Translate Bio : 2019 NACFC Oral Presentation

Safety and Tolerability of a Single Dose of MRT5005, a Nebulized CFTR mRNA Therapeutic, in Adult CF Patients

W17.6: Abstract # 515

JB Zuckerman1, K McCoy2, MS Schechter3, D Dorgan4, M Jain5, KD MacDonald6, C Callison7SD Walker8, S Bodie9, AJ Barbier9, SM Rowe10

1Maine Medical Center, 2Nationwide Children's Hospital/the Ohio State University, 3Children's Hospital of Richmond at Virginia Commonwealth University, 4Perelman School Med, Univ Pennsylvania, 5Northwestern Univ, 6Oregon Health & Science Univ,

7University of Tennessee Medical Center, Knoxville, 8Univ Hospitals, Cleveland Med Cent, 9Translate Bio Inc, Lexington, MA, 10Univ Alabama Birmingham

Disclosure slide for Dr. Zuckerman

• Scientific Advisory Board for Gilead Sciences

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Introduction

		mRNA	Lipid Nanoparticle (LNP)
Transcription
Start		Poly (A) Signal
5' cap	5' UTR	Coding Region	3' UTR	Poly (A) Tail

Start	Stop
Codon	Codon

• MRT5005 is acodon-­optimized human CFTR mRNA, formulated in lipid nanoparticles (LNPs) suitable for nebulization.1
• It is designed to be agenotype-­agnostic therapeutic addressing the underlying cause of cystic fibrosis (CF).
• RESTORE-­CF,a Phase 1/2 clinical trial in adult patients with CF is ongoing in the USA (NCT03375047).

• Today, we report the results of the single -­ascending dose (SAD) portion of the trial, comprising data through one month of follow -­up after a nebulized dose of MRT5005 or placebo (saline).

1Barbier et al., NACFC 2018

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RESTORE-­CF: MRT5005 Phase 1/2 Clinical Trial Design

Design

• Randomized,double-­blind,placebo-­ controlled, staggered dosing
• Each cohort: N=4 (3:1)

Objective

• Evaluate safety and tolerability of single and multiple escalating doses of MRT5005 administered by nebulization

Eligibility & Inclusion

• 18 years+
• ppFEV1≥50% and ≤90%
• Patients with two Class I and/or Class II CFTR mutations

PART A:

Single Ascending Dose

(SAD) Groups

PART B:

8 mg

Multiple Ascending

Dose (MAD) Groups

5 weekly doses

16 mg

Ongoing

24 mg

12 Patients Total

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MRT5005 Phase 1/2 SAD: Patient Demographics Overview

• The study enrolled 12 Caucasian subjects, 9 males, between19-­30 years of age.
• Of the 12 subjects, 11 had at least 1 F508del mutation, and 8 were F508del homozygotes (7 on stable regimen of lumacaftor/ivacaftor or tezacaftor/ivacaftor)
• One subject had no F508del mutation and was considerednon-­amenable to modulator treatment, including elexacaftor/tezacaftor/ivacaftor.

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MRT5005 Phase 1/2 SAD: Results

MRT5005 Phase 1/2 SAD: Safety Overview

Treatment Emergent Adverse Events (TEAEs)	Pooled	MRT5005	MRT5005	MRT5005
Placebo	8 mg	16 mg	24 mg
through Day 29	(N=3)	(N=3)	(N=3)	(N=3)
Overall TEAEs	11	28	25	33
Not Related	9	11	9	10
Related	2	17	16	23
TEAEs by Severity
Mild	11	23	24	21
Moderate	0	5	1	12
Severe	0	0	0	0
Serious TEAEs	0	0	0	0
TEAEs Leading to Discontinuation	0	0	0	0
TEAEs Resulting in Death	0	0	0	0
TEAEs Classified as Pulmonary Exacerbation	0	0	0	2*

* Occurred at Day 25 and Day 27

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MRT5005 Phase 1/2 SAD: ppFEV1Overview

• ppFEV1was measured at screening, Day -­1, Day 1 (prior to dosing), 8 h after dosing, Day 2, Day 3, Day 8, Day 15 and Day 29.
• The average of the Day-­1 and Day 1 (prior to dosing) value was considered as the Baseline value.
• Spirometry was performed using the TrueFlowTMSpirometer according to ATS/ERS2005 criteria and read by a central lab (Biomedical Systems)

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MRT5005 Phase 1/2 SAD: Absolute Change in ppFEV1Over Time, Average Values

%	25
1	20
-­‐ ppFEV
15
Baseline	10
5	8MG
from
0	16MG
Change
-­‐5	24MG
	PLACEBO
(SD)	-­‐10
Mean	-­‐15
-­‐20

StudyVisit

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ppFEV1Change from Baseline - Days 2, 3 and 8

ppFEV1Change fromBaseline

25

20

15

10

5

0 -­‐5

-­‐10

PLACEBO 8MG 16MG 24MG

Day 2

ppFEV1Change fromBaseline

25

20

15

10

5

0

-­‐5

-­‐10

PLACEBO 8MG 16MG 24MG

Day 3

ppFEV1Change fromBaseline

25

20

15

10

5

0

-­‐5

-­‐10

PLACEBO 8MG 16MG 24MG

Day 8

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MRT5005 Phase 1/2 SAD: Pharmacokinetics and

Immunogenicity Data

Pharmacokinetic measurements were taken to evaluate mRNA and/or lipid in the blood

• Low levels of mRNA and/or lipid were detected in the blood of five subjects, 3 of whom were in the 24 mg dose group

Immunogenicity testing was performed using serum or whole blood in validated assays

• Anti-­drugantibodies:No anti-­CFTRanti-­drug antibodies detected
• T-­CellResponse:No detection of T-­cell sensitization

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MRT5005 Phase 1/2 SAD: Summary and Conclusions

• MRT5005, an inhaled,LNP-­formulated mRNA therapy coding for the CFTR protein, was tested in a single-­ascending dose study in 12 adult patients with CF.
• MRT5005 was generally well tolerated at thelow-­ and mid-­dose levels.
• • Mild to moderate febrile reactions were observed in 5 subjects receiving MRT5005, 3 of whom were in the 24 mg dose group. These reactions started approximately4-­10 hours after dosing and ended by 24 hours, allowing for discharge as planned.
• The observation that mRNA and/or lipid could be detected in the blood in some subjects indicates successful delivery of inhaled mRNA through the mucus.
• In 4/9 of the MRT5005 subjects, observed increases in ppFEV1within the 8 days after treatment were higher than expected based on known variability of ppFEV1.

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Acknowledgements

• Patients and investigators who participated in theRESTORE-­CF clinical trial
• Cystic Fibrosis Foundation
• Translate Bio Bioanalytical team

Please see Poster #515 for additional detail!

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Thank you

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