The 25th International Symposium on ALS/MND took place in Brussels, Belgium from 5-7 December 2014. This is the largest medical and scientific conference in the ALS community, and this year boasted close to 900 attendees.
The opening plenary talk was an inspiring presentation by Dr. Alfred Sandrock, M.D., Ph.D., Chief Medical Officer (CMO) of Biogen Idec (and member of Prize4Life’s Scientific Advisory Board). Dr. Sandrock presented his expert opinion of the challenges in ALS drug development and potential solutions to accelerate development of an effective therapy.
The classical approach to ALS drug development, as framed by Dr. Sandrock, would be to leverage insights gained about disease mechanisms to identify a critical pathway and the most promising target within that pathway. The logical next steps would be to begin preclinical testing in animal models, followed, if successful, by early phase clinical studies and culminating in a Phase III clinical trial. Sandrock emphasized the impressive progress that has been made in recent years in gaining insight about disease mechanisms, primarily due to advance in human genetics. However, despite the identification of novel drug targets, there remain significant hurdles in translating these efforts into effective therapies, as demonstrated the late stage failure of Biogen’s drug dexpramipexole in a Phase III trial in 2013 (the EMPOWER Study).
What are some of the remaining challenges to ALS drug development?
Challenges Surrounding the ALS mouse models: Unfortunately, results obtained in the ALS mouse models, such as mice expressing human mutant superoxide dismutase (mSOD1), exhibit limited reproducibility. Dr. Sandrock underscored the need to ensure rigorous testing in ALS mouse models, as laid out in publications by Sean Scott and colleagues of the ALS Therapy Institute (see Mar 2014 news story, Mar 2010 news story) and incorporated into Prize4Life’s ALS Treatment Prize, and to search for robust, reproducible effects under such standards.
Due to the inherent limitations of the animal models, which often also do not exhibit the full spectrum of human ALS, Dr. Sandrock has observed a general shift in the field away from using mouse models as the first and foremost tools in preclinical testing. Instead he presented a possible “second approach” to ALS drug development, where the initial steps involve disease modeling and drug screening in induced pluripotent stem cells (iPSCs) derived from ALS patients. In this approach, animal models are still used to assess safety, target engagement, pharmacodynamic profiles and dosing, but are not the primary model for efficacy studies.
Challenges for Early Phase Clinical Testing: Moving from preclinical to clinical testing, Dr. Sandrock highlighted several challenges for early phase clinical trials.
Clinical Heterogeneity: with the example of Biogen’s EMPOWER study, Sandrock explained that the placebo arm in the study was so diverse that the sample size requirements were unfeasible. One proposed solution would be to introduce a lead-in period of 3 months for tracking patients before they are assigned to a treatment and a control arm in order to enable some form of stratification. Dr. Sandrock also referenced Prize4Life’s ALS Prediction Prize and the potential for using the resulting algorithms for assessing disease progression in ALS patients (for more on the ALS Prediction Prize see Nov 2014 news story, Nov 2012 new story).
Genetic heterogeneity: The EMPOWER study also demonstrated the need to stratify patients based on genetic and molecular profiles – for example, there were wide differences in the cytokine profiles of different patients. Selection of the clinical trial cohort should be based on understanding the drug’s mechanism of action and correctly stratification of the patients. Sandrock underscored the need for biomarkers that can assess the drug effects, the target engagement and the pharmacodynamic responses on a patient-by-patient basis. Since this are so critical for evaluating whether the drug had the intended effect for treating ALS, Sandrock advocated for prioritizing human biomarker studies in both CSF and blood over animal studies.
Another important biomarker for ALS clinical trials is one for measuring disease progression, to allow more rapid and smaller scale early phase trials. Such a biomarker would need to be more sensitive than specific, have high test-retest reliability, and be cost effective and easy to use. In addition, it would need to detect motor neuron loss and correlate with ALSFRS. Currently, according to Sandrock, the most likely candidate would be electrical impedance myography (EIM), developed by Seward Rutkove of the Beth Israel Deaconess Medical Center in Boston, Massachusetts and winner of Prize4Life’s ALS Biomarker Prize (see Feb 2011 news story).
Drug Quality: it is essential to reduce overall risk of the treatment. For small molecules, quality assurance would include sensitivity and specificity, metabolism rate, pharmacokinetics measured in two species, solubility, cardiac channel modulation and protein binding levels.
In conclusion, Dr. Sandrock emphasized his view on the essential components needed for successful ALS drug development. These included 1) optimal drug-like qualities; 2) a variety of relevant and informative biomarkers measuring disease progression, target engagement and biological response; 3) informative experimental design with homogenous groups to the extent possible in both clinical and genetic features 4) a promising therapeutic target derived from genetics. Sandrock ended on an optimistic note – all of these areas have seen great advances in recent years and there is significant improvement in all these fronts.- Neta Zach