t’s not just about survival, it’s about increasing or maintaining function as a patient. While you’re still able to, you know, give a hug to a child, or take a sip of water, … the focus seems to be on survival. And I agree, that is the end game. But functionality until you get to the cure is equally important.” —Steven Kowalski, ALS patient and patient advocate.

Recent advancements in the development of effective therapeutic options for amyotrophic lateral sclerosis (ALS) demonstrate the promise of a range of modalities, progress in the approach to streamlining clinical trials, and the benefits and promise of integrating novel endpoints into research to better describe outcomes. These advancements in the ALS development ecosystem create an opportunity to better integrate patient preferences, consider prioritization of the role of survival versus other endpoints in therapeutic development, and translate lessons to other therapeutic areas.

New Approaches and Trial Designs in ALS

The emergence of new therapies for ALS has led to new approaches to clinical trial design and new ways to measure the impact of these therapies. These new designs and tools have helped pave the way for the success in ALS therapeutic development we see today.

Traditional ALS trials tested a small molecule in a standard parallel design with 1:1 randomization. Participant enrollment criteria were quite broad, and standard outcome measures—survival, ALS Functional Rating Scale-Revised (ALSFRS-R), vital capacity, and isometric strength—were integrated. Biobanking for future biomarker work was a common component.

But medicines in development for ALS today include not only small molecules (some of which are repurposed from prior uses) but also antibodies, antisense oligonucleotides (ASO), gene therapies, and cell therapies. Antisense approaches can target both rare ALS-causative gene mutations and genes with broad application to all forms of ALS, providing the potential for cures as well as for the slowing of disease progression. Gene therapies are in development targeting ALS-causative gene mutations. Finally, cell therapies may be stem cells and precursor cells, meant to reduce inflammation to give neurotrophic factors the chance to be supportive to the motor neurons; or immune regulatory cells, including regulatory T-cells and B-cells that have the potential to bring immune regulation to the disease.

Today, additional outcome measures supplement the ALSFRS-R, including scales related to quality of life and fatigue as well as relatively new functional outcome scales such as the Rasch-built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS). ROADS is a true patient-reported outcome measure, while the ALSFRS-R has historically been administered by an external rater.

Biofluids and biomarkers are also coming of age in ALS trials. For example, neurofilament light, a neuron-specific structural protein, was an important marker contributing to the approval of an ASO. Another molecule, TDP-43, a protein that is mutated or aggregated in most ALS cases, has traditionally been hard to measure due to its sticky biochemical nature. However, surrogate markers can now be evaluated as a proxy for abnormal TDP-43 thanks to the development of new diagnostics. Other new inflammatory biomarkers for ALS are also coming of age.

Finally, digital outcome measures are changing the way we gather data from people with ALS and participants in trials and are making it possible to get more information and make decisions about clinical development more quickly. Electronically capturing task-based objective measures frequently performed by people in their own homes, and passively recording how people live their lives, are all possible with wearables. Digital biomarkers obtained through accelerometers or voice recordings and quantitative motor speech analysis can provide objective quantitative measures of everyday activities. Through electronically captured patient-reported outcomes (ePROs), patients provide subjective reports of how they feel or function.

Modernized trial designs are making strides to reduce placebo burden by moving away from one-to-one randomization, shortening RCTs, reducing in-clinic visits by increasing remote visits, and incorporating nonconcurrent controls or prediction models to try to boost statistical power and replace concurrent placebo arms.

However, major barriers still exist, including which outcome measures to use to inform a trial, and ultimately approval. Both overall survival and the ALSFRS-R are being applied, but inconsistent global regulatory acceptance hinders efficiency in development and scaling solutions.

Survival versus Surrogate Endpoints

Survival endpoints are considered clinically meaningful as they directly measure the goal of treatment, which is to prolong the patient’s life. They provide a clear and objective measure of treatment efficacy, especially in diseases with a well-defined and predictable progression. However, their usefulness can be limited by the time required to observe meaningful differences in patient outcomes, which can prolong clinical trials and delay drug approval. In addition, patient preferences such as quality of life and symptom relief may not be fully captured by survival endpoints, leading to potential discrepancies between treatment benefits and patient needs.

In contrast, surrogate endpoints like Quality of Life (QoL) and ALSFRS-R can offer more accessible and shorter-term measures of treatment efficacy, allowing for faster decision-making in clinical trials. They may also provide insight into the patient experience, capturing aspects of the disease above and beyond survival. One of their disadvantages includes the need to thoroughly assess their validity to ensure that the chosen surrogate endpoints reliably reflect treatment effects on the clinical outcomes. Additionally, the use of surrogate endpoints can be particularly challenging in diseases like ALS, where disease progression and patient status may introduce variability in treatment responses.

Disease and patient status can influence the choice of endpoints used in ALS research. For example:

• Functional endpoints like ALSFRS-R may be more relevant in the early stages of the disease, while survival endpoints might be more appropriate in later stages.
• The use of functional endpoints as primary measures can provide valuable information about treatment effects on patient functionality.
• Quantification of outcomes can help standardize the assessment of treatment effects across different patient populations.
• Assessing QoL and Patient-Reported Outcomes (PROs) can offer insights into the patient’s experience and satisfaction with treatment.

In conclusion, the choice between survival and surrogate endpoints in ALS research involves considering the trade-offs between a relatively long wait for survival endpoints and the shorter-term accessibility and practicality of surrogate measures. Disease and patient status also play a crucial role in determining which endpoints are most relevant and informative. A comprehensive and thoughtful approach is necessary to strike a balance between these considerations and make informed decisions for effective treatment development in ALS.

The Role of Patient Preference

Patient preferences hold significant importance in the treatment of ALS. Since survival outcomes in ALS can vary greatly, understanding and respecting patient choices is essential in managing the disease and determining treatment approaches. Patients’ individual preferences can influence the decisions they make regarding their care, including treatment options, participation in research and trials, and end-of-life decisions.

Assessing patient preferences is also critical for evaluating the quality of care provided and determining the value of different endpoints in clinical trials and research. By considering patient preferences, healthcare providers and researchers can tailor treatments and interventions to better meet the needs and desires of individual patients.

Collecting more patient data on preferences is key to making informed and patient-centered decisions. This data will serve as a foundation for enhancing decision-making processes in ALS care and research. By incorporating patient perspectives, healthcare professionals can improve the overall patient experience and optimize treatment strategies that align with patients’ values and goals.

What is Needed to Integrate This Thinking?

To successfully integrate the above thinking around developing treatment solutions for ALS patients, several steps are necessary. Firstly, collating and analyzing multiple data sets from clinical trials is essential to gaining comprehensive insights into patient preferences and treatment outcomes. This data-driven approach will help inform decision-making and improve patient-centered care.

Second, reaching an agreement on the requirements for standardized endpoints is crucial. Consistency in measurement and assessment will enable better comparison and evaluation of treatment efficacy, leading to more reliable conclusions.

Furthermore, fostering collaboration among various stakeholders, including pharmaceutical companies, regulatory bodies, and payers, is essential. By working together, these entities can pool resources and knowledge to address specific challenges in ALS treatment and research effectively.

Finally, developing evidence-based standards for novel endpoints will contribute to the credibility and reliability of research outcomes. These standards will ensure that the chosen endpoints accurately reflect treatment effects and are relevant to patient experiences.

By implementing these measures, the integration of patient preferences, standardized endpoints, and collaborative efforts will lead to more patient-centric ALS treatments, streamlined research processes, and improved overall patient outcomes.