to age-related macular degeneration.

The pozelimab and cemdisiran combination is being developed under an agreement with Alnylam Pharmaceuticals, Inc.