The SMART Anti-hC5 Antibody (SKY59/RO7112689) Shows Good Safety and Efficacy in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)
Authors: Röth Alexander , Egyed Miklos , Ichikawa Satochi , Kim Jin Seok , Nagy Zsolt , Gaàl Weisinger Julia , Panse Jens P. , Peffault De Latour Regis , Sicre De Fontbrune Flore , Sica Simona , Usuki Kensuke , Yoon Sung-Soo , Winter Erica , Hsu Joy C. , Dieckmann Andreas , Anzures-Cabrera Judith , Jordan Gregor , Shinomiya Kenji , Klughammer Barbara , Bucher Christoph , Jahreis Angelika , Nishimura Jun-Ichi 
Published: October 2019

Abstract

Introduction: SKY59 is an anti-C5 antibody applying SMART* [Fukuzawa et al., SciRep 2017] to allow for infrequent SC dosing. A three-part adaptive clinical trial was conducted in healthy volunteers (part1 -previously reported, Röth et al., Blood 2017 130:4750) and PNH patients who are treatment naive (part 2) or previously treated with eculizumab (ecu) (part 3) to establish dose, safety and efficacy of SKY59.
Methods: Part 2 was an intra-patient dose escalation study. Patients received IV doses of 375mg, 500mg, and 1000mg of SKY59 on days 1, 8 and 22, respectively, followed by weekly doses of SKY59 of 170mg SC starting on day 36.
In part 3 PNH patients who had been on ecu for at least 3 months received an IV loading dose of 1000mg SKY59 on day 1, 2 weeks after their last ecu dose, and were randomized to receive 170mg SC QW, 340mg SC Q2W or 680mg SC Q4W of SKY59 starting on day 8.
After 5 months all patients entered an open-label extension remaining on their previous dose regimen with SKY59.
Terminal complement activity was quantified using an ex vivo liposome immunoassay (LIA).
The study was approved by Ethics Committees and Health Authorities and conducted according to the principles of the declaration of Helsinki.
Results: 17 PNH patients were included (Table 1), 10 in part 2 and 7 in part 3 at the time of writing this abstract.
PK: After SC administration, bioavailability is estimated at 100%. For a patient of 75 kg, the terminal half-life was estimated around 25 days.
PD: Following IV dosing, complete complement inhibition (defined as LIA values < 10 U/mL, the LLOQ of the assay), was achieved at end of infusion in all patients and maintained for all SC dose regimens.
Median baseline (BL) total C5 concentration was 107 μg/mL (range: 66.9 - 130 μg/mL) in part 1, 140 μg/mL (73.6 - 184 μg/mL) in part 2, 295 μg/mL (205 - 354 μg/mL) in part 3. Following treatment with SKY59, patients in Part 2 showed a slight increase in total C5 at week 6 to 215 μg/mL (109 - 331 μg/mL). Patients in part 3 had a significant decrease in total C5 at week 6 to 228 μg/mL (184 - 305 μg/mL), likely reflecting the antigen disposing activity of SKY59.
Treatment-naive patients (including one Arg885His C5 SNP patient [Nishimura et al.; N Engl J Med. 2014]) with PNH had a rapid median reduction in LDH (-79% from BL; median 1.20 x ULN, range 0.8 to 1.7 x ULN) at 6 weeks. LDH of Patients in part 3 did not show a significant change at 6 weeks or later compared to BL except for one C5 SNP patient who normalized LDH.
6/6 of naive (non-transfusion dependent) and 1/5 switch (non-transfusion dependent) patients had an increase in hemoglobin of at least 10g/L from BL to week 20, one patient in Part 2 and one patient in Part 3 normalized their hemoglobin. Overall transfusion requirements were not changed.
QoL: From BL to week 10 treatment naive patients experienced a median change of +11 points (range -1 to 28) in the FACIT fatigue score. Switch patients showed no significant short-term change from BL to week 12 on the same questionnaire.
Safety: Treatment with SKY59 was well tolerated, particularly, no injection site AEs and a low incidence of headache was observed. There were 2 SAEs (break-through hemolysis due to infection and atrial fibrillation) not related to study drug. No AEs resulted in withdrawal from the study or death.
In 2/7 switch patients mild-moderate non-serious, likely drug-target-drug complex (DTDC) mediated reactions with clinical manifestations similar to serum sickness were observed in the initial post-switch period (day 9 and 10 respectively). These manifestations were treated with topical steroids and resolved by day 21 with no interruption in study treatment.
In patients switching from ecu to SKY59, the formation of DTDC composed of SKY59, C5, and ecu are expected due to the different binding epitopes of the two antibodies.
Conclusion: SKY59 administered SC in a low volume is very well tolerated, has a good benefit/risk ratio and is efficacious in treatment naive and ecu-treated patients with PNH. Transient induction of DTDC was not associated with undue toxicity. Furthermore, SKY59 has the potential to provide treatment for patients unresponsive to ecu due to SNP and significantly reduces the treatment burden associated with chronic IV administration.
Updated data will be presented at the meeting.
* Sequential Monoclonal Antibody Recycling Technology

Disclosures
Röth: Bioverativ: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Roche: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Peffault De Latour:Novartis: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding; Pfizer Inc.: Consultancy, Honoraria, Research Funding. Usuki:Takeda Pharmaceutical: Speakers Bureau; Boehringer-Ingelheim Japan: Research Funding; Novartis: Speakers Bureau; Pfizer Japan: Research Funding, Speakers Bureau; Ono Pharmaceutical: Speakers Bureau; Sumitomo Dainippon Pharma: Research Funding, Speakers Bureau; Daiichi Sankyo: Research Funding; Shire Japan: Research Funding; SymBio Pharmaceuticals Limited.: Research Funding; GlaxoSmithKline K.K.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Chugai Pharmaceutical: Speakers Bureau; Celgene Corporation: Research Funding, Speakers Bureau; Sanofi K.K.: Research Funding; Janssen Pharmaceutical K.K: Research Funding; Nippon Shinyaku: Speakers Bureau; Mochida Pharmaceutical: Speakers Bureau; MSD K.K.: Speakers Bureau. Winter:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Hsu:Roche: Employment. Dieckmann:Roche: Employment. Anzures-Cabrera:Roche: Employment. Jordan:Roche: Employment. Shinomiya:Chugai: Employment. Klughammer:F. Hoffmann-La Roche Ag: Employment. Bucher:Roche: Employment. Jahreis:Genentech: Employment, Equity Ownership. Nishimura:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Chugai Pharmaceuticals: Consultancy, Research Funding.