Presented at the virtual XXVIII Congress of the International Society on Thrombosis and Hemostasis (ISTH) on July 12-14, 2020

INTRODUCTIONImmune Thrombocytopenia (ITP)• ITP is characterized by immune-mediated platelet destruction and impairment of platelet production, leading to

thrombocytopenia, a predisposition to bleeding, and adverse impact on patient quality of life1

• Current therapies for adults with ITP include1,2

- Initial: intravenous immune globulin (IVIG), corticosteroids (CS) - Subsequent: splenectomy, thrombopoietin receptor agonists (TPO-RAs), rituximab, fostamatinib, and other immunosuppressive therapies (mycophenolate mofetil, cyclosporine)

• Unmet needs in relapsed or refractory ITP1,2

- Improve remission rates and durability - Avoid TPO-RA treatment-related rapid increase of platelet counts/thrombosis risk - Reduce or eliminate CS use - Provide tolerable and safe therapy that ensures good patient quality of life

Bruton Tyrosine Kinase (BTK)• BTK is an enzyme that plays a critical role in immune signaling pathways and is an essential signaling element

downstream of the B-cell, Fcγ, and Fcε receptors3,4 (Figure 1)

Figure 1. Bruton Tyrosine Kinase (BTK) Inhibition Targets Both Adaptive and Innate Drivers of Immune-Mediated Disease3,4

InnateAdaptive

BTK BTK

BTK

BTK

BTK

BTK

T cells B cells, plasma cells Monocytes, macrophages Mast cells, basophils Neutrophils

BTK inhibition

No effect

Blocks B-cell receptor

Inhibits plasma celldifferentiation and

antibody production

Blocks IgG-mediatedFcγR activation,

phagocytosis,inflammatory mediators

Blocks IgE-mediatedFcεR activation

and degranulation

Inhibits activation,adhesion, recruitment,

oxidative burst

BTK, Bruton tyrosine kinase; FcγR, Fcγ receptor; FcεR, Fcε receptor; Ig, immunoglobulin.

Rilzabrutinib (PRN1008)• Fully reversible, oral inhibitor targeting BTK and designed for immune-mediated diseases4,5 (Figure 2)• Covalent binding that achieves long BTK target engagement and durable inhibition with limited drug exposure5

• Provides potential clinical advantage based on rilzabrutinib’s rapid systemic clearance and long target residence time, which may prolong efficacy while reducing the potential for off-target toxicities4,5

• Rilzabrutinib does not alter platelet aggregation in blood taken from healthy volunteers or patients with ITP6 (Figure 3) - Contrasting significant effects on platelet aggregation observed with ibrutinib in healthy volunteers

Figure 2. Rilzabrutinib (PRN1008) is a Reversible, Covalent, Oral BTK Inhibitor With Durable BTK Occupancy and Low Systemic Exposure4,5

Selectivity

Precise Inhibition

Reversibility

Safety

Durable OccupancyWith Low Exposure

Efficacy

PK E

xpos

ure,

ng/

mL

Time, h

1000

500

0

BTK

Inhibition, %

100

80

60

40

20

00 5 10 15 20 25

Desired InhibitionRange

Occ

upan

cy in

vitr

o, %

Time, h

100

0

20

40

60

80

0 24

BTK

BMX

BLK

RLKTEC

COVALENTBINDING SITE

TARGETSITE

OFF-TARGETSITE

NON-COVALENT

BINDINGREGION

COVALENTBINDINGREGION

BLK, B-lymphoid tyrosine kinase; BMX, bone marrow kinase on chromosome X; BTK, Bruton tyrosine kinase; PK, pharmacokinetics; RLK, resting lymphocyte kinase; TEC, Tec protein tyrosine kinase.

Figure 3. Rilzabrutinib Does Not Impact Platelet Aggregation6,7

% M

axim

um A

ggre

gatio

n

150

100

50

0

5 µM TRAP

10 µM

ADP

1.5 m

g/mL R

istoc

etin

5 µM U

4661

9

5 µg/m

L Coll

agen

2.5 µg

/mL C

ollag

en

% M

axim

um A

ggre

gatio

n

% M

axim

um A

ggre

gatio

n

150

100

50

0

5 µM TRAP

10 µM

ADP

1.5 m

g/mL R

istoc

etin

5 µM U

4661

9

5 µg/m

L Coll

agen

2.5 µg

/mL C

ollag

en

150

100

50

0

5 µM TRAP

10 µM

ADP

1.5 m

g/mL R

istoc

etin

5 µM U

4661

9

5 µg/m

L Coll

agen

2.5 µg

/mL C

ollag

en

Ibrutinib has significant effects on platelet aggregation in healthy volunteers

1 µM Ibrutinib − Healthy Volunteers 1 µM Rilzabrutinib − Healthy Volunteers 1 µM Rilzabrutinib − ITP Patients

Rilzabrutinib does not alter platelet aggregation in blood taken from healthy volunteers or 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.

ADP, adenosine diphosphate; TRAP, thrombin receptor activating peptide.

PATIENTS AND METHODS• PRN1008-010 is a phase I/II adaptive, open-label, dose-finding study of oral rilzabrutinib in patients with relapsed

ITP (NCT03395210; EudraCT 2017-004012-19) • Patients with relapsed/refractory, primary or secondary ITP who had no other available treatment options were

enrolled (Table 1) - Platelet counts at study entry were < 30,000/µL

• Rilzabrutinib intrapatient dose-escalation treatment (Figure 4) - 3+3 study design

• If no responses were observed at a particular dose level in 3 patients from the sentinel cohort for 28 days, the dose was dropped and the next dose was considered the starting dose

• If response was seen at the low dose in 1 of 3 patients, then 3 more patients were added to the cohort - Oral rilzabrutinib was given initially with 200 and 400 mg qd doses, and then escalated to 300 and 400 mg bid doses - Dose escalations were allowed every 28 days up to the 400 mg bid dose - Stable concomitant CS or TPO-RA was allowed alongside rilzabrutinib treatment

Table 1. Patient Eligibility Criteria

Key Inclusion Criteria Key Exclusion Criteria• Adults aged 18 to 80 y with relapsed/refractory ITP• ITP that is primary or secondary to other diseases (eg, chronic

lymphocytic leukemia, systemic lupus erythematosus)• 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

• Pregnant or lactating women• Treatment with rituximab or splenectomy within

3 months• Current drug or alcohol abuse• History of solid organ transplant• Positive screening for human immunodeficiency

virus, hepatitis B, or hepatitis C

Figure 4. Phase I/II Adaptive, Open-Label, Dose-Finding Study of Oral Rilzabrutinib in Relapsed/Refractory Immune Thrombocytopenia

Higher Dose

Continue atInitial DoseInitial Dose

Rilzabrutinib intrapatient dose escalation

• Doses* (24 wk): 200 and 400 mg qd, 300 and 400 mg bid• Oral treatment• 3+3 design• Focus on patients initiating 400 mg bid

Response

No response;escalate to higher dose

NCT03395210; EudraCT 2017-004012-19. bid, twice daily; qd, once daily. *Dose escalation part of the study was completed with all patients currently treated with the 400 mg bid dose.

Primary Endpoint• Two or more consecutive platelet counts ≥ 50,000/µL without requiring rescue medication

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

RESULTSPatient Demographics

Table 2. Patient Characteristics Were Similar Across All Rilzabrutinib Treatment Groups in a Difficult-to-Treat ITP Population

All Patients (N = 47) Initiated 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, × 109/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 1 prior ITP therapy 100% 100%Data cut-off 22Apr2020.

• Baseline patient characteristics and prior therapy were similar for the overall population and for patients who initiated rilzabrutinib 400 mg bid (Table 2)• Patients were heavily pretreated

-Median of 6 prior therapies -Median duration of ITP of 7+ years - 28% had undergone prior splenectomy

• 31 patients (66%) were on ≥ 1 concomitant ITP medication (CS and/or TPO-RA) and were considered inadequate responders

Efficacy• Oral rilzabrutinib treatment for ≥ 12 weeks further improved platelet responses (Table 3)

Table 3. Oral Rilzabrutinib Achieved Primary Endpoint in 50% Patients Treated ≥ 12 Weeks and Responses Were Maintained Over Time

Rilzabrutinib Duration and DosePatients Achieving Platelet Counts ≥ 50 × 109/L (80% CI)

Primary Endpoint* 2 Consecutive 50% of Counts 4 of Final 6 4 of Final 8

All patients enrolled (N = 47)≥ 12 wk (n = 36) Includes patients escalated to 400 mg bid

43% (34, 52)

50% (40, 60)

34% (26, 43)

39% (29, 50)

28% (20, 37)

33% (24, 44)

34% (26,43)

42% (32, 52)

Initiated 400 mg bid (n = 32)≥ 12 wk (initial 400 mg bid; n = 26)

44% (33, 55)50% (38, 62)

38% (27, 49)42% (31, 55)

31% (22, 42)35% (24, 47)

41% (30, 52)46% (34, 59)

Data as of 05May2020.*Primary endpoint was defined as 2 consecutive platelet counts ≥ 50,000/μL without requiring rescue medication.

Figure 5. Platelet Responses Had a Fast Onset and Were Maintained in the Majority of Patients Who Started on Rilzabrutinib 400 mg bid Dose

Plat

elet

Cou

nts

(× 1

09 /L)

Days

0

10

20

30

40

50

60

70

80

90

100100

200

300

400

-20 -10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200

Starting Dose 400 mg bid (n = 32)

Responded within 4 weeksRespondersNon-responders

Figure 6. Rilzabrutinib at All Doses and Treatment Times Achieved Significant, Consistent Responses Across Subgroups

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 ResponseData cut-off 22Apr2020. *Primary endpoint was defined as 2 consecutive platelet counts ≥ 50,000/μL without requiring rescue medication.

Safety• Median treatment duration (range)

- All patients: 17.7 wk (0.6-41.9) - 400 mg bid: 18.0 wk (1.4-24.6)

• Related treatment-emergent adverse events (TEAEs) were reported in 21 patients (45%); all were transient and grade 1 or 2 (Table 4) - No related serious adverse events (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 pemphigus8

Table 4. Oral Rilzabrutinib Was Well Tolerated in ITP Patients

Related TEAEs* (≥ 10%), n (%)

All Patients (N = 47) Initiated 400 mg bid (n = 32)Grade 1 Grade 2 Grade 1 Grade 2

All related TEAEs 10 (21) 11 (23) 6 (19) 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)

Includes all data known by 05May2020. *Related TEAEs are reported by the maximum severity grade that was observed.

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 was seen in 53% of patients who initiated rilzabrutinib at 400 mg bid (platelet counts ≥ 30 × 109/L by the first week of treatment) and in 79% of responders

• Durable responses were achieved 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 treatment-related TEAEs were mild to moderate with no thrombotic events and no bleeding events

REFERENCES1. Cooper N, Ghanima W. N Engl J Med. 2019;381:945-955. 2. Neunert C, Cooper N. Hematology Am Soc Hematol Educ Program. 2018;2018:568-575.3. López-Herrera G, et al. J Leukoc Biol. 2014;95:243-250. 4. Langrish C, et al. JID (ESDR). 2019;139:S216 (abstract 011). 5. Bradshaw JM, et al. Nat Chem Biol. 2015;11:525-531. 6. Langrish C, et al. Blood (ASH). 2017;130:suppl 1 (abstract 1052).7. Kuter DJ, et al. Blood (ASH). 2019;134:suppl 1 (abstract 87). Oral presentation.8. Murrell D, et al. AAD. 2018:LBA 10086.

CORRESPONDING AUTHOR

David KuterEmail: DKUTER@mgh.harvard.edu

• Rilzabrutinib treatment led to platelet responses with a fast onset and responses that were maintained over time in the majority of patients who initiated rilzabrutinib 400 mg bid (Figure 5)

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 for a median of - 71% of time (weeks) at ≥ 50 × 109/L - 88% of time (weeks) at ≥ 20 × 109/L above baseline

• Platelet responses were consistent overall and across subgroups (Figure 6)

• 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)

ACKNOWLEDGEMENTSPatients, families, caregivers, and co-investigators who are participating in the rilzabrutinib ITP trial globallyPrincipia Biopharma Inc. for sponsoring the trial

BulgariaCzech Republic Netherlands Norway United Kingdom

Canada• Ontario• Quebec

USA• Illinois• Maryland• Massachusetts• Michigan• New York• North Carolina• Washington

Australia

50% (38, 62)

Data 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.

Phase I/II, Open-Label, Ongoing Study of Rilzabrutinib (PRN1008), an Oral Bruton Tyrosine Kinase Inhibitor, in Patients With Heavily Pretreated Immune Thrombocytopenia

David J. Kuter,1 Merlin Efraim,2 Jiri Mayer,3 Marek Trněný,4 Vickie McDonald,5 Robert Bird,6 Thomas Regenbogen,7 Mamta Garg,8 Zane Kaplan,9 Olga Bandman,10 Regan Burns,10 Ann Neale,10 Dolca Thomas,10 and Nichola Cooper11

1Massachusetts General Hospital Cancer Center, Boston, MA, USA; 2Multiprofile Hospital for Active Treatment Sveta Marina EAD, Varna, Bulgaria; 3Department of Internal Medicine, Hematology and Oncology, Masaryk University Hospital, Brno, Czech Republic; 4Charles University Hospital, Prague, Czech Republic; 5Barts Health NHS Trust, The Royal London Hospital, London, United Kingdom; 6Princess Alexandra Hospital, Woolloongabba, Queensland, Australia;7MidMichigan Medical Center, Midland, MI, USA; 8Leicester Royal Infirmary, Leicester, United Kingdom; 9Monash Medical Centre, Clayton, Victoria, Australia;10Principia Biopharma Inc., South San Francisco, CA, USA; 11Department of Medicine, Hammersmith Hospital, London, United Kingdom

#PB1318