Long Term Nomacopan Administration Results in Complete Transfusion Independence in Previously Transfusion-Dependent PNH Patients
Authors: Kulasekararaj Austin , Weston-Davies Wynne , Robak Tadeusz , Nunn Miles , Piekarska Agnieszka , Szmigielska-Kaplon Anna , Hill Anita 
Published: November 2019

BACKGROUND
Nomacopan, a small protein biologic previously known as Coversin (AK576), is in Phase III clinical development for PNH. Patients completing COBALT, a three-month Phase II trial in complement inhibitor naïve PNH patients, were eligible to move into CONSERVE, a long-term safety and efficacy surveillance study. Seven of 8 patients completed COBALT and all moved into the long-term safety study and received treatment with nomacopan for between 20 and 28 months. Six of the patients were transfusion dependent prior to treatment with nomacopan.
METHODS
The haematological, clinical and safety results of patients in CONSERVE have been analysed.
RESULTS:
All patients showed reduction of intravascular haemolysis as evidenced by significant fall of lactate dehydrogenase (LDH) levels and stabilisation of haemoglobin between 1 to 19 months. Of 6 patients who were transfusion dependent prior to entry to COBALT 3 (50%) became transfusion independent during the 12 week trial and 1 became transfusion independent in the 6 months following the trial. All 4 of these patients have remained transfusion independent. Since January 2019 both of the last two transfusion-dependent patients have been transfusion independent for more than 6 months. Patients in COBALT and CONSERVE have had no drug related serious adverse events, no major adverse vascular events, complete inhibition of terminal complement activity at all time points and the drug has been well tolerated.
SUMMARY AND CONCLUSIONS:
Long term complement inhibition with eculizumab is known to result in reduction of transfusion requirements in patients with PNH. In a 66-month long-term study of PNH patients treated with eculizumab, 64 of 78 (82.1%) previously transfusion dependent patients achieved transfusion independence. [i] In this, much smaller study, 6 of 6 previously transfusion dependent patients stabilised their haemoglobin and became transfusion independent (defined here as no transfusion for 6 or more months), two of these finally reaching this point between 18 and 21 months after starting treatment. The data indicate that nomacopan is safe and well tolerated for long term treatment of PNH by patient self-administration and offers significant therapeutic benefit to patients in terms of transfusion independence, an outcome of key importance to clinicians. It is possible that nomacopan may assist in improving bone marrow activity through its inhibition of LTB4 and the effect on the innate immune system which has been linked to bone marrow failure and clonal deletion and recovery. [ii] [iii]
[i] Hillmen P et al. Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol 2013 162(1) 62-73
[ii] Bagby GC. The Role of Innate Immune Dysfunction in Inherited Bone Marrow Failure. Blood 2014 124:SCI-19;
[iii] Trompouki E et al. Inflammatory signaling in bone marrow failure and hematopoietic malignancy (Editorial) Front. Immunol. 2017: 8(660).

Disclosures
Kulasekararaj: Alnylam: Membership on an entity's Board of Directors or advisory committees; Ra Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Achillion: Consultancy; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Akari: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Weston-Davies:Akari Therapeutics Plc: Employment, Equity Ownership. Robak:Acerta: Research Funding; Morphosys AG: Research Funding; Takeda: Consultancy, Research Funding; UCB: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grant, Research Funding; Amgen: Consultancy, Other: Travel grant; Roche: Consultancy, Other: Travel grant, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel grant, Research Funding; Gilead: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding. Nunn:Akari Therapeutics Plc: Employment, Equity Ownership. Szmigielska-Kaplon:Novartis: Consultancy, Honoraria; Alexion: Honoraria; Sanofi: Consultancy, Honoraria. Hill:Apellis: Honoraria; Alexion: Honoraria; Akari: Honoraria; Ra Pharma: Honoraria; Bioverativ: Honoraria; Roche: Honoraria; Regeneron: Honoraria; Novartis: Honoraria.