By: Rich Bennett, Executive Director, Therapeutic Strategy Lead, Neuroscience & Lucie Undus, MD PhD, Executive Director, Therapeutic Area Medical Lead, Neuroscience
Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease that presents multiple complications which make study design and conduct particularly challenging. However, with the emergence of new techniques and the application of lessons learned from previous research, the future of ALS clinical development is increasingly optimistic.
Below, we discuss the current considerations and future directions for ALS study design and overcoming the impact of symptom presentation-associated challenges faced by the patient, caregiver, and investigator.
Importance of Controlling for Heterogeneity in Disease Presentation and Progression
ALS is diagnosed based on the evidence of progressive motor impairment and the presence of upper and lower motor neuron involvement. Protein aggregation is a pathological hallmark of ALS; however, the precise pathological effects of it, including how a disturbance of these proteins can result in motor-neuron-specific degeneration, remains an unresolved issue in ALS research. Furthermore, several other mechanisms have been implicated in the pathogenesis of ALS:
The discovery of new druggable targets within these pathways has diversified the therapeutic classes in clinical development. Likewise, the emergence of combination therapies has been a natural development in the field.
ALS is a condition where affected patients develop progressive muscle weakness, eventually leading to death due to respiratory failure, typically 3–5 years after symptom onset. There is, however, a broad heterogeneity in disease progression with slow, intermediate, and fast progressors identified. There are several ALS phenotypes based on the first sign or symptom, the location, and the pattern of progression across the body region. The decline rate may be curvilinear, meaning we expect observations of natural fluctuations in progression rates with plateaus and reversals.
The challenge of studying heterogeneous presentation and progression rates is that the large degree of variability may affect the ability to detect an efficacy signal. Trialists may deploy various methods in attempts to define the studied population to control for disease heterogeneity in ALS:
- Use of diagnostic criteria such as El Escorial criteria, Gold Coast criteria, or Awaji criteria
- Precision regarding permitted first sign/symptom used to define disease onset
- A basic enrichment strategy to define a more homogenous population, typically using factors such as time from onset, level of preserved function (ALSFRS-R score at screening), and respiratory performance (e.g., vital capacity at screening).
- Prediction models are a more comprehensive form of enrichment strategy that use multiple combined prognostic factors that are known to correlate with progression rate such as the ENCALS survival prediction model and El Escorial criteria
- Stratification factors such as bulbar onset, use of permitted background therapies, or predicted prognosis
- Covariates in data analysis
By embracing current technological advancements (e.g., machine-learned prognostic modeling, AI-digital twins, and patient stratification algorithms), we can improve subpopulation-specific predictions in disease progression and optimal study parameter design. It may also be possible to reduce or avoid using placebo control groups and compare study participant outcomes with their own natural history predication.
With enrichment strategies applied in clinical trials designed to detect or confirm efficacy signals, studies with other objectives, such as establishing safety or pharmacokinetic profiles, may benefit from broader entry criteria.
Early Intervention Challenges and Delays in Recruitment and Treatment Possibilities
The work-up required to diagnose ALS is a complex and demanding process during which other disorders with similar clinical manifestation must be ruled out. Medical and clinical history, neurological examination, supported by electrodiagnostic studies and imagining studies can be used to assess the likelihood of ALS. The use of genetic testing varies significantly in clinical practice.
Current diagnostic methods fail to identify the disease before symptom onset, such that a significant proportion of the motor neurons may have atrophied by the time it is diagnosed. The average time from symptom onset to diagnosis is reportedly approaching 12 months. This makes it significantly less likely for a treatment to reverse progression, presenting an overall challenge to establish a sound early intervention strategy.
Diagnostic delays lead to treatment delays, compounded by the impact of variable treatment approaches and study designs (Figure 1), which currently exist to handle the heterogeneous patient population. This highlights the need for optimizing and harmonizing diagnostic criteria to expedite access to treatment. Creative attempts at earlier diagnostics, such as speech analytic tools coupled with AI, are beginning to gain some ground. However, their utility in clinical trials, where the accepted diagnostic criteria prevail, is yet to be seen.
Figure 1. The “diagnostic odyssey” that patients and practitioners traverse.
Endpoint Selection and Observation Period
The variability in progression contributes to the difficulty associated with optimal study parameters and endpoint decisions. Some possible considerations to overcome related challenges include the following:
- EMA & FDA guidelines suggest that survival (including PAV and tracheostomy surrogates as a composite endpoint), functional decline, or respiration should be the primary endpoint for a disease-modifying therapy.
- Combined Assessment of Function and Survival (CAFS) and other joint analyses have been used in longer-duration trials or as secondary endpoints in shorter-duration trials to overcome the confounding effect of survival on function.
- Secondary endpoints may include muscle strength, respiratory function, bulbar function, disease stage, health-related quality of life, and cognition or behavioral screens.
Beyond this, it is essential to emphasize the caregiver, especially as the disorder progresses. Administering the Zarit caregiver burden scale could serve as an additional metric for project success. It would suggest positive results if the treatment group displayed a slower increase in caregiver burden compared to the control.
The length of the study observation period is a crucially important study design parameter that warrants consideration alongside primary endpoint selection. The length must be balanced against many factors, including toxicology coverage, IP supply, study objective, eligibility criteria, and regulatory sentiments. By modeling the study entry criteria, endpoints, and effect size against data in ALS databases such as PRO-ACT, the optimal duration of the study can be determined either by effect size in ALSFRS-R, vital capacity, or several anticipated survival events.
Importance of Patient-Centric Approaches in ALS Research
There are many ongoing and planned ALS studies across all phases of development. However, the geographical locations of trial sites, application of strict entry criteria, and limited patient-centric accommodations in study design or operations can significantly hinder the ability of a person living with ALS to access an experimental medicine through a trial. If successfully enrolled in a trial, participation can be difficult due to the day-to-day challenges inherent to living with ALS and the increasing dependence on their caregiver to facilitate their trial participation.
With the high study volume and small patient population, ALS study sponsors have an obligation and an opportunity to embrace patient-centric approaches within their trial design and operations. Patient-centric optimization presents an opportunity to distinguish your study among patients and caregivers. Adopting patient-centric measures will significantly reduce the burden of participation and engage patients and caregivers as your partners. Patient-forward accommodations for trial design include:
- Increasing the patient voice in clinical trial protocols, design, and operations to ensure a participant-research-partnered review of patient-facing materials
- Prioritizing hybrid-decentralized operations such as the support of home health services, ePRO, telemedicine, and direct-to-patient IP shipments
- Including travel accommodations for the participant and relevant caregiver(s)
- Adjusting the frequency of assessments over time — reduce site visits after initial dosing and safety evaluations
- Emphasizing study endpoints that are vital for the objectives and avoiding extraneous assessments
At Worldwide, our commitment to the patient goes beyond strict requirements, domestically or abroad; we base many of our study design recommendations on the Patient-Centric Trial Design (PaCTD) rating system developed by “I AM ALS” and partner with ALS advocacy groups to promote the patient and caregivers. Read our blog written in partnership with EUpALS for more information about the vital need to prioritize the patient.
Future-Forward: Achieving Better, More Rapid Outcomes
As the wider ALS community continues to share best practices and adopt approaches that have been successful in other indications, there may be greater unification of regulatory sentiments. This lack of unity among regulators has challenged ALS development, since prioritizing specific drug markets has been a critical factor in drug development strategy.
While enrichment strategies exist to support the likelihood of observing or confirming efficacy signals, the unintended outcome has been that people with ALS have a short window after diagnosis to decide whether they will consider a trial. Furthermore, this decision is crucial as it is likely that they will only meet the typical entry criteria once and can only join a single study. Geographical expansion must be the first logical step to increasing access to clinical trials in ALS and the application of technologies that allow for broadening entry criteria where possible.
Embracing new technology and ensuring patient-centric study approaches will improve the design, operations, and burden of participation in ALS trials of the future. By employing new technologies, we set ourselves up for earlier diagnosis, increased signal detection, and less need for data imputation through greater patient retention.
These considerations only scratch the surface of what is needed to run a successful ALS study; at Worldwide, we understand the complexities, burdens, and optimal approaches for success in ALS research. Our experts are ready to speak with you about your ALS trial; contact us today!
