MLS-101-301: A Randomized, Double-Blind, Placebo Controlled, Parallel Arm, Multicenter Phase 3 Study to Evaluate the Efficacy and Safety of Lorundrostat in Subjects with Uncontrolled and Resistant Hypertension

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Mineralys Therapeutics Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

17 Apr 2024 → 25 Jan 2025

Decision date (initial)

2024-04-15

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Mineralys Therapeutics, Inc.

External identifiers

EU CT number

2023-506425-12-00

ClinicalTrials.gov

NCT05968430

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Therapy, Safety, Efficacy

To assess the effect of Lorundrostat when added to prescribed AHT on SBP in subjects with hypertension

Secondary objectives 5

1. • To assess the ability of lorundrostat when added to prescribed AHT therapy to achieve SBP control in subjects with hypertension
2. • To assess the SBP lowering effect of lorundrostat in subjects with uncontrolled hypertension on 2 prescribed AHT medications
3. • To assess the SBP lowering effect of lorundrostat in subjects with resistant resistant uncontrolled hypertension on 3 or more prescribed AHT medications (resistant hypertension)
4. • To assess the effect of obesity on the SBP lowering effect of lorundrostat in subjects with hypertension
5. • To assess the SBP effect of lorundrostat dose escalation from 50 mg QD to 100 mg QD in subjects with hypertension who do not achieve BP control on a lorundrostat dose of 50 mg QD

Conditions and MedDRA coding

Uncontrolled and Resistant Hypertension

Study design 3 periods

Regulatory references

Scientific advice from competent authorities

Medicines Evaluation Board, Swedish Medical Products Agency

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. 1. Written informed consent, obtained before any study-related assessment is performed
2. 2. At least 18 years of age at the time of signing the informed consent form (ICF) and capable of providing informed consent
3. 3. At Screening and Randomization: AOBP SBP of ≥135 and ≤180 mmHg plus AOBP DBP of ≥65 and ≤110 mmHg, or AOBP DBP of ≥90 and ≤110 mmHg
4. 4. Taking between 2 and 5 AHT medications, inclusive, at a stable for at least four weeks dose for 1 month prior to the Screening Visit, of which one must be a thiazide or thiazide-like diuretic. If a subject is not on a thiazide or thiazide like diuretic at the Screening visit, the thiazide or thiazide-like diuretic medication may be initiated prior to, or at the start of the Run-in period and must remain stable until the Randomization visit, unless the medication is not tolerated by the subject or medically contraindicated. Inclusion of a thiazide or thiazide-like diuretic in the prescribed AHT regimen may be waived in these circumstances following discussion with the Medical Monitor. NOTE: MRAs and epithelial sodium channel (ENaC) inhibitors are not allowed. NOTE: each individual AHT agent in a combination pill counts as one AHT medication.
5. 5. History of hypertension lasting at least 6 months prior to Screening
6. 6. Serum cortisol (morning measurement, blood draw as close to 8 a.m. as possible but before 10 a.m.) between 3 and 22 µg/dL, inclusive, at Screening
7. 7. Body mass index (BMI) of ≥18 kg/m2 at Screening
8. 8. Arm circumference <52 centimeters at Screening
9. 9. Fertile male subjects and female subjects of childbearing potential, and their partners, must agree to use either highly effective or acceptable methods of contraception from the Screening Visit to 28 days after the last dose of study drug
10. 10. Willing and able to comply with the study instructions and attend all scheduled study visits

Exclusion criteria 23

1. 1. Women who are pregnant, plan to become pregnant, or are breastfeeding
2. 2. Subjects with known hypersensitivity to lorundrostat or any of the excipients
3. 3. Treatment, or anticipated treatment, with any prohibited medications within the timeframe described in this protocol
4. 4. Participation in a study involving any investigational device or small-molecule drug within 4 weeks or 6 months for biologic (antibody) drugs prior to the Screening Visit
5. 5. eGFR <45 mL/min/1.73m2 at Screening, calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula
6. 6. Serum potassium >5.0 mmol/L at Screening or >4.8 mmol/L at Randomization
7. 7. Serum sodium <135 mmol/L (corrected for hyperglycemia) at Screening. Rescreening of subjects with an exclusionary serum sodium requires 2 consecutive measurements at least one week apart of >135 mmol/L. A decrease in dose of a prescribed AHT diuretic prior to rescreening is allowed if, at the discretion of the Investigator, such adjustment would be safe and tolerable
8. 8. History of clinically significant hyponatremia (requiring hospitalization, treatment, or associated with a sodium <130 mmol/L [corrected for glucose using the Katz formula]) or chronic and/or recurrent mild hyponatremia (sodium <135 mmol/L [corrected for glucose using the Katz formula]) within 1 year prior to Screening
9. 9. Hospitalization for the treatment of urgent or emergent hypertension in subjects treated with at least 2 AHT medications within 1 year prior to Screening
10. 10. History of adrenal insufficiency or an abnormal ACTH stimulation test within 1 year prior to Screening.
11. 11. History of white coat hypertension
12. 12. Current, known or presumed orthostatic hypotension
13. 13. Current, known or presumed autonomic dysfunction (e.g., neurally mediated [reflex] syncope, postural tachycardia syndrome)
14. 14. Current night-shift worker, or anticipated to become a night-shift worker, defined as >14 days per month where work hours extend past midnight
15. 15. Previously proven secondary cause of hypertension with the exception of documented sleep apnea.
16. 16. History of heart failure, myocardial infarction, stroke, or transient ischemic attack within 6 months prior to the Screening Visit. Heart failure of New York Heart Association (NYHA) Class II or more requires approval of the Medical Monitor
17. 17. Diabetes mellitus with a glycosylated hemoglobin (HbA1C) >9% (>74.9 mmol/mol) at Screening
18. 18. Diabetes mellitus with >1 severe hypoglycemic event or severe diabetic ketoacidosis event (events requiring external help) in the 12 months prior to Screening, or with a history of impaired hypoglycemia awareness at Screening
19. 19. Planned major surgery requiring hospitalization during the study period, or performed within 4 weeks prior to the Screening Visit
20. 20. History of malignant neoplasms within the past 5 years prior to Screening, except known basal or squamous cell skin cancer, or any previously treated carcinoma in-situ
21. 21. Treatment with MRAs and/or ENaC inhibitors within 1 month of the Screening Visit
22. 22. Known or suspected abuse of illicit drugs or alcohol within 1 year prior to Screening
23. 23. In the opinion of the Investigator, any other condition that will preclude participation in the study

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change from baseline in automated office BP (AOBP) SBP at Week 6 in subjects randomized to lorundrostat 50 mg QD compared to subjects randomized to placebo

Secondary endpoints 6

1. Proportion of subjects with AOBP SBP <130 mmHg at Week 6 in subjects randomized to lorundrostat 50 mg QD compared to subjects randomized to placebo
2. Change from baseline in AOBP SBP at Week 12 in subjects randomized to lorundrostat 50 mg QC with escalation to lorundrostat 100 mg QD compared to subjects randomized to placebo
3. Change from baseline in AOBP SBP at Week 6 in subjects with uncontrolled hypertension on 2 prescribed AHT medications randomized to lorundrostat 50 mg QD compared to subjects with uncontrolled hypertension on 2 prescribed AHT medications randomized to placebo
4. Change from baseline in AOBP SBP at Week 6 in subjects with uncontrolled hypertension on 3 or more prescribed AHT medications (resistant hypertension) randomized to lorundrostat 50 mg QD compared to subjects with uncontrolled hypertension on 3 or more prescribed AHT medications (resistant hypertension) randomized to placebo
5. Change from baseline in AOBP SBP at Week 6 by obesity status in in subjects randomized to lorundrostat 50 mg QD compared to subjects randomized to placebo
6. Change from baseline in AOBP SBP at Week 12 in subjects who were escalated to lorundrostat 100 mg QD at Week 6 (within-subjects analysis)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 1

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Mineralys Therapeutics Inc.

Sponsor organisation

Mineralys Therapeutics Inc.

Address

150 N Chester Road, Suite F200 Suite F200

City

Radnor

Postcode

19087-5252

Country

United States

Scientific contact point

Organisation

Mineralys Therapeutics Inc.

Contact name

David Rodman

Public contact point

Organisation

Mineralys Therapeutics Inc.

Contact name

Clinical Operations

Third parties 12

Locations

8 EU/EEA countries · 73 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 179 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

9 submissions — initial application plus substantial / non-substantial modifications