Disclosures: David J. Kuter

• Employment: Massachusetts General Hospital

• Consultancy: Actelion (Syntimmune), Agios, Alnylam, Amgen, Argenx, (BMS), Caremark, Daiichi Sankyo, Dova, Kyowa- Kirin, Merck Sharp Dohme, Momenta, Novartis, , Platelet Disorder Support Association, Principia, Protalex, Protalix, Rigel, , 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

1 Oral Rilzabrutinib, a Bruton Tyrosine Kinase Inhibitor, Showed Clinically Active and Durable Platelet Responses and Was Well-Tolerated in Patients With Heavily Pretreated Immune Thrombocytopenia David J. Kuter,1 Merlin Efraim,2 Jiri Mayer,3 Vickie McDonald,4 Robert Bird,5 Thomas Regenbogen,6 Mamta Garg,7 Zane Kaplan,8 Olga Bandman,9 Regan Burns,9 Ann Neale,9 Dolca Thomas,9 and Nichola Cooper10

1Hematology Division, Massachusetts General Hospital, Boston, MA; 2Multiprofile Hospital for Active Treatment Sveta Marina EAD, Varna, Bulgaria; 3Department of Internal Medicine, Hematology and Oncology, Masaryk University Hospital, Brno, Czech Republic; 4Barts Health NHS Trust, The Royal London Hospital, London, United Kingdom; 5Princess Alexandra Hospital, Woolloongabba, Queensland, Australia; 6MidMichigan Medical Center, Midland, MI; 7Leicester Royal Infirmary, Leicester, United Kingdom; 8Monash Medical Centre, Clayton, Victoria, Australia; 9Principia Biopharma Inc, South San Francisco, CA; 10Department of Medicine, Hammersmith Hospital, London, United Kingdom

ASH 2020 annual meeting: abstract #22. 2 BTK Inhibition Targets Both Adaptive and Innate Drivers of Immune-Mediated Disease1,2

B cells, Monocytes, T cells Mast cells, basophils Neutrophils plasma cells macrophages Blocks B-cell receptor Blocks IgG-mediated FcgR Blocks IgE-mediated FceR Inhibits activation, Inhibits plasma cell activation, phagocytosis, activation and adhesion, recruitment, differentiation and antibody No effect inflammatory mediators degranulation oxidative burst production BTK inhibition

BTK BTK BTK

BTK

BTK BTK Adaptive Innate

BTK, Bruton tyrosine kinase; FcgR, Fcg receptor; FceR, Fce 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).

3 Rilzabrutinib (PRN1008) is Specifically Designed for Immune-Mediated Diseases

Desired Inhibition Range

Durable Occupancy With Selectivity Reversibility Low Exposure

Precise Inhibition Safety Efficacy

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. Langrish CL, et al. J Invest Dermatol (SID) 2020:abstract 569.

4 Adaptive, Open-Label, Dose-Finding, Phase I/II Study of Oral Rilzabrutinib in Relapsed/Refractory ITP

Key inclusion criteria • 18-80 y old relapsed or refractory primary or secondary ITP • Response to at least 1 prior ITP therapy; no other available/approved treatment options • ≥2 platelet counts <30×109/L at study entry • Stable concomitant corticosteroid (CS) and/or thrombopoietin receptor agonist (TPO-RA) allowed

Phase I/II: Intrapatient dose escalation (24 wk) Long-term Extension (LTE) Oral Rilzabrutinib 200 and 400 mg qd, 300 and 400 mg bid LTE inclusion: Oral Rilzabrutinib 400 mg bid Minimum effective dose identified as Rilzabrutinib 400 mg bid Platelet counts ≥50×109/L for ≥50% of last 8 wk of treatment Primary endpoint: LTE primary endpoint: ≥2 consecutive platelet counts ≥50×109/L (increased ≥20×109/L from Safety baseline) without requiring rescue medication

Additional endpoints Additional endpoints ▪ Subgroup analyses of select prior therapies on primary endpoint ▪ Durable response and safety in LTE

NCT03395210; EudraCT 2017-004012-19. bid, twice daily; qd, once daily.

5 Patient Disposition

Overall Enrolled Patients (N=53)

Starting Doses With 200 mg qd 400 mg qd 300 mg bid 400 mg bid Intrapatient (n=9) (n=1) (n=5) (n=38) Dose-Escalation

Discontinuations n=1 patient decision n=1 patient decision n=2 other AE n=4 other AE n=1 other AE n=1 rescue n=4 rescue treatment use n=1 erroneously enrolled treatment use n=3 lack of response n=1 rescue treatment use n=1 patient decision

Completed Study (24 wk) n=5 n=0 n=2 n=16

Entered LTE n=1 n=0 n=2 n=10 on 400 mg bid

• 23 patients overall completed the 24-week treatment period and 13 patients entered the long-term extension (LTE)

Data cut-off 20July2020. AE, adverse event.

6 Patient Disposition - Focus on Patients Treated With Rilzabrutinib 400 mg bid Dose

Overall Enrolled Patients (N=53)

Starting Doses With 200 mg qd 400 mg qd 300 mg bid 400 mg bid Intrapatient (n=9) (n=1) (n=5) (n=38) Dose-Escalation

Entered LTE • Dose level prior to LTE entry: 400 mg qd (n=1), n=13 on 400 mg bid 300 mg bid (n=1), and 400 mg bid (n=11)

• Focus on patients initiating rilzabrutinib at 400 mg bid dose; and those receiving 400 mg bid dose in the LTE period

Data cut-off 20July2020.

7 Baseline Patient Characteristics and Prior Treatment

400 mg bid LTE (n=38) (n=13) Median age, y (range) 50 (21-74) 49 (22-65) Female, n (%) 21 (55%) 8 (62%) • 400 mg bid patients ITP classification, n (%) – Median duration of ITP of 6 y Primary ITP 37 (97%) 12 (92%) – Median of 6 prior therapies Secondary ITP 1 (3%) 1 (8%) – 24% had undergone prior splenectomy Median duration of ITP, y (range) 6.0 (0.4-52.5) 3.8 (1.0-18.9) Median baseline platelet count, ×109/L • LTE patients 17 (4-33) 17 (4-28) (range) – Shorter median duration of ITP at baseline (3.8 y) Median number of prior ITP therapies 6 (1-53) 5 (1-19) (range) • All patients had received at least Splenectomy, n (%) 9 (24%) 3 (23%) 1 prior ITP therapy At least one prior ITP therapy 100% 100%

Data cut-off 20July2020.

8 Patients Receiving Oral Rilzabrutinib Achieved the Primary Endpoint Irrespective of Prior Treatment

Platelet Count Responses 2 Consecutive ≥50×109/L (primary endpoint*)

n/n (%) 400 mg bid Rilzabrutinib All patients 16/38 (42%) Prior splenectomy 3/9 (33%) Prior therapy Responded to Prior No Prior Response TPO-RA (n=26) 3/12 (25%) 6/14 (43%) Rituximab (n=17) 2/5 (40%) 3/12 (25%) Fostamatinib (n=6) 2/4 (50%) 1/2 (50%)

Data cut-off 20July2020. *Primary endpoint was defined as ≥2 consecutive platelet counts ≥50×109/L without requiring rescue medication.

9 Patients Initiating 400 mg bid Rilzabrutinib Showed Rapid and Durable Responses Starting Dose 400 mg BID (N=38)

Fast onset by day 8 • 53% of patients initiating 400 mg bid achieved platelets ≥30×109/L by day 8

Responses were maintained in 16 responders • 70% of weeks at ≥50×109/L • 29% of weeks at ≥100×109/L • 85% of weeks at ≥20×109/L above baseline

Data cut-off 20July2020. Data cut-off 20July2020.

10 Platelet Responses Were Maintained During the LTE Period LTE Patients (n=13)

LTE Entry • Median platelet count was 98×109/L (range, 16-321)

Responses were maintained during LTE period • 97% of weeks at ≥30×109/L • 89% of weeks at ≥50×109/L LTE entry • 45% of weeks at ≥100×109/L

Data cut-off 20July2020. Data cut-off 20July2020.

11 Individual Patient Platelet Counts Over Time in LTE Period (n=13)

• 6 patients received rilzabrutinib monotherapy • 7 LTE patients received concomitant ITP therapy (4 CS, 2 TPO-RA, 1 both CS/TPO-RA)

Data cut-off 20July2020.

Data cut-off 20July2020. CS, corticosteroid; qd, once daily; qw, once weekly; TPO-RA, thrombopoietin receptor agonist. *Three TPO-RA doses: 250 µg qw, 125 µg qw, 60 µg qw. †Three TPO-RA doses: 4 µg/kg qw, 180 µg qw, 125 µg qw. ‡CS 7.5 mg qd/TPO-RA 75 mg qd. Vertical orange line represents initiation of the long-term extension period; vertical red line shows patient who stopped and later restarted LTE treatment. 12 Rilzabrutinib Was Well-Tolerated During Phase I/II and LTE Periods

400 mg bid (n=38) LTE Only (n=13) Related TEAEs*, n (%) Grade 1 Grade 2 Grade 1 Grade 2 • Median treatment duration (range) Diarrhea 11 (29) 2 (5) 1 (8) 0 – 19.6 wk (1.4-24.6) for 400 mg bid Nausea 8 (21) 1 (3) 0 0 – 43.6 wk (13.9-68.3) for LTE patients (main study + LTE) Fatigue 3 (8) 1 (3) 0 0 • 47% of patients had related TEAEs; Abdominal pain 0 2 (5) 0 0 all were grade 1/2 and transient

Abdominal distension 2 (5) 0 0 0 – No related SAEs • No treatment-related bleeding or Vomiting 1 (3) 1 (3) 0 0 thrombotic events Vulvovaginal dryness 0 1 (3) 0 1 (8) • Safety profile in the LTE continues to support positive benefit:risk for ITP patients Data cut-off 20July2020. TEAEs, treatment-emergent adverse events. *Includes any treatment-related AEs in ≥2 patients in the 400 mg bid group overall and any events in the LTE period.

13 Conclusions

• 42% of patients initiating rilzabrutinib 400 mg bid (minimum effective dose) achieved clinically significant, primary platelet responses (≥50×109/L) – Responses were observed irrespective of prior splenectomy or response/no response to prior therapy – 53% of patients achieved a clinically meaningful response (≥30×109/L) by day 8 – Those who responded had a response >30×109/L that was durable over time • In responding patients treated beyond 6 months, LTE responses remained consistently reliable for 97% of weeks at ≥30×109/L and 89% of weeks at ≥50×109/L platelet counts • Rilzabrutinib was well tolerated with only grade 1/2 treatment-related TEAEs overall, with only 2 related grade 1/2 events observed in the LTE period • Pivotal ITP studies are enrolling to further demonstrate the magnitude and durability of rilzabrutinib’s clinical benefit – FastTrack status was granted on Oct 15, 2020

14 Acknowledgments • Patients, families, caregivers, and co-investigators who are participating in the current and future trials globally • Principia Biopharma, A Sanofi Company, for sponsoring the trial

Canada (×2) • Ontario Bulgaria (×3) • Quebec Czech Republic (×4) Netherlands (×2) USA (×8) Norway (×2) • Illinois United Kingdom (×3) • Maryland • Massachusetts • Michigan • New York • North Carolina • Washington Australia (×6)

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