Interim TORREY OLE Update and PROSERA Phase 3 Design July 2023
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I. TORREY 24 Week Data 3
Selected Baseline Disease Characteristics (ITT Population) 4 Characteristic Placebo (N=42) Seralutinib (N=44) Total (N=86) Number of PAH background therapies – n (%) 1 2 (4.8) 1 (2.3) 3 (3.5) 2 16 (38.1) 18 (40.9) 34 (39.5) 3 24 (57.1) 25 (56.8) 49 (57.0) WHO FC – n (%) Class II 20 (47.6) 30 (68.2) 50 (58.1) Class III 22 (52.4) 14 (31.8) 36 (41.9) PVR (dyne*s/cm5) – mean (SD) 661.3 (164.91) 675.8 (240.35) 668.7 (205.90) 6MWD (m) – mean (SD) 407.1 (107.02) 408.6 (75.11) 407.9 (91.54) NT-proBNP (ng/L) – mean (SD) 645.6 (1158.75) 611.0 (714.58) 628.3 (956.83) 1) Source: https://doi.org/10.1056/NEJMoa2213558. *As determined by baseline PVR & 6MWD, we believe that TORREY enrolled the most well-controlled PAH patient trial population to meet its primary efficacy endpoint. 6MWD = six-minute walk distance; FC = Functional Class; NT-proBNP = N-terminal pro B-type natriuretic peptide; PVR = pulmonary vascular resistance; WHO = World Health Organization; ITT = intention-to-treat; SD = standard deviation; Pbo = placebo. Heavily pre-treated patient population Hit Primary Endpoint Despite FC Imbalance in Drug & Pbo Arms Mildest baseline PAH disease to see treatment effect* STELLAR Trial Phase 3 NT-proBNP mean baseline was 1,121.1ng/L; PVR was 763.7 dyne*s/cm5 (1)
• Met Primary Endpoint: Statistically significant reduction in PVR in heavily-treated study population • Consistent, favorable PVR benefit seen in all pre-specified sub-groups in favor of seralutinib with enhanced effects in patients with more severe disease at baseline§ • Consistently favorable results for hemodynamic and ECHO endpoints • Well tolerated, avoiding side effect profile associated with systemic imatinib in PAH Overall Study Population Functional Class III REVEAL 2.0 Risk Score ≥ 6 PVR 6MWD PVR 6MWD PVR 6MWD p = 0.0310 p = 0.5972 p = 0.0427 p = 0.0476 p = 0.0134 p = 0.2482 TORREY Study Phase 2 Topline Results 5 * = p-value ≤ 0.05. All p-values in this presentation are nominal, aside from primary endpoint (overall study population delta in PVR). § At baseline, as determined by Functional Class and REVEAL 2.0 Risk Score (pre-specified subgroups). Functional Class II patients showed a placebo adjusted PVR improvement of -66.9 dynes*sec*cm-5 (p = 0.2601) from baseline. -14%* +6.5m -21%* +37.3m* -23%* +21.9m Primary Endpoint
II. New Developments 6
New Developments in the Seralutinib Program • Summary of OLE findings to date: Differentiated efficacy and safety profile emerging • Continued improvement in reduction of PVR • 30 patients with Week 72 PVR data • Early enrollers; milder disease baseline than overall population • Continual improvement seen in ∆6MWD & ∆NT-proBNP • Increased magnitude of effect in Phase 3 target population • Attractive safety profile for chronic treatment • Regulatory feedback supportive of single registrational study evaluating 90mg BID dose • FDA and EMA aligned on all key components of study; protocol finalized • Phase 3 trial incorporating learnings from TORREY targeted to initiate in August • Use of REVEAL Lite and NT-proBNP as enrichment factors for 6MWD success • Use of PPD as CRO helps to de-risk execution of enrollment and 6MWT conduct • Anticoagulants allowed with important patient safety guardrails 7 OLE = open-label extension; PVR = pulmonary vascular resistance; 6MWD = six-minute walk distance; NT-proBNP = N-terminal pro B-type natriuretic peptide; BID = twice daily dosing; CRO = contract research organization; 6MWT = six-minute walk test.
III. Interim TORREY OLE Extension Results Data available to date – Subject to change – Study is ongoing Data as of June 23, 2023. 8
TORREY Open-Label Extension Interim Update • Of 80 TORREY completers (38 seralutinib arm, 42 placebo arm), 73 (91.3%) elected to rollover into the open-label extension • PVR measured via right heart catheterization at Baseline, Week 24, and Week 72 (approximately 1 year into OLE) • As of interim data cutoff date, Week 72 PVR data available for 30 patients • 16 continued-seralutinib, 14 placebo-crossover 9 Screening Open-Label ExtensionBlinded Evaluation Randomization Placebo, n = 42 Seralutinib, n = 44 Continued-Seralutinib, n = 33 Placebo-Crossover to Seralutinib, n = 40 Patients Continue on OLE Week 24 Week 72Baseline Patients Continue on OLE OLE = open-label extension; PVR = pulmonary vascular resistance.
Seralutinib Profile Emerging From OLE ✓Seralutinib treatment leads to hemodynamic improvement in ~60-70% of patients ✓ Almost all patients who have short-term benefit (at 6 months) continue to improve with long-term treatment ✓The continued improvement in PVR, along with the ECHO and FRI data gathered in TORREY, is supportive of a reverse remodeling mechanism of action ✓Safety and tolerability remain relatively benign, with no safety signals emerging or worsening with long-term use ✓Drug delivery via DPI twice daily well-accepted and easy to incorporate into a patient’s daily routine • Seralutinib has the potential to be used prior to more invasive / inconveniently delivered therapies and / or those with challenging safety / tolerability profiles (e.g., prostacyclins) 10 OLE = open-label extension; PVR = pulmonary vascular resistance; ECHO = echocardiogram; FRI = functional resonance imaging; DPI = dry powder inhaler
Interim Analysis Shows Deepening PVR Improvement in Continued-Seralutinib Group * Interim update for first 16 continued-seralutinib patients to reach Week 72 PVR = pulmonary vascular resistance; WHO = World Health Organization; OLE = open-label extension 11 Baseline Week 24 Week 72 Median Baseline PVR: End of TORREY OLE PVR Data Point 541 dyne*s/cm5 Median Change in PVR vs. Baseline: -70.5 dyne*s/cm5 Median Change in PVR vs. Baseline: -142.5 dyne*s/cm5 • 11 / 16 had improvement in PVR • Mean improvement of PVR responders at week 24 = 24% • All 11 initial responders maintained PVR below baseline • 9 / 11 continued to improve • Mean improvement of 9 PVR dual responders = 39% • 3 patients reached a PVR below 200 dyne*s/cm5 • 10 WHO Functional Class II, 6 WHO Functional Class III • 50% on dual background therapy, 50% on triple background therapy
6MWD N = 32 20 18 12 Baseline (m) 409 389 377 368 Further Improvements Seen in 6MWD and NT-proBNP for Phase 3 Target Population in Continued-Seralutinib Group 12 16 4247 71 0 50 100 Week 24 Week 64 Overall Population Phase 3 Target Patient Population* NT-pro BNP N = 32 13 17 9 Baseline (ng/L) 595 875 1,017 1,197 -160 -322 -260 -401 -500 -250 0 Week 24 Week 72 C h a n g e in 6 M W D v s. B a se lin e ( m ) C h a n g e in N T- p ro B N P v s. B a se lin e ( n g /L ) * REVEAL Lite 2 Risk Score ≥ 5 at TORREY baseline. 6MWD = six-minute walk distance; NT-proBNP = N-terminal pro B-type natriuretic peptide.
Encouraging Early Trends Observed in Placebo-Crossover Group 13 • 7 / 14 patients had improvement in PVR after beginning seralutinib treatment in OLE • 11 / 14 patients had improved PVR vs. baseline PVR at Week 72 6MWD N = 40 17 17 7 Baseline (m) 408 415 337 336 0 4 15 25 0 20 40 Week 24 Week 64 Overall Population Phase 3 Target Patient Population* NT-pro BNP 194 386 -27 -87-250 0 250 500 Week 24 Week 72 C h a n g e i n 6 M W D v s. B a se lin e ( m ) C h a n g e i n N T- p ro B N P v s. B a se lin e ( n g /L ) N = 33 15 13 6 Baseline (ng/L) 526 673 1,072 1,375 • 6MWD improvement in OLE driven by Phase 3 target population • NT-proBNP increase while on placebo during TORREY reversed after patients started on seralutinib treatment * REVEAL Lite 2 Risk Score ≥ 5 at TORREY baseline. PVR = pulmonary vascular resistance; OLE = open-label extension; 6MWD = six-minute walk distance; NT-proBNP = N-terminal pro B-type natriuretic peptide.
14 TORREY OLE Safety To Date • Safety results consistent with controlled period – seralutinib generally well tolerated with no new safety concerns • Results support chronic treatment in PAH patients • Reports of cough diminish as patients get used to DPI • Vast majority of patients have reached and maintained 90mg BID dose • Limited dose reductions to date • Limited liver enzyme elevations observed in OLE in similar pattern as TORREY (~5-10% ≥ 3x ULN, similar to placebo rate in TORREY), suggesting potential signal arises early in treatment course and easily monitorable • Safety tables available in appendix OLE = open-label extension; DPI = dry powder inhaler; BID = twice-daily dosing; ULN = upper limit of normal.
IV. PROSERA Phase 3 Overview 15
Regulatory Feedback • FDA & EMA - Alignment on the following key design elements of Phase 3 protocol: • One Dose: Single dose of seralutinib (90 mg BID); 2-arm study, with ~175 patients per arm • Enriched Population: Eligibility criteria for a target PAH population based on prespecified subgroup in TORREY with more severe disease and/or who are at higher risk of disease progression, defined by risk score assessment, functional class, PVR and exercise capacity at baseline • Primary Endpoint: 6MWD at Week 24 • Additional Comments: • FDA recommended consideration of a Phase 2 study to evaluate disease remodeling (withdrawal) • EMA recommended TTCW as key secondary • No safety concerns raised 16 BID = twice-daily dosing; PVR = pulmonary vascular resistance; 6MWD = six-minute walk distance; TTCW = time to clinical worsening.
17 PROSERA Phase 3 Study Design Schema Double Blind Placebo-Controlled Treatment Period (24 weeks) Placebo BID + Background PAH Therapy N = 175 Seralutinib 90mg BID + Background PAH Therapy N = 175 Extended Double Blind Treatment Period (up to an additional 24 weeks)* Primary Endpoint (6MWD) Evaluated at Week 24 Week 48 Open-Label Extension (OLE)Subjects who complete Week 24 who experience a clinical worsening event may proceed directly to OLE Week 24 Screening (up to 4 weeks) *Patients to remain blinded until week 48, until the last patient completes 24-week primary endpoint, after which time the study will be unblinded. BID = twice daily dosing; 6MWD = six-minute walk distance.
PROSERA Study Overview Design • Randomized, double-blind, placebo-controlled, parallel group • Up to 48-week double-blinded treatment period; primary endpoint assessed at Week 24 • Open-label extension option under separate protocol Primary Endpoint • Change in 6MWD at Week 24 from Baseline Key Secondary Endpoints • Time from 1st dose to 1st event of clinical worsening (TTCW) • Proportion of subjects who achieve all components of a composite endpoint of clinical improvement at Week 24 in the absence of clinical worsening: − Decrease in WHO FC or maintenance of WHO FC II − Decrease in NT-proBNP ≥ 30% or maintenance at <300 ng/L − Increase in 6MWD ≥ 10% or ≥ 30 m • Change vs. Baseline in NT-proBNP at Week 24 • Proportion of subjects with ≥ 1 point decrease in REVEAL Lite 2 Risk Score vs. Baseline at Week 24 Stratification at Randomization • WHO FC at screening: II vs III • Receiving parenteral prostacyclin therapy at Screening (yes vs. no) • CTD-APAH (yes vs. no) • Participation in CT sub-study (yes vs. no) 18 6MWD = six-minute walk distance; FC = functional class; NT-proBNP = N-terminal pro B-type natriuretic peptide; WHO = World Health Organization; CTD-APAH = connective tissue disease-associated PAH; CT = computerized tomography.
PROSERA Phase 3 Study Population Key Inclusion Criteria • Adults ≥ 18 and ≤ 75 years old • WHO Group 1 PAH • WHO Functional Class II or III • PVR ≥ 400 dyne•s/cm5 • Baseline 6MWD 150 - 450m* • Either REVEAL Lite 2 Risk Score ≥ 5 or NT-proBNP ≥ 300 ng/L* • Stable treatment with at least one SOC background therapy 19 * Key enrichment criteria. WHO = World Health Organization; PVR = pulmonary vascular resistance; 6MWD = six-minute walk distance; NT-proBNP = N-terminal pro B-type natriuretic peptide; SOC = standard of care
Broad Global Footprint with Trusted Sites and Clinical Partners • Broad global footprint planned: > 160 sites across ~30 countries • Experienced global Gossamer team to support sites, educate, and drive enrollment • Strong CRO partner (PPD) with deep experience in PAH • Enrollment target: 18 months 20 US and Canada: 50+ Sites Latin America: ~25 Sites Europe: 75+ Sites Asia Pacific: 10+ Sites Country with Study Site CRO = contract research organization.
21 Further Validation of REVEAL Lite 2 Enrichment for Phase 3 TORREY Week 24 Δ6MWD with REVEAL Lite 2 Score Incorporated • Right side consists of patients who are • Class II (n=15) • Class III (n=35) • Treatment effect in this population used as a basis for powering phase 3 with a conservative adjustment (Δ = 30 m, SD=70, α=0.025) • >95% power with 175 patient / arm 6MWD = six-minute walk distance; FC = functional class LS = least squares; LSMD = least squares mean difference; MMRM = mixed-effects model with repeated measures; WHO = World Health Organization. Based on MMRM modelling. Source: Data on file. Lowest Risk FC 2 Elevated Risk
Appendix I – OLE Safety 22
Incidence of TEAEs by preferred term: ≥ 5% in total column (Safety Population) 23 Preferred terma Placebo Switch (N=40) Seralutinib Cont. (N=34*) Total (N=74) Number of subjects with a TEAE 38 ( 95.0) 32 ( 94.1) 70 ( 94.6) Headache 9 ( 22.5) 8 ( 23.5) 17 ( 23.0) Cough 9 ( 22.5) 7 ( 20.6) 16 ( 21.6) COVID-19 6 ( 15.0) 7 ( 20.6) 13 ( 17.6) Diarrhoea 8 ( 20.0) 3 ( 8.8) 11 ( 14.9) Nausea 6 ( 15.0) 5 ( 14.7) 11 ( 14.9) Dyspnoea 7 ( 17.5) 2 ( 5.9) 9 ( 12.2) Pyrexia 3 ( 7.5) 4 ( 11.8) 7 ( 9.5) Rash 3 ( 7.5) 4 ( 11.8) 7 ( 9.5) Dizziness 2 ( 5.0) 4 ( 11.8) 6 ( 8.1) Influenza 2 ( 5.0) 4 ( 11.8) 6 ( 8.1) Nasopharyngitis 4 ( 10.0) 2 ( 5.9) 6 ( 8.1) Vomiting 4 ( 10.0) 2 ( 5.9) 6 ( 8.1) Abdominal pain 4 ( 10.0) 1 ( 2.9) 5 ( 6.8) Epistaxis 1 ( 2.5) 4 ( 11.8) 5 ( 6.8) Fatigue 4 ( 10.0) 1 ( 2.9) 5 ( 6.8) Hypokalaemia 3 ( 7.5) 2 ( 5.9) 5 ( 6.8) *One patient from the Phase 1b clinical trial, who remains on drug, is included. Abbreviations: MedDRA, Medical Dictionary for Regulatory Activities; TEAE, treatment-emergent adverse event. a Coded using MedDRA v 24.0
Incidence of TEAEs by preferred term: ≥ 5% in total column (Safety Population) - Continued 24 Preferred terma Placebo Switch (N=40) Seralutinib Cont. (N=34*) Total (N=74) Number of subjects with a TEAE 38 ( 95.0) 32 ( 94.1) 70 ( 94.6) Pneumonia 3 ( 7.5) 2 ( 5.9) 5 ( 6.8) Pulmonary arterial hypertension 3 ( 7.5) 2 ( 5.9) 5 ( 6.8) Alanine aminotransferase increased 4 ( 10.0) 0 4 ( 5.4) Arthralgia 3 ( 7.5) 1 ( 2.9) 4 ( 5.4) Aspartate aminotransferase increased 4 ( 10.0) 0 4 ( 5.4) Back pain 3 ( 7.5) 1 ( 2.9) 4 ( 5.4) Complication associated with device 2 ( 5.0) 2 ( 5.9) 4 ( 5.4) Flushing 3 ( 7.5) 1 ( 2.9) 4 ( 5.4) Iron deficiency 2 ( 5.0) 2 ( 5.9) 4 ( 5.4) Nasal congestion 2 ( 5.0) 2 ( 5.9) 4 ( 5.4) Pain 1 ( 2.5) 3 ( 8.8) 4 ( 5.4) Pain in extremity 2 ( 5.0) 2 ( 5.9) 4 ( 5.4) Palpitations 3 ( 7.5) 1 ( 2.9) 4 ( 5.4) Throat irritation 3 ( 7.5) 1 ( 2.9) 4 ( 5.4) Upper respiratory tract infection 2 ( 5.0) 2 ( 5.9) 4 ( 5.4) Vascular device infection 0 4 ( 11.8) 4 ( 5.4) *One patient from the Phase 1b clinical trial, who remains on drug, is included in this group. Abbreviations: MedDRA, Medical Dictionary for Regulatory Activities; TEAE, treatment-emergent adverse event. a Coded using MedDRA v 24.0
Incidence of Related TEAEs in 2 or More Patients (Safety Population) 25 Preferred terma Placebo Switch (N=40) Seralutinib Cont. (N=34*) Total (N=74) Number of subjects with a related adverse event 16 ( 40.0) 11 ( 32.4) 27 ( 36.5) Cough 7 ( 17.5) 3 ( 8.8) 10 ( 13.5) Headache 2 ( 5.0) 3 ( 8.8) 5 ( 6.8) Throat irritation 3 ( 7.5) 1 ( 2.9) 4 ( 5.4) Alanine aminotransferase increased 2 ( 5.0) 0 2 ( 2.7) Aspartate aminotransferase increased 2 ( 5.0) 0 2 ( 2.7) Fatigue 1 ( 2.5) 1 ( 2.9) 2 ( 2.7) Thrombocytopenia 0 2 ( 5.9) 2 ( 2.7) *One patient from the Phase 1b clinical trial, who remains on drug, is included in this group. Abbreviations: MedDRA, Medical Dictionary for Regulatory Activities; TEAE, treatment-emergent adverse event. a Coded using MedDRA v 24.0
Incidence of TEAEs Leading to Study Drug Discontinuation (Safety Population) 26 *One patient from the Phase 1b clinical trial, who remains on drug, is included in this group. Abbreviations: d/c, discontinuation; MedDRA, Medical Dictionary for Regulatory Activities; TEAE, treatment-emergent adverse event. a Coded using MedDRA v 24.0 Preferred terma Placebo Switch (N=40) Seralutinib Cont. (N=34*) Total (N=74) No. with a TEAE leading to d/c of study drug 9 ( 22.5) 3 ( 8.8) 12 ( 16.2) Cough 4 ( 10.0) 1 ( 2.9) 5 ( 6.8) Alanine aminotransferase increased 2 ( 5.0) 0 2 ( 2.7) Throat irritation 1 ( 2.5) 1 ( 2.9) 2 ( 2.7) Abdominal pain 1 ( 2.5) 0 1 ( 1.4) Acute respiratory failure 1 ( 2.5) 0 1 ( 1.4) Aspartate aminotransferase increased 1 ( 2.5) 0 1 ( 1.4) Blood bilirubin increased 1 ( 2.5) 0 1 ( 1.4) Confusional state 1 ( 2.5) 0 1 ( 1.4) Liver function test abnormal 0 1 ( 2.9) 1 ( 1.4) Nausea 0 1 ( 2.9) 1 ( 1.4) Vomiting 0 1 ( 2.9) 1 ( 1.4)
Appendix II – FLUIDDA CT Sub-Study 27
FLUIDDA CT Sub-Study: Assessing Pulmonary Vascular Remodeling in Patients Treated on Seralutinib • Purpose: Provide evidence consistent with a reverse remodeling effect of seralutinib • Hypothesis: volume of distal pulmonary arteries relative to volume of proximal pulmonary arteries will be increased by seralutinib as expressed by the ratio of BV5A to BV10A (BV510ARatio) • Available data: Baseline and Week 24 HRCTs with pulmonary vascular reconstruction in 7 seralutinib- treated subjects and 12 placebo subjects Thin Slice CTs with Pulmonary Vascular Segmentation at Baseline and Week 24 28 CT = computerized tomography; HRCT = high resolution computerized tomography
29 Pulmonary Vascular Volume of Small Distal Arterial Vessels is Decreased in PAH, Leading to Dilation of Larger Proximal Vessels BV5A= blood vessel volume of pulmonary arteries with a Cross-sectional area (CSA)<5mm2 BV5-10A= blood vessel volume of pulmonary arteries with a CSA Between 5-10 mm2 BV10A= blood vessel volume of pulmonary arteries with a CSA >10 mm2 BV510ARatio= BV5A/BV10A BV5ABV5-10ABV10A BV5ABV5-10ABV10A Remodeling Reverse Remodeling CT imaging can quantify these changes: • Pulmonary Vascular Pruning on CT correlates with histologic pulmonary vascular remodeling* • In PAH the BV5A/BV10A ratio is decreased *Synn et al Pulm Circ 2021.
30 Seralutinib Treatment Increases BV510ARatio, Supporting Reverse Remodeling Hypothesis Parameter LSMD Estimate (95% CI) P-value BV510ARATIO 0.845 (0.105,1.585) 0.028 PAC=pulmonary artery compliance SV=stroke volume Linear regression models adjusted for baseline values and treatment arm; Abbreviations: LSMD, least squares mean difference; BV510ARATIO = Ratio of pulmonary arteries smaller than 5 mm2 in cross sectional area (BV5A) compared to pulmonary arteries larger than 10 mm2 in cross sectional area (BV10A) Seralutinib increases BV510ARatioBV510ARatio correlates with hemodynamics PAC SV Placebo (n=12) Baseline 24wk Seralutinib (n=7) Baseline 24wk B V 5 1 0 A R A T IO Placebo (n=12) Baseline 24wk Seralutinib (n=7) Baseline 24wk Seralutinib Placebo B V 5 1 0 A R A T IO
FRI Imaging Case Study (Placebo Patient) WHO FC2 IPAH Patient on PDE/PRA, treated with Placebo • 6% Decrease in BV5APRA (red areas) • 5% Increase in BV10APRA (blue areas) • Decrease in BV5A/BV10A ratio • 283 dyne•s/cm5 increase in PVR coincident with arterial volume shifts BVA5PRA = Proportion of pulmonary arteries smaller than 5 mm2 in cross sectional area compared to all arteries BVA10PRA = Proportion of pulmonary arteries larger than 10 mm2 in cross sectional area compared to all arteries * Measurements preliminary; do not include the hilum Week 24Baseline 31
32 FRI Imaging Case Study (Seralutinib Patient) WHO FC2 IPAH and Severe RA Patient on Triple Therapy, treated with Seralutinib • 6% Increase in BV5APRA (red areas) • 8% Decrease in BV10APRA (blue areas) • Increase in BV5A/BV10A ratio • 159 dyne•s/cm5 improvement in PVR coincident with arterial volume shifts BVA5PRA = Proportion of pulmonary arteries smaller than 5 mm2 in cross sectional area compared to all arteries BVA10PRA = Proportion of pulmonary arteries larger than 10 mm2 in cross sectional area compared to all arteries * Measurements preliminary; do not include the hilum Week 24Baseline We k 24Baseline 32
33 Summary of FRI Sub-study and Plans for Phase 3 • The BV510ARatio correlates with important measures of RV-PA coupling as measured by pulmonary artery compliance and cardiopulmonary hemodynamics (i.e., Stroke Volume) • There was a significant improvement in the ratio of blood vessel volume in distal vessels relative to larger vessels (BV510ARatio) consistent with a reverse remodeling effect of seralutinib • To increase our understanding of the effect of seralutinib on pulmonary vascular remodeling, an FRI sub-study is planned for Phase 3