What Is Win Ratio, And How Can It Be Used In Rare Disease Research?

A conversation with Amber Salzman, Ph.D., CEO, Epicrispr Biotechnologies

Traditional trial designs can fall short of capturing the full therapeutic impact of emerging therapies or heterogeneous diseases such as facioscapulohumeral muscular dystrophy (FSHD). Enter the win ratio — a statistical approach that integrates multiple clinically meaningful endpoints into a single composite measure of benefit.

Originally popularized in cardiovascular research, and now being used in rare disease research, the win ratio is gaining momentum for its capacity to account for heterogeneity, emphasize meaningful change, and align with patient-centered outcomes.

In this Q&A, Amber Salzman, CEO of Epicrispr Biotechnologies, explains how applying the win ratio in FSHD could transform the way investigators evaluate therapeutic impact, enhance statistical efficiency, and advance the design of trials that better reflect the lived realities of patients.

Clinical Leader: What is the “win ratio,” and why does it matter for FSHD?

Amber Salzman: The win ratio is a statistical method that compares each treated patient with each control patient across a hierarchy of clinically meaningful endpoints, determining whether the treated patient “wins,” “loses,” or “ties” in that comparison. Instead of relying on one dominant primary endpoint, the win ratio evaluates benefit across multiple domains that matter to patients. This makes it highly relevant to FSHD, which is a heterogeneous disease where patients may show improvement in different ways: muscle strength, mobility, fatigue, upper body versus lower body, or other measures. By allowing a therapy to demonstrate benefit even when different individuals improve on different outcomes, the win ratio offers a more patient-centric and realistic way to capture therapeutic effect in FSHD.

How has the win ratio been applied successfully in other rare diseases?

A clear example is late-onset Pompe disease. In a re-analysis of the COMET trial, researchers used the win ratio to jointly assess respiratory function (FVC) and mobility (6MWT). Even though the original study design used traditional hierarchical testing, the win ratio analysis revealed a significant advantage for the experimental therapy: a win ratio of 2.37, meaning treated patients were more than twice as likely to show a better outcome compared to controls when evaluated across both endpoints. This demonstrated how the win ratio can surface meaningful clinical benefit even when improvements manifest differently across patients.

How could Epicrispr use the win ratio approach in an FSHD trial?

Epicrispr could apply the win ratio by first defining a set of clinically significant endpoints that reflect the multi-system nature of FSHD, such as upper limb strength, functional mobility tests, patient-reported outcomes, and possibly respiratory assessments for more advanced cases. These endpoints would be organized into a hierarchy based on clinical importance. For each endpoint, thresholds of “meaningful improvement,” “stabilization,” or “decline” would be prespecified using validated minimal clinically important differences (MCIDs) or expert consensus. The win ratio would then compare treated versus control patients across all endpoints in order, producing a single interpretable measure of overall therapeutic benefit. For a disease as variable as FSHD, this approach allows us to capture patient-specific improvements that might otherwise be missed.

What advantages does the win ratio offer over traditional analyses in FSHD?

The win ratio offers several important advantages. First, it respects disease heterogeneity. FSHD affects individuals differently, so a flexible multi-endpoint framework is more reflective of real-world benefit. Second, it can improve statistical power in small or heterogeneous rare disease populations by leveraging more data across endpoints. Third, it focuses on clinically meaningful change rather than small numerical shifts. And finally, it produces a holistic metric that is intuitive to interpret, for example, showing that treated patients are “X times more likely to experience meaningful clinical benefit” across relevant domains.

What are the challenges of using the win ratio?

The main challenges involve careful planning and methodological rigor. The endpoint hierarchy and thresholds must be defined up front and agreed upon by clinicians, statisticians, and patient advocates; otherwise, results can be questioned. Win ratio calculations exclude pairs that tie across all endpoints, which can bias results if not interpreted properly. Because the method is less conventional outside certain therapeutic areas, regulators and payers may require additional explanation and justification. And operationally, the analysis requires detailed data handling, thoughtful sensitivity analyses, and early alignment with stakeholders.

Why might Epicrispr consider this strategy in FSHD?

For Epicrispr, the win ratio provides a structured, credible way to capture the type of multidimensional benefit that a precision epigenetic therapy may deliver. Because our mechanistic approach has the potential to improve strength, slow or halt progression, reduce fatigue, or improve quality of life, depending on the individual, a traditional single-endpoint readout may underrepresent true patient value. The win ratio allows us to quantify these improvements in a unified metric, strengthening the clinical narrative and potentially increasing the likelihood of a positive study outcome, especially in a rare disease with variable trajectories like FSHD.

What would next steps look like if Epicrispr were to incorporate the win ratio?

The next steps would include convening FSHD clinical experts, statisticians, and patient-advocacy groups to align on the most meaningful endpoints and their proper ordering. We would predefine thresholds of meaningful change and incorporate the method into a prospective statistical analysis plan. Regulatory engagement — early and often — would ensure alignment and clarity on expectations. The goal would be to run the win ratio as a prespecified secondary or supportive endpoint, enhancing interpretability and credibility while capturing the broadest picture of therapeutic benefit for FSHD patients.

About The Expert:

Amber Salzman, Ph.D., is Epicrispr’s chief executive officer and director. Before joining Epicrispr, Dr. Salzman served as the president and CEO of Ohana Biosciences, pioneering the industry’s first sperm biology platform. Before Ohana, she served as the president and CEO of Adverum Biotechnologies and was a co-founder of Annapurna, SAS.

Dr. Salzman began her career as a member of the GSK research and development executive team, where she oversaw global clinical trials with over 30,000 enrolled patients, and managed 1,600 employees and a $1.25B budget. Following her time at GSK, Dr. Salzman served as the CEO of Cardiokine, a pharmaceutical company that developed treatments for the prevention of cardiovascular diseases. Dr. Salzman currently serves on the Osler Diagnostics (UK) and AviadoBio (UK) boards.

Dr. Salzman received her bachelor’s degree from Temple University and holds a Ph.D. in mathematics from Bryn Mawr College. Dr. Salzman also leads the Stop ALD Foundation, a non-profit medical research foundation focused on developing novel gene therapies for adrenoleukodystrophy (ALD).