Company Overview: Precision Oncology Medicines Addressing ... Point... · Company Overview: Precision Oncology Medicines Addressing Treatment Resistant Cancers Athena Countouriotis,

Company Overview:

Precision Oncology Medicines Addressing Treatment Resistant Cancers

Athena Countouriotis, President & CEONovember 20, 2019Jefferies 2019 London Healthcare Conference

Disclaimer

Forward-Looking Statements

Statements in this Presentation that are not statements of historical fact are forward-looking statements. Such forward-looking statements include, without limitation, statements regarding our research and clinical development plans, business strategy and plans, regulatory matters, objectives of management for future operations, market size and opportunity, our ability to complete certain milestones and our expectations regarding the relative benefits of our drug candidates versus competitive therapies. Words such as “believe,” “can”, “continue,” “anticipate,” “could,” “estimate,” “plan,” “predict,” “expect,” “intend,” “will,” “may,” “goal,” “upcoming,” “near term”, “milestone”, “potential,” “target” or the negative of these terms or similar expressions are intended to identify forward-looking statements, though not all forward-looking statements necessarily contain these identifying words. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Risks that contribute to the uncertain nature of the forward-looking statements include, without limitation: our preclinical studies and clinical trials may not be successful; regulatory authorities, including the U.S. Food and Drug Administration (FDA) may not agree with our interpretation of the data from clinical trials of our drug candidates; we may decide, or regulatory authorities may require us, to conduct additional clinical trials or to modify our ongoing clinical trials; we may experience delays in the commencement, enrollment, completion or analysis of clinical testing for our drug candidates, or significant issues regarding the adequacy of our clinical trial designs or the execution of our clinical trials may arise, which could result in increased costs and delays, or limit our ability to obtain regulatory approval; our drug candidates may not receive regulatory approval or be successfully commercialized; unexpected adverse side effects or inadequate therapeutic efficacy of our drug candidates could delay or prevent regulatory approval or commercialization; and we may not be able to obtain additional financing. These forward-looking statements should not be taken as forecasts or promises nor should they be taken as implying any assurance or guarantee that the assumptions on which such forward-looking statements have been made are correct or exhaustive. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date this Presentation is given. Other risks and uncertainties affecting us are described more fully in our filings with the Securities and Exchange Commission. We undertake no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.

This Presentation discusses drug candidates that are under clinical study and which have not yet been approved for marketing by the U.S. Food and Drug Administration. No representation is made as to the safety or effectiveness of these drug candidates for the use for which such drug candidates are being studied.

2

Three Drug Candidates in Four Ongoing Clinical Trials

31 Data cut-off date of July 22, 2019

Novel Structure-Based

Design

Potential Best-in-Class

ROS1 and TRK Inhibitor

Pipeline with Two Additional

Clinical Assets

Cash Position

• Proprietary TKIs designed with small, compact, three-dimensional macrocyclic structure

• Favorable kinase selectivity; ability to overcome intrinsic and acquired resistance

• Lead Program Repotrectinib in ongoing TRIDENT-1 Phase 2 Registrational Study

• Phase 1 portion of TRIDENT-1: ROS1+ advanced NSCLC in 40 patients1:

• TKI-naïve 91% confirmed ORR (cORR) (86% cORR in patients treated at 160 mg QD or above)

• TKI-pretreated 55% cORR in patients treated at 160 mg QD or above with 1 prior TKI

• CNS activity in both populations and manageable safety profile

• Confirmed Response Achieved in TRK TKI-Naïve and –Pretreated Patients

• TPX-0022: MET/CSF1R/SRC inhibitor, Phase 1 clinical trial ongoing

• TPX-0046: RET/SRC inhibitor, Phase 1/2 clinical trial ongoing

• ALK inhibitor candidates: Candidate nomination stage; Inhibition against wildtype and

mutated ALKs

• $424 million in cash, cash equivalents and marketable securities as of Sept. 30, 2019

expected to fund operations beyond 2021

Significant Achievements in 2019: Now 3 Clinical Stage Assets

4

Repotrectinib

TPX-0046

TPX-0022

2019

Investments in Future

Discovery Efforts

April 2019

Initial Public Offering

$175 million

May 31, 2019

ASCO Oral Presentation1

(TRIDENT-1 Ph. 1 Data

Update in ROS1+ NSCLC)

Sept 2019

Follow-on Offering

$189.5 million

Sept. 3, 2019

TPX-0046 (RET/SRC)

Preclinical Data

Presentation

July 2019

TPX-0022

(MET/CSF1R/SRC)

Phase 1 Study Initiated

June 2019

TRIDENT-1 Phase 2

Registrational Study

Initiated

Sept. 3, 2019

TRIDENT-1 Phase 1

Interim Data Update2

Early Pipeline

Development

Data Updates Presented

Four Clinical Trials Initiated

Pipeline Advanced

Nearly $400M Cash Raised3

Goals Achieved Milestones

1 March 4 data cut-off2 July 22 data cut-off3 Net proceeds

Nov 2019

TPX-0046

(RET/SRC)

Phase 1/2 Study Initiated

Nov 2019

Repotrectinib Pediatric


2019

ALK Inhibitor Program

Advancing Toward

Candidate Nomination

Candidate Selection IND Enabling Studies Phase 1 Phase 2 Phase 31 Milestones

Repotrectinib

(ROS1/TRKs/ALK)

TRIDENT-1 Phase 1

enrollment completing,

Initiated registrational

Phase 2 portion in 2H 2019

Initiated Non-registrational cohort

of TRIDENT-1 in 2H 2019

Initiated trial in

2H 2019

Trial design in development

TPX-0022

(MET/CSF1R/SRC)

Initiated trial in

2H 2019

TPX-0046

(RET/SRC)2

Initiated trial in

2H 2019

ALK Inhibitor Candidate selection in 2019

Extensive Pipeline with Lead Candidate Repotrectinib in Registrational Phase 2 TRIDENT-1 Trial

5

1 Not required for Phase 2 registrational clinical trials2 Including NSCLC, thyroid, and other solid tumors with abnormal RET gene

ROS1+ advanced NSCLC in TKI-naïve patients

NTRK+ advanced solid tumors in TKI-naïve patients

NTRK+ advanced solid tumors in TKI-pretreated patients

ROS1+ or ALK+ non-NSCLC advanced solid tumors in TKI-naïve patients

Repotrectinib in pediatric advanced solid tumors

Repotrectinib combinations

ROS1+ advanced NSCLC in TKI-pretreated patients TRIDENT-1

Registrational

cohorts

Advanced solid tumor patients

ALK+ NSCLC

Advanced solid tumor patients

Overall Patient Population: Biomarker Prevalence

Repotrectinib TPX-0022 TPX-0046

Advanced

NSCLCOther Advanced Solid Tumors1 Gastric

Advanced

NSCLC

EGFR Mutated

TKI-Resistant

Advanced

NSCLC3

Advanced

NSCLCThyroid2

U.S.

Patients4,5160,000 520,000 17,500 160,000 12,800 160,000 11,250

EU5 Patients4 117,000 557,900 36,680 117,000 6,230 117,000 11,030

Biomarker

Prevalence6

2%

(ROS1)

0.5%

(NTRK)

0.5%

(ROS1 / ALK)

4%

(MET)

3%

(MET Exon 14)

12.5%

(MET Amplified)

2%

(RET)

16%

(RET)

1 Reflects other solid tumor indications including Brain, Breast, Colon, Melanoma, NSCLC, Pancreas, Sarcoma, and Thyroid, excluding ROS1+ and ALK+ for NSCLC2 Includes papillary and medullary thyroid tumors3 Does not include first line EGFR mutated advanced NSCLC patients. Assumes ~20%, 15%, 11%, 14%, 17% and 12% EGFR mutation prevalence for US, France, Germany, Italy, Spain and UK, respectively4 Estimates include Stage III unresectable and metastatic patient populations, adjusted for treatable population and those that are tested for the targeted biomarkers; assumes 85% biomarker testing rate5 Based on SEER 2015 5-year diagnosed prevalence, grown at 0.7% in line with U.S. population growth; estimated as of 20186 Estimates based on publications and physician and payor interviews in the U.S.

6

Novel Approach for Creating New Kinase Inhibitors and Overcoming Kinase Drug Resistance

Current Available TKIs Often Lead to Treatment ResistanceNo Approved TKIs to address resistance that may arise after prior ROS1, TRK, or RET targeted agents

• ROS1+ NSCLC

• Solvent Front Mutation (SFM: G2032R) reported in up to 41% of Xalkori treated patients1

• NTRK+ Metastatic Solid Tumors

• Emerging SFMs reported after treatment with Vitrakvi and Rozlytrek2

• RET+ NSCLC and Thyroid Cancer

• While BLU-667 and LOXO-292 are effective against gatekeeper mutations, other potential resistant mutations may arise

• Our small, compact TKIs have rigid three

dimensional macrocyclic structures that bind to

mutated kinases that sterically exclude

conventional TKIs

• Our macrocycle platform has the ability to develop

potential best-in-class therapies that may address

limitations of today’s TKIs and prevent common

resistant mutations

• Activity of Repotrectinib against Solvent Front Mutations highlighted in Cancer Discovery3

8

1 Gainor JF et al., JCO Precis Oncol, 20172 Drilon, et al, AACR, Jun 3, 2017; Drilon, et al, NEJM Feb 2018; Cocco et al, Nature Reviews, Dec 20183 Drilon, et al, Cancer Discovery, Aug. 9, 2018

Our TKIs Bind Completely Inside the ATP Pocket, Thereby Potentially Addressing Treatment Resistance

9

Conventional Oversized

Type II TKI

Conventional Oversized

Type I TKISolvent

Front MutationATP Gatekeeper

Mutation

Small and Compact Type I

TKI

ATP

pocket

KinaseSolvent

front

Back

pocket

Kinase inhibitor

competes

with ATP

Development of

solvent front

mutation

Development of

gatekeeper

mutation

Mutation depletes

kinase inhibitor, not

ATP

Our Approach

Repotrectinib (TPX-0005):A Highly Selective, Internally Designed Inhibitor Targeting Wildtype and Mutant ROS1/TRKs/ALK

Repotrectinib: Potential Best-in-Class ROS1 InhibitorData Presented at Annual AACR Conference on April 1

1 Drilon A et al., Cancer Discov 2018

* Other than repotrectinib, data based on evaluation of comparable proxy chemical reagent purchased from commercial sources rather than obtained from the pharmaceutical company developing the kinase inhibitor

Ba/F3 Cell Proliferation Assay IC50 (nM)

No Kinase Domain Mutation ROS1 G2032R ROS1 L2026M

Inhibitor*

CD74-

ROS1

SDC4-

ROS1

EZR-

ROS1

TPM3-

ROS1

CD74-

ROS1

SDC4-

ROS1

EZR-

ROS1

TPM3-

ROS1

EZR-

ROS1

TPM3-

ROS1

Repotrectinib <0.2 0.2 <0.1 <0.1 3.3 3 5 16.3 <0.2 <0.1

Crizotinib 14.6 19.6 19.4 31.1 266.2 4661 660 500.6 95.6 236.2

Lorlatinib 0.2 0.3 0.2 0.3 160.7 352.9 190.5 434.9 1.6 1.9

Entrectinib 10.5 ND 1.5 9.4 1813 ND 2947 1093 13.3 40.7

Cabozantinib 0.5 3 0.4 4.5 11.3 169.4 39.5 60.7 3.4 12.6

11

• Crizotinib and entrectinib are approved for advanced ROS1+ NSCLC

• Limitations of both include lack of activity against resistant mutations and safety profile

• Repotrectinib demonstrated high potency against fusion ROS1s and emerging resistant mutations

• Designed to overcome TKI resistance mutations, especially solvent front ROS1 G2032R1

Ba/F3 Cell Proliferation Assay IC50 (nM)

LMNA-TRKA ETV6-TRKB ETV6-TRKC

TRK Inhibitor* WT G595R G667C F589L

G595R/

F589L WT G639R WT G623R G623E F617I

Repotrectinib <0.1 0.2 9.2 <0.2 13.7 <0.1 1.7 <0.2 1.0 0.6 <0.2

LOXO-195 4.6 15.1 94.9 26.5 480.8 1.4 20.8 4.0 23.9 36.1 40.9

Larotrectinib 18.9 2817 1863 597 >10000 28.2 2500 41.4 7500 1486 4000

Entrectinib 0.4 711 186.7 <0.2 1774 0.6 1577 0.8 1670 1500 54.9

Repotrectinib: Potential Best-in-Class TRK InhibitorData Presented at Annual AACR Conference on March 31

* Other than repotrectinib, data based on evaluation of comparable proxy chemical reagent purchased from commercial sources rather than obtained from the pharmaceutical company developing the kinase inhibitor

12

Key Areas of Differentiation for Repotrectinib

Repotrectinib Xalkori (Crizotinib)1 Rozlytrek (Entrectinib)1 Vitrakvi (Larotrectinib)1

Development Stage

Registrational Phase 2 study

for ROS1+ NSCLC and NTRK+

adv. solid tumors

Approved in ROS1+

NSCLC

Approved for ROS1+

NSCLC and NTRK+ adv.

solid tumors

Approved for NTRK+ adv.

solid tumors

TKI Naïve Activity

(ROS1+ NSCLC) NA

TKI Pretreated Activity

(ROS1+ NSCLC) NA

CNS Activity

(ROS1+ NSCLC)

Not reported NA

No Grade 3 or 4 ALT/AST

Elevation

As of July 22 Data Cut-off

monitor liver tests

monitor liver tests

monitor liver tests

TKI Pretreated Activity in

NTRK+ Adv. Solid Tumors NA Not reported to date Not reported to date

1 Based on published information and data.

13

TRIDENT-1: An Ongoing Phase 1/2 Study of Repotrectinib in Patients with Advanced Solid Tumors Harboring ROS1, NTRK1-3, or ALKRearrangements

Data Reported Sept. 3, 2019(Based on Data Cut-off of July 22, 2019)

15

TRIDENT-1: A Phase 1/2 Study of Repotrectinib

Data cut-off date of July 22, 2019

Study Design/Eligibility (Phase 1)

• Advanced solid tumors harboring ROS1/NTRK1-3/ALK fusions

• No limit on prior lines of therapy

• Asymptomatic CNS metastases allowed

Phase 1 Primary Objective

• Determine the MTD and RP2D

Phase 1 Secondary Objectives

• Safety and tolerability

• Preliminary objective response rate and clinical benefit rate

1 2 ALK patients enrolled.2160 mg QD for one week followed by 160 mg BID; 6 safety patients not evaluable for response in ROS1+ NSCLC cohort include: 2 newly enrolled ROS1+ NSCLC TKI-pretreated patients without post-baseline scans prior to the data cutoff date, 1 NTRK+ patient, 1 ROS1+ patient with gastric cancer, and 2 ROS1+ NSCLC patients (1 naïve and 1 pretreated) with no post-baseline scans.*N=93 patients: 31 were ALK+; 10 were NTRK+ including: 2 GBM, 2 thyroid carcinoma, 2 soft tissue sarcoma, 1 salivary gland carcinoma, 1 squamous NSCLC, 1 cholangiocarcinoma, and 1 biliary gland carcinoma; 52 were ROS1+ advanced tumors (of which 40 ROS1+ advanced NSCLC were evaluable for efficacy by BICR)..

40 mg

QD

80 mg

QD

160 mg

QD

240 mg

QD

160 mg

BID

200 mg

BID1

120 mg QD

w/ Food

160 mg QD

w/ Food

160 mg

QD/BID

w/Food2

Total

Safety population

(ROS1+, NTRK1-3+, ALK+

solid tumors)

13 12 23 10 12 2 3 6 12 93*

Efficacy population

(ROS1+ NSCLC)5 5 10 2 6 0 2 4 6 40

Number of patients per dose cohort

16

Preliminary Efficacy of Repotrectinib in TKI Naïve ROS1+ NSCLC by BICR

Data cut-off date of July 22, 2019

TKI Naïve

(N=11)

1 Estimated using Kaplan-Meier method 2 For patients with CNS measurable disease at baseline

BICR: Blinded Independent Central Review

Clinical Benefit Rate: CR + PR + SD ≥ 2 Cycles

Confirmed ORR, n/N (%)

95% CI (%)

ORR at 160mg QD or above

10/11 (91%)

(59 ─ 100)

6/7 (86%)

Duration of response (DOR), months

% DOR > 18 months1 65%

Range 3.7+ ─ 23.3+

Intracranial ORR (IC-ORR)2, n/N (%)

95% CI (%)

3/3 (100%)

(29 ─ 100)

Clinical Benefit Rate, n/N (%)

95% CI (%)

11/11 (100%)

(72 ─ 100)

Median follow-up time, months

Range

20.1

5.3 – 24.9+

• Median duration of response is not mature, 5 out of 10 (50%)*

responders by BICR were ongoing without an event at the time of

this analysis: 3.7+, 14.8+, 16.4+, 17.6+, and 23.3+ months.

• Duration of cPR in 3 patients with IC-ORR were 14.8+, 17.6+, and

23.1 months.

Overall Response

(N=11)

Intracranial Response

(N=3)

-100%

-90%

-80%

-70%

-60%

-50%

-40%

-30%

-20%

-10%

0%

10%

20%

b

a

c

40

QD

240

QD

160

BID

* *

-100%

-90%

-80%

-70%

-60%

-50%

-40%

-30%

-20%

-10%

0%

10%

20%

Ma

xim

um

ch

an

ge

in

tu

mo

r siz

e (

%)

fro

m b

ase

lin

e

a

c

b

80

QD

40

QD

240

QD

160

QD

160

QD

160

QD

80

QD

40

QD

160

BID

160

QD

cPRcPR

cPR

cPR

cPRcPR

cPRcPR

cPR

a, b, cPatients with intracranial and extracranial cPR

120

QD

* * **

cPR

dPatient responded after dose escalation to 160 mg QD

*

d

17Data cut-off date of July 22, 2019

Preliminary Efficacy of Repotrectinib in ROS1+ NSCLC Patients Pretreated with 1 Prior TKI by BICR

TKI Pretreated with 1 Prior TKI

(N=18)

Confirmed ORR, n/N (%) 7/18 (39%)

95% CI (%) (17 ─ 64)

ORR at 160 mg QD or above• Crizotinib as ONLY prior TKI

6/11 (55%)

4/7 (57%)

IC-ORR1, n/N (%)

95% CI (%)

3/4 (75%)

(19 ─ 99)

Clinical benefit rate, n/N (%)

95% CI (%)

14/18 (78%)

(52 ─ 94)

Median follow-up time, months2

Range

7.3

0.6 – 19.3+

* 2 of 7 patients remain in cPR both at 5.5+ months.

1 For patients with CNS measurable disease at baseline2 For all TKI pretreated patients using reverse Kaplan-Meier method

BICR: Blinded Independent Central Review

Clinical Benefit Rate: CR + PR + SD ≥ 2 Cycles

Overall Response

(N=18)

Intracranial Response

(N=4)

-100%

-90%

-80%

-70%

-60%

-50%

-40%

-30%

-20%

-10%

0%

10%

20%

30%

40%

Ma

xim

um

ch

an

ge

in

tu

mo

r si

ze (

%)

fro

m b

ase

lin

e

120

QD

40

QD

80

QD

#

160

QD

160

BID

40

QD

160

QD

80

QD

160

QD

160

QD

160

QD

80

QD

160

BID

240

QD

#

cPR

160

QD

cPR

cPR

cPR

160

BID

cPR

a

a

a a

40

QD

cPR

cPR

a

a a

Patient with G2032R mutation

# Stable disease

Progressive disease

a Patient at 160 mg QD or above with crizotinib as ONLY prior TKI

160

BID

* *

-100%

-90%

-80%

-70%

-60%

-50%

-40%

-30%

-20%

-10%

0%

10%

20%

30%

40%

40

QD

40

QD

80

QD

cPR cPR

160

QD

cPRa


Preliminary Efficacy of Repotrectinib in ROS1+ NSCLC Patients Pretreated with 2 Prior TKIs by BICR

• 49-year-old Caucasian female

• Diagnosed with stage IV NSCLC in 2012

• Received carboplatin+paclitaxel+bevacizumab

• ROS1 fusion positive

• Received crizotinib for ~5 years

• ROS1 G2032R mutation detected in 2016

• Received lorlatinib for ~4 months

• Started repotrectinib at 160 mg QD, increased to 160 mg BID

and achieved PR in Cycle 2, 100% tumor regression in Cycle

6 and continuing on study treatment

Overall Response

(N=7)

Pretreated with 2 PRIOR TKIs

(N=7)

Case Study

Confirmed ORR*, n/N (%) 2/7 (29%)

95% CI 4 ─ 71

Clinical Benefit Rate, n/N (%) 5/7 (71%)

95% CI (%) 29 ─ 96

* 2 responders remain in response both at

3.7+ months

Baseline Cycle 6 (-100%)

-100%

-90%

-80%

-70%

-60%

-50%

-40%

-30%

-20%

-10%

0%

10%

20%

30%

40%

Ma

xim

um

ch

an

ge

in

tu

mo

r siz

e (

%)

fro

m b

ase

lin

e

160

QD

160

BID

cPR

160

QD

cPR

Patient with G2032R mutation

# Stable disease

Progressive disease

Escalated to 160 BID

160

QD

#

^

160^

QD

160^

QD

160^

QD

#

uCR pending confirmation

* *

a

aa


Preliminary Clinical Activity of Repotrectinib Against ROS1 G2032R Solvent Front Mutation by BICR

Overall Response

(N=7)

-100%

-90%

-80%

-70%

-60%

-50%

-40%

-30%

-20%

-10%

0%

10%

20%

30%

Ma

xim

um

ch

an

ge in

tu

mo

r si

ze (

%)

fro

m b

ase

line

160

QD

160

QD

240

QD

160

QD


1 Prior TKI

2 Prior TKIs

80

QD

#

# Stable disease

Progressive disease

cPR cPR

^

a

a

b

c

c

160^

QD

160^

QD

cPR

G2032R identified in:(a) plasma cfDNA;(b) tumor tissue;(c) plasma cfDNA and tumor tissue

b

b

uCR pending confirmation*

*

• ROS1 G2032R mutation identified in plasma cfDNA or tumor tissue by

NGS in 7 patients who had prior crizotinib

• All 7 patients experienced tumor regressions on repotrectinib

• Confirmed ORR: 3/7 (43%)

• 2/3 (67%) with 1 prior TKI treated at 160 mg QD and above

• 1 cPR with DOR 5.5+ months and on treatment 7.6+ months

• 1 cPR with DOR 4.4 months and on treatment 21.2 months

• 1/3 (33%) with 2 prior TKIs treated at 160 mg QD and above

• 1 cPR with DOR 3.7+ months and on treatment 5.6+ months


Duration of Repotrectinib Treatment in ROS1+ NSCLC by BICR • Intra-patient dose escalation was allowed

• Continuous treatment post radiographic PD was allowed

0 2 4 6 8 10 12 14 16 18 20 22 24 26

160 BID

160 QD

160 QD

160 QD

160 BID

240QD

120 QD

160 QD

40 QD

40 QD

80 QD

160 QD

160 QD

160 BID

160 QD

160 QD

160 QD

160 QD

160 BID

160 QD

160 QD

160 QD

80 QD

120 QD

80 QD

160 QD

160 QD

160 QD

160 BID

160 BID

160 QD

240 QD

160 QD

160 QD

40 QD

160 QD

80 QD

80 QD

40 QD

40 QD

Treatment Duration (month)

Star

ting

Dos

e (m

g)

1 Prior TKI

2 Prior TKIs

0 Prior TKI

Treatment ongoing

Time to response

Radiologic PD


Dose escalated: n=13

Dose reduced: n=7

18 of 40 patients (45%) remain on treatment

^

^

^

^

3 Prior TKIs

^

^

^

TKI Naïve

(N=11)

TKI Pretreated

(N=29)

# (%) of

Patients

Remaining on

Treatment

7 (64%) 11 (38%)

25.7+ 23.0+

25.3+ 21.6+

22.3+ 19.3+

20.0+ 7.6+

19.8+ 7.4+

17.5+ 5.6+

8.8+ 5.5+

5.3+

5.2+

3.6+

2.0+

Duration of

Treatment

(month)


Efficacy Observed in NTRK+ TKI-Naïve and TKI-Pretreated Patients

Baseline Cycle 6 (-68%)

• 68-year-old female, diagnosed in December 2017

• Started repotrectinib at 160 mg QD in February 2019

• Achieved a cPR with 65% tumor regression at Cycle 4 by BICR

assessment, patient in cPR for 3.8+ months

TKI-Naïve

NTRK+ Advanced Thyroid

Cancer

baseline 8 weeks

Baseline Week 8

TKI-Pretreated

ETV6-NTRK3+ Advanced Mammary

Analogue Secretory Carcinoma

• 51-year-old male diagnosed with acquired TRKC G623E solvent

front mutation

• Prior TKI treatment: crizotinib, entrectinib and entrectinib+trametinib

• Confirmed PR with repotrectinib treatment with DOR of 9.8 months

and DOT 17.9 months


Safety Summary: Treatment-Emergent and Treatment-Related AEs

1 Additional Grade 4 TEAEs: cerebrovascular accident, influenza, hyperkalemia, bacterial pneumonia, sepsis (n=1 each), respiratory failure (n=2); None were determined to be related to treatment.

Grade 5 TEAEs: respiratory failure (n=2), pneumonia, sepsis, sudden death (n=1 each); Only the case of sudden death was determined to be possibly related to treatment.

All Treated Patients (N=93)

TEAEs (≥10% of patients) TRAEs

Adverse Event All Grades Grade 3 Grade 41 Grade 3 Grade 4

n(%) n(%) n(%) n(%) n(%)

Dizziness 54 (58.1) 3 (3.2) --- 3 (3.2) ---

Dysgeusia 45 (48.4) --- --- --- ---

Anemia 28 (30.1) 11 (11.8) --- 3 (3.2) ---

Constipation 28 (30.1) --- --- --- ---

Fatigue 28 (30.1) 2 (2.2) --- --- ---

Dyspnea 27 (29.0) 5 (5.4) 1 (1.1) 1 (1.1) ---

Paraesthesia 27 (29.0) --- --- --- ---

Nausea 21 (22.6) 2 (2.2) --- --- ---

Cough 18 (19.4) --- --- --- ---

Pyrexia 17 (18.3) --- --- --- ---

Headache 15 (16.1) 1 (1.1) --- --- ---

Vomiting 13 (14.0) --- --- --- ---

Ataxia 12 (12.9) --- --- --- ---

Myalgia 11 (11.8) --- --- --- ---

Upper respiratory tract

infection11 (11.8) --- --- --- ---

Abdominal pain 10 (10.8) --- --- --- ---

Muscular weakness 10 (10.8) 1 (1.1) --- --- ---

Pain in extremity 10 (10.8) 1 (1.1) --- --- ---

• Repotrectinib was generally well tolerated

• Most treatment emergent adverse events (TEAEs)

and treatment-related adverse events (TRAEs)

were Grade 1 or 2

• No Grade 4 TRAEs

• The most commonly reported TEAE was low grade

dizziness, and majority did not require dose

interruptions or reductions.

• Of the 54 patients who reported dizziness,

43 (80%) reported Grade 1

• No cases of dizziness have led to treatment

discontinuation

• No Grade 3 or Grade 4 ALT or AST elevations

were reported

23

Pivotal Phase 2 Portion of TRIDENT-1: Enrollment Ongoing

ROS1+ Advanced NSCLC

Pivotal Cohorts

(up to n=190)

NTRK+ Advanced Solid Tumors

Pivotal Cohorts

(up to n=90)

EXP-3

2 Prior

ROS1 TKIs

ROS1+

advanced

NSCLC

(n=40)

EXP-1

ROS1

TKI-naïve

ROS1+

advanced

NSCLC

(n=50)

EXP-2

1 Prior

ROS1 TKI

ROS1+

advanced

NSCLC

(n=100)

EXP-5

TRK

TKI-naïve

NTRK+

advanced

solid tumors

(n=50)

EXP-6

TRK

TKI-pretreated

NTRK+

advanced solid

tumors

(n=40)

Exploratory

Cohort

(up to n=26)

EXP-4

ROS1 or ALK

TKI-naïve ROS1+

or ALK+ advanced

solid tumors

(non-NSCLC)

(n=12-26)

• Phase 2 Primary Objective

• cORR by BICR in each expansion cohort

• Phase 2 Secondary Objectives• DOR, PFS, and OS • IC-ORR and CNS-PFS

Single-agent repotrectinib studied in six cohorts

~100 sites activating in ~14 countries; Total number of patients ~310

Dose regimen: 160 mg QD, which may be increased after 14 days to 160 mg BID based on tolerability

Anticipate Early Interim Data from Initial

Patients in Some of the Registrational

Cohorts in 2H 2020

Pipeline Programs:

TPX-0022 MET/CSF1R/SRC Inhibitor

TPX-0046 RET/SRC Inhibitor

TPX-0022 MET/CSF1R/SRC Inhibitor: Phase 1 Study Initiated in 2H 2019

25

• Advanced solid tumors with abnormal MET/HGF or CSF1R/CSF1 signaling

• Unmet medical need due to limitations of current MET inhibitors

Target Patient

Populations

• Selective multi-targeted kinase inhibitor of MET/CSF1R/SRC

• Novel MOA by simultaneously targeting MET-driven tumor cells and modulating the TME

• Highly potent towards MET mutations/rearrangements such as exon 14 skipping mutations

Mechanism of Action

• Demonstrated high potency in inhibiting MET, SRC and CSF1R in enzymatic and cell-based assays

• Anti-tumor activity and inhibition of MET phosphorylation in xenograft tumor modelsPreclinical Data

• Initiated Phase 1 study in 2H 2019, Early Interim Phase 1 Data anticipated in 2H 2020Development Status

TPX-0022 Phase 1 Study Ongoing

Dose Escalation (n=~30)1

• Adult advanced solid tumor

patients with MET genetic

alterations

• Starting dose: 20 mg QD x 28

days

• Presence of MET alteration

measured by local testing

RP2D

Dose Expansion(n= ~80)

MET Exon14 deletion

Non-Small Cell Lung Cancer (NSCLC)

MET inhibitor naïve

MET inhibitor pre-Tx

MET Amplification

NSCLC, Gastric or Gastro-Esophageal Junction Cancers,

Hepatocellular Carcinoma

MET KD mutation/MET fusions

All cancers, Exploratory

Confidential

Key Endpoints

Primary: Incidence of Dose Limiting Toxicities, Recommended Phase 2 Dose

Secondary: Objective Response Rate by Blinded Independent Central Review, Clinical Benefit Rate, Time to

Response, Duration of Response, Progression Free Survival, Intracranial Objective Response Rate

26

1 Food effect study will also be conducted in additional n=~10.

TPX-0046 Novel RET/SRC Inhibitor: Phase 1/2 Study Initiated in 2H 2019

27

• Advanced solid tumors with abnormal RET genes (both TKI-pretreated and TKI-naïve)

• Unmet medical need for potential emerging treatment resistance

Target Patient

Populations

• Selective multi-targeted kinase inhibitor of RET and SRC

• Novel structure compared to other RET inhibitors to potentially address resistant mutations that may emerge

• Inhibition of SRC has the potential to reduce bypass resistance and increase the effect seen with RET inhibitors

Mechanism of Action

• Comparable potency against WT RET to proxy chemical compounds1 for BLU-667 and LOXO-292, and only drug candidate with reported potency against the RET solvent-front mutation G810R

• Strong potency against wildtype (WT) and mutated RETs

• Showed dose-dependent inhibition in cancer cell- and patient-derived tumor models

Preclinical Data

• Initiated Phase 1/2 trial in 2H 2019Development Status

1Data for BLU-667 and LOXO-292 based on evaluation of each corresponding proxy chemical compound purchased from commercial sources rather than from the pharmaceutical companies

developing the respective kinase inhibitor.

TPX-0046 Potently Inhibited RET and SRC in Enzymatic and Cell Assays and Demonstrated Dose-Dependent Tumor Growth Inhibition in Xenograft Models

28

NR: Not reported1 All of the compounds were tested on the same plates in multiple experiments and the data represents an average of the results2 Data based on evaluation of corresponding proxy chemical compound purchased from a commercial source rather than from the pharmaceutical company commercializing or developing the kinase inhibitor

0 5 1 0 1 5 2 0 2 5 3 0

0

5 0 0

1 0 0 0

1 5 0 0

2 0 0 0

2 5 0 0

D a y o f T re a tm e n t

Tu

mo

r V

olu

me

(m

m3)

V e h ic le B ID

T P X -0 0 4 6 1 m g /k g B ID

T P X -0 0 4 6 5 m g /k g B ID

t re a tm e n t s to p p e d

Antitumor effect of TPX-0046 in the CR1520

patient-derived xenograft model of colorectal

cancer with the NCOA4-RET fusion gene

2 8 3 2 3 6 4 0 4 4 4 8 5 2 5 6

0

2 0 0

4 0 0

6 0 0

8 0 0

D a y P o s t In o c u la tio n

Tu

mo

r V

olu

me

(m

m3)

V e h ic le B ID

T P X -0 0 4 6 2 m g /k g B ID

T P X -0 0 4 6 5 m g /k g B ID

Antitumor effect of TPX-0046 in a TT cell-derived

xenograft tumor model of medullary thyroid

carcinoma with the RET C634W mutation

1 0 1 2 1 4 1 6 1 8 2 0 2 2 2 4

0

2 0 0

4 0 0

6 0 0

8 0 0

D a y P o s t In o c u la tio n

Tu

mo

r V

olu

me

(m

m3)

V e h ic l e

T P X -0 0 4 6 5 m g /k g B ID

T P X -0 0 4 6 1 m g /k g B ID

T P X -0 0 4 6 1 0 m g /k g B ID

Antitumor effect of TPX-0046 in a Ba/F3 cell-

derived xenograft tumor model with the KIF5B-

RET fusion harboring the G810R mutation

Enzymatic Kinase Activity at 10 mM ATP IC50 (nM)1 Cell Proliferation IC50 (nM)1

Inhibitor RETRET-

CCDC6

RET

M918T

RET

S891A

RET

Y806HSRC VEGFR2

Ba/F3

KIF5B-RET

WT

Ba/F3

KIF5B-RET G810R

(solvent front mutation)

Ba/F3

KIF5B-RET V804M

(gatekeeper mutation)

TPX-0046 1.0 0.5 0.3 0.2 2.6 1.0 >1000 0.4 16.9 533

BLU-6672 1.7 0.8 0.5 0.6 3.7 NR NR 0.7 749 1.1

LOXO-2922 1.9 0.9 0.4 0.8 3.5 NR NR 0.2 568 23.4

TPX-0046 Phase 1/2 Study: Initiated in 2H 2019

RP2D

Phase 1 Dose Escalation (n=~40)1

1. RET fusion+ NSCLC

RET TKI naïve

2. RET fusion+ NSCLC

1 Prior RET TKI treated

3. RET mutation + Medullary Thyroid Carcinoma

RET TKI naïve

4. RET mutation + Medullary Thyroid Carcinoma

1 Prior RET TKI treated

Phase 2 (n=~300)

5. RET fusion or mutation + Other solid tumors

RET TKI naïve

6. RET fusion or mutation + Other solid tumors

RET TKI-Pretreated

1 Food effect study will also be conducted in additional n=~12.

29

• Adult advanced solid tumor patients

with RET genetic alterations

(mutations or fusions)

• Starting dose: 10 mg QD

• 3+3 Design (Intra-patient dose

escalation allowed)

• Alternate regimen (e.g. BID dosing)

may be tested based on emerging

clinical data

Key Milestones

30

20202019

Repotrectinib

TPX-0046

TPX-0022 April 2019

AACR Poster

Presentations

1H 2019

TPX-0022

(MET/CSF1R/SRC)

IND Cleared

Mid-2019

ASCO Oral Presentation

(TRIDENT-1 Ph. 1 Data

Update in ROS1+ NSCLC)

2H 2020

TRIDENT-1 Phase 2

Planned Interim Data

Update

2H 2019

TPX-0046 (RET/SRC)

IND Cleared

3Q 2019

TPX-0046 (RET/SRC)

Preclinical Data

Presentation (ESMO 2019)

2H 2019

TPX-0022

(MET/CSF1R/SRC)

Phase 1 Study Initiated

2H 2020

TPX-0022 Phase 1

Planned Interim Data

Update

Note: Gray shading and checkmarks reflect completed milestones

April 2019

AACR Poster

Presentations

2H 2019

TRIDENT-1 Phase 2

Registrational Study

Initiated

3Q 2019

TRIDENT-1 Phase 1

Interim Data Update

(ESMO 2019)

2H 2019

ALK Candidate

Nomination

ALK Inhibitor

2H 2019

TPX-0046 (RET/SRC)


2H 2019

Phase 1/2 Study in

Pediatric Advanced Solid

Tumors Initiated

1H 2020

Combination Strategy

Preclinical Data

Company Overview:

Precision Oncology Medicines Addressing Treatment Resistant Cancers

Athena Countouriotis, President & CEONovember 20, 2019Jefferies 2019 London Healthcare Conference

Documents

Company Overview: Precision Oncology Medicines Addressing ... Point... · Company Overview: Precision Oncology Medicines Addressing Treatment Resistant Cancers Athena Countouriotis,