Initial Data in Paroxysmal Nocturnal Hemoglobinuria Patients from Ongoing Phase 1/2 Clinical Study with ALN-CC5 Support Potential for Eculizumab Sparing and Improved Disease Control for Eculizumab Inadequate Responders

We reported data from 6 patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) enrolled in Part C of our ongoing Phase 1/2 clinical study with ALN-CC5, an investigational RNAi therapeutic targeting complement component 5 (C5) for the treatment of complement-mediated diseases. These data were presented at the 21st Congress of the European Hematology Association (EHA) Meeting in Copenhagen, Denmark, held June 9-12, 2016.  In this part of the study, ALN-CC5 was evaluated as a monotherapy or as an adjunct to eculizumab, an approved anti-C5 monoclonal antibody indicated for the treatment of PNH.

Preliminary results in PNH showed that administration of ALN-CC5 as monotherapy achieved clamped and robust knockdown of serum C5 and inhibition of complement comparable to that seen in healthy volunteers.  Lowering of lactate dehydrogenase (LDH), a biomarker of red blood cell hemolysis was achieved, although LDH levels did not reach the goal of less than 1.5 times the upper limit of normal (ULN). To investigate the eculizumab sparing potential of ALN-CC5, an exploratory data analysis was conducted in eculizumab naïve patients (N=3) who received a single dose (600 mg) of eculizumab after ALN-CC5 dosing was completed in order to treat ongoing hemolysis. In the context of ongoing ALN-CC5 knockdown of serum C5 >95%, a single dose of eculizumab achieved lowering of LDH below 1.5 times the ULN that was sustained out to 4 weeks. These results suggest that the use of ALN-CC5 as a foundational therapy can potentially reduce the dose and frequency of eculizumab for PNH patients. This novel treatment paradigm has the potential to improve overall disease management and quality of life, as well as potentially reduce the economic burdens associated with intravenous anti-C5 monoclonal antibody therapy.

In the group of patients being treated with background eculizumab (N=3) at baseline, ALN-CC5 also achieved robust C5 knockdown and inhibition of complement activity. This group included a patient who had an inadequate response to eculizumab and was being treated with higher than labeled doses, but was still experiencing elevated LDH and breakthrough hemolysis at the time of study entry. In this patient, ALN-CC5 administration resulted in reduction of LDH to below 1.5 times the ULN and an over 1 g/dL increase in hemoglobin. Following ALN-CC5 administration, the investigator successfully reduced eculizumab from a dose of 1200 mg every 2 weeks to the labeled dose of 900 mg every 2 weeks. These preliminary data support the potential of ALN-CC5 to improve disease control in patients with an inadequate response to eculizumab.

ALN-CC5 was generally well tolerated in patients with PNH, with no drug related serious AEs or discontinuations due to AEs in the study. One patient, who was concomitantly taking eculizumab, cyclosporine, and anabolic steroids, experienced a transient grade 3 elevation of liver transaminases that was deemed possibly related to study drug, and dosing of ALN-CC5 was interrupted.  All other AEs reported were mild or moderate in severity, three patients experienced mild, transient ISRs, and there were no clinically significant changes in vital signs, EKG, or laboratory results.

We believe that ALN-CC5 has the potential to transform the management of PNH, where clamped inhibition of hepatic C5 synthesis has the potential to provide the foundation for reduced frequency and doses of eculizumab, as well as improved disease control for eculizumab inadequate responders. We are encouraged by these data as we work to advance potential therapeutic options for PNH patients, and patients with other complement-mediated diseases, such as Atypical Hemolytic Uremic Syndrome (aHUS), and Myasthenia Gravis (MG). We look forward to the continued development of ALN-CC5 as we strive to address unmet needs and improve the lives of patients living with complement-mediated diseases.