Zagociguat for MELAS Syndrome

(PRIZM Trial)

Recruiting at 26 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?

PRIZM is a Phase 2b randomized, double-blind, placebo-controlled, 3-treatment, 2-period, crossover study evaluating the efficacy and safety of oral zagociguat 15 and 30 mg vs. placebo when administered daily for 12 weeks in participants with genetically and phenotypically defined MELAS.

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.

What data supports the effectiveness of the drug Zagociguat for MELAS Syndrome?

Zagociguat is a drug that has been shown to be well-tolerated and can penetrate the central nervous system, which is important for treating brain-related conditions. It works by stimulating a pathway involved in learning and memory, similar to other drugs used for neurodegenerative diseases. ^{1 2 3 4 5}

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

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]

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]

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]

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]

Citations

1. England 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. [2023]

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

Riociguat for the treatment of pulmonary hypertension: Chinese subgroup analyses and comparison. [2020]

3. United States 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. [2023]

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

Riociguat (adempas): a novel agent for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. [2020]

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

Riociguat for Sarcoidosis-Associated Pulmonary Hypertension: Results of a 1-Year Double-Blind, Placebo-Controlled Trial. [2023]