I Baltcheva (1), C Bartels (1), M Dahlke (1), G Junge (1), N Rouyrre (1), J Yu (2)
(1) Novartis Pharma AG, Basel, Switzerland (2) Novartis Pharmaceuticals, USA
Introduction: The small patient numbers inherent to rare diseases present many challenges to the traditional drug development paradigm, especially with respect to dose finding. Despite these challenges, regulators expect that clinical investigations evaluate the effect of more than one dosage in rare disease development programs [1]. The need for optimized and efficient drug development requires the use of innovative trial designs combined with nontraditional analysis approaches. We present here a program designed to generate quantitative evidence related to dose-exposure-response (DER) resulting from the collaboration of a cross-disciplinary team including Pharmacometrics scientists.
Iptacopan is the first oral complement inhibitor targeting factor B to selectively inhibit the alternative pathway of the complement system. Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening hematological disorder characterized by complement-mediated lysis of red blood cells (RBC) with associated hemolytic anemia often requiring RBC transfusions [2]. Iptacopan was recently approved by the FDA for the treatment of adults with PNH. Continuous treatment with iptacopan resulted in hemoglobin (Hb) increase to near-normal levels (≥12 g/dL) and blood transfusion avoidance in the majority of patients in two Phase 3 clinical trials [3-5].
Objectives
- To illustrate how longitudinal PKPD modeling enabled characterization of dose-exposure-Hb response of iptacopan despite the lack of traditional parallel group dose-range finding studies.
- To highlight trial design features that were appropriate for dose assessment in rare diseases and elements that were crucial to an informative PKPD modeling.
Methods: The clinical development program of iptacopan in PNH consisted of two Phase 2 [6,7] and two Phase 3 trials [4,5]. The iptacopan dose investigated in registration trials was 200 mg bid. The first Phase 2 trial [6] investigated patients (n=10) treated with iptacopan 200 mg bid (initially as add-on to the standard-of-care). A second cohort of that trial (n=6) was treated with 50 mg bid for a limited duration (12-24 weeks). Data on low doses originated mainly from the second Phase 2 trial [7], where patients were randomized to receive iptacopan 25 mg bid for 4 weeks followed by iptacopan 100 mg bid for 8 weeks (n=7), or iptacopan 50 mg bid for 4 weeks followed by iptacopan 200 mg bid for 8 weeks (n=6). Importantly, the intra-patient dose escalation was preplanned and provided up to 4 weeks of PK and Hb data on the lowest doses (25 and 50 mg bid) versus >12 weeks on 100 and 200 mg bid.
Data from the above 4 trials was used to build a longitudinal mixed-effects PKPD model for Hb, a key efficacy marker in PNH and main component of the primary endpoint used in registration trials. The turnover model accounted for the observed delay between iptacopan exposure and Hb response. The model was used to predict the long-term Hb response for various iptacopan dose levels (25-200 mg bid) and predicted the proportion of patients achieving Hb normalization (≥12 g/dL) for each dose level.
Results: The pooled modeling dataset included rich Hb (2587) and PK (1577) samples in 161 patients. Modeling of Hb dynamics allowed precise estimation of all parameters and in particular EC50 (concentration of iptacopan required to achieve 50% of the maximum Hb response) despite the small number of patients, the relatively short duration of treatment with low doses and limited wash-out data.
The PKPD model allowed quantifying the proportion of patients expected to achieve normal Hb levels for various dose levels (70%, 64%, 57% and 48% for 200, 100, 50 and 25 mg bid, respectively), thus providing quantitative evidence that 200 mg bid is the dose achieving Hb normalization in the highest proportion of patients. This result constituted an important element of the dose justification in the PNH submission dossier.
The Phase 2 trial design implementing the intra-patient dose escalation spanning 4 dose levels was rich in exposure-response information. Proactive involvement of PMX scientists to influence design elements such as dose range, duration of treatment with low doses and sampling schemes was crucial to the robust characterization of DER.
Conclusion: The development program of iptacopan in PNH is an example of model-informed drug development. The combination of innovative trial designs with pharmacometrics analysis methods resulted in a solid dose justification that was approved and referred-to by health authorities.
References:
[1] Rare Diseases: Considerations for the Development of Drugs and Biological Products. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/rare-diseases-considerations-development-drugs-and-biological-products
[2] Brodsky RA (2014), Paroxysmal nocturnal hemoglobinuria. Blood; 124(18):2804-11.
[3] Risitano AM, Kulasekararaj A, R?th A, et al. Factor B Inhibition with Oral Iptacopan Monotherapy Demonstrates Sustained Long-Term Efficacy and Safety in Anti-C5-Treated Patients (pts) with Paroxysmal Nocturnal Hemoglobinuria (PNH) and Persistent Anemia: Final 48-Week Results from the Multicenter, Phase III APPLY-PNH Trial. Presented at: 65th American Society of Hematology Annual Meeting & Exposition (ASH); December 9-12, 2023; San Diego, CA
[4] Risitano AM, R?th A, Kulasekararaj A, et al. Oral Iptacopan Monotherapy Has Superior Efficacy to Anti-C5 Therapy in Patients with Paroxysmal Nocturnal Hemoglobinuria and Residual Anemia: Results from the Phase III APPLY-PNH Study. Presented at: 49th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT); April 23-36, 2023; Paris, France.
[5] Risitano AM, Han B, Ueda Y, et al. Oral Complement Factor B Inhibitor Iptacopan Monotherapy Improves Hemoglobin to Normal/Near-Normal Levels in Paroxysmal Nocturnal Hemoglobinuria Patients Naïve to Complement Inhibitors: Phase III APPOINT-PNH Trial. Presented at: 49th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT); April 23-36, 2023; Paris, France.
[6] Risitano AM, Röth A, Soret J, et al. Addition of iptacopan, an oral factor B inhibitor, to eculizumab in patients with paroxysmal nocturnal haemoglobinuria and active haemolysis: an open-label, single-arm, phase 2, proof-of-concept trial. Lancet Haematol. 2021;8(5):e344-e354. doi:10.1016/S2352-3026(21)00028-4
[7] Jang H, Wong L, Ko BS, et al. Iptacopan monotherapy in patients with paroxysmal nocturnal hemoglobinuria: a 2-cohort open-label proof-of-concept study. Blood Adv. 2022;6(15):4450-4460. doi:10.1182/bloodadvances.2022006960
Reference: PAGE 32 (2024) Abstr 11086 [www.page-meeting.org/?abstract=11086]
Poster: Drug/Disease Modelling - Other Topics