pxt3003 overview · pleo-cmt: onls and 10mwt in sap# primary population # statistical analysis plan...

PXT3003 overview

January 2020

Charcot-Marie-Tooth Disease Type 1A

SYMPTOMSMuscle atrophyin extremities causing

severe walking and hand disabilities,

pain, cramps and fatigue

DIAGNOSIS~50% of patients have symptoms

before the age of 20, confirmed by genetic

testing

NATURAL

HISTORY

Genetic disease; symptoms starting in

teenage years, slowly declining

through life, resulting in braces,

surgery and wheelchair

POPULATIONMore than 100,000 people affected

with mild to moderate CMT1A in US

and EU5 (core market)

TREATMENT

OPTIONS

No drug approved; only supportive care

available

No other candidates in late stage clinical

development

Chronic, Severe, Debilitating Inherited Neuropathy

BACLOFEN

PXT3003 Novel Design and Mechanism of Action

Opioid/ Alcohol dependence

Spasticity

Constipation

CMT1A disease at-a-glance Network analysis Design of PXT3003

Current Indication

Opioid receptors

GABAreceptors

Muscarinic receptors

Current Dose

50mg

120mg

1.4mg

12mg

OPIOIDReceptors

MUSCARINICReceptors

GABAReceptors

420mg

15g

CMT1A - Axonaldysfunction andmuscle loss

NALTREXONE

SORBITOLNormal

Pharnext Dose

Mechanism of action of PXT3003 in CMT1APreclinical data demonstrate that PXT3003 acts on different cell types of the motor unit in CMT1A

Increases number of myelinated

axons and axonal diameter in rats

Downregulates PMP22 in rats Improves Akt/Erk signaling dysbalance in rats

Schwann cell differentiation

*p<0.05, **p<0.01, ***p<0.001 vs placebo

Num

ber

of to

tal m

yelin

ate

d

axons

Con

trol

Place

bo

PXT30

03

0

2000

4000

6000

8000

10000

12000

***

**

Con

trol

Place

bo

PXT30

03

3.0

3.5

4.0

4.5

5.0

5.5

Axon d

iam

ete

r (µ

m)

***

*

Con

trol

Place

bo

PXT30

03

100

110

120

130

140

150

160

PM

P22 m

RN

A e

xpre

ssio

n(s

cia

tic n

erv

e)

-31%

*

***

Very fast fibers in red

Improves muscle function in rats

Restores functional Neuromuscular junctions in rats

Control Placebo PXT300370

80

90

100

% Innerv

ate

d N

MJ ** **

TG high dose

WT placebo TG placebo


40

50

60

70

% F

ast fibers

per

cro

ss s

ection

*

AT

P L

evel (A

.U)


500

1000

1500

2000

***

***

Improves global energy

expenditure in vitro

*p<0.05, **p<0.01, ***p<0.001 vs placebo

Mechanism of action of PXT3003 in CMT1APreclinical data demonstrate that PXT3003 acts on different cell types of the motor unit in CMT1A

All Components of PXT3003 Synergistic to Activity in CMT1A

110

105

100

9 5

9 0

115

125

120

130M yelin atio n

%Im

pro

ve

m e

nt

m y

elin

len

gth

S

S in g le D u o s

* * *

S

P la ce b o B C L + N L X B C L + S R B N L X +S R B P X T3 0 0 3

4

5

6

7G rip s tre n g th a t e n d o f tr ia l

Gri

ps

tre

ng

th(N

)

(ch

an

ge f

rom

ba

se

lin

e)

***

###

#######

#

In CMT1A neurons on myelination in vitro In CMT1A animals in vivo

***p<0.001 vs CMT1A placebo/Control, ANOVA + Dunnett test#p<0.05, ###p<0.001 vs PXT3003, ANOVA + Dunnett test

S: synergy

BCL = Baclofen (GABA receptor)

NTX = Naltrexone (opioid receptor)

SRB = Sorbitol (muscarinic receptor)

Robust Phase 2 Results for PXT3003 in CMT1AExploratory multi-center, randomized, double-blind, placebo-controlled Phase 2 study

DOSE 1n=21

DOSE 3n=19

PLACEBOn=19

DOSE 2n=21

Dose Reduction

1/10001/2001/250

1/5001/1001/125

1/1001/201/25

NAL

BAC

SOR

80Mild to

Moderate Patients

• All doses safe and well

tolerated

• Effect achieved at 12 months with Dose 3, which was used to design the Ph3 study

Source: Attarian et al, Orphanet Journal of

Rare Diseases (2014),9:199

20%

10%

0%

-10%

%IM

PR

OV

EMEN

Tin

ON

LS

DOSE 3

PLACEBO

BASELINE 12 Mths

DOSE 2

DOSE 1

PHASE 2 DURATION: 12 MONTHS

Efficacy and dose-effect demonstrated with Overall Neuropathy Limitation Scale (ONLS)

PLEO-CMT: First Pivotal Phase 3 Study Design and EndpointsInternational, randomized, double-blind, placebo-controlled

Primary endpoint: ONLS after 12 -15 months

▪ ONLS: a 12-point scale evaluating disability

▪ 90% of the patients scored 2-4 (mild-to-moderate)

▪ A 0.3-point ONLS difference vs. placebo was determined to be

meaningful

- Stabilizing or even improving disease versus placebo or natural

yearly evolution estimated at 0.1/0.2 point.

- 50% Placebo standard deviation (Cohen J., 1988)

▪ FDA and EMA agreed on using ONLS as the primary endpoint

for this study.

Secondary endpoints analysis include:

▪ 10-meter walk test (10-MWT)

▪ Nine-hole peg test (9-HPT)

▪ 2 subsets of CMTNSv2 (CMT Impairment Score)

(Clinical + Electrophysiological items = CMTNSv2)

- Sensory subset*

- Clinical subset = purely clinical items (CMTES)**

ONLS = Overall Neuropathy Limitation Scale

* Sensory subset of CMTNSv2: items 1,4 and 5

** CMTES is derived from CMTNSv2, items 1 to 7 excluding nerve conductions

PHASE 3 DURATION: 15 MONTHS

SOR

0.7 mg 6 mg 210 mg

PLACEBO

DOSE 3

(Phase 2 highest dose)

DOSE 4

(2x Dose 3)

NAL

BAC

SOR

323Mild to

Moderate Patients

(age:16 – 65 y)1.4 mg12 mg420 mg

Phase 3 Study – CMC Event Interrupted High Dose ArmStatistical Significance at Interruption with Original Stat Plan

Dec 2015

Study Start

Sept 2017

High

dose stop

Mar 2018

Study End

Oct 2017: Variability

Nov 2017: Futility read

Phase 3 Trial n=323 patients

44 completers + 12 dropouts = 56



High Dose (Dose 4) n=113

Low Dose (Dose 3) n=109

Placebo n=101



85 completers

80 completers

49 completers5 completers

per original stat plan* at CMC event, ONLS p=0.012

modified SAP*, ONLS p=0.008

per original SAP*, ONLS p=0.04

CMC event

July 2017

Germany stop

( all arms)

52 patients – no data

due to CMC event

Oct 2018

Study

Read-out

*Original statistical plan adapted to account for “missing data” from stopping high dose arm due to CMC event (using ICH guidelines)

Statistical model not modified (ANCOVA) but adaptation of populations considered

• Original plan → primary population = FAS (n=323) / missing data due to drop-out (DO) imputed like placebo for all study arms (conservative)

• Modified SAP → primary population = mFAS (n=235 = completers + DO related to treatment) / missing data due to DO related to drug imputed like Placebo for all

study arms / missing data due to all other DO excluded from analysis (considered at random)

PLEO-CMT: ONLS and 10MWT in SAP# Primary Population

# Statistical Analysis Plan frozen and sent to USFDA before unblinding the data

*, ** Dose 4 vs Placebo, ANCOVA with multiple imputation (Missing data implemented by multiple imputations following the placebo trend) *** Average of 12 and 15 Month, or 12 Month if 15 Month is missing

Dose 4 (n=55)

Dose 3 (n=93)

Placebo (n=87)

p = 0.008

ONLS

p = 0.016

10mWT

Baseline 6 months 12+15 months*** Baseline 6 months 12+15 months***

PLEO-CMT: Safety and Tolerability

▪ Treatment emergent adverse events (TEAE) similar among three groups; majority mild

▪ TEAEs leading to treatment withdrawal similar in all three groups

▪ Single treatment-related serious TEAE occurred in lower dose group (gastroenteritis)

▪ Safe and well tolerated; showed a similar safety profile as in Phase 2

PLEO-CMT-FU Open Label Extension Study Design

PLEO-CMT Phase 3 Study PLEO-CMT-FU Study

15 monthsDouble blind – Placebo Controlled

9 monthsOpen Label – No Placebo**

High dose (D2)

Low dose (D1)

Placebo (P)

High dose (D2)

Low dose (D1)

187 Patients*

69 Patients

62 Patients

54 Patients

8 Patients

46 Patients

D2-D2

D1-D1

P-D2

P-D1

* 187 patients were enrolled, however 2 patients were excluded as outliers due to extraordinary circumstances, we considered unrelated to treatment

** Initial extension study design was blinded. Intercurrent event caused the extension study to be unblinded and therefore open label due to the change in dosing

for high dose patients switching to twice the low dose to equal the high dose amount of drug.

High dose (D2)

Low dose (D1)

ONLS Results for All Extension Study Participants(PLEO-CMT + Interruption + PLEO-CMT-FU Trials)

Intercurrent event caused an average 5-month treatment interruption between Phase 3 PLEO-CMT and extension study

All cohorts during extension vs placebo during PLEO-CMTestimate/year: -0.30 95%CI[-0.48; -0.12], p = 0.001

Placebo during extension vs placebo during PLEO-CMTestimate/year: -0.24 95%CI[-0.47; -0.01], p = 0.038

D2-D2 cohort from start of PLEO-CMT through extension –total of 25 months of study timeImproved by -0.26 points

Results must be cautiously interpreted because of open label extension PLEO-CMT-FU design

Other Anticipated PXT3003 Milestones and Anticipated Path Forward

Feb 2, 2019: FDA Fast Track Designation granted

Jan 6, 2020: Announced top-line results of extension study (PLEO-CMT-FU) of long-term safety

and efficacy of PXT3003

1H 2020: Expect to finalize second Phase 3 trial protocol in CMT1A with FDA

2H 2020: Expect to Initiate second Phase 3 trial in CMT1A (potential for data in late 2022/early

2023)

pxt3003 overview · pleo-cmt: onls and 10mwt in sap# primary population # statistical analysis plan...

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