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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