Translational CNS Summit 2014: Highlights of the Meeting

Prize4Life recently took part in the Translational CNS Summit 2014 organized by Hanson Wade on April 30th, 2014 in Boston, MA. The meeting centered on approaches for derisking CNS drug development improving success rates of clinical trials. The Summit offers a unique forum for brainstorming discussions among top executives and leaders in the neurological disease space on approaches to overcome key challenges to drug development for neurological disease. While many of the session included thought-provoking discussions, here we focus on a few highlights with potential relevance to ALS.

The session on Biomarker and Imaging Technologies opened with Jeffrey David Lewine, Ph.D., Professor of Translational Neuroscience at the Mind Research Network discussing imaging and electrophysiological approaches to identify biomarkers for neurological diseases. Dr. Lewine presented the impressive infrastructure for biomarker screening at the MIND Research Network (MRN), a non-profit organization headquartered in Albuquerque, New Mexico, with a broad range of capabilities in genetics, electrophysiology, behavioral studies and biomarkers. The MRN also has extensive expertise in analysis and informatics, including approaches for integrating multimodal brain imaging and genetics data and using sophisticated multivariate methods to identify the best clinical correlates. Dr. Lewine focused his presentation on some of the cutting edge translational research programs at MRN. In the area of autism, they are using magnetoencephalography (MEG) to monitor activity profiles in children with epileptiform activity during sleep. Their analysis methods are able to distinguish autistic children that will respond to steroid treatments from non-responders based on their distinctive MEG profiles.  In a separate project, in collaboration with a California-based company, they are developing a portable 32-channel electroencephalography (EEG) hat with an easy set-up that can be used for research in the clinic and at home. And what about partnerships with MRN? The MRN has a wide range of partnerships, with academic institutions as well as with pharmaceutical companies interested in identifying biomarkers to improve predictability of their clinical studies.   Although they don’t currently have an ALS program, they would likely be a great resource for biomarker studies in ALS.

Enchi Liu, Senior Director, Clinical Development, Janssen Alzheimer Immunotherapy raised questions about the utility of biomarkers for accelerating therapy development for Alzheimer’s disease (AD) with a focus on two recent high-profile clinical trials in AD that failed in phase III, solanezumab and bapineuzumab. Dr. Liu started by posing two questions to the audience: can biomarkers be used to select patients for therapeutic clinical trials for AD? Can use of biomarkers as therapeutic monitoring tools accelerate therapy development for AD? These are also pertinent questions for ALS, given the heterogeneity of the disease and difficulty translating findings from preclinical models to humans. To address the first question, post-hoc analysis of amyloid-positron emission tomography (PET) imaging data from clinical trial subjects from both Phase III trials showed that 20-30% of the patients enrolled were amyloid negative, despite the fact that both drugs target Aβ (mid-region and N-terminal region, respectively). In addition, the amyloid positive patients performed worse on baseline cognition than amyloid negative subjects and declined more rapidly over 18 months. These findings suggest that in future studies, exclusion of amyloid negative subjects may improve the ability to detect a treatment effect, and also focus the treatment on the patient subpopulation most likely to benefit based on the mechanism of action of the drug. Dr. Liu also discussed another useful screening biomarker in AD, fluorodeoxyglucose (FDG)-PET. This approach can segregate AD subjects from frontal dementias (FTD) and Lewy Body disease (LBD) patients, and has potential for predicting  rate of clinical decline in interventional trials for AD.

However, the utility of biomarkers for therapeutic monitoring was less clear. Can biomarkers be leveraged to make early go/no-go decisions about candidate therapies? Review of the biomarker data from the Phase II bapineuzimab trial suggests otherwise. In the Phase II studies of bapineuzimab, biomarker studies showed reduced Aβ burden by Pittsburgh Compound B (PiB)-PET, and exploratory studies showed reduced the levels of total tau and phospho-tau in the cerebrospinal fluid (CSF), suggesting a positive effect of the drug on neuronal degeneration. Both findings supported further clinical testing of bapineuzimab in Phase III studies. However, in Phase III, no clinical benefit with bapineuzimab therapy was detected, despite an effect based on the amyloid-PET and CSF tau biomarker profiles. So, why did bapineuzimab treatment fail? Is Aβ the correct target? Were the doses too low, or the drug administered too late in the course of disease?  One of the main conclusions is that primarily clinical outcome needs to be distinguished from the biomarker activity, and correlative biomarkers may not be a good marker for effects on the underlying causes of disease. Lessons learned from biomarker studies in AD will also likely help inform future biomarker studies in clinical trials for other neurodegenerative diseases such as ALS.

Another exciting talk of the day was given by Franz Hefti, CEO of Acumen Pharmaceuticals, Inc., discussing the company’s promising soluble Aβ oligmers (sAβo)-targeting immunotherapy for AD. The sAbo are the most synaptotoxic, albeit rare, Aβ  species, causing inhibition of long-term potentiation and disruption of calcium homeostasis, as well as promoting neurodegenerative processes such as oxidative stress. Acumen’s antibody, ACU-193, is a fully humanized, IgG2 monoclonal antibody that shows very high selectivity for sAβo vs. monomeric Aβ, amyloid plaques or vascular amyloid. ACU-193 exhibits excellent PK, biodistribution and brain penetration in the range typical for therapeutic antibodies. The company has already completed safety and toxicity studies in monkeys and demonstrated an excellent safety profile for the antibody.  The company expects to file an IND within one year and will initiate a Phase 1b study that incorporates companion biomarker studies as well as exploratory functional endpoints, such as visual long-term potentiation (LTP).  The company anticipates that within 3 months beneficial effects of the treatment on cognition and memory in mild to moderate-AD patients will be obtained. We look forward to hearing about the outcome of the trial and the utility of the biomarkers in translating this promising therapeutic to humans.

Richard Margolin, VP of Clinical Development at CereSpir, Inc., gave a thorough overview of the history of clinical trials for AD and factors contributing to their failure in the clinic. The challenges he raised are very reminiscent of those faced in drug development for ALS: at the preclinical stage, there exist a multitude of mouse models with different time courses and deficits, and efficacy of drugs in the mouse models have failed to translate into human benefit; at the clinical development stage, challenges are due to uncertainty of target engagement, heterogeneity of the disease phenotype, and chronicity of the disease requiring long and expensive trials.  In addition, the field has been largely focused on drugs targeting Aβ, overlooking other relevant and important targets, such as neuroinflammation.  Dr. Margolin then delved into the wealth of evidence supporting an inflammatory component of pathophysiology very early in course of disease. First, epidemiological studies support a reduced incidence of AD in individuals taking anti-inflammatory medications for other medical conditions, with greater benefit with early and prolonged consumption. In addition, basic research studies provide evidence for neuroinflammatory processes in AD, and the ability of non-steroidal anti-inflammatory drugs (NSAIDs) to modulate γ-secretase activity, possibly mediating their beneficial effect. However, anti-inflammatory drugs have either failed in clinical testing for AD or been discontinued due to severe cardiac side effects. Would earlier treatment potentially be more beneficial? This question remains unanswered.

Dr. Margolin then went on to present Cerespir’s promising new candidate therapeutic for AD called CHF 5074, a first in class small molecule microglial modulator. Microglia are resident immune cells of the nervous system, and alternate between pro-phagocytic (M2) and proinflammatory (M1) phenotypes. Under healthy conditions, microglia remove pathogens and waste products, including Aβ aggregates, but their function is impaired in AD leading to further accumulation, of Aβ as well as inflammation. CHF5074 has a dual effect of reducing the inflammatory phenotype of microglia and their ability to remove neurotoxic Aβ aggregates by phagocytosis. The company is preparing to embark on a two Phase III studies in 2014, building on strong preclinical and clinical data. In AD transgenic models, CHF5074 reduces neuroinflammation and tau pathology, reduced Aβ plaque burden and reverse memory deficits.  Completed Phase I and II studies have already demonstrated drug safety in mild cognitive impairment (MCI) and AD patients.  Evidence from the companion biomarkers supports efficacy of the drug, as CHF5074 treatment leads to reduction in pharmacodynamic biomarkers of inflammation (TNFα and CD40L) but not in other biomarkers such as Aβ42 and phospho-tau. As a side note, CD40L has been shown to be a potentially relevant target for ALS therapy (Lincecum et. al., 2010) and might be further indication of the potential of this drug to treat neuroinflammatory processes in ALS.  Hopefully this will be a success story in clinical trials for AD!

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