ALS Clinical Trials: What’s Wrong? And updates on NP001, sNN0029, Tirasemtiv and PreFALS

The International Symposium on ALS/MND Research is the preeminent meeting of the global ALS/MND community. It brings together hundreds of neuroscientists, neurologists, and associated health professionals for three days in a different country each year. 

Founded and operated by the MND Association, the 2014 meeting was the 25th annual installment and was held at the Square in the city of Brussels, Belgium, and hosted locally by the ALS Liga Belgie.  It was estimated that approximately 900 people attended the conference.  The meeting is typically split into two simultaneous tracks; one on basic science and the other spanning the issues and developments in clinical trials and related clinical topics, such as respiratory and palliative care topics. Several satellite meetings and poster sessions are also held.

This summary spans some of the talks offered.  Since many of the presentations made were pre-publication, presenters were asked to indicate whether or not outside reporting could be done on their talks.  Happily, most were offered without embargo.

What’s Wrong with ALS Clinical Research?

It is estimated by most that there are at least 400,000 people living with ALS/MND worldwide.  However, there are no currently effective treatments available. This reality inspired the opening plenary talk, from Alfred Sandrock, M.D., Ph.D., Chief Medical Officer at Biogen Idec.  He offered his expert opinion on drug development based on his experience as both a clinician and a scientist. Sandrock summarized that the biggest issues in ALS drug development are the lack of robustly predictive disease models, coupled with the inability to do well designed phase 1 and 2 clinical trials. He reviewed the work on dexpramipexole briefly and referenced a paper from Sean Scott of the ALS Therapy Development Institute which suggested that drugs screened in the SOD1 mouse model have failed to translate to the clinic due to poor preclinical design and the limitation of that model to recapitulate the relevant biology of many of the drugs screened in it to date.  On animal model development and use, Sandrock suggested to the audience that it was paramount to use animal models as tools to investigate specific disease biology and that no model is a perfect model of all aspects of ALS disease onset or progression.

In offering a path forward, Sandrock offered the audience an alternative approach, which may accelerate ALS drug development in certain cases.  This “Approach 2” as he termed it, would use human induced pluripotent stem cells as a basic model of disease, measuring specific genetic and biology to screen potential therapeutics.  As these cells are characterized, they could be used for drug screening directly.  He emphasized, however, the crucial role of developing a dosing strategy and relevant biomarkers and pharmacodynamics for compounds.  These two steps are where different animal models may be able to help greatly, according to Sandrock.

”We really need to look at surrogate endpoints before efficacy screening in people,” said Sandrock in hammering this point home.  One of the more direct recommendations that he offered to the trial designers and operators in the crowd was to do early stage trials correctly, which he suggested meant more than 100 people in each arm and including a placebo controlled arm of a trial.

PreFALS and the 29 Month Journey to Getting into Clinical Trials

Michael Benatar, MD, PhD, of the Miller School of Medicine at the University of Miami (USA), provided the opening talk of this session, in which he reviewed the extensive data from the PreFALS study which he and his collaborators have been conducting for the last several years. Before getting into specific FALS related data, Benatar commented about a significant problem in ALS: a delay in diagnosis and enrolling PALS into clinical research programs.  According to Benatar’s research, it takes on average 12 months to diagnosis a person from the onset of their symptoms, and an additional 17 months from there to successfully enroll that person into a clinical research program.  This delay can cause challenges for drug development.  However, in the PreFALS study, those diagnosed with ALS saw a much quicker enrollment path into clinical research: less than 5 months following their diagnosis on average, according to Benatar.

“On average, general practitioners see one or two cases of ALS during their career.  I don’t think we want to get the word out that every fasciculation should lead to a diagnosis,” said Benatar.  Specific efforts have been set up to attempt to address the diagnosis delay in PALS, including the identification of Red Flags, which can be distributed to general practitioners.  For example, the Red Flags identified and being distributed by the MND Association to general practitioners in the United Kingdom.

All told there have been 226 people screened for the PreFALS study, with 85 enrolled and providing a total of 227 “people years” of data currently. The idea is to enroll people that are asymptomatic for ALS in the study and to identify triggers of the disease by following them for a significant amount of time.  Benatar reported that seven people in the program have “phenoconverted”, meaning that they developed clinical symptoms of ALS/MND. A series of clinical visits and tests are included in the PreFALS study and 2 case studies of phenolconverters were provided for this presentation. The first, a 57 year old female with the SOD1A4V mutation presented with measurable denervation in laboratory tests six weeks prior to presenting symptoms of the disease. Her disease course lasted about 14 months from diagnosis. Denervation was also measured in the second phenoconverter, a 52 year old female, 28 weeks before her symptoms developed. That person had the SOD1-1113T mutation and survived almost 19 months from her diagnosis. The PreFALS data suggests that “disease progression is gradual early on and speeds up later on”, according to Benatar.  However, a recent paper of the PRO-ACT database, first discussed by Sandrock in the opening plenary, showed the first three months of disease progression can predict overall speed of the disease course; meaning that a quick disease onset will likely equate to a more rapidly progressing disease and vice versa for slower onset and progression rate.

VEGF Safe and Tolerable in Early Clinical Trial in Belgium

Philip Van Damme, PhD, of the University of Leuven (Belgium) reported the outcomes from a Phase 1 study of a vascular endothelial growth factor (VEGF) clinical study.  VEGF is thought to play a role in the health of motor neurons, and the company NeuroNova began a clinical trial of their VEGF compound sNN0029 to in 2008.  Earlier preclinical studies were conducted in SOD1 rats and in SOD1 mice, both quite small. But they produced modest improvements in survival overall, which provided the company information to launch their clinical research efforts. 

The clinical trial of sNN0029 included three different doses of the compound as well as placebo arm.  This multi-arm clinical trial is now completed.  In total, there were 19 PALS enrolled in the study, which included two different cohorts; one placebo control (N=10) and the other not (N=8).  In the placebo controlled cohort, four PALS received the high dose (2ug/day) and three received a lower dose (0.8 ug/day), and were compared to three additional PALS given a placebo.  The other cohort looked at a lower dose as well (0.2 ug/day) in 2 PALS, 2 at the middle dose and 4 at the high dose.  Van Damme was clear to the audience that the study was in no way powered to measure efficacy, but that the data suggested clearly that sNN0029 was safe and tolerated in all PALS in the trial.

It is interesting to note that 66% of the trial’s participants were male, and on average the onset age of enrolled PALS was 48 years old.  During the post-presentation discussion, audience members asked Van Damme if he thought that a higher dose of VEGF would be tolerable, which he responded he thought perhaps but that any follow up trial would likely use the doses informed on in the early trial.  A timeline for additional clinical research efforts on sNN0029 was not provided, however Van Damme said that he expects a follow-up will occur when asked casually later in the meeting hall.

LPS Levels May Dictate NP001 Trial Enrollment Going Forward

The compound known as NP001 has been in the news of ALS clinical research for several years now, following the completion of both Phase 1 and Phase 2 clinical research studies on the compound. Presenting updated analysis of the trial data was Michael McGrath, MD, PhD, co-founder of Neuraltus, the virtual biotechnology company which is conducting research of the compound in several different diseases, including ALS.  NP001 (sodium chlorite) targets activated macrophages.  It is now widely accepted that the immune system in ALS patients is highly active, causing several things to go awry in the body as a result of increased inflammation.

“It is highly purified sodium chlorite,” said McGrath in outlining what NP001 is for the audience to begin his talk. Chlorite is a pro-drug that gets converted inside the body, and is being pursued for its ability to down regulate certain aspects of the innate immune system, specifically macrophage that are activated in ALS.  The study included as many as 136 PALS overall, with smaller groups in each category; including a placebo arm and both high and low doses. According to McGrath and team’s analysis of the data, 10% of placebo PALS in the study did not progress at all during the clinical trial, whereas 19% of those on the low dose remained stable, and 27% of those which tolerated and completed the high-dose arm remained unchanged in ALSFRS-R measures. It was a small study and not powered to measure efficacy. However, encouraging data was offered by McGrath related to the target of NP001, activated macrophages.

The amount of these cells present in the blood stream can be measured using a variety of markers, including lipopolysaccharides (LPS).  McGrath reported that PALS in the study with higher levels of LPS reacted more positively to treatment with NP001.  While the numbers of PALS which fell into this category was admittedly small, it could provide a clinical enrollment criteria going into larger and perhaps pivotal clinical trials of NP001, suggested McGrath.

When asked during the follow-up session is he would only enroll PALS with high levels of LPS in these potential future studies, McGrath said that it is something that his scientific advisory board and he are discussing as a reality. It is important to note that no timeline for a follow up clinical trial of this compound was reported at the meeting, however during casual conversations there are talks going on to fund these follow up studies and more information is expected within the next year.

Slow Vital Capacity on Fast Track as Primary Endpoint for Tirasemtiv?

Several other presentations were made during the session, including an overview of the latest data of the tirasemtiv Phase 2 clinical trial. In ALS, the motor axon separates from the muscle, causing the muscle to lose its ability to contract voluntarily. Overtime as the axons separate (a process known as “denervation”) from individual muscles (there are many connections per muscle), the muscle will atrophy.  Tirasemtiv is a fast skeletal muscle troponin activator and, in essence, amplifies the force of the muscle contraction. 

As has been reported in the past, that compound failed to reach statistically significant outcomes on its primary endpoint, ALSFRS-R.  However, the drug’s effect on the clinical measure of slow vital capacity (SVC) was interesting and Cytokinetics is making the case to pursue SVC as a potential primary endpoint in future studies. 

Jinsey Andrews, M.D., provided the overview during the session, in which it was reported that SVC improvement was statistically significant at each time point in the trial (a week 5, 10, and 15).  This was most interesting as the final time point was post-drug, suggesting that tirasemtiv may have had a lasting effect. Andrews suggested that SVC may be a more sensitive measure to the effects of tirasemtiv, because troponins may be better at augmenting muscle contractibility in submaximal ways.  

Additional reports will be provided from the Research Symposia.  However, a review of the meetings official hashtag, #alssymp, is suggested.  An overview of social media at the conference is provided here and compiled by SymPlur.