investor conference call: phase 3 seal data update

November 20, 2020

Investor Conference Call: Phase 3 SEAL Data Update

2©2020 Karyopharm Therapeutics Inc.

On Today’s Call

• Michael G. Kauffman, MD, PhD, Chief Executive Officer, Karyopharm

• Sant P. Chawla, MD, FRACP, Director of the Sarcoma Oncology Center, Santa Monica, CA

• Jatin Shah, MD, Executive Vice President, Chief Medical Officer, Karyopharm

• Sharon Shacham, PhD, President and Chief Scientific Officer, Karyopharm

• Mrinal M. Gounder, MD, Sarcoma Service and Developmental Therapeutics Service, Memorial Sloan Kettering Cancer Center

Prepared Remarks

Joining for Q&A Session


Forward-looking Statements and Other Important Information This presentation contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Such forward-looking statements include those regardingKaryopharm’s expectations and plans relating to XPOVIO for the treatment of patients with advanced unresectable dedifferentiated liposarcoma commercialization of XPOVIO or any of itsdrug candidates and the commercial performance of XPOVIO; submissions to, and the review and potential approval of selinexor by, regulatory authorities, including the Company’sregulatory strategy, the anticipated availability of data to support such submissions, timing of such submissions and actions by regulatory authorities and the potential availability ofaccelerated approval pathways; the expected design of the Company’s clinical trials; and the therapeutic potential of and potential clinical development plans for Karyopharm's drugcandidates, especially selinexor. Such statements are subject to numerous important factors, risks and uncertainties, many of which are beyond Karyopharm's control, that may causeactual events or results to differ materially from Karyopharm's current expectations. For example, there can be no guarantee that Karyopharm will successfully commercialize XPOVIO; thatregulators will agree that selinexor qualifies for conditional approval in the E.U. as a result of data from the STORM study or confirmatory approval in the U.S. or EU based on the BOSTONstudy in patients with relapsed or refractory multiple myeloma; or that any of Karyopharm's drug candidates, including selinexor, will successfully complete necessary clinical developmentphases or that development of any of Karyopharm's drug candidates will continue. Further, there can be no guarantee that any positive developments in the development orcommercialization of Karyopharm's drug candidate portfolio will result in stock price appreciation. Management's expectations and, therefore, any forward-looking statements in thispresentation could also be affected by risks and uncertainties relating to a number of other factors, including the following: the risk that the COVID-19 pandemic could disrupt Karyopharm’sbusiness more severely than it currently anticipates, including by negatively impacting sales of XPOVIO, interrupting or delaying research and development efforts, impacting the ability toprocure sufficient supply for the development and commercialization of selinexor or other product candidates, delaying ongoing or planned clinical trials, impeding the execution of businessplans, planned regulatory milestones and timelines, or inconveniencing patients; the adoption of XPOVIO in the commercial marketplace, the timing and costs involved in commercializingXPOVIO or any of Karyopharm’s drug candidates that receive regulatory approval; the ability to retain regulatory approval of XPOVIO or any of Karyopharm’s drug candidates that receiveregulatory approval; Karyopharm's results of clinical trials and preclinical studies, including subsequent analysis of existing data and new data received from ongoing and future studies; thecontent and timing of decisions made by the U.S. Food and Drug Administration and other regulatory authorities, investigational review boards at clinical trial sites and publication reviewbodies, including with respect to the need for additional clinical studies; the ability of Karyopharm or its third party collaborators or successors in interest to fully perform their respectiveobligations under the applicable agreement and the potential future financial implications of such agreement; Karyopharm's ability to obtain and maintain requisite regulatory approvals andto enroll patients in its clinical trials; unplanned cash requirements and expenditures; development of drug candidates by Karyopharm's competitors for diseases in which Karyopharm iscurrently developing its drug candidates; and Karyopharm's ability to obtain, maintain and enforce patent and other intellectual property protection for any drug candidates it is developing.These and other risks are described under the caption "Risk Factors" in Karyopharm's Quarterly Report on Form 10-Q for the quarter ended September 30, 2020, which was filed with theSecurities and Exchange Commission (SEC) on November 2, 2020, and in other filings that Karyopharm may make with the SEC in the future. Any forward-looking statements contained inthis presentation speak only as of the date hereof, and, except as required by law, Karyopharm expressly disclaims any obligation to update any forward-looking statements, whether as aresult of new information, future events or otherwise. Karyopharm regularly uses its website to post information regarding its business, drug development programs and governance.Karyopharm encourages investors to use www.karyopharm.com, particularly the information in the section entitled “Investors,” as a source of information about Karyopharm. References towww.karyopharm.com in this presentation are not intended to, nor shall they be deemed to, incorporate information on www.karyopharm.com into this presentation by reference. Unlessotherwise noted, this presentation contains data that are interim and unaudited based on site reports. In addition, data included in this presentation have not been updated and are as of thecutoff date for the applicable medical conference presentation. Other than the accelerated approval of XPOVIO, selinexor, eltanexor, KPT-9274 and verdinexor are investigational drugsthat have not been approved by the FDA or any other regulatory agency, and the safety and efficacy of these drugs has not been established by any agency.


Core Pillars of Cancer Drug Therapy

CHEMO-THERAPY

TARGETEDAGENTS

TUMORSUPPRESSOR PROTEIN

ACTIVATION

VASCULAR-TARGETING

IMMUNO-THERAPY

Harnessing the body’s own natural defense mechanisms


Innovation with a Purpose: Demonstrate Meaningful Activity in Difficult to Treat Patient Populations and Then Expand, Dramatically

2nd Line+ multiple myeloma in combination with standard of care drugs • Selinexor + Pomalidomide +

Dexamethasone (Phase 3 expected to start in 2021)

• BOSTON Study (Phase 3)• STOMP Study (Phase 1b/2)

2nd Line+ DLBCL in combination with standard of care drugs• XPORT-DLBCL-025 (Phase 1/2)• XPORT-DLBCL-030 (Phase 2/3)

Broad utility across numerous solid tumor indications

• Melanoma (Phase 1/2 expected to start in 2021)

• CRC (Phase 1)• Lung Cancer (Phase 1)• GBM (Phase 1/2)

• Endometrial Cancer (Phase 3)

STORM Study• Penta-refractory MM• Positive top-line data: 2018• FDA Approval: 2019

Multiple Myeloma1

SADAL Study• 3rd line+ DLBCL• Positive top-line data: 2018• FDA Approval: 2020

DLBCL2

SEAL Study• 3rd line+ dedifferentiated liposarcoma• Positive data presented: Nov 2020

Solid Tumors3

Significant Growth Opportunities

FoundationalBeginnings

Note: MM= multiple myeloma, DLBCL = diffuse large B-cell lymphoma, GBM = glioblastoma, CRC = colorectal cancer


Soft Tissue Sarcomas (STS) – A Diverse Group of Malignant Tumors that Originate From Mesenchymal Cells in Soft Tissue

Annual Incidence of STS (US)2:

~13,000(~5,350 Deaths in 2019)

Common First-Line Treatments:Radiation

SurgeryChemotherapy

• There are over 50 types of STS that can be found anywhere in the body• STS primarily originate in the extremities, retroperitoneal and visceral tissue• Liposarcoma occurs in the fat cells in the body, most often in the muscles of the limbs or abdomen

1 Brennan, M. et. al. Ann Surg. 2014. 2 NCI/SEER; https://seer.cancer.gov/statfacts/html/soft.html

1


Overview and Epidemiology

(US)

• Particularly aggressive form of liposarcoma (most common subtype of STS) associated with high rates of metastatic recurrence and mortality

• ~2,500 new incident cases of liposarcoma, annually; ~20% are DDLS1

• Median overall survival of DDLS patients is 2.5 to 5 years

Current Treatment Paradigm

• Standard first-line therapy• Doxorubicin – 1st line alone: Overall response rate (ORR) 6%2

• Doxorubicin + Ifosfamide: ORR 21%2

• Common second line therapy• Trabectedin – median progression free survival (PFS) for DDLS patients: 2.2 months3

• Eribulin – median PFS for DDLS patients: 2.0 months4

Dedifferentiated Liposarcoma (DDLS) Background

1 Bock, S et al. Int. J. Environ. Res. Public Health. 2020. 2 Stacchiotti_ Chemo in liposarcoma EORTC_ESMO2020. 3 Demetri et al. JCO 2016. 4 Demetri et al. JCO 2017.


US Sarcoma Centers of Excellence:SEAL trial sites (26) at the Sarcoma Alliance-affiliated centers (90)

Sarcoma Alliance Criteria for Centers ≥50 sarcoma patients annually Patient enrollment in sarcoma clinical trials Association with sarcoma-oriented medical

organization, e.g., Connective Tissue Oncology Society (CTOS)

Sarcoma publications and tumor boards All necessary specialties – e.g., surgical,

orthopedic and medical oncologists, radiologists, oncology nursing

Sarcoma Alliance-Affiliated Sarcoma CentersSEAL Trial Sites (US)

Source: www.sarcomaalliance.org

9

Mrinal Gounder1, Albiruni Abdul Razak2, Neeta Somaiah3, Sant Chawla4, Javier Martin-Broto5, Giovanni Grignani6, Scott Schuetze7, Bruno Vincenzi8, Andrew J. Wagner9, Bartosz Chmielowski10, Robin L. Jones11, Richard F. Riedel12, Silvia Stacchiotti13, Elizabeth T. Loggers14, Kristen N.

Ganjoo15, Axel Le Cesne16, Antoine Italiano17, Xavier Garcia del Muro18, Melissa Amber Burgess19, Sophie Piperno-Neumann20, Christopher Ryan21, Didier Cupissol22, Antonio Lopez-Pousa23, Mary Mulcahy24, Charles Forscher25, Nicolas Penel26, Tracey Duncan27, Osnat Ben-Shahar27,

Yosef Landesman27, Dayana Michel27, Hongwei Wang27, Jatin J. Shah27, Sharon Shacham27, Michael G Kauffman27, Steven Attia28

1Memorial Sloan Kettering Cancer Center, New York, NY; 2Princess Margaret Cancer Centre, Toronto, ON; 3Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; 4Sarcoma Oncology Center, Santa Monica, CA; 5Virgen del Rocio University Hospital, Institute of Biomedicine Research (IBIS)/CSIC/Universidad de Sevilla, Seville, Spain; 6Division of Medical Oncology, Candiolo Cancer

Institute, FPO-IRCCS, Candiolo (TO), Italy; 7University of Michigan, Ann Arbor, MI; 8Policlinico Universitario Campus, Bio-Medico, Rome, Italy; 9Dana-Farber Cancer Institute, Boston, MA; 10Division of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA; 11The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, United Kingdom; 12Duke Cancer Institute, Duke University Medical Center,

Durham, NC; 13Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 14Fred Hutchinson Cancer Research Center, Seattle, WA; 15Stanford Cancer Institute, Stanford, CA; 16Institut Gustave Roussy, Villejuif, France; 17Institut Bergonié, Bordeaux, France; 18Catalan Institute of Oncology, IDIBELL, University of Barcelona, Barcelona, Spain; 19University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA; 20Institut Curie, Paris, France; 21Oregon Health & Science University, Portland, Oregon; 22Department of Medical Oncology, Centre Val d'Aurelle, Montpellier, France; 23Department of Cancer Medicine, Hospital de la Santa Creu i Sant Pau,

Barcelona, Spain; 24The Robert H Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; 25Cedars-Sinai Medical Center, Los Angeles, CA; 26Centre Oscar Lambret and Lille University, Lille, France; 27Karyopharm Therapeutics Inc., Newton, MA; 28Mayo Clinic, Jacksonville, FL

SEAL: Phase 3, Randomized, Double Blind, Cross-Over, Study of Selinexor versus Placebo in Advanced

Unresectable DeDifferentiated Liposarcoma (DDLS)

Source: Grounder M. et al. CTOS 2020. Paper 20.

Presented by Sant P. Chawla, M.D., Director of the Sarcoma Oncology Center, Santa Monica, CA

Selinexor in Liposarcoma

Selinexor demonstrated anti-tumor activity against DDLS in preclinical studies

• XPO1 was overexpressed in liposarcoma cell lines and selinexor induced cell cycle arrest and apoptosis in these cell lines and xenografts

Selinexor demonstrated anti-tumor activity in DDLS in Phase 1 clinical study• Selinexor induced a reduction in target lesion size in 6/15 (40%)

and stable disease for 4 months or longer in 7/15 (47%); GMI >1.33

Nakayama, 2016, Figure 2b

Nakayama and Wagner, 2016; Garg, 2017; Gounder M, JCO 2016

Source: Grounder M. et al. CTOS 2020. Paper 20.

DD Liposarcoma

10

Patients with

Relapsed DDLS:

2-5 Lines of

Therapy

N=285

Selinexor60 mg BIWq 6 weeks

Placeboq 6 weeks

Cross over Open –label

Selinexor60 mg BIW

Secondary:OS

(non-inferiority)

* PD based on Independent Radiology Review using RECIST 1.1Imaging done q 6 weeks C1 throughC5, C6 on q 12 weeks

R 2:1

*PD

SEAL: Phase 3, Randomized, Double Blind, Cross-Over, Study of Selinexor versus Placebo in Advanced Unresectable Dedifferentiated Liposarcoma (DDLS) Study Design

Stratification Factors: 1) prior eribulin use 2) prior trabectedin and 3) # prior therapies (2 versus ≥ 3)

*PD Primary: *PFS

Secondary:TTP, ORR,

DOT, TTNT

Source: Grounder M. et al. CTOS 2020. Paper 20. 11

Inclusion Criteria

• Pathology confirmation of De-differentiated Liposarcoma

• Investigator assessed radiologic evidence of disease progression within 6 months prior to randomization and requiring systemic treatment

• Must have received at least 2 but no more than 5 prior systemic therapies for the treatment of liposarcoma

• Adequate laboratory functional values:• Absolute neutrophil count (ANC) ≥1500/• Platelets ≥100,000/mm3• Hemoglobin (Hb) ≥9 g/dL

• Adequate hepatic function and adequate renal function: Serum creatinine clearance of ≥ 30 mL/min

SEAL: Study Design


SEAL: Baseline Demographics and Clinical Characteristics are Comparable for the Two Study Arms

Characteristic Selinexor(N = 188)

Placebo(N = 97)

Age1, yearsMedian (Range)

Distribution — no. (%)18–64 yr65–74 yr≥75 yr

65.0 (33 – 84)

92 (48.9)73 (38.8)23 (12.2)

65.0 (31 – 85)

46 (47.4)41 (42.3)10 (10.3)

Sex n (%)FemalesMales

114 ( 60.6)74 ( 39.4)

64 ( 66.0)33 ( 34.0)

Race n (%)AsianBlack or African AmericanWhiteOther/Missing

9 (4.8)3 (1.6)

139 (73.9)37 (19.7)

3 (3.1)1 (1.0)

80 (82.5)13 (13.4)

Geographic Region n (%)North AmericaEurope and Israel

90 (47.9)98 (52.1)

55 (56.7)42 (43.3)

Characteristic Selinexor(N = 188)

Placebo(N = 97)

ECOG2 Performance Status, n (%)01

71 (37.8)117 (62.2)

41 (42.3)56 (57.7)

Median duration from most recent progression (range) — months 0.90 (0.1 - 6.97) 0.72 (0.1 – 16.5)

Median duration from initial diagnosis (range) — yr 4.3 (0 - 27) 4.3 (1 - 25)

Disease Stage Category at Study Entry, n (%)Localized/Locally advanced and

unresectableDistant MetastasisUnknown/Missing

37 ( 19.7)129 ( 68.6)22 ( 11.7)

15 ( 15.5)70 ( 72.2)12 ( 12.4)

Primary Site of Initial Liposarcoma Lesion, n (%)

Extremity (Lower + Upper)RetroperitoneumOther

188 ( 100.0)11 ( 5.9)

148 ( 78.7)29 ( 15.4)

95 ( 97.5)3 ( 3.1)

73 ( 75.3)19 ( 19.6)

[1] Age is the age at date of randomization. [2] ECOG=Eastern Cooperative Oncology Group.


Patients in SEAL were not Amenable to Surgery, were Heavily Pretreated, and had Exhausted All Available Treatment Options

Prior Therapies Selinexor (N = 188) Placebo (N = 97)Number of Prior Antineoplastic Regimen

Median (range)Mean (STD)

Distribution – Number of Prior Regimen, n (%)≤2*≥3

2 (1 - 6)* 2.7 (1.08)

104 (55.3)84 (44.7)

2 (1 - 7)*2.8 (1.19)

54 (55.7)43 (44.3)

Previous Systemic TherapyEribulinAnthracyclinesTrabectedinOthers

66 (35.1)168 (89.4)

69 (36.7)61 (32.4)

35 (36.1)86 (88.7)36 (37.1)30 (30.9)

Prior radiotherapy, n(%)Yes 86 (45.7) 45 (46.4)

Prior surgery, n(%)Yes

Number of Prior SurgeriesMedian (range)Mean (STD)

168 (89.4)

2 (1 - 10)2.3 (1.53)

82 (84.5)

2 (1 - 7)2.1 (1.15)


Total Patients Randomized N= 285

SelinexorNumber of patients randomized N=188

Number of patients dosed N=187

PlaceboNumber of patients randomized N=97

Number of patients dosed N=97

On TreatmentN=7

On TreatmentN=18

Discontinued Treatment n (%) =169 (90.4)Reasons for Discontinuation, n (%)

Disease progression 108 (57.8)Clinical progression 16 (8.6)Adverse event 19 (10.2)Patient withdrawal 10 (5.3)Physician decision 2 (1.1)Death due to disease progression 9 (4.8)Death due to AE 2 (1.1)Lost to follow-up/other 3 (1.6)

SEAL: Patient Disposition

Discontinued Treatment n (%) =90 (92.8)Reasons for Discontinuation, n (%)

Disease progression 67 (69.1)Clinical progression 6 (6.2)Adverse event 3 (3.1)Patient Withdrawal 8 (8.2)Physician decision 1 (1.0)Death due to disease progression 1 (1.0)Death due to AE 2 (2.1)Lost to follow-up/other 2 (2.1)


PFS Based on Independent Radiology Review – ITT

Final analysis based on 209 PFS events

Selinexor PlacebomPFS (months) 2.83 2.07HR (95% CI) 0.7026 (0.5191-0.9509)Two-sided P-value 0.0228


SEAL: Overall Survival by Treatment Arm – ITT Phase 3

Selinexor Placebo mOS (months) 9.99 12.91 HR (95%CI) 1.0039 (0.7214-1.3971)Two-sided P-value 0.9836

57/97 (58%) patients on placebo

did crossover to selinexor


• Pre-specified sensitivity analysis to examine the effect of selinexor on overall survival among patients randomized to selinexor versus patients randomized to placebo and did not crossover to open-label selinexor (i.e., never received selinexor)

• Results suggest a trend towards an improvement in overall survival due to selinexor (not statistically significant)

SEAL: Overall Survival - Selinexor vs Patients on Placebo Who Did NOT Crossover Post Progression (i.e. never received selinexor)

Selinexor P-No OLmOS (months) 9.99 9.07 HR (95%CI) 0.6880 (0.4271, 1.1082)Two-Sided P-value 0.1216


SEAL: Best Overall Response During Blinded Treatment – ITT(7.5% had reduction in disease burden > 15%)

Selinexor Arm

Placebo Arm

(%) C

hang

e in

Sum

of T

arge

t Les

ions

from

Bas

elin

e Patients with Target Lesion Reduction

Selinexor(N = 188)

Placebo(N = 97)

>=15% Reduction:

N (%)14 (7.5 %) 0

>=30% Reduction:

N (%)5 (2.7 %) 0


SEAL: Best Overall Response to Selinexor who did Crossover During Open Label – (5.3% had reduction in disease burden > 15%)

(%) C

hang

e in

Sum

of T

arge

t Les

ions

from

Bas

elin

e

Patients with Target Lesion Reduction

Selinexor(N = 57)

>=15% Reduction: N (%) 3 (5.3%)

>=30% Reduction: N (%) 2 (3.5%)

-100

-80

-60

-40

-20

0

20

40

60

80

100

-30


SEAL: Selected Non-Haematological TEAEs* – Phase 3Selinexor Arm (N = 187) Placebo Arm (N = 97)Any Grade Grade 3/4 Any Grade Grade 3/4

GINausea 80.7 5.3 39.2 0Decreased appetite 60.4 7.5 22.7 1.0Vomiting 49.2 2.7 12.4 3.1Constipation 37.4 0.5 23.7 0Diarrhoea 40.1 2.7 17.5 2.1Abdominal pain 23.5 5.3 32.0 2.1Dysgeusia 26.7 0 4.1 0ConstitutionalFatigue 51.3 6.4 32.0 3.1Weight decreased 41.7 0.5 9.3 0Asthenia 31.0 10.2 10.3 0OtherDyspnoea 19.3 2.1 12.4 2.1Hyponatraemia 27.3 10.7 9.3 0Increased creatinine 21.4 1.6 13.4 0Dizziness 22.5 1.1 6.2 0Blurred vision 22.5 1.1 3.1 0*Events that have occurred in ≥15% of patients and had > 5% difference between the arms. 21

SEAL: Selected Haematological TEAEs* – Phase 3

• No reported febrile neutropenia

Selinexor Arm(N = 187)

Placebo Arm(N = 97)

Any Grade Grade 3/4 Any Grade Grade 3/4

Anaemia 46.5 18.7 22.7 8.2

Thrombocytopenia 38.0 10.2 5.2 0

Neutropenia 19.3 9.1 1.0 0

*Events that have occurred in ≥15% of patientsSource: Grounder M. et al. CTOS 2020. Paper 20. 22

• Selinexor is novel first in class therapy that inhibits XPO1, activates Tumor Suppressor Proteins(TSP) and reduces onco-proteins, leveraging patients own innate TSP function and is foundational to cancer biology

• SEAL is the first and largest global phase 3 trial in patients with relapsed DDLS (n=285)

• SEAL met the primary endpoint • Selinexor significantly prolonged the PFS of heavily pretreated DDLS patients (HR 0.70, p = .0228)

• Side effects of oral selinexor in DDLS patients are well characterized, predictable and reversible • The most common TEAEs (nausea, fatigue, decreased appetite, anemia, vomiting, and thrombocytopenia) were generally

low grade• Oral selinexor was well tolerated in DDLPS patients with supportive care and dose modifications

SEAL Trial Conclusions

In Patients with DDLS who have received at least 2 prior therapies, if approved, twice-weekly oral selinexor offers an effective, convenient, novel oral therapy


Final thoughts on significance of SEAL data in support of broader solid tumor clinical development…

Michael G. Kauffman, MD, PhD Chief Executive Officer, Karyopharm

24


Current Solid Tumor Studies

Exploring Future Solid Tumor

Studies

Current and Potential Future XPOVIO Company-Sponsored Studies in Solid Tumors

GynecologicalCancer

Brain Cancer

Lung Cancer

Colorectal Cancer

Melanoma

• Endometrial: SIENDO Study in frontline maintenance setting (single agent vs. placebo) / Phase 3

• GBM: 1st and 2nd line settings with radiation + / -temozolomide, or lomustine / Phase 1/2

• NSCLC: 2nd line setting in combination with docetaxel

• CRC: 1st line setting in combination with FOLFOX and 2nd line in combination with FOLFIRI

• Ovarian: Resistant or refractory to platinum in combination with paclitaxel

• Endometrial and Ovarian: Multiple arms and combinations

• Melanoma: 1st line in combination with pembrolizumab• Melanoma: Multiple arms and combinations

• GBM: Combinations with other active drugs to be conduced through our CRADA partnership

• NSCLC: 1st line in combination with check-point inhibitors• NSCLC: 2nd and 3rd line settings (KRAS mutant and

wildtype) in combination with either docetaxel / Phase 1

• CRC: 2nd and 3rd line settings in combination with pembrolizumab / Phase 1

Note: NSCLC = non-small cell lung cancer, GBM = glioblastoma, CRC = colorectal cancer


Questions?Answers.

investor conference call: phase 3 seal data update

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