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Transcript of Delivering CFTR mRNA - Translate Biotranslate.bio/wp-content/uploads/2020/10/TBIO-NACFC-2020...The...
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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
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Presenter Disclosure
Richard Wooster, Ph.D.
The following relationships exists related to this presentation:
• Translate Bio, employee and shareholder
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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
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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
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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
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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
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8 October 2020
mRNA Therapeutics Have the Potential to Address the Unmet Need in Cystic Fibrosis
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How is mRNA Therapy Different than Other Genetic Modalities?
9 October 2020
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mRNA can be Designed and Synthesized for Therapeutic Applications
10 October 2020
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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
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RESTORE-CF: MRT5005 Phase 1/2 Clinical Trial Design
Presented at NACFC 201912 October 2020
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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
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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
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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
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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
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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
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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
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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
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Next-Generation CFTR Protein is Expressed When Administered In Vivo
20 October 2020
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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
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Acknowledgements
22 October 2020
• Patients and investigators who participated in the RESTORE-CF clinical trial
• Cystic Fibrosis Foundation
• Translate Bio team
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Thank you