The SMART-IgG Anti-hC5 Antibody (SKY59/RO7112689) Has Favorable PK, PD, Subcutaneous Bioavailability, and Safety Profile in Phase I HV Study

Introduction:

Complement component 5 (C5) is a validated target in paroxysmal nocturnal hemoglobinuria (PNH). Inhibition of C5 with eculizumab has resulted in significant reduction of hemolysis, reduction of thromboembolic events and increased survival in patients with PNH. However, eculizumab requires frequent intravenous (IV) infusions and some patients may still experience breakthrough hemolysis.^1-3

RO7112689, originally developed by Chugai Pharmaceutical, is a novel anti-hC5 antibody applying the SMART-IgG* recycling technology.⁴ It is currently being assessed in a three-parts phase 1/2 study in healthy volunteers (HVs; Part 1) and patients with PNH (Parts 2 and 3). Herein we report the safety and tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of RO7112689 in HVs, following single IV or subcutaneous (SC) administration (Part 1).

Methods:

Part 1 was a randomized, double blind, adaptive, placebo-controlled, single ascending dose, parallel group study in HVs. The primary objective was to evaluate the safety and tolerability of single doses of RO7112689 in HVs. Secondary objectives were the characterization of PK and PD in HVs. Eligible subjects were healthy males between 21 and 55 years of age, inclusive, with a body mass index between 18 and 30 kg/m², inclusive. Prior to enrollment all subjects had a negative nasopharyngeal culture for Neisseria meningitidis. At each dose-level/cohort 5 HVs were randomized (3:2) to receive a single IV (Cohorts 1 and 2) or SC (Cohort 3) dose of RO7112689 or placebo. Dose levels for cohorts 1, 2 and 3 were 75 mg IV, 125 mg IV, and 100 mg SC, respectively. Based on preclinical data, transient reduction of complement activity was predicted. Terminal complement inhibition was assessed using a validated liposome immunoassay⁵ and a lab-developed immunoassay to assess free C5. The study was approved by the Ethic Committees and health authorities and conducted according to the principles of the declaration of Helsinki.

Results:

Fifteen HVs were enrolled into 3 cohorts. Each cohort consisted of 3 individuals who received active treatment and 2 who received a matching placebo. Following IV doses, exposure was dose proportional from 75 to 125 mg. Based on single dose administration the estimated terminal half-life (t_1/2) for a typical patient of body weight 70 kg was approximately 25 days. Following SC administration, RO7112689 exposures peaked around day 7 and the bioavailability was estimated to be around 90%. In line with predictions, dose dependent reduction of terminal complement activity was achieved in HVs dosed with 75mg and 125 mg RO7112689 IV. Transient complete complement inhibition was observed in 2 out of 3 subjects receiving 125 mg RO7112689 IV. In addition, rapid and transient reduction of free C5 levels was observed.

In part 1 no severe or serious adverse events (AEs) were reported and no subject was prematurely withdrawn from the study due to an AE. A total of 14 AEs of mild or moderate intensity were noted in 12 HVs. Only one subject experienced a drug related AE of generalized pruritus and rash in the lowest dose group. All other AEs were rated unrelated to treatment.

Detailed clinical and laboratory assessments have not identified any significant safety concerns. Two subjects out of 9 were found to have anti-drug antibodies on day 81 after a single RO7112689 dose of 125 mg IV or 100 mg SC with no associated safety findings.

Conclusion:

Single ascending doses of RO7112689 in HVs were well tolerated, without severe or serious AEs. PD parameters correlated well with the observed PK resulting in a rapid and transient reduction of free C5 paralleled by transient terminal complement inhibition. Initial results suggest that RO7112689 is a promising therapy for inhibiting complement in PNH and other complement-mediated diseases. The high bioavailability supports the SC mode of administration reducing the treatment burden for patients. This is currently being assessed in treatment naïve patients with PNH in part 2 of the study. Part 2 data may be presented if they are available in time.

* Sequential Monoclonal Antibody Recycling Technology

1) Hillmen et al., N Engl J Med; 355:12; 2006

2) Hill et al., Blood; 106:2559-2565 2005

3) Loschi et al., Am J Hematol:91:366-70; 2016

4) Fukuzawa et al., Scientific Reports; 7: 1080

5) http://www.wakodiagnostics.com/r_ch50.html