JTT-861 for Heart Failure

(POWER-HF Trial)

Recruiting at 64 trial locations

Overseen By Takanori Nemoto, M.S.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Akros Pharma Inc.

Must be taking: RAAS inhibitors, β-blockers

Disqualifiers: Recent MI, Unstable angina, Renal insufficiency, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

300 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will evaluate the efficacy, safety, tolerability and pharmacokinetics of JTT-861 administered once daily for 12 weeks in subjects with heart failure with reduced ejection fraction (HFrEF) who are on a stable, guideline-directed medical therapy for heart failure.

Will I have to stop taking my current medications?

The trial requires participants to be on stable, guideline-directed therapy for heart failure, so you will need to continue your current heart failure medications.

What evidence supports the effectiveness of the drug JTT-861 for heart failure?

Research on similar drugs, like bosentan, which block endothelin receptors, shows they can improve heart function in heart failure patients by reducing blood vessel constriction and improving blood flow. However, more studies are needed to confirm these benefits for JTT-861 specifically. ^{1 2 3 4 5}

What safety data exists for JTT-861 in humans?

JAK inhibitors, a class of drugs that includes JTT-861, have been associated with certain safety concerns such as an increased risk of viral infections like herpes zoster (shingles) and deep vein thrombosis (blood clots in veins). While these drugs are effective for treating immune-related conditions, monitoring for these side effects is important. ^{6 7 8 9 10}

How does the drug JTT-861 differ from other heart failure treatments?

JTT-861 is unique because it targets endothelin-1 (ET-1), a peptide that causes blood vessels to constrict, by blocking its receptors, which may help improve heart function in heart failure patients. This approach is different from many standard heart failure treatments that do not specifically target the endothelin system. ^{1 5 11 12 13}

Eligibility Criteria

This trial is for people who have had heart failure symptoms for at least 90 days, are in NYHA class II or III, and have been on stable heart failure medication as per guidelines. They should also have a left ventricular ejection fraction of 35% or less and certain levels of NT-pro-BNP. People with recent heart attacks, unstable angina, recent or planned heart surgeries, severe kidney issues, or other specific cardiovascular conditions cannot participate.

Inclusion Criteria

My heart condition limits my physical activity but I can still perform light tasks.

I have been on a stable heart failure treatment for over 4 weeks, following major heart association guidelines.

Your heart's pumping ability, measured as LVEF, is less than or equal to 35%.

Exclusion Criteria

I had a heart attack or unstable chest pain in the last 90 days.

I have had heart surgery or a procedure to improve blood flow to the heart within the last 3 months.

I am currently receiving extra treatment for worsening heart failure.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive JTT-861 or placebo once daily for 12 weeks

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• JTT-861

Trial Overview The study tests JTT-861 capsules against placebo capsules over a period of 12 weeks to see if they're effective and safe for treating chronic heart failure with reduced ejection fraction (HFrEF). Participants must be on stable medical therapy according to current guidelines while taking part in the trial.

Participant Groups

Group I: Placebo Experimental Treatment 1 Intervention

Placebo Capsules orally once daily for 12 weeks

Group II: JTT-861 Dose 2 Experimental Treatment 1 Intervention

JTT-861 Capsules Dose 2 orally once daily for 12 weeks

Group III: JTT-861 Dose 1 Experimental Treatment 1 Intervention

JTT-861 Capsules Dose 1 orally once daily for 12 weeks

Who Is Running the Clinical Trial?

Akros Pharma Inc.

Lead Sponsor

Trials

24

Recruited

2,800+

ICON Clinical Research

Industry Sponsor

Trials

52

Recruited

15,100+

Findings from Research

Endothelin-1 (ET-1) is a significant prognostic marker in severe heart conditions, such as heart failure and myocardial infarction, indicating its role in adverse cardiovascular outcomes.

Clinical trials are currently investigating the effects of ET receptor antagonists, which may counteract the harmful effects of ET-1, such as increased blood pressure and vascular hypertrophy, in patients with heart failure and other cardiovascular diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endothelin receptor antagonists in cardiology clinical trials. Neunteufl, T., Berger, R., Pacher, R.[2019]

A study involving 399 chronic heart failure patients showed that implementing a computer-based reminder system for physicians improved guideline-based beta-blocker prescriptions by 12.3% after one year.

The use of the reminder system also increased the prescription of aldosterone antagonists for severe heart failure from 35% to 44.2%, indicating a positive impact on medication adherence to treatment guidelines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Innovative strategy for implementing chronic heart failure guidelines among family physicians in different healthcare settings in Berlin. Braun, V., Heintze, C., Rufer, V., et al.[2022]

Despite advancements in heart failure treatments like beta-blockers and renin-angiotensin system antagonists, there remains a significant need for more effective therapies for many patients.

Recent research has identified new potential targets for heart failure therapy based on a better understanding of disease mechanisms, emphasizing the importance of addressing key issues to enhance the success of new treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug discovery for heart failure: a new era or the end of the pipeline? Kaye, DM., Krum, H.[2007]

Elevated levels of endothelin-1 are linked to chronic heart failure, and using bosentan, an endothelin-1 receptor antagonist, has shown promising improvements in heart function and hemodynamics in patients when added to standard therapy.

Short-term treatment with bosentan reduced the activity of the renin-angiotensin system and lowered plasma aldosterone levels, suggesting a beneficial effect on heart failure management, but further long-term studies are needed to confirm its clinical benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hemodynamic effects of bosentan in patients with chronic heart failure. Kiowski, W., Sütsch, G., Oechslin, E., et al.[2019]

Endothelin-1 (ET-1) is implicated in chronic heart failure, with elevated levels correlating to worse heart function, suggesting that targeting ET-1 could be beneficial for treatment.

Both mixed and selective ET-1 receptor antagonists have shown promise in improving heart function in chronic heart failure, indicating potential for similar benefits in acute heart failure, but further clinical trials are needed to confirm these effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationale and perspective of endothelin-1 antagonism in acute heart failure. Kiowski, W., Suetsch, G., Oechslin, E., et al.[2019]

ABT-494, a selective JAK 1 inhibitor, demonstrated favorable pharmacokinetics and safety in healthy subjects and those with rheumatoid arthritis, with mild to moderate side effects and no significant drug interactions with methotrexate.

The study involved 56 healthy participants for single dosing and 44 for multiple dosing, showing that ABT-494 had a manageable elimination half-life and dose-proportional exposure, supporting its potential for further testing in phase IIb trials for rheumatoid arthritis and Crohn's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, Safety and Tolerability of ABT-494, a Novel Selective JAK 1 Inhibitor, in Healthy Volunteers and Subjects with Rheumatoid Arthritis. Mohamed, MF., Camp, HS., Jiang, P., et al.[2018]

JAK inhibitors (JAKi) are showing efficacy comparable to or better than traditional biologic treatments for inflammatory arthritis, with tofacitinib and baricitinib being the first generation approved for use.

Next-generation selective JAK1 inhibitors like upadacitinib and filgotinib are promising, but all JAKi share a safety concern regarding increased risk of viral infections, particularly herpes zoster, highlighting the need for ongoing post-marketing surveillance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The new entries in the therapeutic armamentarium: The small molecule JAK inhibitors. Bechman, K., Yates, M., Galloway, JB.[2023]

A study analyzing 114,005 adverse event reports found that JAK inhibitors (baricitinib, tofacitinib, and upadacitinib) are associated with an increased risk of deep vein thrombosis (DVT), particularly in older adults (ages 65-100) and males.

Baricitinib and tofacitinib showed stronger signals for DVT compared to upadacitinib, indicating a need for further research to confirm these safety concerns and understand the mechanisms involved.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Investigating the risk of deep vein thrombosis with JAK inhibitors: a disproportionality analysis using FDA Adverse Event Reporting System Database (FAERS). Mytheen, S., Varghese, A., Joy, J., et al.[2023]

ABT-494, a selective JAK-1 inhibitor, demonstrated significant efficacy in improving symptoms of moderate-to-severe rheumatoid arthritis in patients who had inadequate responses to anti-TNF agents, with 53-71% of patients achieving a 20% improvement in symptoms (ACR20) compared to 34% in the placebo group after 12 weeks.

The treatment was well-tolerated, with common side effects including headache and infections, but no serious infections or deaths reported, indicating a favorable safety profile similar to other medications in its class.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase IIb Study of ABT-494, a Selective JAK-1 Inhibitor, in Patients With Rheumatoid Arthritis and an Inadequate Response to Anti-Tumor Necrosis Factor Therapy. Kremer, JM., Emery, P., Camp, HS., et al.[2022]

In a review of 66 randomized clinical trials involving 38,574 patients, JAK inhibitors showed a numerically higher risk of venous thromboembolism (VTE) compared to active comparators, particularly in studies with follow-up durations of 12 months or more.

No increased risk of VTE was observed when comparing JAK inhibitors to placebo, and while there was a trend towards increased major adverse cardiac events (MACE), it did not reach statistical significance, indicating a need for further long-term studies to better understand the safety of JAK inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular and Venous Thromboembolic Risk With Janus Kinase Inhibitors in Immune-Mediated Inflammatory Diseases: A Systematic Review and Meta-Analysis of Randomized Trials. Maqsood, MH., Weber, BN., Haberman, RH., et al.[2023]

Endothelin-1 (ET-1) plays a significant role in heart failure, and targeting its activity with endothelin receptor blockers may offer new therapeutic strategies for patients, despite current treatments showing limited effectiveness.

Most existing studies on endothelin receptor blockers have involved small patient groups and short follow-up periods, focusing on surrogate endpoints rather than hard clinical outcomes, with larger trials currently underway to determine the best approach for receptor blockade.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of endothelins in congestive heart failure. Moe, GW., Rouleau, JL., Nguyen, QT., et al.[2014]

The new endothelin receptor antagonist T-0201 effectively inhibits the blood pressure response to endothelin-1 in normal dogs, demonstrating its potential as a treatment for congestive heart failure (CHF) by blocking both ETA and ETB receptors.

In a chronic study with dogs suffering from CHF, T-0201 significantly improved cardiorenal function and prevented further deterioration, indicating its efficacy in managing CHF over a 15-day treatment period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic effects of a novel, orally active endothelin receptor antagonist, T-0201, in dogs with congestive heart failure. Ohnishi, M., Wada, A., Tsutamoto, T., et al.[2019]

In a rat model of chronic heart failure (CHF), endothelin-1 (ET-1) levels were significantly elevated compared to control rats, indicating a potential role of endothelin in the progression of heart failure.

The endothelin receptor antagonist bosentan effectively reduced mean arterial pressure in CHF rats, suggesting that targeting endothelin could be a promising therapeutic strategy for managing heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of endothelin in the maintenance of blood pressure in conscious rats with chronic heart failure. Acute effects of the endothelin receptor antagonist Ro 47-0203 (bosentan). Teerlink, JR., Löffler, BM., Hess, P., et al.[2019]

References

1. England pubmed.ncbi.nlm.nih.gov

Endothelin receptor antagonists in cardiology clinical trials. [2019]

2. England pubmed.ncbi.nlm.nih.gov

Innovative strategy for implementing chronic heart failure guidelines among family physicians in different healthcare settings in Berlin. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Drug discovery for heart failure: a new era or the end of the pipeline? [2007]

4. United States pubmed.ncbi.nlm.nih.gov

Hemodynamic effects of bosentan in patients with chronic heart failure. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

Rationale and perspective of endothelin-1 antagonism in acute heart failure. [2019]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, Safety and Tolerability of ABT-494, a Novel Selective JAK 1 Inhibitor, in Healthy Volunteers and Subjects with Rheumatoid Arthritis. [2018]

7. Netherlands pubmed.ncbi.nlm.nih.gov

The new entries in the therapeutic armamentarium: The small molecule JAK inhibitors. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Investigating the risk of deep vein thrombosis with JAK inhibitors: a disproportionality analysis using FDA Adverse Event Reporting System Database (FAERS). [2023]

9. United States pubmed.ncbi.nlm.nih.gov

A Phase IIb Study of ABT-494, a Selective JAK-1 Inhibitor, in Patients With Rheumatoid Arthritis and an Inadequate Response to Anti-Tumor Necrosis Factor Therapy. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Cardiovascular and Venous Thromboembolic Risk With Janus Kinase Inhibitors in Immune-Mediated Inflammatory Diseases: A Systematic Review and Meta-Analysis of Randomized Trials. [2023]

11. Canada pubmed.ncbi.nlm.nih.gov

Role of endothelins in congestive heart failure. [2014]

12. United States pubmed.ncbi.nlm.nih.gov

Chronic effects of a novel, orally active endothelin receptor antagonist, T-0201, in dogs with congestive heart failure. [2019]

13. United States pubmed.ncbi.nlm.nih.gov

Role of endothelin in the maintenance of blood pressure in conscious rats with chronic heart failure. Acute effects of the endothelin receptor antagonist Ro 47-0203 (bosentan). [2019]