MLYS
Targeting Aldosterone in the
Treatment of Cardiorenal
Diseases
J a n u a r y 2 0 2 5
Mineralys:
Targeting Aldosterone
in the Treatment
of Hypertension, CKD,
OSA and Beyond
Lorundrostat is a selective aldosterone synthase inhibitor (ASI) targeting aldosterone
Obesity epidemic is driving abnormally elevated aldosterone contributing to hypertension, chronic kidney disease (CKD), obstructive sleep apnea (OSA) and heart failure
Lorundrostat is a highly selective ASI that reduces aldosterone ~70% with once-daily dosing
Proof-of-Concept trial demonstrated substantial overall BP reduction with once-daily dosing; enhanced response in obese subjects; well- tolerated with modest increase in potassium
Pivotal HTN program initiated in 2023 with first pivotal trial readout in March of 2025 and the second trial readout in mid first half 2025
Proof-of-Concept CKD and hypertension trial readout in 2Q 2025
Proof-of-Concept OSA and hypertension trial to be initiated in 1Q 2025
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Lorundrostat Potential Benefit Across Spectrum of CRMS
Targeting dysregulated aldosterone in overlapping CRMS conditions with high CV risk and large unmet need
CKD in the U.S.
u/rHTN &
HTN in the U.S.
Obesity
CKD / HTN
Endotype
Nephropathy
Obesity highly correlated to rHTN
Obesity link to dysregulated aldo
~20M u/rHTN patients
>25% in CV risk vs controlled HTN Kidney injury link to hyper-perfusion ~23M HTN + CKD patients
OSA in the U.S.
OSA /
Nighttime BP link to CV risk
Nocturnal
70-80% prevalence of rHTN in OSA
HTN
~24M Moderate-to-Severe OSA
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Mineralys Therapeutics, Inc. ©2023. All Rights Reserved.
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Abnormally Elevated Aldosterone Impacts Multiple Biological Pathways and Is a Key Driver in Multiple Cardiorenal Diseases
Genomic Effects
(mineralocorticoid receptor)
Na+ and water retention drives blood volume and blood pressure
ALDOSTERONE
Non-Genomic Effects
(GPR30 receptor)
Drives endothelial and renal tubular oxidative stress, microvascular fibrosis, inflammation and HF
Aldosterone-driven Cardiorenal Disorders
T-cell
DC
M⍬
Vascular and systemic
Inflammation 4
1. Sim JJ, Bhandari SK, Shi J, et al. Am J Hypertens. 2012;25(3):379-388. 2. Hundemer GL, Curhan GC, Yozamp N, Wang M, Vaidya A. Hypertension. 2018;72(3):658-666.3. Monticone S, D'Ascenzo F, Moretti C, et al. Lancet Diabetes Endocrinol. 2018;6(1):41-50. 4) Ferreira N, Tostes RC, Paradis P, Shiffrin E. Am J Hypertens. 2021, 34(1):15-27. 5.
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Mineralys Therapeutics, Inc. ©2023. All Rights Reserved.
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Prevalence of Elevated Aldosterone Linked to Rise in Obesity
As percent of population with obesity has risen in
the US, so has hyperaldosteronism
50%50%
Obesity in the US1
45%
40%
of Population
40%
35%
Hyperaldosteronism
30%30%
Percentage
25%
20%
20%
15%
Age >65 Years
10%
10%
5%
0%
0%
1950 1960 1970 1980 1990 2000 2010 2020 2030
BMI is significantly correlated with
aldosterone levels2
1. https://usafacts.org/articles/obesity-rate-nearly-triples-united-states-over-last-50-years. 2. Dudenbostel T, Ghazi L, Liu M, Li P, Oparil S, Calhoun DA. Hypertension. 2016;68(4):995-1003.
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In Obesity, via Visceral Adipocytes, Leads to Elevated Aldosterone Levels
Lorundrostat targets both the RAAS-dependent and -independent axes, providing a more complete solution to abnormally elevated aldosterone
RAAS-dependent Axis
RAAS-independent Axis
Blocks RAAS-dependent
Lorundrostat
ACEI
ARBs
Renin
Blocks
RAAS-independent
+
Lorundrostat
Adipocytes
- Angiotensin
Aldosterone
++
Adipokines
Leptin, other
+
+
Aldosterone
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Lorundrostat Is a Highly Selective, Best-in-Class ASI
Aldosterone Synthase Inhibitor Comparison Table
Lorundrostat
LCI699
Baxdrostat
BI690517
(Mineralys)
(Novartis)1
(Astra Zeneca)2, 3
(Boehringer Ingelheim)4
Selectivity
374X
3.6X
100X
250X
Half-life
10-12 hours
~4 hours
25-31 hours
noted to be "short"
Reduction in PAC
65-70%
65-70%
65-70%
66%
Adrenal insufficiency
no
yes
no
yes
or decrease in cortisol
Metabolism
Hepatic
Hepatic
Renal
n/a
Best-in-class selectivity
Aldosterone inhibition with reduced risk of cortisol inhibition or off-target AEs
Optimal half-life
Aldosterone inhibition with rapid reversibility- essential for patients who may not tolerate a significant BP drop or are at risk for hyperkalemia, including patients with CKD
1. Schumacher CD, Steele RE, Brunner HR. J Hypertens. 2013;31(10):2085-2093. 2. Bogman K, Schwab D, Delporte ML, et al. Hypertension. 2017;69(1):189-196. 3. CinCor S1 filing 2020, 4. BI presentation at ASN meeting.
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Phase 2 Proof -of-Concept Study Design
Evaluating the safety, efficacy and dose-response of lorundrostat in uncontrolled and resistant hypertension
2-4 weeks
Pre-Screening
Part-1
PRA <1.0
N=180
Inclusion criteria:
BP >130/80 on >2 AHTs
eGFR >60
Part-2
PRA >1.0
N=36
2 weeks
Screening
Single-Blind Run-In
Background
Regimen of 2+
Medications
8 weeks
Double-Blind Treatment
Placebo QD N=30
lorundrostat 12.5 mg QD N=30
lorundrostat 50 mg QD N=30
lorundrostat 100 mg QD N=30
lorundrostat 12.5 mg BID N=30
lorundrostat 25 mg BID N=30
lorundrostat 100 mg QD N=30
& Placebo QD N=6
2-4 weeks
Washout
Primary efficacy endpoint:
Change in AOBP sysBP at 8 weeks compared to placebo
Key secondary endpoint:
ABPM measurement of average 24h and overnight BP
Randomization
Primary Efficacy and Safety
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Baseline Demographics and Disposition
90% of the randomized patients completed Part 1 of the Target-HTN trial
Category
Systolic BP (mm Hg)
Diastolic BP (mm Hg)
Body Mass Index (kg/m2)
Mean Baseline eGFR
Race % Black or African American
Sex % Male
Ethnicity % Hispanic or Latino
Diabetes
Heart Failure
Previous Myocardial Infarction
Number of Background Antihypertensive Medications
Use of Thiazide or Thiazide-like Diuretic
Use of ACE or ARB
Mean ± SEM of Baseline
2 medications = 52.8% / 3 or more medications = 47.2%
56.4%
77.9%
Confidential Property of Mineralys Therapeutics, Inc.
Mineralys Therapeutics, Inc. ©2023. All Rights Reserved.
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Disclaimer
Mineralys Therapeutics Inc. published this content on January 08, 2025, and is solely responsible for the information contained herein. Distributed by Public, unedited and unaltered, on January 08, 2025 at 19:06:09.138.