Karyopharm Therapeutics Inc. · NASDAQ:KPTI

Karyopharm Therapeutics — Technical Presentation (March 2022)

25 slides from Karyopharm Therapeutics's technical presentation, March 2022

  1. Slide 1: Phase III SIENDO Study of Oral Selinexor/Placebo as Maintenance Therapy in Endometrial Cancer

    PROSPECTIVE DOUBLE-BLIND, RANDOMIZED PHASE III ENGOT-EN5/GOG-3055/SIENDO STUDY OF ORAL SELINEXOR/PLACEBO AS MAINTENANCE THERAPY AFTER FIRST-LINE CHEMOTHERAPY FOR ADVANCED OR RECURRENT ENDOMETRIAL CANCER Ignace Vergote,1 Alejandro Pérez Fidalgo,2 Erika Hamilton,3 Giorgio Valabrega,4 Toon Van Gorp,1 J

  2. Slide 2: Declaration of Interests

    DECLARATION OF INTERESTS Ignace Vergote: • Consulting for: Agenus, Aksebio, AstraZeneca, Bristol Myers Squibb (2021), Deciphera Pharmaceuticals, Eisai, Elevar Therapeutics, F. Hoffmann-La Roche Ltd, Genmab, GSK, Immunogen Inc., Jazzpharma, Karyopharm, Mersana, MSD, Novocure, Novartis, Oncoinvent AS,

  3. Slide 3: Selinexor: XPO1 Inhibition

    SELINEXOR: XPO1 INHIBITION Exportin 1 (XPO1) is the major nuclear export protein for:1 • Tumor suppressor proteins (TSPs, e.g., p53, IkB, PTEN, and FOXO1) Inhibition of XPO1 results in:1 • The increase in nuclear levels and activation of TSPs • Reduction of oncoprotein levels Selinexor is an oral se

  4. Slide 4: Selinexor Activity in Gynecological Malignancies

    SELINEXOR ACTIVITY IN GYNECOLOGICAL MALIGNANCIES SIGN study - endometrial cohort - • Selinexor, alone or in combination with platinum, N = 23 reduced tumor growth in platinum-resistant PDX mice as well as ovarian-cancer patients.1,2 • SIGN phase 2 study2, selinexor monotherapy in gynecological malig

  5. Slide 5: Trial Design

    ENGOT-EN5/GOG-3055/SIENDO TRIAL DESIGN endometrioid, Stage IV or first relapse of endometrial cancer serous, undifferentiated, or carcinosarcoma (NCT03555422) Created with BioRender.com **140 PFS events needed to provide 80% power to detect a hazard ratio of 0.6 (median PFS 4.5 months for placebo an

  6. Slide 6: Disposition

    ENGOT-EN5/GOG-3055/SIENDO DISPOSITION Enrolled (n=263) Selinexor (n=174) Placebo (n=89) Received at least one dose 171 (100)* Received at least one dose 88 (100)* Discontinued 111 (64.9) Discontinued 52 (59.1) Disease progression 75 (43.5) Disease progression 50 (56.8) Withdrawal by patient 15 (8.8)

  7. Slide 7: Patient Characteristics

    ENGOT-EN5/GOG-3055/SIENDO PATIENT CHARACTERISTICS Selinexor Placebo CHARACTERISTIC N = 174 N = 89 Age, years median (range), n (%) 65.5 (40-81) 64.0 (33-81) <70 years, n (%) 116 (66.7) 61 (68.5) ≥70 years, n (%) 58 (33.3) 28 (31.5) ECOG performance status, n (%) 0 99 (56.9) 54 (60.7) 1 71 (40.8) 35

  8. Slide 8: Primary Endpoint: PFS in ITT Population

    ENGOT-EN5/GOG-3055/SIENDO PRIMARY ENDPOINT: PFS IN ITT POPULATION (BASED ON AUDITED STRATIFICATION FACTORS)* 1.00 + Censored Median PFS (Investigator assessed) 72.4% Selinexor vs. Placebo • Selinexor (n=174): 5.7 mo (95% CI 3.81-9.20) 66.4% • Placebo (n=89): 3.8 mo (95% CI 3.68-7.39) Progression-fre

  9. Slide 9: Subgroup PFS: By Histological Subtype

    ENGOT-EN5/GOG-3055/SIENDO SUBGROUP PFS: BY HISTOLOGICAL SUBTYPE (BASED ON AUDITED STRATIFICATION FACTORS) Endometrioid Carcinoma Serous Carcinoma 1.00 1.00 PFS: Selinexor: 9.2 mo PFS: Selinexor: 3.8 mo PFS: Placebo: 3.8 mo PFS: Placebo: 3.7 mo Probability of Progression-free Survival Probability of

  10. Slide 10: Subgroup PFS: Patients with Wild Type p53 EC

    ENGOT-EN5/GOG-3055/SIENDO SUBGROUP PFS: PATIENTS WITH WILD TYPE P53 EC (BASED ON AUDITED STRATIFICATION FACTORS) 1.00 + Censored Selinexor Placebo 0.75 Progression-free Survival Median PFS • Selinexor (n=67): 13.7 mo (95% CI 9.20-NR) Probability of 0.50 • Placebo (n=36): 3.7 mo (95% CI 1.87-12.88) •

  11. Slide 11: Subgroup Patient Characteristics: p53 Wild Type

    ENGOT-EN5/GOG-3055/SIENDO SUBGROUP PATIENT CHARACTERISTICS: P53 WILD TYPE Selinexor Placebo CHARACTERISTIC N = 67 N = 36 Age, years median (range), n (%) 64.0 (40-81) 61.0 (33-74) <70 years, n (%) 46 (68.7) 29 (80.6) ≥70 years, n (%) 21 (31.3) 7 (19.4) ECOG performance status, n (%) 0 36 (53.7) 23 (

  12. Slide 12: Safety: Treatment-Emergent Adverse Events

    ENGOT-EN5/GOG-3055/SIENDO SAFETY: TREATMENT-EMERGENT ADVERSE EVENTS Selinexor Placebo (n=171)* (n=88)* 84% 10% 1% 34% 52% 2% 1% 17% 37% 1% 2% 38% 37% 6% 0 35% 1% 7% 35% 6% 1% 15% 34% 2% 23% 31% 6% 1% 21% 28% 5% 5% Any grade in ≥20% pts 25% 9% 6% Grade 3 in ≥2% pts 18% 2% 17% Grade 4** *Four patients

  13. Slide 13: Safety

    ENGOT-EN5/GOG-3055/SIENDO SAFETY Selinexor Placebo Event n=171* n=88* n (%) n (%) (per patient) (per patient) TEAE leading to: Dose reduction 85 (49.7) 3 (3.4) Dose interruption 88 (51.5) 16 (18.2) Discontinuation 18 (10.5) 1 (1.1) Death 0 0 *Four patients did not receive treatment (n=3 selinexor; n

  14. Slide 14: QOL - Patient-Reported Outcomes (EORTC QLQ-C30)

    ENGOT-EN5/GOG-3055/SIENDO QOL -PATIENT-REPORTED OUTCOMES (EORTC QLQ-C30) No significant differences in global health, physical functioning or symptoms Global Health Status/QoL Physical Functioning Score Score Baseline Day 85 Day 169 Day 253 Baseline Day 85 Day 169 Day 253 Diarrhea Nausea and Vomitin

  15. Slide 15: Summary and Conclusions

    ENGOT-EN5/GOG-3055/SIENDO SUMMARY AND CONCLUSIONS • Selinexor demonstrated in the audited ITT population, a 30% decrease of risk for progression and/or death compared to placebo (HR: 0.705; CI: 0.499-0.996; median PFS 5.7 vs 3.8 months, respectively) which was statistically significant (one-sided p=

  16. Slide 16: Eligibility

    ENGOT-EN5/GOG-3055/SIENDO ELIGIBILITY Key Inclusion Criteria Key Exclusion Criteria • Female patients ≥ 18 years • Sarcomas, small cell carcinoma with neuroendocrine • Histology: Endometrioid, serous, differentiation, or clear cell carcinosarcoma, or carcinomas undifferentiated • Previous treatment

  17. Slide 17: Selinexor Induces Nuclear Accumulation of p53

    SELINEXOR INDUCES NUCLEAR ACCUMULATION OF P53 • p53 wild type tumors account for 45-65% of all endometrial cancers o Generally endometrioid in histology and occurs in younger patients • Inhibition of XPO1 leads to nuclear accumulation of tumor suppressor proteins such as p53 • Selinexor induces nucl

  18. Slide 18: Subgroup Patient Characteristics: By Histological Subtype

    ENGOT-EN5/GOG-3055/SIENDO SUBGROUP PATIENT CHARACTERISTICS: BY HISTOLOGICAL SUBTYPE Endometrioid Carcinoma Serous Carcinoma Others CHARACTERISTIC Selinexor Placebo Selinexor Placebo Selinexor Placebo N = 96 N = 48 N = 49 N = 28 N = 29 N = 13 Age, years median (range), n (%) 64.0 (40-81) 60.5 (40-74)

  19. Slide 19: Subgroup PFS: By Histological Subtype - Other

    ENGOT-EN5/GOG-3055/SIENDO SUBGROUP PFS: BY HISTOLOGICAL SUBTYPE - OTHER* 1.00 0.75 Median PFS • Selinexor: 3.7 mo (95% CI 1.94, not reached) Progression-free Survival • Placebo: 5.2 mo (95% CI 3.71, not reached) Probability of 0.50 • HR 1.103 (95% CI 0.459, 2.652) • One-sided P value = 0.592 0.25 +

  20. Slide 20: Subgroup PFS: By Disease at Time of Taxane-Platinum Therapy

    ENGOT-EN5/GOG-3055/SIENDO SUBGROUP PFS: BY DISEASE AT TIME OF TAXANE-PLATINUM COMBINATION THERAPY Primary Stage IV Disease Recurrent Disease 1.00 1.00 PFS: Selinexor, 5.7 mo PFS: Selinexor, 5.8 mo PFS: Placebo: 5.7 mo PFS: Placebo: 3.8 mo HR 0.820 (95% CI 0.489, 1.373) HR 0.647 (95% CI 0.407, 1.031)

  21. Slide 21: Subgroup PFS: By PR vs CR Stratification

    ENGOT-EN5/GOG-3055/SIENDO SUBGROUP PFS: BY PR VS CR STRATIFICATION PR CR 1.00 1.00 1.00 1.00 PFS: Selinexor, 3.7 mo PFS: Selinexor, 11.8 mo PFS: Placebo: 3.6 mo PFS:Placebo: 9.3 mo HR 0.646 (95% CI 0.431, 0.970) HR 0.872 (95% CI 0.460, 1.653) One-sided P value = 0.018 0.75 0.75 One-sided P value = 0

  22. Slide 22: Subgroup PFS: Patients with MSS/pMMR Endometrial Cancer

    ENGOT-EN5/GOG-3055/SIENDO SUBGROUP PFS: PATIENTS WITH ENDOMETRIAL CANCER WITH MSS/PMMR 1.00 0.75 Progression-free Survival Median PFS Probability of • Selinexor: 6.9 mo (95% CI 5.42-10.94) 0.50 • Placebo: 5.4 mo (95% CI 3.61-7.49) • HR=0.593 (95% CI 0.388-0.905) 0.25 0.25 • One-sided P value = 0.007

  23. Slide 23: Use of IRT vs eCRF

    ENGOT-EN5/GOG-3055/SIENDO USE OF IRT VS ECRF • SIENDO primary analysis used IRT, but a misclassification of data made resulting analysis erroneous • Errors corrected by Investigators before database lock and unblinding • eCRF is correct and appropriate to use in primary endpoint analysis of PFS • Da

  24. Slide 24: Incorrect Stratification at Randomization

    ENGOT-EN5/GOG-3055/SIENDO INCORRECT STRATIFICATION AT RANDOMIZATION • Per SAP (v3.0), the stratified analysis (based on IRT value of the disease status after chemotherapy, CR vs. PR) is the primary analysis for PFS, which was determined to be erroneous for the SIENDO study  The baseline disease sta

  25. Slide 25: Reasons for Reduction, Interruptions, Discontinuations

    ENGOT-EN5/GOG-3055/SIENDO REASONS FOR REDUCTION, INTERRUPTIONS, DISCONTINUATIONS Treatment-Emergent Dose Reduction Dose Interruption Discontinuation Event Leading to Selinexor Placebo Selinexor Placebo Selinexor Placebo Thrombocytopenia 28 (16.4) 0 24 (14.0) 0 1 (0.6) 0 Nausea 23 (13.5) 1 (1.1) 19 (

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