VICORE PHARMA AB Untangling the Dualistic Components of the RAS in - - PowerPoint PPT Presentation

VICORE PHARMA AB

Untangling the Dualistic Components

• f the RAS in PF the Yin and Yang

Dr Rohit Batta Chief Medical Officer Vicore Pharma

Vicore – at a glance

Patients with fibrotic lung disease

FOCUS

Unmet medical needs – every day matters

GUIDING PRINCIPLE

Two clinical stage differentiated and complementary assets

PIPELINE

1) IPF 2) other fibrotic lung diseases evaluated 3) COVID-19 (VP01)

INDICATIONS

Address Fibrosis, vasculopathy & Inflammation (VP01); improving cough and QoL (VP02)

DIFFERENTIATION

Team of patient centric drug developers

TEAM

Listed on Nasdaq Stockholm Main Market

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Vicore Team

Rare Diseases Day 2019 (Stockholm)

It’s not all about hand painting…

• Patient centric
• Experienced, cognitively diverse, drug developers

Unearthing of the Renin-Angiotensin System

• Renin was discovered at the Karolinska in 1898 by

Robert Adolph Armand Tigerstedt and his student Per Bergman

• Hypothesis: A blood-pressure raising substance is formed in the kidneys

and passed into the blood

• Finding: “Substance sui generis”
• Association of the RAS with the cardiovascular system that set the tone

for RAS research for almost 100 years to follow(2)

• During this time, intricate “machinery” relating to AT1R was discovered
• Birth of many blockbuster drugs that prevented countless lives
• 1. Marks et al ., Hypertension, Vol 1, No 4, Jul-Aug 1979; 2. Sumners et al 10.1111/apha.13280

Robert Adolph Armand Tigerstedt(1)

Discovery of the Protective Arm

In the 1990s, there were four unexpected findings1:

• 1. The identification of different subtypes of angiotensin receptors like AT2R
• 2. AT1R and AT2R mediate opposing effects
• 3. Ang II (through its receptor subtypes) has a direct effects on inflammation, fibrosis,
• rgan remodelling, cell proliferation, cell differentiation, and apoptosis
• 4. Identification of angiotensin fragments such as Ang 1-7 having their own receptors

and counteracting AT1R mediated actions of Ang II

• 1. Sumners et al 10.1111/apha.13280

Angiotensin II has 2 receptors with opposite actions ANG II AT1R

Vasoconstriction Inflammation Fibrosis Vasodilation Anti-inflammation Anti-fibrosis

AT2R In certain disease states like IPF, ANG II binding to AT1R dominates

Classical & Protective Arms - Yin and Yang

VP01 (AT2R agonist) product development

Orphan drug designation Non-clinical safety

• 3-month toxicology in rat, dog, non-human primate

CMC

• Developed as an immediate- release dry capsule

Phase I

• 3 phase I studies up to 200 mg bid
• No serious adverse events, no G-I intolerability
• Thorough cardiovascular monitoring
• Sufficient exposure for AT2R activation

Phase II

• Mechanistic study in SSc ongoing
• Proof of concept in IPF - CTA’s approved by multiple

regulatory agencies and due to start

• Proof of concept ongoing in COVID-19 patients

Good safety profile and well tolerated at the clinical study dose

Idiopathic Pulmonary Fibrosis

250,000 patients in the US and EU

• Male predominance

Progressive disease

• 3-5 years life expectancy
• Loss of lung function, severe cough
• Pulmonary hypertension ranges widely
• 32-85% of pts

Two drugs approved

• Reduce functional loss
• GI side effects

Presence of PH in IPF Correlates with mortality

AT2R in lung fibrosis

• Described as a 7TM receptor; tissue-specific signaling mechanisms
• Upregulated and active during fetal development and then only in processes of scarring and regeneration
• Upregulated in IPF both in septal areas and vessels
• Stimulation of the receptor results in prevention or even reversal of fibrosis as demonstrated

in multiple pre-clinical disease models

Bleomycin model

VP01 nearly completely inhibits CTGF expression and normalises collagen deposition induced by bleomycin

• 27%
• 27%
• 58%
• 38%
• 100%
• 64%
• 13%
• 100%
• 80%
• 60%
• 40%
• 20%

0%

Reduction in collagen increase (D hydroxyproline)

Pirfenidone

Roche

10mg/kg 30mg/kg 100mg/kg 3mg/kg 10mg/kg 30mg/kg 0.03mg/kg

Pamrevlumab

anti-CTGF, FibroGen

VP01

• 91%
• 100%
• 80%
• 60%
• 40%
• 20%

0%

Reduction of increased CTGF expression

0.03mg/kg VP01

Oku 2008; Wang 2011; Rathinasabapathy 2018

Company derived analyses, not head to head studies

Monocrotaline model

Representative images of lung fibrosis

VP01 reverses cardiopulmonary fibrosis and reduces PH

20 40 60 80 100

Right Ventricular systolic pressure

1 2 3 4

Relative AT2 Receptor Expression

1 2 3 4

Relative TGF-β Gene Expression

5 10 15 20

% Interstitial Lung Fibrosis

Sugen Hypoxic PH model

Hyperproliferation of EC characterizes the plexiform lesions of human PAH

Sakao et al., Respiration 2011;81:253–261; DOI: 10.1159/000322011

Sugen Hypoxic PH model

Target - Right medicine at the right time for the right ventricle

10 20 30 40 50 60 70 80 Control (Nx) SuHx + Vehicle SuHx + VP01 SuHx + VP01 20mg/Kg

Systolic PAP (mmHg)

0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 Control (Nx) SuHx + Vehicle SuHx + VP01 2mg/Kg SuHx + VP01 20mg/Kg RV hypertrophy (RV/LV+S, Fulton's Index)

• VP01 did not affect systemic BP

2mg/Kg

VP01 AIR study

Status

• Regulatory approval

in multiple countries

• Planned first subject

screened Q3 2020 (subject to COVID-19 pandemic)

ATS 2020

VP01 COVID-19 Study

Anticipated top line results Q4 2020

COVID-19 versus IPF

• No immediately-obvious pathogenic link between virally-induced severe acute respiratory disorder and

idiopathic chronic lung disease

• Most distinctive comorbidities of patients with COVID-19 diabetes and hypertension, often treated with

ACE2-stimulating drugs (ACE inhibitors and/or ARBs) - expected to increase the risk of developing severe/fatal SARS infections1

• Later, analysis of COVID-19 patients after hospital discharge suggested that many recovered patients develop

fibrotic abnormalities2 Looking back:​

• Similarities in terms of most severely-affected patients (e.g. elderly males) and dysregulated repair3
• May start with lung injury and/or have vasculopathy as a key feature3
• It is hoped that, by stimulating AT2R directly, VP01 will have therapeutic effects in COVID-19
• 1. Fang et al, Lancet Respir. Med. (2020), https://doi:10.1016/S2213-2600(20)30116-8); 2. Vasarmidi et al 2020 DOI: 10.3892/etm.2020.8980; 3. Gisli et al. 2020 Orchid ID 0000-0002-7929-2119

We hope that our studies will show whether IPF & C-19 are really ‘apples and oranges’,

• r whether they turn out to be two varieties of essentially the same fruit

Conclusion – Yin & Yang

• 120 years of RAS cosmology
• Demystified dichotomous AT2R Protective Arm
• Diseases such as IPF and COVID-19 upset this

classical/protective equilibrium and create crises

• Three Ph II studies in 2020 - IPF, COVID-19 and

mechanistic RP-SSc study will show whether VP01 has anti-fibrotic, anti-inflammatory, vasodilatory & vascular remodeling effects and can create harmony (Yin & Yang).

COVID-19 IPF PF-ILD Other

A Rare Disease Company with a Focus

• n Patients with Fibrotic Lung Disease