Zagociguat for MELAS Syndrome

(PRIZM Trial)

Recruiting at 27 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Tisento Therapeutics

Disqualifiers: Low blood pressure, Orthostatic hypotension, Active cancer, Severe gastrointestinal dysmotility, 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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 7

44 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called zagociguat to evaluate its effectiveness and safety for individuals with MELAS syndrome, a condition that affects energy production and can cause stroke-like episodes and fatigue. Participants will receive either zagociguat or a placebo (a pill with no active medicine) in different sequences to compare the effects. Suitable candidates for this trial have experienced stroke-like episodes due to MELAS and suffer from fatigue. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, providing participants an opportunity to contribute to significant medical advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it mentions that current use of prohibited medication will be reviewed by the investigator. It's best to discuss your medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that zagociguat is safe and well-tolerated in earlier studies. Specifically, previous trials suggest that most patients handle the drug well, with no major safety issues reported. Early results also indicate that zagociguat can be safely absorbed by the body and even reach the brain, which is crucial for treating conditions like MELAS syndrome, a rare disorder affecting energy production in cells.

The safety data from these studies is promising for those considering joining clinical trials, as they suggest that zagociguat has not been linked to serious side effects so far. However, as with any new treatment, researchers continue to monitor for possible side effects. Participants should stay informed and discuss any concerns with trial staff. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about zagociguat for MELAS syndrome because it offers a new approach compared to existing treatments like L-arginine or L-citrulline supplements. Zagociguat works by targeting the nitric oxide signaling pathway, potentially improving mitochondrial function and energy production in cells. This mechanism is different from standard treatments and might lead to more effective management of symptoms associated with MELAS syndrome. Additionally, by evaluating different doses and sequences of zagociguat and placebo, researchers aim to optimize its benefits and better understand its impact on this condition.

What evidence suggests that zagociguat might be an effective treatment for MELAS?

Studies have shown that zagociguat may improve symptoms of MELAS syndrome, which affects the brain and muscles. Research indicates that this drug targets issues in cellular energy production, a major problem in MELAS. Previous findings suggest that zagociguat could alleviate thinking difficulties and tiredness, common symptoms of this condition. Early data appears promising, as patients have demonstrated potential benefits in these areas. Although more research is needed, these initial results offer hope for managing MELAS symptoms. Participants in this trial will receive either zagociguat or a placebo in different sequences to further evaluate its effectiveness. ^{1 2 3 6 7}

Are You a Good Fit for This Trial?

This trial is for individuals with MELAS syndrome, a condition that affects many parts of the body, particularly the brain and nervous system. Participants must have genetic markers confirming their diagnosis. Specific details on who can't join are not provided here.

Inclusion Criteria

I have had stroke-like episodes confirmed by MRI.

Other criteria per the protocol

Signed consent form

Exclusion Criteria

I have not had bleeding disorders or unexplained bleeding in the last 6 months.

My cancer is not affecting the study's outcomes.

Systolic blood pressure (BP) 90 mmHg or diastolic BP 60 mmHg

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment Period 1

Participants receive either zagociguat or placebo once daily for 12 weeks

12 weeks

3 visits (in-person), 2 visits (in-person or home)

Washout

A 4-week washout period between treatment periods

4 weeks

Treatment Period 2

Participants receive the alternate treatment (zagociguat or placebo) once daily for 12 weeks

12 weeks

3 visits (in-person), 2 visits (in-person or home)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

What Are the Treatments Tested in This Trial?

Interventions

• Zagociguat

Trial Overview The study tests zagociguat at two different doses (15mg and 30mg) against a placebo to see which is more effective in treating MELAS symptoms. It's a double-blind study, meaning neither participants nor researchers know who gets the real drug or placebo during the trial.

How Is the Trial Designed?

Group I: Zagociguat 30mg then Placebo Experimental Treatment 2 Interventions

Participants first receive zagociguat 30 mg once a day for 12 weeks. Then after a 4-week washout, they receive placebo once a day for 12 weeks.

Group II: Zagociguat 15mg then Placebo Experimental Treatment 2 Interventions

Participants first receive zagociguat 15 mg once a day for 12 weeks. Then after a 4-week washout, they receive placebo once a day for 12 weeks.

Group III: Placebo then Zagociguat 30mg Experimental Treatment 2 Interventions

Participants first receive placebo once a day for 12 weeks. Then after a 4-week washout, they receive zagociguat 30 mg once a day for 12 weeks.

Group IV: Placebo then Zagociguat 15mg Experimental Treatment 2 Interventions

Participants first receive placebo once a day for 12 weeks. Then after a 4 week washout, they receive zagociguat 15 mg once a day for 12 weeks.

Zagociguat is already approved in United States for the following indications:

Approved in United States as Zagociguat for:

• Mitochondrial disease (Orphan Drug designation)

Who Is Running the Clinical Trial?

Tisento Therapeutics

Lead Sponsor

Trials

6

Recruited

250+

Published Research Related to This Trial

In pivotal phase III trials, riociguat significantly improved the 6-minute walking distance (6MWD) in Chinese patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH), with increases of +46 m in PATENT-1 and +102 m in CHEST-1.

Riociguat was well tolerated and also led to improvements in secondary endpoints such as pulmonary vascular resistance (PVR) and WHO functional class, indicating its efficacy and safety in this specific patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Riociguat for the treatment of pulmonary hypertension: Chinese subgroup analyses and comparison. Wang, C., Jing, ZC., Huang, YG., et al.[2020]

Riociguat (Adempas) is an innovative medication specifically designed to treat pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH), conditions that cause high blood pressure in the lungs.

Clinical studies have demonstrated that riociguat effectively improves exercise capacity and overall functional status in patients with these types of pulmonary hypertension, making it a valuable treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Riociguat (adempas): a novel agent for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Khaybullina, D., Patel, A., Zerilli, T.[2020]

In a double-blind placebo-controlled trial involving 16 patients with sarcoidosis-associated pulmonary hypertension, riociguat significantly delayed clinical worsening compared to placebo, with no patients on riociguat meeting the worsening criteria versus five on placebo.

Riociguat also improved exercise capacity, as shown by a median increase of 42.7 meters in the 6-minute walk distance (6MWD) compared to a decrease of 55.9 meters in the placebo group, indicating its efficacy without significant adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Riociguat for Sarcoidosis-Associated Pulmonary Hypertension: Results of a 1-Year Double-Blind, Placebo-Controlled Trial. Baughman, RP., Shlobin, OA., Gupta, R., et al.[2023]

Zagociguat, a stimulator of the nitric oxide-sGC-cGMP signaling pathway, was found to be well-tolerated in a phase 1b study involving 24 healthy participants aged 65 and older, with a notable ability to penetrate the blood-brain barrier.

While zagociguat caused modest reductions in blood pressure, no significant pharmacodynamic effects were observed, suggesting that further studies in individuals with cognitive impairment may be necessary to fully evaluate its potential benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized placebo-controlled crossover study to assess tolerability and pharmacodynamics of zagociguat, a soluble guanylyl cyclase stimulator, in healthy elderly. van Kraaij, SJW., Borghans, L., Klaassen, ES., et al.[2023]

Zagociguat (CY6463) is a novel stimulator of soluble guanylate cyclase (sGC) that was well-tolerated in healthy participants across various doses, indicating its safety for further development in treating neurodegenerative diseases.

The drug demonstrated central nervous system (CNS) penetration and induced significant reductions in blood pressure, but no consistent effects on neurocognitive function were observed, suggesting that while it may have cardiovascular effects, its impact on learning and memory needs further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-human trial to assess safety, tolerability, pharmacokinetics, and pharmacodynamics of zagociguat (CY6463), a CNS-penetrant soluble guanylyl cyclase stimulator. van Kraaij, SJW., Gal, P., Borghans, LGJM., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06402123

A Phase 2b Study of Zagociguat in Patients With MELAS The goal of this clinical trial is to learn about the effectiveness of zagociguat in patients with MELAS. ... (MELAS Syndrome). Mitochondrial Encephalopathy ...

2. chop.edu chop.edu/news/childrens-hospital-philadelphia-researchers-find-promising-preclinical-data-expanding-use-drug

Children's Hospital of Philadelphia Zagociguat is currently being evaluated for MELAS in a phase 2B clinical trial ongoing at multiple sites, including at CHOP. With promising ...

3. clinicaltrialsarena.com clinicaltrialsarena.com/news/tisento-study-zagociguat-melas/

Tisento doses first subject in Phase IIb study of zagociguat ... The trial is designed to assess the therapy's influence on cognitive impairment, fatigue, and other significant disease aspects. Discover B2B ...

4. mountsinai.org mountsinai.org/clinical-trials/phase-2b-study-of-zagociguat-in-patients-with-melas

A Phase 2b Study of Zagociguat in Patients with MELAS PRIZM is a Phase 2b randomized, double-blind, placebo-controlled, 3-treatment, 2-period, crossover study evaluating the efficacy and safety of oral zagociguat ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT04475549

NCT04475549 | Phase 2a Study of IW-6463 in Adults ... Prior genetic confirmation of a known mitochondrial disease mutation · Neurological features of MELAS (can be based on medical history) · Elevated plasma lactate ...

6. medchemexpress.com medchemexpress.com/zagociguat.html?srsltid=AfmBOoq16ddZ7FYE0iwvyUBtzE7Xs1kosdoIPV44Uyq-7XvdcgUVzO1G

Zagociguat (CY-6463) | Soluble Guanylate Cyclase ... Mitochondrial Encephalopathy, Lactic Acidosis and Stroke-Like Episodes (MELAS Syndrome) ... SAFETY DATA SHEET (SDS). English - EN (252 KB) Français - FR (252 KB) ...

7. clinicaltrials.eu clinicaltrials.eu/trial/study-on-the-safety-of-zagociguat-for-patients-with-melas-syndrome/

Long-term safety study of zagociguat tablets in patients ... This study examines the long-term safety and tolerability of Zagociguat, also known as IW-6463, in treating patients with Mitochondrial ...