ALBERT

Description: Background: PNH is a rare, acquired blood disorder. A somatic mutation in the PIGA gene of one or more hematopoietic stem cells generates a clone of abnormal erythrocytes (RBCs) that lack alternative pathway (AP) regulatory complement proteins CD55 and CD59. This leads to uncontrolled complement activation on affected RBCs and intravascular hemolysis (IVH). Standard of care is C5 inhibition to prevent membrane attack complex (MAC) formation. Despite preventing MAC-mediated IVH, many patients experience extravascular hemolysis (EVH). Despite C5 inhibition, ~ 70% of patients remain anemic and 〉1/3 were transfused 〉 1 time in the prior 12 months. Factor D (FD), a serine protease, catalyzes complement factor B cleavage, allowing formation of AP C3 convertase. By inhibiting FD, oral danicopan blocks C3 convertase formation, the control point for AP activation and amplification of all pathways. This leads to inhibition of C3 cleavage, C3 fragment deposition, terminal pathway activation and MAC formation. Thus, danicopan can control both IVH and EVH therefore, making FD a promising target. Aim: Demonstrate that danicopan is a potential treatment for PNH patients with an inadequate response to C5 inhibition. Methods: Data are presented for this Ph 2, dose-finding, proof of concept trial of danicopan in patients with an inadequate response to eculizumab who were transfusion dependent. Additional criteria in Table 1. In addition to the current eculizumab regimen, danicopan starting doses were 100-150 mg TID, with dose escalation up to 200 mg TID, based on clinical and biochemical response, at protocol defined time points (Figure 1). The primary endpoint was change in Hgb at Treatment Week (TW) 24. Secondary efficacy parameters included transfusion needs, effect on lactate dehydrogenase (LDH), and an exploratory an endpoint of Functional Assessment of Chronic Illness Therapy (FACIT) FATIGUE scores. General safety, tolerability, and PK/PD of danicopan were measured. After TW 24, patients entered a long-term extension. Results: Twelve patients received at least one dose of danicopan. One patient discontinued after 2 doses, due to a serious adverse event of worsening of an underlying condition (pulmonary hypertension/edema), considered unlikely related to danicopan. This patient is excluded from this analysis. Eleven patients continue to receive treatment. Dose titrations are shown in Table 2. Benefits were observed in multiple laboratory markers of PNH, shown in Table 3. Hgb improved in all patients, with a mean Hgb gain of 2.6 g/dL at 24 Weeks of treatment (n=4). Meaningful improvement in FACIT Fatigue scores were reported, with a mean increase of 8 points relative to the baseline on eculizumab. A 3-point change is clinically meaningful on this scale. Transfusion needs dramatically reduced, with one patient receiving one transfusion during the trial, as compared to 34 transfusions (58 units) in 10 patients, in the 6 months prior to screening. One patient (who does not accept blood products due to religious objections and also has hereditary elliptocytosis) had a baseline Hgb=5 g/dL with a 3.5 g/dL improvement at TW24 and significant improvement in fatigue. C3 fragment deposition was inhibited; reticulocytes, total/ direct bilirubin and LDH returned to normal range. Baseline C5 inhibition (classical pathway activity) was essentially inhibited (mean=1 [range 60-144]). Three of 11 patients received 〉 900 mg eculizumab, making PK a less likely reason for inadequate response. Danicopan has been well tolerated; 96% of treatment emergent adverse events (TEAEs) were mild to moderate in severity and no discontinuations due to TEAEs. Two patients had Grade 3 TEAEs which resolved and continued in the trial. Conclusion: Proof of concept is established with danicopan, an oral, small molecule FD inhibitor in the treatment of PNH in combination with eculizumab. Meaningful improvements in Hgb, transfusion needs, FACIT-FATIGUE and other parameters of interest were achieved. These clinically significant improvements demonstrate that further benefit can be achieved by blocking the alternative pathway at FD with danicopan, in combination with C5 inhibition. This benefit is likely due to the prevention of C3-mediated EVH, in addition to control of IVH. Danicopan targets an unmet need in PNH and will be further evaluated in a pivotal trial in combination with standard of care C5 inhibition. Disclosures Kulasekararaj: Achillion: Consultancy; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; 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; Amgen: Consultancy, Honoraria, 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; Akari: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alnylam: Membership on an entity's Board of Directors or advisory committees. Risitano:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; Achillion: Research Funding; Amyndas: Consultancy; Apellis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Samsung: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Research Funding, Speakers Bureau; Alexion: Honoraria, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Research Funding; Achillion: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ra Pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Biocryst: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ra Pharma: Research Funding; Samsung: Membership on an entity's Board of Directors or advisory committees; Apellis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Maciejewski:Novartis: Consultancy; Alexion: Consultancy. Notaro:Alexion: Membership on an entity's Board of Directors or advisory committees, Other: letture fees. Browett:Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Beigene: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Achillion: Research Funding. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding. Huang:Achillion: Employment, Equity Ownership. Geffner:Achillion: Employment, Equity Ownership. Brodsky:Alexion: Membership on an entity's Board of Directors or advisory committees, Other: Grant funding; Achillion: Research Funding.

Description: Background: 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 alternative pathway (AP) regulatory proteins, CD55 and CD59, leading to uncontrolled complement activation on affected erythrocytes (RBCs) and membrane attack complex (MAC)-mediated lysis. Factor D (FD), a serine protease, catalyzes the cleavage of complement factor B into Ba and Bb, which allows for the formation of the AP C3 convertase. By inhibiting FD, danicopan, an oral small molecule FD inhibitor, blocks C3 convertase formation, the control point for AP activation as well as the amplification of all pathways. This leads to inhibition of C3 cleavage, C3 fragment deposition, terminal pathway activation and MAC formation. Therefore, FD is a promising target in diseases of excess activation of the AP, such as PNH. Aims: Correlation between complement activity biomarkers and clinical/laboratory efficacy of danicopan, administered as monotherapy, in the treatment of PNH. Given that danicopan is potential first in class AP inhibitor for the treatment of PNH, it is important to investigate changes and relationships among relevant biomarkers of the AP to better understand the mechanism of action of danicopan in vivo. Methods: Danicopan starting doses ranged from 100-150 mg Q8H, with subsequent dose escalation based on clinical and biochemical response to doses as high as 200 mg Q8H. Danicopan plasma concentrations were determined by liquid chromatography/tandem mass spectrometry (LC/MS-MS). Danicopan pharmacodynamics (PD) were determined by measuring serum AP activity (AP Wieslab). Plasma Bb concentration, serum FD concentration, serum complement C3 and C4 concentrations, and serum classical pathway (CP) activity were also measured. C3 fragment deposition on RBCs was measured by flow cytometry with FITC conjugated anti- human C3d antibody. Results: Clinical results were previously presented, Table 1. Pharmacokinetic (PK) and PD analysis of danicopan concentration and AP activity measured ex vivo showed a clear correlation: ≤10% AP activity was seen for 6 hours following dosing with some recovery in AP activity prior to the next danicopan dose, Figure 1. Mean baseline Bb levels in this untreated PNH population were elevated relative to the reference range, demonstrating ongoing AP activity. Bb levels decreased into normal range with danicopan, demonstrating decreased in vivo C3 convertase formation, Figure 2. A strong positive correlation existed between Bb concentration and LDH level, demonstrating Bb as a reliable biomarker of AP activation in vivo during therapeutic complement inhibition in PNH. Strong correlations were also observed between danicopan concentration with Bb concentration (positive), AP activity (negative) and LDH level (positive), validating the role of danicopan in the changes of these endpoints. As expected, serum FD concentration was unchanged throughout treatment as was CP activity, which was measured with an in vitro assay designed to exclude any AP contribution. Notably, in contrast with C5 inhibition, C3 fragment deposition was not observed (95% inhibition of AP at steady state. Disclosures Risitano: Apellis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Samsung: Membership on an entity's Board of Directors or advisory committees; Achillion: Research Funding; Alexion: Honoraria, Research Funding, Speakers Bureau; Ra Pharma: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Apellis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Biocryst: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ra Pharma: Research Funding; Alexion: Honoraria, Research Funding, Speakers Bureau; Biocryst: Membership on an entity's Board of Directors or advisory committees; Achillion: Research Funding; Amyndas: Consultancy; Alnylam: Research Funding; Amyndas: Consultancy; Alnylam: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Samsung: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lee:Achillion: Research Funding; Alexion: Consultancy, Honoraria, Research Funding. Notaro:Alexion: Membership on an entity's Board of Directors or advisory committees, Other: letture fees. Brodsky:Alexion: Membership on an entity's Board of Directors or advisory committees, Other: Grant funding; Achillion: Research Funding. Kulasekararaj:Akari: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Achillion: Consultancy; Alexion: Consultancy, 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; Ra Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Alnylam: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Alexion: Consultancy; Novartis: Consultancy. Huang:Achillion: Employment, Equity Ownership. Geffner:Achillion: Employment, Equity Ownership. Browett:AbbVie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Achillion: Research Funding; Amgen: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Research Funding.