Guest Column | May 28, 2019

How Development Of A Clinical Rating Scale Provided Deeper Insights In A Rare Disease Trial

By Joseph P. Horrigan, M.D., chief medical officer, AMO Pharma


In research related to many rare genetic diseases, availability of long-term benchmark data to support the development of accurate assessments is limited1. This can have a detrimental effect on new product development.2 To address this challenge and ensure that clinical development efforts render meaningful results, there is a need to develop outcome measures that assess the entire characteristic clinical phenotype of any given rare genetic condition.

Consider the challenges, for example, in assessing and developing a therapeutic agent to treat a rare and complex disease like myotonic dystrophy (MD). There are two types of this disease, including myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2). DM1, or Steinert disease, results from abnormalities within the DMPK gene on chromosome 19, while DM2 involves the ZNF9 gene on chromosome 3.3 DM1 is the most common form of myotonic dystrophy, and it can be broken down into separate subtypes, including congenital, juvenile, and adult onset.4 People living with congenital DM1 typically experience lifelong difficulties with thinking, problem solving, and speech and experience symptoms of autism, as well as weak muscles, muscle cramping, or myotonia. Other organ systems, such as the GI tract, can be adversely affected. There are currently no approved therapies for any form of DM1; most patients are treated with medical interventions designed to address individual symptoms as they arise.

Use of a systematic scale in assessment of clinical response can provide broader and more accurate insights that could lead to more targeted and effective treatment decisions. Conversely, the use of outcome measures that focus on only a limited subset of the signs and symptoms of a condition like congenital DM1 may confer a lower chance of success in identifying benefit in intervention trials or may inadvertently convey an impression of limited utility and therapeutic attractiveness. An overly narrow focus in symptomatic assessment may also not be aligned with contemporary FDA guidance concerning the development of therapeutic agents for muscular dystrophies5 or may generate concerns about pseudo-specificity.

Professor Chad Heatwole at the University of Rochester was among the first to develop a rating scale or index to assess therapeutic change in DM1. Through his work, the Myotonic Dystrophy Health Index (MDHI) was introduced as a tool to provide more precise and complete assessments of disease progression and quality of life compared to other widely used but non-specific outcome measures. MDHI offers a patient-reported outcome (PRO) measure specifically engineered and validated to assess developmental changes in people living with adult onset myotonic dystrophy. This scale was not designed to address the specific characteristics of congenital and childhood onset DM1. To address this issue, Dr. Nicholas Johnson, in conjunction with Heatwole, worked to develop the Congenital and Childhood Myotonic Dystrophy Health Index (CCMDHI), based on extensive registry work, a review of natural history studies, and patient and caregiver surveys.

These scales have been extensively validated and are the subject of multiple peer-reviewed publications, and they formed the basis for further development of a clinician-completed derivative of the CCMDHI for use in clinical trials, with the aim of assessing the entire clinical phenotype of congenital DM1, a severe form of the disease, affecting about one in 40,000 people.6

A team at AMO Pharma worked closely with Johnson and Heatwole to develop this clinician-administered derivative for congenital DM1, called the CDM1-RS rating scale, which is intended to canvas the key areas of potential impairment in individuals affected by early-onset myotonic dystrophy. The development process leveraged the AMO Pharma team’s prior work to assess the characteristics of other rare genetic disorders, including Rett syndrome and fragile X syndrome. The CDM1-RS rating scale was designed as a fit-for-purpose scale that identifies and assesses 11 observable characteristics of CDM1 and rates each on a four-point Likert scale. Characteristics reflected in the scale include:

  1. Limitations with mobility or walking
  2. Problems with hands or arms
  3. Signs of fatigue
  4. Signs of pain
  5. Gastrointestinal issues
  6. Communication difficulties
  7. Impaired sleep or daytime sleepiness
  8. Difficulty thinking
  9. Myotonia
  10. Breathing difficulties
  11. Choking or swallowing issues

The scale was refined over two years during discussions with the FDA and addresses the essential need to assess the entire range of symptoms of congenital DM1, including central nervous system (CNS) issues that are often overlooked when significant muscle-based symptoms are present. The utility of this rating scale and its capacity to detect clinical meaningful changes were investigated in a Phase 2a study of AMO-02 in adolescents and adults with early onset DM1.

AMO-02 (tideglusib) is an oral inhibitor of glycogen synthase kinase 3 beta (GSK3ß). In cellular and animal models of DM1 and Duchenne muscular dystrophy, as well as in muscle biopsies from patients, activity of glycogen synthase kinase 3 beta (GSK3ß) has been shown to be increased. Inhibitors, including AMO-02, have in some cases been shown to correct the activity of regulatory proteins such as CUGBP1 and splice variants of tissue differentiating proteins in muscle tissue from patients and in animal models of DM1.

The Phase 2a study to evaluate AMO-02 involved 16 patients between the ages of 13 and 34 living with myotonic dystrophy type 1. Patients received either an oral dose of placebo, 1,000 mg/day of AMO-02, or 400 mg/day of AMO-02 over a 14-week treatment period. The study used the scale as a primary endpoint. Subsequently, AMO-02 was shown to be safe and well tolerated, with no early discontinuations or dose adjustments required. Most patients treated with AMO-02 also showed clinical benefits that were reflected in changes in the rating scale, including improvements in cognitive function, levels of fatigue, and the ability to perform daily tasks. AMO-02 also rendered improvement in co-occurring autism symptoms in several patients. There was a demonstrated greater response in patients who received 1,000 mg/day of AMO-02 versus the 400 mg/day dose.

Following the Phase 2a study, AMO conducted a concordant analysis of the entire set of results that corroborated the initial conclusions about the potential therapeutic utility of AMO-02, as well as the potential value of this novel rating scale. The FDA has subsequently agreed to the use of this clinician-completed rating scale as the primary outcomes measure in a Phase 2/3 registration-caliber study in children and adolescents with CDM1 that is being planned by AMO Pharma. This scale is also being validated in an ongoing natural history study in children and adolescents with congenital DM1.

The process of creating this scale, implementing it in a Phase 2 clinical trial to evaluate an investigational therapy, and then completing analysis of the results to ensure consistency of the findings highlights the essential steps necessary to guide clinical research that may ultimately provide new therapeutic options for patients living with CDM1. This effort also represents a model for similar rare or orphan diseases that have been relatively understudied compared to more common disorders. Efforts to develop high-quality clinical rating scales represent an important step in the path toward bringing the benefits of research to individuals affected by these rare disorders with the hope of ultimately improving their lives.


  1. McDowell I. Measuring Health: A Guide to Rating Scales and Questionnaires. 3rd ed. New York, NY: Oxford University Press; 2006.
  2. Unutzer J, Harbin H, Schoenbaum M. The collaborative care model: an approach for integrating physical and mental health care in Medicaid health homes. Accessed May 7, 2019. 
  3.  “Myotonic Dystrophy - Genetics Home Reference - NIH.” U.S. National Library of Medicine, National Institutes of Health, Nov. 2010,
  4. Bird TD. Myotonic Dystrophy Type 1. 1999 Sep 17 [updated 2015 Oct 22]. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from
  5. Center for Drug Evaluation and Research. “Duchenne Muscular Dystrophy and Related Dystrophinopathies.” FDA, FDA, Feb. 2018,
  6. Wesstrom G, Bensch J, Schollin J. Congenital myotonic dystrophy. Incidence, clinical aspects and early prognosis. Acta Paediatrica Scandinavica. 1986;75:849–54.

About The Author:

Joseph P. Horrigan, MD, chief medical officer at AMO Pharma, is a pediatric neuropsychiatrist with 20 years’ experience in the pharmaceutical and biotech industries. Previously, he was the senior director in the Neurosciences Medicines Development Center at GlaxoSmithKline, served as assistant VP and head of medical research for patient advocacy organization Autism Speaks, and acted as VP of clinical development and medical affairs for Neuren Pharmaceuticals Limited. He received his Sc.B. degree from Brown University and his medical degree from the University of Rochester, and he is currently a consulting associate professor at Duke University.