confidential 2 Ph2 clinical program with IMB101 in multiple indications with data read out in 202122 IMB101 is an NCE with allowed claims and priority date in 2017 IMB101 is well differentiated in both common and rare CV disease with large market potential and potential to be first in class ID: 931194
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Slide1
Corporate deck
May 2021
Slide2Imbria value proposition highlights
confidential
2
Ph2 clinical program with IMB-101 in multiple indications with data read out in 2021/22
IMB-101 is an NCE with allowed claims and priority date in 2017
IMB-101 is well differentiated in both common and rare CV disease with large market potential and potential to be first in class in the USA
In Ph1 IMB-101 was safe and well tolerated. Simple dosing with no need for dose titration
IMB-203, a preclinical candidate, has potential in rare diseases of the mitochondria and may be IND ready in 2022
Financed through 2022
Seeking partners for IMB-101 and IMB-203
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2
3
6
4
5
Slide3Experienced team with broad expertise in biotech and CV drug development
confidential
3
Anne
Prener
, MD, PhD
CHIEF EXECUTIVE OFFICER
Paul Chamberlin, MD
HEAD OF CLINICAL DEVELOPMENT
Jai Patel, MRCP(UK)
CHIEF MEDICAL OFFICER
Karen Jauregui
HEAD OF REGULATORY AFFAIRS AND QUALITY
Arash Yavari , MRCP(UK), DPhil
SENIOR DRUG DEVELOPMENT PHYSICIAN
Matt Harding
DIRECTOR, NON-CLINICAL DEVELOPMENT
TEAM
BOARD
Michael Frenneaux, FACC, FESC, FRCP,
FMedSci
CHIEF SCIENTIFIC OFFICER
Houman
Ashrafian
, MD, PhD
DIRECTOR
Andrew Levin, MD, PhD
CHAIR, DIRECTOR
Jim
Januzzi
, MD
DIRECTOR
Slide4Mission: Improving lives of patients with cardiovascular and mitochondrial diseases
Confidential
4
Cardiovascular disease
- Common as well as rare
IMB-101
pFOXi
Rare diseases of the mitochondria
-
Anaplerotic therapyIMB-203
SuccinateprodrugOur focus
Therapeutic areas
Candidate MoA
PhaseIndications
Phase 2Non-obstructive HCMAnginaDiabetic cardiomyopathy
IND-enabling
Complex 1 disease
PA
MMA
pFOXi
- partial fatty acid oxidation inhibitor, HCM – Hypertrophic cardiomyopathy, Complex 1 disease includes Leigh syndrome, MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes) and LHON (
Leber’s
Hereditary Optic Neuropathy), PA - Propionic acidemia, MMA - methylmalonic acidemia
Improve mitochondrial energetics
Modulating mitochondrial metabolism to increase the efficiency of ATP generation
Slide5Pipeline includes IMB-101 and IMB-203, both products have potential in multiple indications
confidential
5
Research/Nonclinical
Phase 1
Phase 2
Diabetic
cardiomyopathy
Stable angina
Non-obstructive
HCM
HFpEF
IMB-203
Target engagement study, results 2021/22
Results 2022
Results 2022
Potential to be IND ready 2022
Ph2 start pending results of Target engagement study
Rare diseases of
the mitochondria
Indications
Program
IMB-101
Slide6Energetic impairment is a hallmark of major forms of heart disease
confidential
6
The heart cycles through ~30kg of ATP/day obtained by converting chemical energy from metabolic substrates (fatty acids, glucose) to fuel contraction, active relaxation & maintain ionic homeostasis
Diabetes is both a risk factor for IHD and associated with abnormal cardiac metabolism (excessive reliance on fatty acid oxidation) driving energy deficiency, predisposing the diabetic heart to cardiac injury and HF
Ischemic heart disease (IHD)
Heart failure (HF)
Hypertrophic cardiomyopathy (HCM)
HCM most commonly arises from inherited mutations in
sarcomeric
proteins which increase the energy requirements of the myosin ATPase leading to energetic deficit, driving both hypertrophy and the impaired cardiac response to exercise
Myocardial ischemia induces dramatic changes in cardiac metabolism impairing energy production, leading to lactate and proton accumulation, reduced cardiac efficiency and dysfunction
HF is associated with profound myocardial metabolic remodeling and energy deficiency
due to defects at several stages in the energy generation pathway, resulting in impaired cardiac function
Slide7pFOX
inhibition increases efficiency of ATP production by returning mitochondrial oxidation toward homeostasis
confidential
7
Source: Lopaschuk et al.
Myocardial Fatty Acid Metabolism in Health and Disease
. Physiol. Rev 90: 207-258, 2010
pFOX (3-KAT) INHIBITION
↑ Glucose oxidation & ↓ FFA oxidation
↓ Lactate, ↓ H+ and ↓ Reactive Oxygen Species
↑ ATP production per molecule of O
2
ISCHEMIC HEART
↓ Overall aerobic ATP generation
Glycolysis ↑ by 25% but ↓ glucose oxidation↑ Lactic acid and ↑ Reactive Oxygen Species
CELL MEMBRANE
Fatty Acid
Glucose
Glycolytic Pathway
Pyruvate
PDH
MITOCHONDRIA
Acyl CoA
β-oxidation
Acetyl CoA
TCA
Cycle
ADP+Pi
ATP
Lactate
CELL MEMBRANE
Fatty Acid
Glucose
Glycolytic Pathway
Lactate
Pyruvate
PDH
MITOCHONDRIA
Acyl CoA
β-oxidation
Acetyl CoA
TCA
Cycle
ADP+Pi
ATP
3-KAT Inhibition
Slide8IMB-101 is a novel cardiovascular drug candidate designed to complement existing cardiovascular therapeutic approaches
confidential
↑ ATP Production per O
2
Molecule
and ↓ Lactate Production
↑ Oxygen
Supply
↓ Oxygen Demand
pFOX inhibition
↑ Efficiency of Cardiac Energy Generation
↓ Heart Rate
↓ Vascular Resistance
Revascularization
Principal anti-ischemic
a
pproach
Mechanism
Therapeutic classes
8
-
blockers
Nitrates
Calcium Channel Blockers
The extent to which blood pressure or heart rate can be lowered is by nature limited and associated with adverse effects
pFOX
inhibition may complement other approaches without impacting hemodynamics
Boden et al.
Optimal Medical Therapy with or without PCI for Stable Coronary Disease
(“COURAGE Trial”).
NEJM 2007; 356:1503-1516
Neubauer S .
The Failing Heart — An Engine Out of Fuel.
NEJM 2007; 356:1140-1151
Slide9confidential
IMB-102 is an active metabolite of IMB-101 and is partly converted to trimetazidine
confidential
9
Potentiates IMB-102 and TMZ in animal models
n
iacin
Novel structural analog of TMZ
Improved results over TMZ in animal models
Reduced affinity for the dopamine receptor
as compared to TMZ
IMB-102
Approved in the EU for angina since the 1970s
45 million patient-years of experience
Strong clinical data in angina and HFrEF
t
rimetazidine
(TMZ)
NCE, exclusivity to 2037
Pro-drug of IMB-102
and niacin
Well tolerated in Phase 1 clinical trials
IMB-101
Slide10Imbria strategy in cardiovascular diseases offers opportunities for value creation in both common cardiovascular diseases and rare disease areas
confidential
10
Common CV diseases
Value proposition IMB-101
Rare CV diseases
Supported by three clinical studies with initial read-out 2021
IMPROVE-
DiCE
IMPROVE-ISCHEMIA
IMPROVE-HCM
DiCE
:
Di
abetic
c
ardiac
e
nergetics. Target engagement study in T2DM to inform of pharmacodynamic response to IMB-101, dosing, duration of action and provide proof-of mechanism in T2DM with insights into potential use in
HFpEF
Phase 2 study in chronic stable angina will provide robust validation of drug mechanism using state-of-the-art multi-modality imaging. The findings will also inform the potential for IMB-101 in conditions where ischemia is an important contributory factor e.g. HFrEF
Non-obstructive HCM is an orphan disease with high unmet need and limited treatment options
Slide11IMB-203: Substrate replacement of the citric acid cycle via oral route
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IMB-203 is a succinate prodrug designed to deliver high doses of succinate
Succinate is not inherently bioavailable, and presently, there are no approved options to deliver
oral
succinate
Lack of succinate is a key driver behind a variety of inborn errors of metabolism
Anaplerotic
replacement bypasses the need for internally generated succinate via the affected metabolic pathways
Nonclinical studies completed to support clinical dosing for up to 28 days
Slide12Mitochondrial disorders are potential indications for IMB-203 and include a range of rare diseases with high unmet needs
confidential
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Source
: Unless specified otherwise, NORD.
Complex I disorders
Leigh syndrome
Prevalence: 1 / 36,000-40,000
MELAS
Incidence: 1/4,000 births
LHON
Prevalence of vision loss due to LHON: 1/50,000
Propionic acidemia (PA)
Methylmalonic acidemia (MMA)
Prevalence: 1/25,000
Prevalence: 1/61,000
Long-chain fatty acid oxidation disorders
Multiple acyl-CoA dehydrogenation deficiency
Prevalence: 1/100,000
Prevalence: 1/17,000 (US, source:
Ultragenix
)
MELAS: Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes, LHON: Leber’s Hereditary Optic Neuropathy