Delivering CFTR mRNA: An Inhaled, Mutation-agnostic Approach to Treat CF

Richard Wooster, Ph.D.Chief Scientific Officer

Translate Bio, Lexington, MA

Presenter Disclosure

Richard Wooster, Ph.D.

The following relationships exists related to this presentation:

• Translate Bio, employee and shareholder

Outline

4 October 2020

• Overview of Cystic Fibrosis and the continuing unmet need

• Discovering mRNA therapeutics

• MRT5005: the first CFTR mRNA therapeutic being evaluated in individuals with

cystic fibrosis

• A Next-Generation CFTR mRNA

Scientific and Medical Advances have had a Significant Impact for Individuals with Cystic Fibrosis

5 October 2020

Sources: American Journal of Respiratory and Critical Care Medicine2018 U.S. CFF Patient Registry

47 years

Median Predicted Survival Age

6 months

Approx. Life Expectancy 29 years

Median Predicted Survival Age

By Genotype ~10% of CF Patients Are Not Amenable to CFTR Modulators

Sources: 2018 U.S. CFF Patient Registry; 2017 ECFS Patient Registry.6 October 2020

A Significant Number of CF Patients Gain Little to No Benefit from CFTR Modulators

Sources:2018 U.S. CFF Patient Registry; 2017 ECFS Patient Registry.1. N Engl J Med 2019; 381:1809-1819; Lancet. 2019 Nov 23;394(10212):1940-1948.

7 October 2020

8 October 2020

mRNA Therapeutics Have the Potential to Address the Unmet Need in Cystic Fibrosis

How is mRNA Therapy Different than Other Genetic Modalities?

9 October 2020

mRNA can be Designed and Synthesized for Therapeutic Applications

10 October 2020

Inhaled Lipid Nanoparticles Can Deliver mRNA to the Lungs

High ResolutionLow Resolution Medium Resolution

Saline control mRNA in LNP

• WT CD-1 mice administered

Firefly luciferase mRNA to the

lungs

• Radiance detection at 24 hours

• Blue = low expression, red = high

expression

Saline control mRNA in LNP

• TdTomato transgenic mice

• Silent Tomato reporter flanked by lox sites

• Cre recombinase mRNA administered by

nebulization

• Cryofluorescence Tomography at 48 hours

• Red = low expression, white = high

expression

mRNA in LNP

• WT mice

• mRNA for a therapeutic protein

administered to the lungs

• Protein detected by

immunohistochemistry

• Brown = protein expression

11 October 2020

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

Presented at NACFC 201912 October 2020

Marked Increases in ppFEV1 Observed in the Single Ascending Dose Study of MRT5005, Primarily at Mid-Dose

13 October 2020

In the 8-Day Post-Dosing Period:

• Patients in the 16 mg dose demonstrated:

– Mean maximum increase from baseline of 15.7%

– Individual maximal ppFEV1 increases of 11.1%, 13.6% and

22.2% • 2 of the 3 had a stable CFTR modulator treatment regimen

(Orkambi® or Symdeko®)

• the third had genotype non-amenable to CFTR modulator

treatments

• Increases in ppFEV1 were higher than expected based on

known variability of ppFEV1• Time course of ppFEV1 improvements potentially support a

CFTR-related mechanism

• Data suggest MRT5005 can enable production of functional

protein

Presented at NACFC 2019

MRT5005 Generally Well-Tolerated at Low- and Mid-Dose Levels in The Single Ascending Dose Study

14 October 2020Presented at NACFC 2019

• No SAEs at any dose

• Most common AEs – cough, headache

• Generally well-tolerated at low- and mid-dose

levels

• Primarily at high dose, patients experienced

transient, mild-moderate febrile reactions– Occurred ~4-10 hours post dosing

– Symptoms resolved within 24 hours

– All patients discharged from study center on Day 2 as

planned

Positive Interim Results: First-in-Human Phase 1/2 Clinical Trial of MRT5005 in Patients with CF

15 October 2020

• First mRNA therapeutic administered for a chronic disease and first to be administered via

inhalation

• Generally well-tolerated at low- and mid-dose levels; No serious adverse events reported at any

dose level

• Marked increases in ppFEV1 after single MRT5005 dose, primarily at mid-dose level

• Increases in ppFEV1 observed in patient with mutations not amenable to CFTR modulators;

increases also observed in patients on stable background of CFTR modulators

• The Multiple Ascending Dose part of this Phase 1/2 study is ongoing

Presented at NACFC 2019

A Next-Generation CFTR mRNA Medicine

16 October 2020

• Encouraging interim data from MRT5005

• Combining knowledge and advances to design a NextGen CFTR mRNA

o Learnings from MRT5005

o Advances in our platform

o Understanding of CFTR biology

• Target profile

o Match or increase the potential clinical benefit from MRT5005

o Increase tolerability

o Reduce administration time

Advanced mRNA Codon Optimization Boosts CFTR Activity

17 October 2020

Increasing the amount of protein produced from each

mRNA molecule has potential to:

• Increase efficacy

• Reduce dose

Multiple aspects of mRNA biology have been evaluated:

• Codon redundancy

• tRNA availability

• Ribosomal pausing

Encouraging results

• Increased protein expression per unit of mRNA

• Increased functional measurements

Rational Protein Engineering of CFTR to Increase Chloride Flow

See Poster 515 for further details

18 October 2020

• The opening of the CFTR channel is regulated by phosphorylation at multiple sites in the R domain

• Substituting serine(S) and threonine(T) amino acids in the R domain for phosphomimetic aspartic acids(D) could lower

the threshold for CFTR opening

• The forskolin EC50 for CFTR is proportional to the number of S/T to D substitutions

Novel Lipids for Pulmonary Delivery Achieve >50 Fold Increase in Target Protein Expression

19 October 2020

• Target lipid profile:

o Potency – high levels of protein

production

o Tolerability – no/minimal side effects

with clearance and metabolism

aligned to dosing schedule

• The screening cascade prioritized >100

novel lipids to evaluate in vivo

• Firefly luciferase mRNA was administered

by inhalation

• Expression was assessed by whole body

imaging

• Multiple novel lipids have >50x increase in

pulmonary protein expression

Next-Generation CFTR Protein is Expressed When Administered In Vivo

20 October 2020

Summary

21 October 2020

• There remains an unmet need for individuals with cystic fibrosis not amenable to

CFTR modulators or who gain no or little benefit from these medicines

• mRNA can be synthesized and packaged in LNPs for delivery to the lungs

• Positive interim results from the Phase 1/2 study of MRT5005 are encouraging

• We have advanced our mRNA platform and technology

• A Next-Generation CFTR mRNA and LNP incorporates learnings from MRT5005

with our current technology and a detailed investigation of CFTR biology

Acknowledgements

22 October 2020

• Patients and investigators who participated in the RESTORE-CF clinical trial

• Cystic Fibrosis Foundation

• Translate Bio team

Thank you