Mitochondrial diseases represent some of medicine’s most complex research and treatment challenges. When mitochondria malfunction, the body’s ability to produce energy deteriorates. This causes cascading effects across organ systems. 

Among these disorders, MELAS stands out for its combination of neurological decline, muscle weakness, and recurrent metabolic crises that can trigger stroke-like episodes. Currently, there are no approved drugs for people with MELAS. Its variable presentation and extremely rare nature also mean that MELAS is generally poorly understood. 

Drug development and clinical trials for MELAS, as a result, face considerable obstacles. Studies must account for small and often geographically scattered patient populations. Because the disease is rare and not well understood, there has not been a standardized approach to measure disease progression. And, because MELAS affects multiple body systems simultaneously, researchers must track numerous endpoints that could signal treatment efficacy.

But biotechnology research company Tisento Therapeutics is up for the challenge. The company leads with a mission to develop drugs designed to improve the lives of individuals with complex, life-altering diseases. Their approach aims to reshape how mitochondrial disease research and drug development is conducted – all while keeping the patient at the center of importance. 

Tisento Therapeutics recently sat down with Rareatives to discuss the Phase 2b PRIZM trial evaluating zagociguat as a potential therapeutic option for MELAS. In our discussion, we examine how the PRIZM study incorporates new strategies for patient participation, symptom management, and data collection – and what those methodological advances could mean for MELAS. 

Jessica Lynn (JL): Thank you so much for taking the time to sit down for an interview. To start off, please tell me more about Tisento Therapeutics and its mission.

We are a biotech company focused on developing medicines with the potential to make a significant impact for patients who have few options, beginning with MELAS and other genetic mitochondrial diseases.

Ti sento means “I hear you” in Italian. Our approach to innovation begins with listening to patients and then channeling what we learn into decisive actions that shape our research and clinical programs. 

In your words, what is MELAS? How is MELAS currently managed?

Short for Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like episodes, MELAS is a rare mitochondrial disease that affects multiple organ systems, especially organs with high energy demands like the brain and muscles.

MELAS can cause severe and burdensome symptoms, including:

• Chronic physical and mental fatigue
• Memory and other cognitive issues
• Muscle weakness
• Exercise intolerance
• Headaches
• Seizures
• Stroke-like episodes 

MELAS is also associated with shortened life expectancy. There are no approved treatments for MELAS, and current disease management options are primarily limited to symptomatic treatments and lifestyle changes—all of which are inadequate to manage this chronic disease.

Disease management approaches include:

• A combination of dietary supplements (“mito cocktail”) which often includes arginine or citrulline, typically given to help combat mitochondrial dysfunction.
  • There are some tolerability challenges with the mito cocktail because large, frequent doses are required. 
• Acute management of metabolic strokes often consists of intravenous arginine, especially in the U.S. 
• Symptom-specific treatments (e.g., anti-seizure medications, diabetes medications) 
• Lifestyle changes to minimize energy loss and optimize energy gains (e.g., avoiding stressors, adequate rest, nutrition, exercise) 

Rare disease research and drug development can be a challenging space. Why choose to focus on MELAS and other rare mitochondrial diseases? 

We are motivated by the potential to positively impact patients’ lives and make a real difference for those with few or no treatment options. When working on a new treatment for a rare disease, there’s often a lot of groundwork that needs to be laid to understand the disease itself, identify clinically meaningful endpoints, and chart a path to regulatory approval.

Blazing these new trails can be challenging, but it’s also incredibly rewarding to be pioneers for a patient community that does not have approved treatment options and is desperately in need of innovation.

We are also science-driven, and there’s strong scientific rationale to support the potential of our lead asset, zagociguat, as a treatment for MELAS. Based on the results we’ve seen and our understanding of the unmet need in MELAS, we are beginning our development of zagociguat in this focused patient population.

We believe zagociguat has potential in other mitochondrial diseases as well and may expand our clinical program to additional indications in the future. However, we’re currently a small company with 12 employees, so we are entirely focused on the development of zagociguat for MELAS at this time. 

Tell me more about zagociguat. How does its mechanism of action potentially address the underlying pathology in MELAS?

Our investigational medicine zagociguat acts directly on a pathway that is dysregulated in MELAS and that plays an essential role in fundamental physiological processes. 

Zagociguat is a pill taken once-a-day in our clinical trials. Prior to the launch of Tisento, zagociguat was studied in a Phase 2a study evaluating the therapy in eight participants with MELAS. In this study, zagociguat showed an excellent safety profile, exposure in the central nervous system (meaning it is brain-penetrant), evidence of improvements in mitochondrial and neuronal function, and increases in blood flow to the brain. 

Importantly, based on these Phase 2a results, as well as supporting preclinical and healthy volunteer data, we believe zagociguat has the potential to address two hallmark features of MELAS: fatigue and cognitive impairment. 

We are currently evaluating zagociguat’s ability to improve fatigue, cognition, and other key aspects of MELAS in our global, Phase 2b PRIZM study. The first patient was recently dosed in the PRIZM study. 

Before we move into specifics about the PRIZM study, how does Tisento Therapeutics ensure patient needs and the patient experience are centered in your work?

We aim to live up to our name – “I hear you” – and always take the approach of listening first. To listen well, we must seek out patient community voices, ask good questions, and let what we hear shape our understanding and our actions. 

We deeply value our relationships with patient advocacy organizations who provide essential perspectives and connections with the patient communities we serve. Since our launch, we’ve worked closely with the United Mitochondrial Disease Foundation, Mito Action, Mitocon, the Mito Foundation, The Lily Foundation, and Mito Canada. We are grateful for the many ways they amplify the voices of patients.

We are also proud to support the vital work of advocacy organizations, whether by attending their conferences, sponsoring patient walks, or amplifying their initiatives on our social media accounts. As an example, we sponsored the United Mitochondrial Disease Foundation (UMDF)’s creation of a series of MELAS patient story videos to help raise awareness about the disease and give a platform for patients and families living with MELAS.

Our work with MELAS is focused on conducting controlled clinical trials to understand whether zagociguat can bring meaningful benefit to patients. Specifically, we have centered the patient experience by working to lower barriers to clinical study participation and ensuring the endpoints we are measuring are relevant and meaningful. 

To this end, we are measuring what matters most to the MELAS community. Our MELAS interview study helped build our understanding of the signs, symptoms, and impact of MELAS from the patient perspective and ensured our clinical assessments measure the concepts that emerged as most meaningful. 

Based on what we learned from advocacy groups and the patient community, we incorporated several features into the PRIZM study that maximize convenience for participants, including:

• At-home assessments
• The potential for at-home study visits
• Door-to-door travel support

With door-to-door travel support, Tisento provides support for travel coordination and covers the cost of travel to and from the required in-clinic visits via any mode of transportation (air, car, train, etc.) based on patient preference. This is provided as requested by participants to support their individual needs and personal situations.

Given that there are no approved treatments for MELAS, ensuring access to the investigational medicine is another important element of PRIZM for patients. Because of the study’s crossover design, all participants will receive zagociguat during one period of the study. Participants who complete the study may be eligible for continued access via an open-label extension (OLE) study. 

Can you walk me through that patient interview study? What were the most significant insights you discovered?

The interview study collected valuable insights from both clinicians and patients to ensure that the PRIZM clinical study is measuring what matters most to people with MELAS. In addition, the interview study supported the readability, relevance, and comprehensiveness of our patient-reported outcome (PRO) measures. 

The interview study included:

• Qualitative clinician interviews (60 min) with therapeutic-area experts to obtain insight into the signs, symptoms, and impacts of MELAS from the clinician perspective and to inform the conduct of patient interviews
• Qualitative concept elicitation patient interviews (45 min) with adults (≥18y) with MELAS, using a series of open-ended questions to elicit spontaneous descriptions of the signs, symptoms, and impacts of MELAS 
• Cognitive debriefing patient interviews (45 min), conducted with the adults with MELAS, to assess readability, relevance, and comprehensiveness of the PROs
• Concept mapping to assess whether patient- and clinician-reported concepts were captured by the PROs and performance outcomes

Through the interview study, we gained a deeper understanding of the symptoms that are most bothersome to patients and that they feel are most important to improve. These findings reinforced our understanding that both central and peripheral impacts need to be addressed and helped us ensure that the endpoints we’re measuring in PRIZM are clinically meaningful to those living with the disease.

In particular, we found that not only is physical fatigue a common and bothersome symptom in MELAS, but that mental fatigue is as well. Mental fatigue is complex and can show up as challenges with processing speed and executive function.

What are the key endpoints in the PRIZM study?

PRIZM is investigating whether zagociguat improves fatigue (lack of energy), cognitive impairment (e.g., mental fatigue, problems with memory, difficulty concentrating) and other symptoms of people living with MELAS.

PRIZM has two primary endpoints. One is focused on safety, specifically the incidence of adverse events. The other primary endpoint is focused on the effectiveness of zagociguat; it quantifies improvement on: 

• A patient-reported questionnaire on MELAS-specific fatigue
• Cognitive performance tests of processing speed and executive function

In addition, secondary endpoints include performance outcomes assessing exercise intolerance and learning and working memory, a patient-reported questionnaire on MELAS-specific cognitive function, as well as a disease biomarker measured in the blood.

With no currently approved MELAS treatments, what regulatory considerations went into designing this trial to potentially support an approval pathway?

When we launched Tisento in mid-2023, the regulatory groundwork had been laid to enable us to execute efficiently and effectively on our near-term priorities – conducting the interview study and starting up the global PRIZM study.

The Phase 2a study of zagociguat in MELAS was complete, and we had actionable advice from FDA on our planned Phase 2b trial and our comprehensive approach to assessing the efficacy of zagociguat. Zagociguat had also received FDA Orphan Drug designation for the treatment of mitochondrial disease.

Our PRIZM trial design includes comprehensive measurement of MELAS impacts, including a mix of subjective and objective assessments. In addition, the crossover design enables adequate control with a small number of patients so we can observe the efficacy and safety of zagociguat.

From the initial planning stages for the PRIZM study, we have consistently shared information and collaborated with FDA to support patient participation in the zagociguat development program, current and future, including considerations of endpoints in the PRIZM trial.

Additionally, we communicate regularly with Global Health Authorities and look forward to continued collaboration in support of patients in all regions that have an unmet treatment need for MELAS.

What safety monitoring protocols are in place, particularly given that this is a first-in-class investigational MELAS treatment?

As with all clinical studies, each participant’s safety is closely monitored by the investigators and site study staff. Adverse events and the results of routine safety assessments are closely tracked and reported. In the case of a significant adverse event, participants may be given lower doses of study drug or treatment may be stopped immediately if needed.

Zagociguat is a first-in-class, investigational medicine for MELAS, but PRIZM is not the first study of zagociguat in people with MELAS. Zagociguat has been evaluated in 5 clinical trials involving over 200 people, including in a Phase 2a study in MELAS. Zagociguat was well tolerated in the Phase 2a study, and all participants completed the treatment period. 

How is the trial considering the often-overlooked psychological aspects of living with MELAS, particularly given the progressive nature of the disease?

That’s a great question and an often over-looked impact of chronic diseases like MELAS. We know that living with MELAS is challenging. We have included measures to understand the psychological status of participants in the PRIZM trial and we monitor for any changes in their psychological wellbeing.

How is the trial team maintaining ongoing communication with participants and their families throughout the study? What feedback mechanisms are in place to address any concerns or suggestions?

To remain compliant, all direct communication to trial participants and families is handled by site study staff. Tisento ensures that the sites have all the information and support they need and has also worked to make clear to patients who are interested in the study exactly how they can reach site coordinators to learn more about the study. 

Site staff collect any feedback, questions, or concerns from participants and address them with support from Tisento as needed. This study also includes exit interviews with participants. One of the primary goals of these interviews is to develop an understanding of what it was like participating in the study (e.g., what they liked/didn’t like, what worked/didn’t work) so improvements can be made to future studies.

How can the MELAS community get involved in this study or future studies?

Our PRIZM study is currently enrolling at mitochondrial disease centers of excellence in the U.S. with centers in Italy, Germany, United Kingdom, Australia, and Canada soon to follow. Those who are interested in learning more can visit www.tisentotx.com/prizm or ClinicalTrials.gov (NCT06402123) or reach out to their physicians.

We are also recruiting for an interview study of adolescents with MELAS (ages 12-17 years) to better understand the experiences of this age group. Those interested in learning more can view our parent flyer or our teen flyer.

About Tisento Therapeutics

Tisento Therapeutics, a privately held biotech company, is developing novel medicines to treat diseases with significant unmet need, beginning with MELAS and other genetic mitochondrial diseases. Tisento is guided by a high-caliber internal team of biopharma veterans and an extensive external network of expert physicians, patient advocacy groups, researchers, industry-leading vendors, and other close collaborators who are partners in our mission to develop meaningful treatments for mitochondrial diseases. 

Learn more at our website, www.tisentotx.com, or follow on LinkedIn, Facebook, or X to get in touch with us and stay updated on the PRIZM study.