David J. Kuter,1 Ralph V. Boccia,2 Eun-Ju Lee,3 Merlin Efraim,4 Nikolay Tzvetkov,5 Jiri Mayer,6Marek Trněný,7 Milan Kostal, MD,8 Roman Hajek,9 Vickie McDonald,10 Olga Bandman,11
Regan Burns,11 Ann Neale,11 Dolca Thomas,11 and Nichola Cooper12
1Massachusetts General Hospital Cancer Center, Boston, MA, USA; 2Center for Cancer and Blood Disorders, Bethesda, MD, USA; 3Department of Medicine, Weill Cornell Medical College-New York, Presbyterian Hospital, New York, NY, USA; 4Multiprofile Hospital for Active Treatment Sveta Marina EAD, Bulgaria; 5MHAT Dr. Georgi Stranski,
Clinic of Hematology, Pleven, Bulgaria; 6Department of Internal Medicine, Hematology and Oncology, Masaryk University Hospital, Brno, Czech Republic; 7Charles University Hospital, Prague, Czech Republic; 8Faculty of Medicine Hradec Kralove, Charles University, Prague, Czech Republic; 9Department of Haemato-Oncology,
University Hospital Ostrava and Faculty of Medicine University of Ostrava, Ostrava, Czech Republic; 10Barts Health NHS Trust, The Royal London Hospital, London, United Kingdom; 11Principia Biopharma Inc, South San Francisco, CA, USA; and 12Department of Medicine, Hammersmith Hospital, London, United Kingdom
Safety and Efficacy of Rilzabrutinib (PRN1008), an Oral Bruton Tyrosine Kinase Inhibitor, in
Relapsed/Refractory Patients With Primary or Secondary Immune Thrombocytopenia:
Phase I/II Adaptive Study
#S316
Disclosures: David J. Kuter
Employment: Massachusetts General Hospital Consultancy: Actelion (Syntimmune), Agios, Alnylam, Amgen, Argenx, Bristol Myers
Squibb (BMS), Caremark, Daiichi Sankyo, Dova, Kyowa-Kirin, Merck Sharp Dohme, Momenta, Novartis, Pfizer, Platelet Disorder Support Association, Principia, Protalex, Protalix, Rigel, Sanofi, Genzyme, Shionogi, Shire, Takeda (Bioverativ), UCB, Up-To-Date, Zafgen
Research funding: Actelion (Syntimmune), Agios, Alnylam, Amgen, Argenx, Bristol Myers Squibb (BMS), Kezar, Principia, Protalex, Rigel, Takeda (Bioverativ)
Honoraria: Actelion (Syntimmune), Agios, Alnylam, Amgen, Argenx, Bristol Myers Squibb (BMS), Caremark, Daiichi Sankyo, Dova, Kyowa-Kirin, Merck Sharp Dohme, Momenta, Novartis, Pfizer, Platelet Disorder Support Association, Principia, Protalex, Protalix, Rigel, Sanofi, Genzyme, Shionogi, Shire, Takeda (Bioverativ), UCB, Up-To-Date, Zafgen
Patents and royalties: Up-to-Date
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InnateAdaptive
B cells, plasma cells
Monocyte, macrophage
Mast cells, basophils Neutrophils
Blocks B-cell receptorInhibits plasma cell
differentiation and antibody production
Blocks IgG-mediated FcγRactivation, phagocytosis, inflammatory mediators
Blocks IgE-mediated FcεRactivation and degranulation
Inhibits activation, adhesion, recruitment,
oxidative burst
BTK inhibition
Bruton Tyrosine Kinase (BTK) Inhibition Targets Both Adaptive and Innate Drivers of Immune-Mediated Disease1,2
BTK
BTK
BTKBTK
BTK
BTK
3 FcγR, Fcγ receptor; FcεR, Fcε receptor; Ig, immunoglobulin.1. López-Herrera G, et al. J Leukoc Biol. 2014;95:243-250. 2. Langrish C, et al. JID (ESDR). 2019;139:S216 (abstract 011).
T cells
No effect
Rilzabrutinib (PRN1008) is Specifically Designed for Immune-Mediated Diseases
BLK, B lymphoid tyrosine kinase; BMX, bone marrow kinase on chromosome X; BTK, Bruton tyrosine kinase; RLK, resting lymphocyte kinase; TEC, Tec protein tyrosine kinase.
Reversibility
Safety
Durable Occupancy With Low Exposure
Efficacy
Desired Inhibition Range
Selectivity
Precise Inhibition
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BTK
RLK
TEC
BMX
BLK
Rilzabrutinib Does Not Impact Platelet Aggregation
Rilzabrutinib does not alter platelet aggregation in blood taken from healthy volunteers or ITP patients
Ibrutinib has significant effects on platelet aggregation in HV
1 µM Rilzabrutinib − Healthy Volunteers
1 µM Ibrutinib − Healthy Volunteers
1 µM Rilzabrutinib − ITP Patients
Platelet-Rich Plasma (PRP) was adjusted to 200,000-300,000 in healthy volunteers. Platelet count >125,000 in ITP patients was required for inclusion in the study.
5 Langrish C, et al. Blood (ASH). 2017;130:suppl 1 (abstract 1052).
Adaptive, Open-Label, Dose-Finding, Phase I/II Study of Oral Rilzabrutinib in Relapsed/Refractory ITP
Key inclusion criteria
Adults age 18-80 y with relapsed/refractory ITP Primary or secondary to other diseases (eg, SLE, CLL) No other available/approved treatment options ≥ 2 platelet counts < 30,000/μL at study entry Adequate hematologic, hepatic, and renal function Stable concomitant CS or TPO-RA was allowed
Rilzabrutinib intrapatient dose escalation Doses* (24 wk): 200 and 400 mg qd, 300 and 400 mg bid Oral treatment 3+3 design
NCT03395210; EudraCT 2017-004012-19. bid, twice daily; CLL, chronic lymphocytic leukemia; qd, once daily; SLE, systemic lupus erythematosus. *Dose escalation part of the study was completed with all patients currently treated with the 400 mg bid dose.
Higher Dose
ResponseContinue at Initial Dose
No response; escalate to higher dose
Initial Rilzabrutinib
Dose
Additional endpoints Any 2 platelet counts ≥ 50,000/µL Platelet responses over time, by duration of treatment, and clinical
benefit (≥ 30,000/μL)
Stable response (platelet counts ≥ 50,000/μL at ≥ 50% visits for 4 of 8 last weeks of active treatment)
Safety
Two or more consecutive platelet counts ≥ 50,000/μL without requiring rescue medicationPrimary Endpoint
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ITP Patient Characteristics Were Similar Across All Treatment Groups In a Difficult-to-Treat Population
All Patients(N = 47)
400 mg bid(n = 32)
Median age, y (range) 50 (21-74) 50 (21-74)Female, n (%) 27 (57) 20 (63)ITP classification, n (%)
Primary ITP 44 (94) 31 (97)Secondary ITP 3 (6) 1 (3)
Median duration of ITP, y (range) 7.8 (0.4-52.5) 7.3 (0.4-52.5)
Median baseline platelet count, x109/L (range) 14 (3-33) 13 (4-33)
Median number of prior ITP therapies (range) 6 (1-54) 6 (1-54)
Splenectomy, n (%) 13 (28) 9 (28)
At least one prior ITP therapy 100% 100%
Patients were heavily pretreated− Median of 6 prior therapies− Median duration of ITP of 7+ years− 28% had undergone prior
splenectomy
31 (66%) patients were on ≥ 1 concomitant ITP medication (CS and/or TPO) and were considered inadequate responders
7 Data cut-off 22Apr2020.
Oral Rilzabrutinib Achieved Primary Endpoint in 50% Patients Treated > 12 weeks and Responses were Maintained Over Time
Treatment Duration and Dose
Patients Achieving Platelet Counts ≥ 50 × 109/L (80% CI)
Primary Endpoint*2 consecutive 50% of Counts 4 of Final 6
All patients enrolled (N = 47) 43% (34, 52) 34% (26, 43) 28% (20, 37)
≥ 12 wk treatment (n = 36)Includes patients escalated to 400 mg bid 50% (40, 60) 39% (29, 50) 33% (24, 44)
Initiated 400 mg bid (n = 32) 44% (33, 55) 38% (27, 49) 31% (22, 42)
≥ 12 wk treatment (initial 400 mg bid)(n = 26) 50% (38, 62) 42% (31, 55) 35% (24, 47)
Data as of 05May2020.*Primary endpoint was defined as 2 consecutive platelet counts ≥ 50,000/μL without requiring rescue medication.
Rilzabrutinib treatment for ≥ 12 weeks further improved platelet responses
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Platelet Responses Had a Fast Onset and Were Maintained in the Majority of Patients Who Started on Rilzabrutinib 400 mg bid Dose
Fast onset By day 8: platelets ≥ 30×109/L*
− 53% of patients initiating 400 mg bid− 79% of primary endpoint responders
By week 4: 57% of responders achieved the primary endpoint†
Responses were maintained Responders maintained platelet counts
− 71% of time (weeks) at ≥ 50×109/L− 88% of time (weeks) at ≥ 20×109/L
above baseline
9Data cut-off 22Apr2020.*Day 8 is the first platelet count taken after the start of treatment.†Primary endpoint was defined as 2 consecutive platelet counts ≥ 50,000/μL without requiring rescue medication.
Starting Dose 400 mg bid (n = 32)
Responded within 4 weeks (orange)Responders (colored dots/lines)Non-responders (gray)
Rilzabrutinib at All Doses and Treatment Times Achieved Significant, Consistent Responses Across Subgroups
Data cut-off 22Apr2020.*Primary endpoint was defined as 2 consecutive platelet counts ≥ 50,000/μL without requiring rescue medication.
Overall, 43% of patients met the primary endpoint*, which increased with ≥12 weeks of rilzabrutinib
Rilzabrutinib showed 15/38 (40%) heavily pretreated patients responding (≥ 4 prior therapies)
Similar responses were achieved in patients receiving rilzabrutinib monotherapy (n=7/16) and inadequate responders on concomitant therapy (n=13/31)
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43%
50%
40%
40%
44%
42%
0% 25% 50% 75% 100%
Primary Response (N = 47)
Completed ≥12 Wk Rilzabrutinib (n = 36)
Baseline Platelets ≤15K (n = 25)
Heavily Pretreated (≥4 Prior Therapies) (n = 38)
Rilzabrutinib Monotherapy(n = 16)
Rilzabrutinib + ConcomitantTherapy (n = 31)
Platelet Response
Rilzabrutinib Was Well-Tolerated in ITP Patients
Median treatment duration (range)
− All patients: 17.7 wk (0.6-41.9)
− 400 mg bid: 18.0 wk (1.4-24.6)
Related TEAEs were reported in 21 patients (45%); all were transient and grade 1 or 2
− No related SAEs
No treatment-related bleeding or thrombotic events
No significant changes in the ITP-BAT bleeding scale from baseline to last visit
Safety profile is consistent with safety observed to date in pemphigus1
Related TEAEs (≥ 10%), n (%)
All Patients(N = 47)
400 mg bid(n = 32)
Grade 1 Grade 2 Grade 1 Grade 2
All related TEAEs 10 (21) 11 (23) 15 (47) 11 (34)
Diarrhea 14 (30) 2 (4) 11 (34) 2 (6)
Nausea 12 (26) 1 (2) 8 (25) 1 (3)
Fatigue 5 (11) 1 (2) 3 (9) 1 (3)
11Data cut-off 22Apr2020. TEAEs, treatment-emergent adverse events.1. Murrell D, et al. AAD. 2018:LBA 10086.
Conclusions
50% of patients achieved the primary endpoint response when initiated on rilzabrutinib 400 mg bid and treated for 12 weeks or more
Rapid onset seen in 53% patients initiated at 400 mg bid (platelet counts ≥ 30 × 109/L by the first week of treatment) and in 79% of responders
Durable responses in the majority of responding patients
− 71% of weeks with ≥ 50 × 109/L platelets
− 88% of weeks with ≥ 20 × 109/L platelets above baseline
Oral rilzabrutinib was well-tolerated across all doses (all related TEAEs were mild to moderate) with no thrombotic events
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Acknowledgments
Patients, families, caregivers, and co-investigators who are participating in the rilzabrutinib ITP trial globally
Principia Biopharma for sponsoring the trial
Bulgaria (×3)Czech Republic (×4)Netherlands (×2)Norway (×2)United Kingdom (×3)
Canada (×2)• Ontario• Quebec
USA (×8)• Illinois• Maryland• Massachusetts• Michigan• New York• North Carolina• Washington Australia (×6)
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