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

2

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

4

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

6

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

8

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)

10

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

12

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)

13