When it comes to treatment options, there is a huge unmet need in the rare disease community broadly. 95% of rare diseases do not have FDA-approved treatments, meaning people with rare conditions like MELAS—a rare, inherited mitochondrial disease that impairs the body’s ability to produce energy at the cellular level—are left without options. 

In February 2025, I spoke with biotechnology research company Tisento Therapeutics (“Tisento”) on the company’s Phase 2b PRIZM study, which is evaluating Tisento’s lead therapeutic candidate zagociguat for the treatment of MELAS. Zagociguat is an investigational, once-daily sGC stimulator. As Tisento explains: 

Zagociguat is hypothesized to rebalance dysregulated cellular pathways in MELAS. By restoring cellular functions that support mitochondria, zagociguat is also able to help restore mitochondrial energy production and physiological function.

Zagociguat exhibited a favorable safety profile in a prior Phase 2a open-label study, and Tisento was enrolling individuals with MELAS into the Phase 2b study during our last conversation. Excitingly, there have been several developments since that time. Zagociguat received Fast Track designation from the U.S. Food and Drug Administration (FDA) in June 2025; Tisento completed enrollment for the PRIZM trial in January 2026; and the company sponsored the first Externally-Led Patient-Focused Drug Development Meeting (EL-PFDD) for MELAS in February 2026. 

Recently, I spoke with Chad Glasser, PharmD, MPH—the Vice President of Clinical Research at Tisento Therapeutics—about PRIZM, the importance of patient-centricity, and why he and the company continue to push forward to make a difference for people living with MELAS. 

What is MELAS?

Before we dive into the interview, it’s important to understand what MELAS is. MELAS, sometimes referred to as MELAS syndrome, stands for Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes. The disease affects organs and tissues throughout the body, since mitochondria are part of all cells. 

MELAS is heterogenous, meaning no two patients experience the disease in the same way. This variability is largely driven by heteroplasmy, where differing proportions of mutated mitochondrial DNA across tissues and individuals lead to variations in symptoms, disease onset, and severity. People can show signs of MELAS during adolescence or more commonly in adulthood.

People with MELAS also deal with a wide variety of symptoms and manifestations, including (but not limited to):

• Severe and recurrent headaches
• Vomiting
• Muscle weakness and pain
• Chronic fatigue
• Focal and/or generalized seizures
• Learning disabilities or delayed milestones in childhood
• Stroke-like episodes with unilateral paralysis or numbness
• Peripheral neuropathy
• Cognitive issues, such as difficulty thinking or memory problems 
• Progressive hearing loss
• Short stature
• Diabetes 

Planning PRIZM

Glasser explains that Tisento took these symptoms into account when designing the study. But more than that, Tisento invited patients to share their lived experience.

“One of the most impactful parts of my role is designing studies that effectively assess whether a drug can help patients. There’s a lot of work that goes into thoughtfully considering what types of patients to enroll and the best outcome measures to evaluate disease changes. Without all that thought and prework, you might end up with a study that isn’t designed to answer the primary research question,” he explains. 

Before initiating the PRIZM study, the company conducted a qualitative interview study designed to better understand the lived experiences of individuals with MELAS, ensuring that patient voices informed the trial from the outset. As Glasser explains, these conversations provided critical direction. While physical fatigue is widely recognized across mitochondrial diseases, many MELAS patients consistently emphasize the profound impact of cognitive dysfunction on their daily lives, often describing it as one of the most disruptive and overlooked aspects of the condition.

In response, Tisento prioritized fatigue and cognition within the study design, incorporating both objective assessments and patient-reported measures to capture a more complete, nuanced picture of the patient experience. Glasser describes this approach as intentional. Insights from the interview study shaped not only what was measured, but how the trial itself was structured, reinforcing a design grounded in real-world patient priorities. 

Getting this trial right is extremely important for Glasser. A pharmacist by training, he earned his doctorate at the University of Kentucky and has spent more than a decade in clinical research, including seven years focused on zagociguat. “It’s been really interesting working on that molecule and seeing it develop from Phase 1,” he says. 

As you can imagine, committing so much time and energy into developing a therapy, and getting to know the patient population, has only motivated Glasser further to help expand MELAS understanding and get a treatment option into the hands of those who need it. 

PRIZM Study Enrollment

Running a clinical trial on its own is already challenging, requiring meticulous planning, strict regulatory compliance, substantial funding, coordinated teamwork, and careful management of patient safety and data integrity.

Running a clinical trial in the rare disease space adds another layer of complexity. In a 2013 paper published in the Journal of Child Neurology, the authors discuss how therapeutic development in the rare disease space faces obstacles “such as incomplete understanding of natural history to inform trial design, need for alternatives to the randomized controlled clinical trial, requirement for more sensitive outcome measures to quantify disease, [and] limited access to resources required to mount a clinical trial (including funding).” 

Tisento designed the PRIZM trial to overcome some of these barriers. In the past, individuals with MELAS have been involved in larger studies centered around primary mitochondrial diseases. To focus on recruiting the right group of participants, Tisento focused on enrolling a relatively homogenous population based on a strict definition of MELAS. 

Glasser explains, “I’m always surprised by how differently each patient with MELAS might describe their disease experience. Heterogeneity is one of the greater challenges as a drug developer in that no two patients are exactly the same. There’s not always a one-size-fits-all method that can be used across all groups of patients. At a very high level, the way we design studies in rare heterogeneous diseases needs to be changed. It was really important for us to recruit a more homogenous population because having too many types of patients leads to data variability.” 

Although Glasser acknowledges that completing enrollment under the strict criteria took longer than Tisento had hoped, he’s also proud of where the company landed. “It shows that this can be done, that you can focus your eligibility criteria and still achieve your goals,” he says. 

Additional Trial Innovation

Reflecting on his proudest professional accomplishment, Glasser points to signing off on the PRIZM study protocol, informed by the voices and experiences of individuals living with MELAS. Rather than treating patient engagement as a separate step, the protocol itself reflects those insights in both the study’s design and its endpoints. 

“We’re innovating and not just conducting the more traditional, randomized, double-blind, parallel-group, placebo-controlled study,” he explains to me. Specifically, a key feature of the PRIZM study is its crossover design, which Glasser shares “allows every patient to serve as their own control. You can give every patient active drug and placebo, and within each patient, see how they respond to each.” 

By enabling these comparisons, the design allows for more individualized and precise assessment of treatment response, aligning with the MELAS patient community’s emphasis on meaningful, patient-relevant change. The study’s global scope also reflects a commitment to inclusivity, ensuring that insights are drawn from a broad and representative patient population.

Another innovation is combining several outcome measures into a single statistical test. “This increases the study’s power and recognizes that not every endpoint is perfect for every patient, while still showing we’re improving multiple parts of the disease experience,” Glasser says. “We want to show, based on the results, that this is having a meaningful impact on patients and their quality of life.” 

Final data from the PRIZM trial is forthcoming, with readout expected in Q4 of 2026. Glasser is ready to see what the data shows. “We’ll be one step closer to Phase 3 and, hopefully, an approved treatment,” he says. Even if the data are not as positive as expected, Glasser also still sees this as valuable. He adds, “Positive or negative, we hope it furthers the field and our knowledge of MELAS will increase. Reviewing data has the potential to increase everyone’s understanding of the disease and the patient experience. We hope to eventually publish this for the mitochondrial community and clinicians.” 

EL-PFDD Meeting

On February 10, 2026, the MELAS community reached a significant milestone through the first Externally Led Patient-Focused Drug Development (EL-PFDD) meeting, led by MitoAction in partnership with the MELAS community. PFDD meetings are, as the name suggests, externally-led—essentially, rather than being hosted by the FDA, these specialized meetings bring together patient organizations, patients, caregivers, advocates, and clinicians to share the patient perspective on their diseases, symptoms, treatments, and other aspects of their lived experience. 

“They can share live testimony, submit comments, and respond to polling questions and surveys,” says Glasser. “We sponsored the event because it’s important to educate the FDA and other drug developers. MitoAction did a fantastic job. And, in terms of the content, the heartbreaking stories were tough to hear but reminded us why we do what we do and how significant the unmet needs are.” 

Beyond serving as a reminder for the many burdens the MELAS community must carry, the EL-PFDD meeting played a critical role in advancing research. The insights gathered during the sessions contribute to a formal “Voice of the Patient” report submitted to the FDA, helping to ensure that regulatory decision-making and clinical trial design are grounded in what matters most to patients. In this way, the EL-PFDD meeting created a tangible pathway for patients to influence how treatments are evaluated and which outcomes are prioritized. 

Glasser also emphasized the broader significance of the event for the MELAS community, noting, “The EL-PFDD meeting was a great step forward for patients with MELAS who sometimes get overshadowed or lumped into the broader primary mitochondrial disease population, even though they have a very unique experience.”

Importantly, the perspectives shared during the meeting closely aligned with earlier qualitative research conducted by Tisento, reinforcing that the company’s focus on fatigue and cognitive dysfunction reflects the community’s most pressing and consistently articulated needs. 

As he looks to the future now, Glasser is hopeful that what Tisento learns, from the patient perspective directly and from study data, will get the first approved MELAS treatment to patients. “We’re so appreciative of the community and the stakeholders who have supported us,” he says. “Without patients, we never could have gotten to this point.” 

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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, X, or Bluesky to get in touch with us and stay updated on the PRIZM study.

About Chad Glasser

Chad Glasser, PharmD, MPH, is Vice President of Clinical Research at Tisento Therapeutics. Chad brings more than 12 years of clinical research experience, having worked on a range of preclinical to late-stage programs spanning infectious disease, oncology, and multiple rare disease therapeutic areas. For the last five years, he has focused on advancing the zagociguat clinical program, first at Cyclerion then through the transition to Tisento. Prior to Cyclerion, Chad was a clinical scientist at Acceleron Pharma (acquired by Merck), and before that, he completed a two-year post-doctoral clinical research fellowship and started his career at Cubist Pharmaceuticals (acquired by Merck).

Chad’s thoughtful, calm, and data-driven approach to problem-solving allows him to overcome the complex and seemingly insurmountable challenges of rare disease drug development. Within each stakeholder relationship, whether it be a physician, a regulator, or a patient advocate, Chad strives to maintain the highest degree of credibility and authenticity, with the goal of establishing meaningful and long-lasting collaborations.