VICORE PHARMA AB Untangling the Dualistic Components of the RAS in PF the Yin and Yang Dr Rohit Batta Chief Medical Officer Vicore Pharma
Vicore – at a glance FOCUS Patients with fibrotic lung disease GUIDING Unmet medical needs – every day matters PRINCIPLE PIPELINE Two clinical stage differentiated and complementary assets INDICATIONS 1) IPF 2) other fibrotic lung diseases evaluated 3) COVID-19 (VP01) Address Fibrosis, vasculopathy & Inflammation (VP01); DIFFERENTIATION improving cough and QoL (VP02) TEAM Team of patient centric drug developers SHARE Listed on Nasdaq Stockholm Main Market
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 Robert Adolph Armand Tigerstedt (1) 1. Marks et al ., Hypertension, Vol 1, No 4, Jul-Aug 1979; 2. Sumners et al 10.1111/apha.13280
Discovery of the Protective Arm In the 1990s, there were four unexpected findings 1 : 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, organ 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 Angiotensin II has 2 receptors with opposite actions In certain disease states like IPF, ANG II binding to AT1R dominates ANG II AT1R AT2R Vasoconstriction Vasodilation Inflammation Anti-inflammation Fibrosis Anti-fibrosis 1. Sumners et al 10.1111/apha.13280
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 Good safety profile and well tolerated • at the clinical study dose 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
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 Reduction in collagen increase (D hydroxyproline) Reduction of increased CTGF expression Pirfenidone Pamrevlumab VP01 VP01 Roche anti-CTGF, FibroGen 0.03mg/kg 10mg/kg 30mg/kg 100mg/kg 3mg/kg 10mg/kg 30mg/kg 0.03mg/kg 0% 0% -13% -20% -20% -27% -27% -38% -40% -40% -58% -64% -60% -60% -80% -80% -91% -100% -100% -100% VP01 nearly completely inhibits CTGF expression and normalises collagen deposition induced by bleomycin Company derived analyses, not head to head studies Oku 2008; Wang 2011; Rathinasabapathy 2018
Monocrotaline model Representative images of lung fibrosis Relative TGF- β Right Ventricular Relative AT2 % Interstitial systolic pressure Receptor Expression Lung Fibrosis Gene Expression 20 100 4 4 80 15 3 3 60 10 2 2 40 5 1 1 20 0 0 0 0 VP01 reverses cardiopulmonary fibrosis and reduces PH
Sugen Hypoxic PH model Sakao et al., Respiration 2011;81:253–261; DOI: 10.1159/000322011 Hyperproliferation of EC characterizes the plexiform lesions of human PAH
Sugen Hypoxic PH model RV hypertrophy (RV/LV+S, Fulton's Index) Systolic PAP (mmHg) 80 0,8 70 0,7 60 0,6 50 0,5 40 0,4 0,3 30 0,2 20 0,1 10 0 0 Control SuHx + SuHx + VP01 SuHx + VP01 Control SuHx + SuHx + SuHx + VP01 (Nx) Vehicle 2mg/Kg 20mg/Kg (Nx) Vehicle VP01 20mg/Kg 2mg/Kg • VP01 did not affect systemic BP Target - Right medicine at the right time for the right ventricle
VP01 AIR study ATS 2020 Status • Regulatory approval in multiple countries • Planned first subject screened Q3 2020 (subject to COVID-19 pandemic)
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 infections 1 • Later, analysis of COVID-19 patients after hospital discharge suggested that many recovered patients develop fibrotic abnormalities 2 Looking back: • Similarities in terms of most severely-affected patients (e.g. elderly males) and dysregulated repair 3 • May start with lung injury and/or have vasculopathy as a key feature 3 • It is hoped that, by stimulating AT2R directly, VP01 will have therapeutic effects in COVID-19 We hope that our studies will show whether IPF & C-19 are really ‘apples and oranges’, or whether they turn out to be two varieties of essentially the same fruit 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
Conclusion – Yin & Yang • 120 years of RAS cosmology IPF • 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 COVID-19 PF-ILD harmony (Yin & Yang). Other
A Rare Disease Company with a Focus on Patients with Fibrotic Lung Disease
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