EX-99.2
Exhibit 99.2 Phase I/II, Open-Label, Adaptive Study of Oral Bruton
Tyrosine Kinase Inhibitor PRN1008 in Patients With Relapsed/Refractory Primary or Secondary Immune Thrombocytopenia 1 2 3 4 5 6 David J. Kuter, Ralph V. Boccia, Eun-Ju Lee, Merlin Efraim, Nikolay Tzvetkov, Jiri Mayer, 7 8 9 10 11 Marek
Trněný, Milan Kostal, MD, Roman Hajek, Vickie McDonald, Olga Bandman, 11 11 11 12 Regan Burns, Ann Neale, Dolca Thomas, and Nichola Cooper 1 2 3 Massachusetts General Hospital Cancer Center, Boston, MA, USA; Center for Cancer and Blood
Disorders, Bethesda, MD, USA; Department of Medicine, Weill Cornell 4 5 Medical College-New York, Presbyterian Hospital, New York, NY, USA; Multiprofile Hospital for Active Treatment Sveta Marina EAD, Bulgaria; MHAT Dr. Georgi Stranski, 6 Clinic of
Hematology, Pleven, Bulgaria; Department of Internal Medicine, Hematology and Oncology, Masaryk University Hospital, Brno, Czech Republic; 7 8 9 Charles University Hospital, Prague, Czech Republic; Faculty of Medicine Hradec Kralove, Charles
University, Prague, Czech Republic; Department of Haematooncology, 10 University Hospital Ostrava and Faculty of Medicine University of Ostrava, Ostrava, Czech Republic; Barts Health NHS Trust, The Royal London Hospital, London, 11 12 United
Kingdom; Principia Biopharma Inc, South San Francisco, CA, USA; and Department of Medicine, Hammersmith Hospital, London, United Kingdom Exhibit 99.2 Phase I/II, Open-Label, Adaptive Study of Oral Bruton Tyrosine Kinase Inhibitor PRN1008 in Patients
With Relapsed/Refractory Primary or Secondary Immune Thrombocytopenia 1 2 3 4 5 6 David J. Kuter, Ralph V. Boccia, Eun-Ju Lee, Merlin Efraim, Nikolay Tzvetkov, Jiri Mayer, 7 8 9 10 11 Marek Trněný, Milan Kostal, MD, Roman Hajek, Vickie
McDonald, Olga Bandman, 11 11 11 12 Regan Burns, Ann Neale, Dolca Thomas, and Nichola Cooper 1 2 3 Massachusetts General Hospital Cancer Center, Boston, MA, USA; Center for Cancer and Blood Disorders, Bethesda, MD, USA; Department of Medicine, Weill
Cornell 4 5 Medical College-New York, Presbyterian Hospital, New York, NY, USA; Multiprofile Hospital for Active Treatment Sveta Marina EAD, Bulgaria; MHAT Dr. Georgi Stranski, 6 Clinic of Hematology, Pleven, Bulgaria; Department of Internal
Medicine, Hematology and Oncology, Masaryk University Hospital, Brno, Czech Republic; 7 8 9 Charles University Hospital, Prague, Czech Republic; Faculty of Medicine Hradec Kralove, Charles University, Prague, Czech Republic; Department of
Haematooncology, 10 University Hospital Ostrava and Faculty of Medicine University of Ostrava, Ostrava, Czech Republic; Barts Health NHS Trust, The Royal London Hospital, London, 11 12 United Kingdom; Principia Biopharma Inc, South San Francisco,
CA, USA; and Department of Medicine, Hammersmith Hospital, London, United Kingdom
Immune 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 life (QOL) § Current therapies for adults with ITP include −
Initial: IVIG, corticosteroids (CS) − Subsequent: splenectomy, thrombopoietin receptor agonists (TPO-RAs), rituximab, fostamatinib, and other immunosuppressive therapies (MMF, cyclosporine) § Unmet needs in relapsed or refractory ITP
− Improved remission rates and durability − Avoid rapid increase of platelet counts/thrombosis risk − Steroid-free regimens − A tolerable and safe therapy that ensures good patient QOL IVIG, intravenous immune globulin; MMF,
mycophenolate mofetil. 2 1. Neunert C, Cooper N. Hematology Am Soc Hematol Educ Program. 2018;2018:568-575. 2. Cooper N, Ghanima W. N Engl J Med. 2019;381:945-955.Immune 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 life (QOL) § Current therapies for adults with ITP include − Initial: IVIG,
corticosteroids (CS) − Subsequent: splenectomy, thrombopoietin receptor agonists (TPO-RAs), rituximab, fostamatinib, and other immunosuppressive therapies (MMF, cyclosporine) § Unmet needs in relapsed or refractory ITP − Improved
remission rates and durability − Avoid rapid increase of platelet counts/thrombosis risk − Steroid-free regimens − A tolerable and safe therapy that ensures good patient QOL IVIG, intravenous immune globulin; MMF, mycophenolate
mofetil. 2 1. Neunert C, Cooper N. Hematology Am Soc Hematol Educ Program. 2018;2018:568-575. 2. Cooper N, Ghanima W. N Engl J Med. 2019;381:945-955.
Bruton Tyrosine Kinase (BTK) Inhibition Mechanisms for 1,2 Targeting
Drivers of Immune-Mediated Disease BTK BTK BTK BTK BTK BTK B cells, Monocyte, Mast cells, Neutrophils T cells plasma cells macrophage basophils Blocks B-cell receptor Blocks IgG-mediated FcγR Blocks IgE-mediated FcεR Inhibits activation,
Inhibits plasma cell activation, phagocytosis, activation and adhesion, recruitment, differentiation and antibody inflammatory mediators degranulation oxidative burst No effect production BTK inhibition FcγR, Fcγ receptor; FcεR,
Fcε receptor; Ig, immunoglobulin. 3 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). Bruton Tyrosine Kinase (BTK) Inhibition Mechanisms for 1,2 Targeting Drivers of
Immune-Mediated Disease BTK BTK BTK BTK BTK BTK B cells, Monocyte, Mast cells, Neutrophils T cells plasma cells macrophage basophils Blocks B-cell receptor Blocks IgG-mediated FcγR Blocks IgE-mediated FcεR Inhibits activation, Inhibits
plasma cell activation, phagocytosis, activation and adhesion, recruitment, differentiation and antibody inflammatory mediators degranulation oxidative burst No effect production BTK inhibition FcγR, Fcγ receptor; FcεR, Fcε
receptor; Ig, immunoglobulin. 3 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).
PRN1008: Reversible, Covalent Inhibitor Selects for BTK High Occupancy,
Low Systemic Exposure for Use in Immunology Ibrutinib PRN1008 Kinase Selectivity Kinase Selectivity PRN1008 has improved kinase selectivity In a 251-kinase panel, >90% inhibition was achieved in § 21 kinases for ibrutinib (1 µM) §
6 kinases for PRN1008 (1 µM) PRN1008 Desired Inhibition PRN1008 is designed with Range ® Tailored Covalency for optimized clinical activity with minimal drug exposure and benefits of reversibility 4 1. Langrish C, et al. JID (ESDR).
2019;139:S216 (abstract 011). 2. Bradshaw JM, et al. Nat Chem Biol. 2015;11:525-531. 3. Data on file, Principia Biopharma Inc. PRN1008: Reversible, Covalent Inhibitor Selects for BTK High Occupancy, Low Systemic Exposure for Use in Immunology
Ibrutinib PRN1008 Kinase Selectivity Kinase Selectivity PRN1008 has improved kinase selectivity In a 251-kinase panel, >90% inhibition was achieved in § 21 kinases for ibrutinib (1 µM) § 6 kinases for PRN1008 (1 µM) PRN1008
Desired Inhibition PRN1008 is designed with Range ® Tailored Covalency for optimized clinical activity with minimal drug exposure and benefits of reversibility 4 1. Langrish C, et al. JID (ESDR). 2019;139:S216 (abstract 011). 2. Bradshaw JM, et
al. Nat Chem Biol. 2015;11:525-531. 3. Data on file, Principia Biopharma Inc.
PRN1008: No Impact on Platelet Function Ibrutinib has significant
effects PRN1008 does not alter platelet aggregation in on platelet aggregation in HV blood taken from healthy volunteers or ITP patients 1 µM Ibrutinib − 1 µM PRN1008 − 1 µM PRN1008 − Healthy Volunteers Healthy
Volunteers 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. 5 1. Langrish C, et al. Blood (ASH). 2017;130(suppl, abstr):1052. 2. Data on file, Principia Biopharma Inc. PRN1008: No Impact on Platelet Function Ibrutinib has significant effects PRN1008 does not alter platelet aggregation in
on platelet aggregation in HV blood taken from healthy volunteers or ITP patients 1 µM Ibrutinib − 1 µM PRN1008 − 1 µM PRN1008 − Healthy Volunteers Healthy Volunteers 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. 5 1. Langrish C, et al. Blood (ASH).
2017;130(suppl, abstr):1052. 2. Data on file, Principia Biopharma Inc.
Adaptive, Open-Label, Dose-Finding, Phase I/II Study of PRN1008 in
Relapsed/Refractory Immune Thrombocytopenia (ITP) Key inclusion criteria (N ≤ 40) Intrapatient dose escalation of PRN1008 § PRN1008 doses* (24 wk): 200 and 400 mg qd § Adults age 18-80 y 300 and 400 mg bid § Relapsed/refractory
ITP § 3+3 design − If response was observed in 1 of 3 patients, then 3 more § Primary or secondary to other diseases (eg, SLE, CLL) patients were added to the dose level § No other available/approved treatment options − If
no response in 3 patients for 28 d, dose was dropped and patients were escalated to higher doses and all subsequently § ≥ 2 platelet counts < 30,000/μL at study entry enrolled patients started treatment at the higher dose §
Adequate hematologic, hepatic, and renal function § Stable concomitant CS or TPO-RA was allowed Higher Dose No response; escalate to higher dose Continue at Initial Dose Initial Dose Response NCT03395210; EudraCT 2017-004012-19. bid, twice
daily; CLL, chronic lymphocytic leukemia; qd, once daily; SLE, systemic lupus erythematosus. 6 *Dose escalation part of the study was completed with all patients currently treated with the 400 mg bid dose.Adaptive, Open-Label, Dose-Finding, Phase
I/II Study of PRN1008 in Relapsed/Refractory Immune Thrombocytopenia (ITP) Key inclusion criteria (N ≤ 40) Intrapatient dose escalation of PRN1008 § PRN1008 doses* (24 wk): 200 and 400 mg qd § Adults age 18-80 y 300 and 400 mg bid
§ Relapsed/refractory ITP § 3+3 design − If response was observed in 1 of 3 patients, then 3 more § Primary or secondary to other diseases (eg, SLE, CLL) patients were added to the dose level § No other available/approved
treatment options − If no response in 3 patients for 28 d, dose was dropped and patients were escalated to higher doses and all subsequently § ≥ 2 platelet counts < 30,000/μL at study entry enrolled patients started
treatment at the higher dose § Adequate hematologic, hepatic, and renal function § Stable concomitant CS or TPO-RA was allowed Higher Dose No response; escalate to higher dose Continue at Initial Dose Initial Dose Response NCT03395210;
EudraCT 2017-004012-19. bid, twice daily; CLL, chronic lymphocytic leukemia; qd, once daily; SLE, systemic lupus erythematosus. 6 *Dose escalation part of the study was completed with all patients currently treated with the 400 mg bid
dose.
Key Study Endpoints 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 - defined as platelet counts ≥ 50,000/μL at ≥ 50% visits during last 8 weeks of active treatment (4 of 8) § Safety 7Key Study Endpoints 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 - defined as platelet counts ≥ 50,000/μL at ≥ 50% visits during last 8 weeks of active treatment (4 of 8) § Safety 7
Patient Demographics and Prior ITP Therapy Demographics N = 31 Prior ITP
Therapy N = 31 Median age, y (range) 50 (21-74) Median number of prior ITP therapies 6 (1-41) (range) Female, n (%) 18 (58) Splenectomy, n (%) 8 (26) ITP classification, n (%) Prior ITP therapies, n (%) Primary ITP 29 (94) Corticosteroids 26 (84)
Secondary ITP 2 (6) TPO-RA 17 (55) Median duration of ITP, y (range) 7.8 (0.5-42.4) IVIG/Anti-D 11 (35) 9 Median baseline platelet count, x10 /L 13 (3-28) Rituximab 10 (32) (range) § At enrollment, patients had ITP for a median duration of 7.8
y, were heavily pretreated (median of 6 prior therapies), and 26% had undergone a prior splenectomy § During the study, 10 patients (32%) received PRN1008 monotherapy and 21 patients (68%) were on ≥ 1 concomitant ITP medication 8 Data
cut-off 13Nov2019. Patient Demographics and Prior ITP Therapy Demographics N = 31 Prior ITP Therapy N = 31 Median age, y (range) 50 (21-74) Median number of prior ITP therapies 6 (1-41) (range) Female, n (%) 18 (58) Splenectomy, n (%) 8 (26) ITP
classification, n (%) Prior ITP therapies, n (%) Primary ITP 29 (94) Corticosteroids 26 (84) Secondary ITP 2 (6) TPO-RA 17 (55) Median duration of ITP, y (range) 7.8 (0.5-42.4) IVIG/Anti-D 11 (35) 9 Median baseline platelet count, x10 /L 13 (3-28)
Rituximab 10 (32) (range) § At enrollment, patients had ITP for a median duration of 7.8 y, were heavily pretreated (median of 6 prior therapies), and 26% had undergone a prior splenectomy § During the study, 10 patients (32%) received
PRN1008 monotherapy and 21 patients (68%) were on ≥ 1 concomitant ITP medication 8 Data cut-off 13Nov2019.
Summary of Platelet Response by Treatment Duration and Dose Patients
Achieving 9 Platelet Counts ≥ 50 × 10 /L (80% CI) Treatment Duration and Dose Primary Endpoint* Any 2 4 of Final 8 (data cut-off 13Nov2019) 2 consecutive All patients enrolled 39% (28%-50%) 45% (34%-57%) 29% (20%-40%) (N = 31) ≥ 4
wk, all doses 46% (34%-59%) 54% (41%-66%) 35% (24%-47%) (n = 26) ≥ 12 wk, all doses 47% (33%-62%) 59% (43%-73%) 35% (22%-51%) (n = 17) ≥ 12 wk at 300 and 400 mg bid 54% (37%-70%) 62% (44%-77%) 39% (23%-56%) (n = 13) § Primary
endpoint was met in 39% of all patients § Platelet response was further improved with longer treatment and at higher doses of PRN1008 9 *Primary endpoint was defined as 2 consecutive platelet counts ≥ 50,000/μL without requiring
rescue medication.Summary of Platelet Response by Treatment Duration and Dose Patients Achieving 9 Platelet Counts ≥ 50 × 10 /L (80% CI) Treatment Duration and Dose Primary Endpoint* Any 2 4 of Final 8 (data cut-off 13Nov2019) 2
consecutive All patients enrolled 39% (28%-50%) 45% (34%-57%) 29% (20%-40%) (N = 31) ≥ 4 wk, all doses 46% (34%-59%) 54% (41%-66%) 35% (24%-47%) (n = 26) ≥ 12 wk, all doses 47% (33%-62%) 59% (43%-73%) 35% (22%-51%) (n = 17) ≥ 12 wk
at 300 and 400 mg bid 54% (37%-70%) 62% (44%-77%) 39% (23%-56%) (n = 13) § Primary endpoint was met in 39% of all patients § Platelet response was further improved with longer treatment and at higher doses of PRN1008 9 *Primary endpoint
was defined as 2 consecutive platelet counts ≥ 50,000/μL without requiring rescue medication.
Individual Platelet Counts By Dose Levels Over Time to Date Responders*
(colored dots/lines) Non-responders (gray) Data cut-off 13Nov2019. *Patients who achieved ≥ 50,000/μL platelet counts at least once. 10Individual Platelet Counts By Dose Levels Over Time to Date Responders* (colored dots/lines)
Non-responders (gray) Data cut-off 13Nov2019. *Patients who achieved ≥ 50,000/μL platelet counts at least once. 10
Subset Analyses of Primary Platelet Responses* Primary Response
(N=31)§ Overall, 39% of patients met the primary endpoint 39% independent of dose or time on treatment* Heavily Pretreated § PRN1008 showed 10/25 (40%) heavily pretreated 40% (≥4 Prior Therapies) (n=25) patients responding (≥ 4
prior therapies) § Similar responses were achieved in patients PRN1008 Monotherapy 40% receiving PRN1008 monotherapy (4/10 patients) (n=10) and concomitant therapy (8/21 patients) PRN1008 + Concomitant 38% Therapy (n=21) 0% 20% 40% 60% Platelet
Response Data cut-off 13Nov2019. 11 *Primary endpoint was defined as 2 consecutive platelet counts ≥ 50,000/μL without requiring rescue medication.Subset Analyses of Primary Platelet Responses* Primary Response (N=31)§ Overall, 39%
of patients met the primary endpoint 39% independent of dose or time on treatment* Heavily Pretreated § PRN1008 showed 10/25 (40%) heavily pretreated 40% (≥4 Prior Therapies) (n=25) patients responding (≥ 4 prior therapies) §
Similar responses were achieved in patients PRN1008 Monotherapy 40% receiving PRN1008 monotherapy (4/10 patients) (n=10) and concomitant therapy (8/21 patients) PRN1008 + Concomitant 38% Therapy (n=21) 0% 20% 40% 60% Platelet Response Data cut-off
13Nov2019. 11 *Primary endpoint was defined as 2 consecutive platelet counts ≥ 50,000/μL without requiring rescue medication.
PRN1008 Treatment Was Well-Tolerated in ITP Patients (N = 31) §
Median treatment duration at data cut-off Related TEAEs was 12.0 weeks (range, 0.1-41.9) Grade 1/2 (≥ 2 Patients), n (%) § Related TEAEs were reported in 11 patients All TEAEs 11 (35) (35%); all were grade 1 or 2 Nausea 8 (26) § No
treatment-related bleeding or thrombotic events Diarrhea 7 (23) § No significant changes in the ITP-BAT Abdominal distension 3 (10) bleeding scale from baseline to last visit Fatigue 3 (10) § No dose-limiting toxicities § Safety
profile is consistent with safety 1 observed to date in pemphigus Data cut-off 13Nov2019. TEAEs, treatment-emergent adverse events. 12 1. Murrell D, et al. AAD. 2018:LBA 10086.PRN1008 Treatment Was Well-Tolerated in ITP Patients (N = 31) §
Median treatment duration at data cut-off Related TEAEs was 12.0 weeks (range, 0.1-41.9) Grade 1/2 (≥ 2 Patients), n (%) § Related TEAEs were reported in 11 patients All TEAEs 11 (35) (35%); all were grade 1 or 2 Nausea 8 (26) § No
treatment-related bleeding or thrombotic events Diarrhea 7 (23) § No significant changes in the ITP-BAT Abdominal distension 3 (10) bleeding scale from baseline to last visit Fatigue 3 (10) § No dose-limiting toxicities § Safety
profile is consistent with safety 1 observed to date in pemphigus Data cut-off 13Nov2019. TEAEs, treatment-emergent adverse events. 12 1. Murrell D, et al. AAD. 2018:LBA 10086.
Unrelated Serious Adverse Events (Grade 2-3) Patient Serious Adverse
Event Description Rectal hemorrhage, grade 2 Patient was discontinued from the study because rescue medications were used during 0211-003 Start: study day 37, 400 mg bid hospitalization. 9 9 Stop: study day 42 Platelet counts: 16×10 /L at
baseline (average of 3 counts); 3×10 /L on study day 29. Iridocyclitis, grade 2 Patient was hospitalized due to a need for monitoring. Event as ”secondary to ulcerative colitis 0213-005 Start: study day 73, 400 mg bid and due to
autoimmune predisposition”. There were no changes to the study drug dosing. 9 9 Stop: study day 76, 400 mg bid Platelet counts: 8×10 /L at baseline (average of 2 counts); 14×10 /L at study day 70 Head contusion (due to fall), grade 3
Rescue medications were used during hospitalization. This event was the reason for drug and Start: study day 29, next day after 0434-001 study discontinuation. the last dose of 300 mg bid 9 9 Platelet counts: 3×10 /L at baseline (average of 3
counts); 14×10 /L on study day 28. Stop: study day 30 Gastrointestinal bleeding, grade 3 Patient with a history of GERD experienced two episodes of melena and was hospitalized. 0102-002 Start: study day 10, 400 mg bid Treatment included
platelet transfusion. Patient was discontinued from the study. 9 9 Stop: study day 15 Platelet counts: 18×10 /L at baseline (average of 3 counts), 37×10 /L at study day 8. 13Unrelated Serious Adverse Events (Grade 2-3) Patient Serious
Adverse Event Description Rectal hemorrhage, grade 2 Patient was discontinued from the study because rescue medications were used during 0211-003 Start: study day 37, 400 mg bid hospitalization. 9 9 Stop: study day 42 Platelet counts: 16×10 /L
at baseline (average of 3 counts); 3×10 /L on study day 29. Iridocyclitis, grade 2 Patient was hospitalized due to a need for monitoring. Event as ”secondary to ulcerative colitis 0213-005 Start: study day 73, 400 mg bid and due to
autoimmune predisposition”. There were no changes to the study drug dosing. 9 9 Stop: study day 76, 400 mg bid Platelet counts: 8×10 /L at baseline (average of 2 counts); 14×10 /L at study day 70 Head contusion (due to fall), grade 3
Rescue medications were used during hospitalization. This event was the reason for drug and Start: study day 29, next day after 0434-001 study discontinuation. the last dose of 300 mg bid 9 9 Platelet counts: 3×10 /L at baseline (average of 3
counts); 14×10 /L on study day 28. Stop: study day 30 Gastrointestinal bleeding, grade 3 Patient with a history of GERD experienced two episodes of melena and was hospitalized. 0102-002 Start: study day 10, 400 mg bid Treatment included
platelet transfusion. Patient was discontinued from the study. 9 9 Stop: study day 15 Platelet counts: 18×10 /L at baseline (average of 3 counts), 37×10 /L at study day 8. 13
Conclusions § 54% primary endpoint response rate with bid doses
for ≥ 12 weeks − Overall 39% response rate in all patients with median of 6 prior therapies (55% had received prior TPO-RA) § Rapid onset (platelet counts > 30K by the first week of treatment) § Responses were durable in the
majority of patients § PRN1008 was well-tolerated across all doses (all TEAEs were mild to moderate) with no thrombotic events § Confirmed optimal safety and efficacy dose is 400 mg bid § Further studies are being planned
14Conclusions § 54% primary endpoint response rate with bid doses for ≥ 12 weeks − Overall 39% response rate in all patients with median of 6 prior therapies (55% had received prior TPO-RA) § Rapid onset (platelet counts >
30K by the first week of treatment) § Responses were durable in the majority of patients § PRN1008 was well-tolerated across all doses (all TEAEs were mild to moderate) with no thrombotic events § Confirmed optimal safety and efficacy
dose is 400 mg bid § Further studies are being planned 14
