SerpinPC in persons with severe hemophilia (PwH): long-term treatment from a multi- center, multi-part, first-in-human study T Baglin*, A Koch, I Mocanu+, L Makhaldiani$, J Huntington* *Centessa Pharmaceuticals plc, 1 Ashley Road, Altrincham, Cheshire, United Kingdom, WA14 2DT, Simbec-Orion Clinical Pharmacology, Merthyr Tydfil, CF48 4DR, United Kingdom, +Arensia Exploratory Medicine, Testemitanu Str. 30, Chisinau, Republic of Moldova, $Arensia Exploratory Medicine, 13a Tevdore Mgvdeli Str. 0112, Tbilisi, Georgia
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SerpinPC: a subcutaneously administered biologic inhibitor of APC 3 • Unprecedented biology with novel pharmacology • Intended for subcutaneous prophylaxis across hemophilia subtypes • Modified a1 anti-trypsin with 3 substitution mutations to confer selective inhibition of activated protein C (APC) • Prevents bleeds by inhibiting APC to prolong prothrombinase activity and allow sufficient thrombin generation in the absence of intrinsic tenase 3D-model of SerpinPC* * SerpinPC is an investigational agent that has not been approved by the FDA or any other regulatory authority
SerpinPC and thrombin generation 4 Extrinsic Tenase Intrinsic Tenase Prothrombinase Prothrombin Thrombin SerpinPC APC Protein C
1.2 mpk Q2W AP-0101 study design: adaptive first-in-human study to investigate the safety, tolerability, efficacy and PK of SerpinPC 5 60 mg Q4W Part 2 MAD PwH (n=23) Part 3 OLE at flat dose (n=22) Part 4 OLE at 1.2 mpk Q2W (n=21) Part 1b SAD PwH (n=12) Week 1 to 24 Week 25 to 72 Week 73 to 96Timing 0.3 / 0.6 / 1.2 mpk Q4W 24 weeks 48 weeks 24 weeksDuration Today’s presentation Up to 0.3 mpk 0.1 to 1.2 mpk Part 1a SAD HV (n=15)
AP-0101 Parts 2-4: demographics, baseline characteristics and early terminations 6 * “Target joint” = joint with >3 bleeds in any 6-month period ** Determined by Safety Review Group Characteristic Value Age, median (min to max) 39 (21 to 56) Number of subjects 23 (including 12 from Part 1b SAD) Prospective baseline Annualized Bleed Rate (ABR), median (min to max) 34.1 (22.8 to 53.0) % subjects receiving previous prophylaxis 0% % subjects with target joints* 100% No. of target joints, median (min. to max.) 2.5 (1 to 4) Part Early termination Part 2 1 subject due to skin-rash – treatment-related** Part 3 1 subject due to emigration to another country Part 4 1 subject due to recto-sigmoid cancer – not related to treatment** Demographics and baseline characteristics Early terminations
AP-0101 Parts 3 and 4: no observations of treatment-related adverse events 7* Determined by Safety Review Group Part 3 (n=22) Part 4 (n=21) Treatment Emergent Adverse Events Subjects with event No. (%) Treatment-related* Subjects with event No. (%) Treatment-related* Elevated ALT 3 (14%) 0 3 (14%) 0 Elevated gamma-GT 0 NA 2 (10%) 0 COVID-19 infection 2 (9%) 0 1 0 Hepatic fibrosis 1 0 1 0 Chronic hepatitis C 0 NA 1 0 Fever 0 NA 1 0 Urinary tract infection 0 NA 1 0 Fracture 1 0 1 0 Radiculopathy 1 0 1 0 Elevated creatinine phosphokinase 1 0 0 NA Anemia 1 0 1 0 Elevated sodium 0 NA 1 0 Rectosigmoid cancer 0 NA 1 0 Low neutrophil count 1 0 0 NA
AP-0101 Parts 3 and 4: no observations of treatment-related, non-transient elevations in D-dimer 8 * For Part 3, one subject with rectosigmoid cancer and one subject with traumatic hip bleed **For Part 4, one subject with rectosigmoid cancer Result Subjects in Part 3 (n=22) No. (%) Subjects in Part 4 (n=21) No. (%) Any result ≥ 500 ng/ml 5 (23%) 3 (14%) 2 consecutive results ≥ 500 ng/ml 2 of 5* 1 of 3** Unexplained sustained elevation of D-dimer 0 of 5 0 of 3 >96% of D-dimer measurements were ≤ 500 ng/ml (384 of 398 measurements)
AP-0101: Anti-drug Antibodies (ADAs) and Pharmacokinetics (PK) 9 • Samples for ADA characterization including neutralizing capacity and cross-reactivity ongoing • PK analysis ongoing, including exposure-response modeling
AP-0101 Parts 3 and 4: reduction in Annualized Bleed Rate (ABR) 10 Part Median ABR from prospective baseline Median ABR observed in this part Median % change from baseline Part 3 (n=22) 34.1 6.2 -83% Part 4 (n=21) 35.5 2.2 -93% Part Median ABR from prospective baseline Median ABR observed in this part Median % change from baseline Part 3 (n=22) 27.5 4.3 -86% Part 4 (n=21) 28.3 2.2 -93% All bleed ABR Spontaneous joint bleed ABR
11 HemA HemB AP-0101 Part 3: ABR at 60mg Q4W flat dose All bleeds ABR Spontaneous joint bleeds ABR Medians Part 3 48 weeks of treatment Baseline -60 -40 -20 0 20 40 60 ABR 4.327.5Medians Baseline Part 3 48 weeks of treatment -60 -40 -20 0 20 40 60 ABR 6.234.1
12 HemA HemB AP-0101 Part 4: ABR at 1.2 mpk Q2W -60 -40 -20 0 20 40 60 2.2 28.3 2.2 -60 -40 -20 0 20 40 60 ABR ABR All bleeds ABR Spontaneous joint bleeds ABR Baseline Part 4 24 weeks of treatment Part 4 24 weeks of treatment Baseline 35.5Medians Medians
AP-0101: All bleed median ABR by dose level 13 8.6 8.8 6.2 4.4 2.2 0.3 0.6 ~0.8 1.2 2.4 Effective monthly dose (mpk) * 60 mg Flat dose which was equivalent to ~0.8 mpk * n=7n=7 n=8 n=22 n=21 Part 2 Part 2Part 2 Part 3 Part 4
Summary 14 • SerpinPC – Novel MoA: inhibition of APC to rebalance coagulation – Broad potential to treat all subtypes of hemophilia – Subcutaneous route of administration • Results of Phase 2, Parts 3 and 4 – No observations of treatment-related adverse events – No observations of treatment-related sustained elevations of D-dimer – All bleed median ABR of 2.2 (median percentage reduction from baseline of 93%) in Part 4
15 Thank you to all the persons who have and continue to participate in this study
