A PHASE 2 OPEN-LABEL PROOF OF CONCEPT STUDY OF THE ORAL, SMALL MOLECULE FACTOR D INHIBITOR, ACH-4471, IN UNTREATED PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH)
Author(s): ,
Peter Browett
Affiliations:
Department of Molecular Medicine and Pathology,University of Auckland,Auckland,New Zealand
,
Austin Kulasekararaj
Affiliations:
King's College Hosptial-NHS Foundation Trust & King's College London,London,United Kingdom
,
Jong Wook Lee
Affiliations:
Seoul St. Mary's Hospital, The Catholic University of Korea,Seoul,Korea, Republic Of
,
Rosario Notaro
Affiliations:
Azienda Ospedaliera Universitaria Careggi,Firenze,Italy;Instituto per lo Studio, la Prevenzione e la Rete Oncologica,Firenze,Italy
,
Robert Brodsky
Affiliations:
Johns Hopkins University School of Medicine,Baltimore,United States
,
Mingjun Huang
Affiliations:
Achillion Pharmaceuticals,New Haven,United States
,
Michael Geffner
Affiliations:
Achillion Pharmaceuticals,Blue Bell,United States
Antonio Risitano
Affiliations:
Universita Federico II di Napoli,Napoli,Italy
EHA Library. Browett P. Jun 15, 2019; 267447; S864
Peter Browett
Peter Browett
Contributions
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Abstract

Abstract: S864

Type: Oral Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 12:15 - 12:30

Location: Hall E106

Background
Factor D (fD) is a highly specific serine protease that cleaves factor B as its only substrate. It is the rate-limiting step of the alternative pathway (AP) of complement. Therefore, fD is a promising target in diseases of excess activation of the AP, such as paroxysmal nocturnal hemoglobinuria (PNH).   In PNH, a somatic mutation in the PIGA gene of one or a few hematopoietic stem cells generates a clone of abnormal erythrocytes which lack two key AP regulatory proteins (CD55 and CD59), leading to uncontrolled complement activation on affected erythrocytes (RBCs) and membrane attack complex (MAC)-mediated lysis.

Aims
Based on preclinical research regarding inhibitory effects on hemolysis of PNH RBCs (Yuan et al; haematol.2016.171977) and Phase 1 research for pharmacokinetics (PK), pharmacodynamics (PD), tolerability and safety (Ellis-Pegler et al, EHA 2016), we hypothesize that ACH-4471, an oral, small molecule fD inhibitor, represents a potential treatment option for PNH patients, even in monotherapy.

Methods
Data are presented for this Phase 2, dose-finding, proof of concept trial in PNH patients not currently receiving complement inhibitor treatment.  Ten adult PNH patients were included with anemia (Hgb < 12 g/dL and adequate reticulocytosis per investigator), PNH Type III RBC/granulocyte clone size > 10%, LDH > 1.5X ULN, platelets > 50,000 µL and were willing to be vaccinated for N. Meningiditis, H. Influenzae and S. Pneumoniae. Starting doses ranged from 100-150 mg TID, with subsequent dose escalation based on response (clinical and biochemical) to doses as high as 200 mg TID. The primary efficacy parameter was the change in LDH versus baseline at Day 28. Secondary efficacy parameters were the effects on hemoglobin relative to baseline at Days 28 and 84 and change in LDH versus baseline at Day 84. General safety, tolerability, PK/PD of ACH-4471 and patient reported outcomes (PRO) were also measured.   After 12 weeks of treatment, patients deriving clinical benefit entered a separate long-term extension study.

Results
Ten patients were dosed with ACH-4471. Two patients discontinued; one withdrew for personal reasons unrelated to safety and the other, was discontinued for a serious adverse event of elevated ALT/AST coincident with breakthrough hemolysis, which resolved without sequelae. The remaining 8 patients completed treatment and entered the long-term extension study. The mean LDH for these 8 patients was 5.6X ULN at baseline, 1.5X ULN at Day 28 and 2.15X ULN at Day 84.  The mean hemoglobin at baseline was 9.7 g/dL and the mean increase versus baseline was 1.2 g/dL and 1.8 g/dL at Day 28 and Day 84, respectively. Mean reticulocyte counts and total bilirubin levels were also decreased to the normal range with ACH-4471 treatment.  The mean baseline FACIT-FATIGUE score at baseline was 37 and increased by 10 and 13 points at Day 28 Day 84, respectively.

Conclusion
Proof of concept has been demonstrated with ACH-4471 as a novel, oral, small molecule inhibitor of fD. Meaningful improvements in LDH, hemoglobin and PRO versus baseline were achieved. Notably, these improvements were observed in monotherapy, confirming the concept that upstream complement inhibition at the level of fD is able to prevent MAC-mediated intravascular hemolysis in the absence of terminal pathway blockade (i.e., anti-C5 agents). Further improvements in clinical efficacy is expected with next-generation, oral fD inhibitors, with increased potency allowing for significantly higher trough concentrations and twice daily administration.

Session topic: 12. Bone marrow failure syndromes incl. PNH - Clinical

Keyword(s): Complement, Hemolytic anemia, Paroxysmal nocturnal hemoglobinuria (PNH)

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