xpovio (selinexor) accelerated approval by the fda in dlbcl

June 22, 2020

XPOVIO® (selinexor) Accelerated Approval by the FDA in DLBCL

2©2020 Karyopharm Therapeutics Inc.

• Ian Karp, MBA, Vice President, Investor and Public Relations• Michael G. Kauffman, MD, PhD, Chief Executive Officer • John Demaree, MBA, Chief Commercial Officer

On Today’s Call

Prepared Remarks

• Sharon Shacham, PhD, MBA, President and Chief Scientific Officer • Jatin Shah, MD, Chief Medical Officer• Christopher Primiano, JD, MBA, Chief Business Officer & General Counsel• Mike Mason, MBA, Chief Financial Officer

Joining for Q&A Session


This presentation contains forward-looking statements within the meaning of the “safe harbor” provisions of The Private Securities LitigationReform Act of 1995. Such forward-looking statements include those regarding Karyopharm’s beliefs regarding XPOVIO’s ability to treat patientswith diffuse large B-cell lymphoma (DLBCL), the potential benefits of and expected market size and commercial opportunity for XPOVIO to treatDLBCL patients, including expected total U.S. sales, the design of future selinexor studies and expectations related to other XPOVIO regulatorysubmissions. Such statements are subject to numerous important factors, risks and uncertainties, many of which are beyond Karyopharm'scontrol, that may cause actual events or results to differ materially from Karyopharm's current expectations. For example, there can be noguarantee that any positive developments in the development or commercialization of Karyopharm’s drug candidate portfolio will result in stockprice appreciation. Management’s expectations and, therefore, any forward-looking statements in this presentation could also be affected by risksand 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 reducing sales of XPOVIO, interrupting or delaying research and developmentefforts, impacting the ability to procure sufficient supply for the development and commercialization of selinexor or other product candidates,delaying ongoing or planned clinical trials, impeding the execution of business plans, planned regulatory milestones and timelines, orinconveniencing patients; the adoption of XPOVIO in the commercial marketplace, the timing and costs involved in commercializing XPOVIO orany of Karyopharm’s drug candidates that receive regulatory approval; the ability to retain regulatory approval of XPOVIO or any of Karyopharm’sdrug candidates that receive regulatory approval; Karyopharm's results of clinical trials and preclinical studies, including subsequent analysis ofexisting data and new data received from ongoing and future studies; the content and timing of decisions made by the U.S. Food and DrugAdministration and other regulatory authorities, investigational review boards at clinical trial sites and publication review bodies, including withrespect to the need for additional clinical studies; the ability of Karyopharm or its third party collaborators or successors in interest to fully performtheir respective obligations under the applicable agreement and the potential future financial implications of such agreement; Karyopharm'sability to obtain and maintain requisite regulatory approvals and to enroll patients in its clinical trials; unplanned cash requirements andexpenditures; development of drug candidates by Karyopharm’s competitors for indications in which Karyopharm is currently developing its drugcandidates; and Karyopharm’s ability to obtain, maintain and enforce patent and other intellectual property protection for any drug candidates it isdeveloping. These and other risks are described under the caption "Risk Factors" in Karyopharm’s Quarterly Report on Form 10-Q for the quarterended March 31, 2020, which was filed with the Securities and Exchange Commission (SEC) on May 5, 2020, and in other filings thatKaryopharm may make with the SEC in the future. Any forward-looking statements contained in this presentation speak only as of the datehereof, 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.

Forward-looking Statements


• DLBCL Overview and Approval of XPOVIO• SADAL Study• Future Clinical DLBCL Trials• Commercial Overview

Agenda


• Cure is the goal of initial therapy, achieved in 50% - 60% of patients3

• For those eligible, autologous stem cell transplant is often performed in 2nd line

• No standard of care for patients after 2 lines of therapy

• Recent FDA approvals of CAR-T therapy (2017 and 2019) and polatuzumab + bendamustine + rituximab (2019)

• No previously approved all-oral treatment regimens

• XPOVIO approved by the FDA on June 22, 2020 for the treatment of adult patients with RR DLBCL

DLBCL is the Most Common Type of Non-Hodgkin Lymphoma with Limited Treatment Options in the Relapsed or Refractory (RR) Setting

>30,000

Annual New Patients in the U.S.1

66 years

Median age at diagnosis2

~63%

5 year relativesurvival3

1 Decision Resources NHL and CLL Landscape and Forecast, 2019. 2 SEER Cancer Stat Facts, 2020. National Cancer Institute. 3 Coiffier B, et al. Blood. 2010.


XPOVIO (selinexor) Accelerated Approval by the FDA in RR DLBCL

XPOVIO is indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least 2 lines of systemic therapy1

1XPOVIO Prescribing Information

Full Prescribing Information and Medication Guide available at www.XPOVIO.com

• XPOVIO is now the only single-agent, oral therapy approved for the treatment of patients with relapsed or refractory DLBCL

• XPOVIO is the first and only Nuclear Export Inhibitor approved by the FDA for use in two hematologic malignancies (multiple myeloma and DLBCL)

This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

New Indication

Now Approved for RR DLBCL


Safety Highlights from the XPOVIO Prescribing Information1

• No Black Box Warnings • No Contraindications• Patient Medication Guide• Monitoring Instructions and Recommended Concomitant Treatments

― Monitor complete blood count (CBC) with differential, standard blood chemistries, body weight, nutritional status, and volume status at baseline and during treatment as clinically indicated. Monitor more frequently during the first three months of treatment

― Patients advised to maintain adequate fluid and caloric intake throughout treatment. IV hydration should be considered for patients at risk of dehydration

― Patients receiving XPOVIO should be provided prophylactic treatment with a 5-HT3 receptor antagonist and other anti-nausea agents prior to and during treatment with XPOVIO

― Recommended XPOVIO dosage reductions and dosage modifications for adverse reactions are included in the Prescribing Information

• Warnings and Precautions ― Thrombocytopenia

― Neutropenia

― Gastrointestinal Toxicity

― Hyponatremia

Full Prescribing Information and Medication Guide available at www.XPOVIO.com1XPOVIO Prescribing Information

― Serious Infection

― Neurological Toxicity

― Embryo-Fetal Toxicity


• Patients with < Partial Response (PR) in second line therapy have ≤5 month survival• Overall Response Rate: ~26% with traditional chemotherapy agents

• Median Overall Survival (OS): < 6.3 months (2-year survival rate: 20%)• Relapsed or refractory DLBCL represents a significant unmet medical need: ~10K deaths/year in U.S.

Significant Level of Unmet Medical Need Exists for Patients with Relapsed or Refractory DLBCL

1 Crump M, et al. Blood. 2017. 2 Sehn L, et al. Journal of Clinical Oncology. 2020 3 Gisselbrecht C, et al. Journal of Clinical Oncology. 2010.

SCHOLAR-1Doublet/Triplet1

GO29365Bendamustine + Rituximab (BR)2

Lenalidomide vs Investigator Choice3

median OS=5.1 months median OS=4.7 months (BR Arm) median OS=4.4 (lenalidomide) vs 3.5 (investigator choice) months

9

CR or PR

DLBCL Treatment Landscape in 2020 and Beyond

Partial Response or Relapse after Initial Complete

Response

Chemoimmunotherapy

Possible Cure /Complete Response

~40% No Response or Progressive Disease

• R-EPOCH• R-CHOP • R-GCVP • Other

~50% ~10%

Source: Adapted from NCCN guidelines

©2020 Karyopharm Therapeutics Inc.

Initial Therapy: Majority of patients will receive rituximab (R) + chemotherapy

2nd Line / Consolidation Therapy: For those patients fit enough for stem cell transplant

• R-ICE• R-DHAP• R-ESHAP

Stem Cell Transplant

Fit Patients / Transplant Eligible• R-GemOx• R-GDP• Others

3rd line+ :For those patients whose disease continues to progress despite previous treatments (and 2nd Line+ for non-transplant eligible patients following initial treatment)

• R-Benda-Polatuzumab• R-Bendamustine• R-GemOx, R-GDP• Revlimid + R (R2)• Brentuximab vendotin• Tafasitamab + Revlimid

(BLA submitted)

Unfit / Transplant Ineligible Patients

XPOVIO now approved for adult patients with relapsed or refractory DLBCL after at least 2 lines of systemic therapy

CAR-T Cell Therapy

Source: Adapted from NCCN Guideline and estimated response data from Coiffier B, et al. Blood. 2010.



Agenda

11©2020 Karyopharm Therapeutics Inc. 11

FDA Approved on June 22, 2020

SADAL1: A Phase 2b Study In DLBCL

1 Selinexor Against Diffuse Aggressive Lymphoma

• Top-line data reported at ASH 2018 and updated at ICML 2019• sNDA accepted by FDA with Priority Review granted in Feb 2020

• PDUFA date set for June 23, 2020

N=134

selinexor twice weekly(4 week cycle)

60mgOral Selinexor

Relapsed or Refractory or Transformed DLBCL

• Study included patients with at least two prior multi-agent therapies and who were ineligible for transplantation

• Included patients with Germinal Center B-Cell (GCB) and non-GCB subtypes


Selinexor 60mg twice weekly (n=134)

SADAL Efficacy Results

OVERALL RESPONSE RATE (ORR)1

Complete Response (CR)

13%Partial Response (PR)

16%

All Patients 29%

1XPOVIO Prescribing Information. 2 Kalakonda N, et al. ICML 2019. Abstract 031. Kalakonda N et al. is currently in press and publication expected in the near term (Lancet Haematology 2020).

MEDIAN DURATION OF RESPONSE (DOR)2

Response at 3 Months1



56%

38%

15%

9.3 months


Additional Efficacy Data from SADAL Supports Future Randomized Study

Category Median OS (months) 95% CI

All Patients 9.0 (6.2 – 13.7)

CR/PR Patients Not Reached (13.7 – NE)

SD Patients 18.3 (11.1 – 28.0)

PD/NR Patients 4.1 (3.0 – 5.2)

Median follow-up of 11 monthsSD = Stable Disease; PD = Progressive Disease; NR =No Response

Source: Kalakonda N, et al. ICML 2019. Abstract 031. Kalakonda N et al. is currently in press and publication expected in the near term (Lancet Haematology 2020).


Tumor Response Data from the SADAL Study

53 of 86 patients (62%) with a post-baseline assessment had reductions in tumor burden†‡

† Changes in anatomical tumor burden shown for all patients. Metabolic changes not shown.‡ Number has been updated to 56 of 86 patients (65%) in pending publication of SADAL data.* Denotes CR patient

Source: Kalakonda N, et al. ICML 2019. Abstract 031. Kalakonda N et al. is currently in press and publication expected in the near term (Lancet Haematology 2020).


Safety Overview From SADAL Study

Key Patient Characteristics1

(n=134)

• Median age was 67 (range: 35-91)

• Median number of prior therapies was 2 with 34% of patients having received 3 or more prior therapies

• 53% of patients had disease relapse less than 1 year from their first DLBCL treatment (poor prognostic feature)

• 47% of patient’s disease was of GCB histology (poor prognostic feature)

• 23% of patients had transformed DLBCL (poor prognostic feature)

• 30% had prior autologous HSCT

Summary of Safety Profile1

(n=134)

• Safety profile observed was qualitatively consistent with the established and approved safety profile in relapsed or refractory multiple myeloma

• Most common treatment related non-hematologic adverse events (AEs) were fatigue, nausea, decreased appetite, and diarrhea, primarily Grade 1/2, and most were manageable with dose modifications and/or supportive care

• Most common Grade 3/4 AEs were thrombocytopenia, lymphopenia, neutropenia, and anemia, and most were also manageable with dose modifications and/or supportive care

• Frequency of the Grade 3 or 4 adverse events observed in the SADAL study (dose 60 mg BIW) was lower than that observed in the STORM study (dose 80 mg BIW)

1XPOVIO Prescribing Information and Kalakonda N, et al. ICML 2019. Abstract 031. Kalakonda N et al. is currently in press and publication expected in the near term (Lancet Haematology 2020).



Agenda


XPORT-DLBCL-030 Modified Study Design

Selinexor 40mg QWR-GDP

Primary endpoint: BORPatient Eligibility:

• 1-2 prior therapies RR DLBCL• Transplant/CAR-T not-intended

(10% due to active disease, 90% due to other reasons)

N = 40 per arm

Selinexor 40 mg QW

Placebo QW

Combination (up to 6, 21-day cycles)

Continuous therapy (until disease progression/toxicity)≥ PR

Selinexor 60mg QWR-GDP

Primary endpoint: BOR evaluated after all patients have the opportunity to complete at least 3 cycles of combination therapy

Secondary endpoints: PFS, response at end of treatment, DOR, OS, BOR based on RECIL and modified Lugano classification, safety

Phase 2, randomized, placebo-controlled study

Placebo QW R-GDP

Selinexor 60 mg QW1:1:1

Abbreviations: BOR = Best Overall Response; R = rituximab; G = gemcitabine; D= dexamethasone; P= platinum therapy (cisplatin)


Selinexor TBD QWR-GDP

Primary endpoint PFSPatient Eligibility:

• 1-2 prior therapies RR DLBCL• Transplant/CAR-T not-intended

(10% due to active disease, 90% due to other reasons)

N= 322 (216 PFS event)

Selinexor TBD QW

Placebo QW

Phase 3, randomized, placebo-controlled, double blinded study to serve as confirmatory study supporting accelerated approval

Placebo QW R-GDP

1:1

Combination (up to 6, 21-day cycles)

Continuous therapy (until disease progression/toxicity)≥ PR

Primary endpoint: PFS per Independent Review Committee based on Lugano classification

Secondary endpoints: BOR, response at end of treatment, DOR, OS, BOR based on RECIL and modified Lugano classification, safety

XPORT-DLBCL-030 Modified Study Design



Agenda


Total U.S. Drug Sales in Relapsed or Refractory DLBCL Expected to Grow from $762M in 2018 to Over $3B by 2028

1 Decision Resources NHL and CLL Landscape and Forecast, 2019

Net

Sal

es ($

M)

2018 2028

Total Drug Sales in Relapsed or Refractory DLBCL1

$762M

>$3B


An Estimated 9,000 DLBCL Patients Being Treated in the 3rd and 4th Line+ Setting in the U.S.

~16,000

1L

2L

3L

4L+Number of patients with relapsed or

refractory disease is growing annually, on a percentage basis, by low to mid-single

digits due to population growth and increased life expectancy as a result of

newly available treatment options

~57,000 Patients treated

with drug therapy in 2019

Estimated U.S. DLBCL Patients Treated by Line of Therapy

~2,000

~7,000

Patients by Line of Treatment

~32,000

Sources: Karyopharm analysis based on data from Decision Resources, Kantar Cancer Impact and SEER Cancer Stat Facts. National Cancer Institute.


Commercial Strategy for XPOVIO in DLBCL

Prescriber Base1XPOVIO Positioning

• Successfully launch XPOVIO as the preferred DLBCL treatment option after two prior lines of therapy instead of traditional intravenous chemotherapy by educating physicians on the deep and durable efficacy achieved in clinical studies with oral, single-agent, novel, XPOVIO

• XPOVIO offers compelling efficacy with a manageable safety profile and is now:

• First oral therapy approved for RR DLBCL• First single agent approved in any line of DLBCL

treatment• First therapy a RR DLBCL patient can take at home

• ~3,000 physicians treat ~80% of U.S. DLBCL patients

• ~75% of targeted physicians are community-based

• >50% overlap between Karyopharm’s multiple myeloma and DLBCL targets

• Karyopharm U.S. sales force of ~70 already sized to reach core physician audience

1 Based on analysis of Symphony claims data


Key Features of XPOVIO for the Treatment of Patients With RR DLBCL

• Clinical efficacy

• Previous therapies / approaches

• Subtype and histology

• Comorbidities

• Functional status, age, frailty

• Patient preferences / logistical dynamics

Factors That Influence Treatment Choice Key Features of XPOVIO

• 29% ORR1

• 13%CR1

• Clinically meaningful duration of response1

Similar efficacy seen across both ABC and GCB patient sub-types

Novel mechanism of action

Common adverse events do not include:• Peripheral neuropathy

• Cardiac, liver or kidney toxicity• Opportunistic infections

• Oral route of administration taken only twice per week

• Single agent, not combined with chemotherapy

1XPOVIO Prescribing Information


Summary of Today’s Call

• Approval in DLBCL marks 2nd approval for XPOVIO in less than a year─ A 3rd NDA was submitted in May 2020 as a potential new treatment for patients with

multiple myeloma after at least one prior line of therapy

• XPOVIO is now the only single-agent, oral therapy approved for the treatment of patients with relapsed or refractory DLBCL

• XPOVIO is the first and only therapy approved to treat both MM and DLBCL• Commercial launch will begin immediately• Field force and patient/physician support initiatives already in place to

immediately support commercial launch

A special thank you to all of the patients, physicians, caregivers, advocacy organizations, Karyopharm employees, and investors in our company who have helped us get to this monumental day!


Questions?Answers.

xpovio (selinexor) accelerated approval by the fda in dlbcl

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