Innovator Spotlight

Q: What is the purpose and scope of the ALS Therapy Development Institute’s new Precision Medicine Program?

The Precision Medicine Program (PMP) seeks to gain critical new insight into the mechanisms of amyotrophic lateral sclerosis (ALS) onset and progression. This will be accomplished by obtaining a comprehensive background on 750 ALS patients’ medical history, demographic information, and lifestyle history. The questionnaires on lifestyle will deeply explore each participant’s employment history, military service, participation in organized sports, exercise habits, nutritional preferences, and history of sickness and injury. These data will be compiled with an integrative analysis of each participating patient’s genetic data obtained by full genome sequencing. The progression of disease will be tracked by collecting monthly data on wellness using the ALS Functional Rating Scale (FRS), quantitative tracking of movement using accelerometers, and changes in speech and swallowing using monthly voice recordings. ALS FRS is a quality of life questionnaire on one’s ability to perform routine daily activities. The answers are subjective and can change day to day based on mood, energy level, time of day, and a number of other non-quantifiable variables.

In addition to their health data, patients can donate blood samples, and new drug development tools will be created from patient-derived cells that will be instrumental for identification of subsets of ALS patients.

Importantly, the PMP program is providing all participants access to their data via a secure online portal. Patients can track the workflow from blood sample collection, to preparation of DNA from the blood sample, to completion of a full genome sequence. The results of ALS-associated genetic variation will be provided if a participant wants access to this information. There are similar work flows that will graph monthly self-reported ALS FRS, voice recordings and the activity data from accelerometers.

Q: What was the need you saw that the Precision Medicine Program was created to address?

There are three major challenges with current drug development processes in ALS:

(1)    The vast majority of ALS patients do not have the genetically inherited form of the disease. Yet preclinical models to understand disease mechanisms, and to develop lead candidate molecules, are based on genetic mutations representing only a small fraction of ALS patients.

(2)    The site of disease onset and progression rates of ALS patients are highly heterogeneous. At time of diagnosis it is impossible to predict if an ALS patient will survive six months or ten years. Patient heterogeneity complicates clinical trial design, requiring large numbers of patients to reach statistical significance.

(3)    Current clinical trial endpoints are subjective and not quantitative. In the last decade, more than 50 phase II and phase III ALS clinical trials have failed to reach clinical endpoints using the ALS FRS as a primary endpoint.

Q: What have been the biggest challenges in planning, launching and sustaining this effort? What lessons have you learned? 

There have been numerous unforeseen challenges along the way. A significant obstacle was obtaining IRB approval for an e-consent clinical study. One must work very closely with the IRB in order to create an online regulatory compliant system that ensures a participant’s understanding of every aspect of the study. An additional challenge was building custom web-based data and knowledge management systems required to collect and analyze disparate data types in a Precision Medicine Study. It is amazing that there are no “off the shelf” bioinformatics tools to aggregate clinical data, genetics data, wellness data, voice recordings etc. These systems currently need to be custom built to suit the needs of the study. Participant compliance in a longitudinal study can also be challenging. One must build reminders and incentives into participation in order to collect quality data over time.

Q: Are there any early successes you can point to?

There are several exciting outcomes from the program at this time. Preliminary data suggests that voice recording and accelerometer data are more accurate predictors of disease progression. These types of outcome measures could change the design and interpretation of phase II and phase III clinical trials. They may be capable of patient stratification and earlier assessment of disease modification. In addition, sharing genetics data has dramatically impacted several families in the program by either identifying a de novo mutation with no known history of ALS, identifying a rare genetic cause not typically screened for, or by eliminating the possibility of familial ALS.

Q: What advice would you give other foundations that might be interested in undertaking a similar effort?

  • Do not underestimate the data infrastructure required.
  • Do not underestimate the financial investment.
  • Do not forget that patients are now part of the drug development process. Wearable technologies, at-home blood monitoring, and other non-invasive outcome measures will shift some focus from clinical visits to at-home monitoring in real time. But by bringing the patient into the process of monitoring disease activity, the demands to share and interpret complex data can be challenging to scientists and clinicians.