Evaluation of Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Data of PTI-428, A Novel CFTR Amplifier, in

Patients with Cystic FibrosisPatrick Flume, M.D.

Medical University of South Carolina-Charleston, SC

GS Sawicki, PA Flume, D Layish, NF Mehdi, S Nasr, BS Quon, PE Bialek, S Wilson, L Kang, B McLaughlin, P-S Lee, GS Gilmartin

Presenter Disclosure

Patrick Flume, M.D.

Dr. Flume has received grant support from Proteostasis Therapeutics, Inc

Introduction

• PTI-428 is a novel CFTR modulator, referred to as a CFTR amplifier.

• PTI-428 is designed to increase production of immature CFTR protein

through enhanced translation of CFTR protein regardless of mutation class.

• In this study, PTI-428-01 was evaluated in patients with CF both with and

without background treatment with a CFTR modulator.

Amplifiers Are Designed To Improve The Efficiency of CFTR Translation

CFTR mRNA binds to the ribosome

Signal sequence emerges and recognized by the signal recognition particle (SRP)

SRP binds mRNA-ribosome complex to form the Ribosome-Nascent Chain Complex (RNC)

SRP shuttles the RNC to the ER surface and immature CFTR protein is available

SRP, signal recognition particle

PTI-428 Has Been Shown to Increase CFTR Activity in HBE Cells Across CF Mutation Classes with F508del on the Other Allele

5

ClassI

Stop Codon Mutation

IIProcessing Mutation

IIIGating

Mutation

IVConductance

Mutation

DefectProtein translation

prematurely stoppedMisfolded protein fails

to reach surfaceAbnormal regulation

of ion flow

Faulty channelconductance slows

ion flow

HBE Genotype Tested

G542X/F508delClass I/II

F508del/F508del

Class II/IIG551D/F508del

Class III/IIR117H/F508del

Class IV/II

In vitroincrease

in ion flow from PTI-428

combinationsa

aAmplifier added to indicated compound(s).

HBE, human bronchial epithelium.

G54

2X/F

508

del

-CFT

R p

rote

in a

ctiv

ity

(% o

f co

rrec

tor

+ p

ote

nti

ato

r)

F508

del

-CFT

R p

rote

in a

ctiv

ity

(% o

f co

rrec

tor

+ p

ote

nti

ato

r)

G55

1D/F

508

del

-CFT

R p

rote

in a

ctiv

ity

(%

of

po

ten

tiat

or)

R11

7H/F

508

del

-CFT

R p

rote

in a

ctiv

ity

(%

of

po

ten

tiat

or)100%

190%

potentiator + corrector

potentiator+ corrector+ amplifier

100%

184%

potentiator + corrector

potentiator+ corrector+ amplifier

100%

160%

potentiator potentiator+ amplifier

100%

193%

potentiator potentiator+ amplifier

• PTI-428 delivered about a 2 fold increase in vitro activity across all genotypes• In Vitro studies demonstrated that PTI-428 also increased the amount of unfolded CFTR protein

CORRECTOR

PTI-428, an investigational CFTR Amplifier, May Be Used In Combination with CFTR Correctors and Potentiators

Amplifiers, such as PTI-428, selectively increase the amount of immature CFTR protein in the cell, providing additional substrate for correctors and potentiators to act upon

Potentiators, such as KALYDECO® (ivacaftor), act by increasing the opening time of the CFTR channel, resulting in higher ion flow

Correctors, such as ORKAMBI® (lumacaftor/ ivacaftor), are thought to facilitate the processing of mutated CFTR protein substrate, leading to improved delivery to the cell membrane

POTENTIATOR

AMPLIFIER

ORKAMBI® and KALYDECO® are registered trademarks of Vertex Pharmaceuticals Inc.

PTI-428-01, Study Design and Methods

• Each cohort followed by SRC

review of PK and safety data

• Part B is ongoing in CF subjects on

background treatment with

Orkambi

• Preliminary data from multiple

dose cohorts (Part A) is presented

• Treatment with PTI-428 has also

been evaluated in SAD and MAD

cohorts in healthy volunteers

Study Design and Methods, Multiple Dose Cohorts

• CF subjects:

– CF subjects ≥18 years of age

– Background treatment with ORKAMBI® or no background CFTR modulator therapy

• Study Design:

Randomized 6:2 (active:placebo)Treatment for 7 days with daily doses of PTI-428 or placebo followed by a 7 day

follow-up period• Primary objective: Assessment of safety and tolerability

• Secondary objective: Assessment of the PK of PTI-428, Ivacaftor and Lumacaftor (insubjects on background treatment with ORKAMBI®)

• Exploratory objectives: Include CFTR expression from nasal brushings

Subject Disposition, Multiple Dose Cohorts

CF Subjects (n=8)

Placebo (n=2)

Completed Dosing (n=2)

Completed Study (n =2)

Active

(n=6)

Completed Dosing (n=6)

Completed Study (n = 6)

CF Subjects on Orkambi (n=11)

Placebo (n=2)

Completed Dosing (n=2)

Completed Study (n =2)

Active

(n=9)

Completed Dosing (n=9)

Completed Study (n = 9)

PTI-428 Multiple Dose, Monotherapy Cohort (Cohort 2)

PTI-428 Multiple Dose, Background Orkambi Cohort (Cohort 1)

Results-SafetySingle Ascending Dose Cohorts

In the three SAD cohorts 4 subjects experienced a TEAE

•No severe AEs, SAEs or AEs leading to discontinuation of treatment

•No AE term reported in more than one subject

Multiple Dose Cohorts

Monotherapy cohort

• 6 subjects experienced TEAE (1 in the placebo group)

• All were moderate or mild. One (cough) occurred twice: once in subject on placebo and once in subject dosed with PTI-428

Orkambi ® cohort

• 4 subjects experienced TEAE (3 in the active and 1 in the placebo group)

• 1 subject reported possibly related AEs

• No severe AEs, SAEs or AEs leading to discontinuation of treatment

• No AE term reported in more than one subject

• In both multiple dose cohorts there were no laboratory safety or hematology AEs

Results-Preliminary Pharmacokinetics

PTI-428 Showed Dose ProportionalityPTI-428 Exposure Similar, Regardless Of Background Treatment with Orkambi®

• Exposure to PTI-428 increased in an approximately dose proportional manner in patients with CF• T ½ ~ 14-15 hours

No Clinically Important Pharmacokinetic Interaction Between PTI-428 and Ivacaftor or Lumacaftor

Ivacaftor ExposuresLumacaftor Exposures

Day 1

Day 7

Exp

ecte

d

0

2

4

6

8

Iv a c a fto r A U C (0 -1 2 )

AU

C(0

-12

)(h

*µ

g/m

L)

O rk a m b i L a b e l

W ith P T I-4 2 8

P la c e b o

Day 1

Day 7

Exp

ecte

d

0

2

4

6

8

Iv a c a fto r A U C (0 -1 2 )

AU

C(0

-12

)(h

*µ

g/m

L)

O rk a m b i L a b e l

W ith P T I-4 2 8

P la c e b o

Baseline CFTR Protein Correlated with Baseline Sweat Chloride

R² = 0.5304

70

80

90

100

110

120

0 100 200 300 400 500

Swe

at C

hlo

rid

e (m

M)

CFTR Protein (ng/mg)

BASELINE SWEAT CHLORIDE VS BASELINE CFTR PROTEIN(PTI-428 MULTIPLE DOSE IN ORKAMBI® COHORT)

Multiple Dose Monotherapy Cohort Responded to PTI-428 with Rapid Increase in CFTR Protein

CF Patients PTI-428-01 Study Multiple Dose Cohorts**

Treatment

Average CFTR Protein Fold Change During Treatment

Period*(Day 1 through Day 7)

Average CFTR Protein Fold Change During Follow-up

Period* (Day 14)

PTI-428 8.1 2.0

Pooled Placebo 1.3 1.6

*across all available samples **Biomarker analysis is based on 70% nasal samples that met QC criteria for the CFTR ELISA collected from all 19 CF subjects

in vitro HBE cells

TreatmentAverage CFTR

Protein Fold Change F508del/F508del

Average CFTR Protein Fold Change

normal CFTR

PTI-428 1.9 1.5

Control 1.0 1.0

• Subjects in the monotherapy cohort demonstrated on average an 8 fold increase in proteinduring the treatment period and a return to approximately baseline levels at the end of thefollow up period.

• Changes in biomarker levels in PTI-428 treated CF patients were higher than those seen invitro.

R² = 0.9488

R² = 0.46320.5

1

2

4

8

16

32

64

1 10 100 1000

CFT

R F

old

Ch

ange

Fro

m B

ase

line

Baseline CFTR Protein (ng/mg)

Baseline CFTR Protein Levels Predicted CFTR Protein Increase During Treatment Period in Multiple Dose Monotherapy Cohort

Max CFTR Fold Change During Treatment

CFTR Fold Change During Washout

Conclusions and Next Steps

Conclusions• Amplifiers are a new class of CFTR modulators

• Treatment was generally well tolerated

• No laboratory safety or hematology AEs in Part A single and multiple dose cohorts

• Exposure to PTI-428 increased in a dose proportional manner

• PK profile similar in CF subjects regardless of background treatment with a CFTR modulator

• Nasal biomarker analysis suggests PTI-428 treatment leads to higher than expected increasein CFTR protein in CF subjects

Next Steps• Phase 2, Part B (28 day) cohort is ongoing in subjects with CF on background treatment with

Orkambi

Poster #196-Evaluation of Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Data of PTI-428, A Novel CFTR Amplifier, in Patients with Cystic Fibrosis

Thank You

Investigator Institution

Patrick Flume Medical University of South Carolina

Daniel Layish Central Florida Pulmonary Group

Richard Ahrens University of Iowa Hospitals & Clinics

Alice Gray Duke University Health System

Jorge Lascano University of Florida

Manu Jain Northwestern University Memorial Hospital

Tacjana Pressler University of Copenhagen Rigshospitalet

Robert Vender Penn State Milton S. Hershey Medical Center

Gregory Sawicki Boston’s Children’s Hospital

Adrian O’Hagan University of Louisville

Bradley Quon St. Paul's Hospital Pacific Lung Research Center

Lara Bilodeau Institut Universitaire de Cardiologie et de Pneumologie de Québec

Investigator Institution

Karen Miller St. Luke's Cystic Fibrosis Center of Idaho

Yael Yonker Massachusetts General Hospital

Mark Wylam Mayo Clinic

Carsten Schwartz Charite - Campus Virchow-Klinikum

James Tolle Vanderbilt University Medical Center Macey

Julie Macey Groupe Hospitalier Pellegrin - Hôpital des Enfants

Isabelle Fajac Hopitaux Universitaires Paris Centre Cochin

Wolfgang Gleiber J.W. Goethe University Hospital

Deepika Polineni University of Kansas Medical Center Research Institute, Inc.

Samya Nasr University of Michigan Health System

Francois Tremblay Institut de Recherches Cliniques de Montréal

Nighat Mehdi University of Oklahoma Health Sciences Center

On behalf of the PTI-428-01 Study Investigators