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Presentation C1: A. Sandrock, Biogen: What is necessary to make a potential medicine enter clinical trial faster; the perspective of a biotech company. 

The discovery of the genetic cause of ALS has accelerated the discovery of biological processes and targets for potential medicines that might change the progress of the disease.

What is needed to get a potential medicine faster into clinical trials? The answer is complex and varies according to the person who has to answer the question.

A publication of Professor Robberecht was shown.

The old model is the one where animal research - questioning the predicting character of the animal model – moves on to early phase 1 research. There might be a gap to translate the results to phase 2 research and there might arise questions about the risks of this phase that clash with the costs of phase 3.

Biogen presented a new model where the normal biology of humans is studied first, and then the disease. This is possible by means of genetics, with the help of iPS Cells and extra animal toxicity studies. Then, the potential medicine is studied, for example antibodies that attack cells selectively. This is made possible with the help of the development of specific targets through biomarkers (for example EIM) and through extra safety studies on animals. To avoid fake negative studies, sensitivity comes before specificity. It is problematic that substances see RNA as a target and might arouse immunogenicity (for example with AAV viral vectors). 

ALS clinical trials: what is going wrong? Updates about NP001, sNN0029, Tirasemtiv and PrefALS

The International Symposium ALS/MND research is the most prominent conference about ALS/MND research in the world. It brings together hundreds of neuroscientists, neurologists and health professionals for three days, each year in a different country.

Founded and organized by the MND Association, this meeting of 2014 was the 25^th yearly edition and took place in the congress centre Square in Brussels, Belgium, with the Belgian ALS League as a host. An estimated 900 people attended the conference. As usual, the meeting is organized in two equal sessions; one about fundamental science and the other one about the problems and developments in clinical studies and clinical subjects, like breathing and palliative care. There were also several satellite meetings and poster sessions.

This overview contains some of the subjects that were discussed. Since many of the presentations were held before the publication of the data, the presenters were asked to indicate whether it was allowed to communicate their presentations to the outside world. Thankfully, most of the speakers allowed it.

The opening session will be summarized in the following article.

PrefALS and the 29-month journey to enter clinical trials

Michael Benatar, MD, PhD, from the Miller School of Medicine at the University of Miami (USA), gave this presentation at the opening of this meeting, where he extensively ran through the data of the PrefALS study that he and his co-workers have been carrying out during the last few years. Before giving specific fALS, Benatar commented on an important problem in ALS: delay caused by diagnosis and late registration of pALS in clinical research centers. According to Benatar, it takes about 12 months to be diagnosed after the first symptoms start to show up, and then another 17 months to let this person enter a programme of clinical research successfully. This delay might cause challenges for the development of a cure. However, according to the PrefALS study this person that had been diagnosed with ALS was registered a lot faster in clinical research: less than five months after they had been diagnosed, says Benatar.

On average, family doctors encounter one or two cases of ALS during their carrier. I do not think that we want it to happen that the word ‘fasciculation’ has to lead to a diagnose every time,” said Benatar. Specific efforts have been set up to try to deal with the delayed diagnose of pALS, including the identification of a flashing signal, that can be passed on to family doctors. For example, flashing signals have been identified and divided by the association of MND family doctors in the United Kingdom.

All in all, 226 people have been screened for the PrefALS study, of which 85 enclosed, and at the moment there are 227 “human years” of supplied data. The idea is to enclose people that are asymptomatic and to find triggers of the disease by following them long enough. Benatar reported that seven people in the programme “fenoconverted”, which means that they developed clinical symptoms for ALS/MND. A series of clinical visits and tests are part of PrefALS’ study and two cases of this study of fenoconverters were presented during this presentation. The first patient, a 57-year old woman with the SOD1A4V mutation, showed measurable denervation in lab tests, six weeks before the symptoms of the disease appeared. The progress of her illness took about 14 months after the diagnose. Denervation was also measured in the second fenoconverter, a 52-year old woman, 28 weeks before her symptoms started to develop. That person had the SOD1-1113T mutation and stayed alive for almost 19 months after her diagnose. The PrefALS data suggest that “the progress of the disease initially evolves slowly, and accelerates later on,” according to Benatar. A recent article of the Pro-ACT database, which has been discussed by Sandrock earlier on during the plenary meeting, showed however that, as for the general speed of the course of the disease, the first three months can predict the progress of the disease. This means that a fast start of the disease probably equals a faster progress of the disease and vice versa for a slow start and a slow progression.

VEGF: endure safe and well in phase I clinical trial in Belgium

Philip Van Damme, MD, Phd, of the University of Leuven (Belgium) reported the results of phase 1 clinical trial with the vascular endothelial growth factor (VEGF). VEGF is supposed to play an important role in the health of motoric neurons; the company Newron started a clinical test with their VEGF product sNN0029 in 2008. Earlier preclinical trials were tested on SOD1 rats and SOD1 mice, both in rather small numbers. But they produced moderate improvements in general survival, whereby the company was equipped with data to launch their activities in clinical research.

The clinical trial with sNN0029 studied three groups with several doses of the substance, next to a placebo group. This clinical trial with several groups has now been completed. A total of 19 pALS were enclosed in the study, in two different cohorts; the cohort with placebo control (N = 10) and the one without (N = 8). Four pALS received the high dose (2ug/day) and three received a lower dose (0,8mg/day) in the placebo-controlled cohort, and they were compared with three pALS under placebo. The other cohort had two pALS with a lower dose (0,5 mg/day), two with an average dose and four with a high dose. Professor Van Damme clearly indicated that this study was by no means intended for measuring the effectiveness, but that the data clearly show that all pALS tolerated sNN0029 well and safely.

It is interesting to notice that five participants were fALS and that one pALS had the bulbar form; the product was still administered after the study. Two out of 18 patients died after all. During the discussion that followed the presentation, Professor Van Damme was asked whether he believed that a higher dose VEGF would also be tolerated well, and he replied that he used a higher dose in the new study. A dose study on apes preceded, and there were no indications of vascular neoformations. It was also explained during the discussion that there is probably no connection between the only serious side effect, pulmonary embolism, and the product.

LPS levels can help forward the enclosure in the NP001 trial: subsequent analysis 

The substance known as NP001 has made it to the news during the last few years, concerning ALS clinical trial after the completion of phase 1 and phase 2 clinical trial with this substance. Improved analyses of the study data were presented by Michael McGrath, MD, PhD co-founder of Neuraltus, the virtual biotechnology company that researches several diseases with this substance, including ALS. NP001 (sodium chlorite) has effect on activated macrophages. It is now generally accepted that ALS patients have a very active immune system, which causes several things to go wrong because of the increased infections.

“It is very pure sodium chloride”, McGrath said in a survey about what NP001 is as an introduction for the public. Chloride is a pro-drug (precursor of the medicament) that is converted in the body. It is administered because of its ability to regulate certain aspects of the innate immune system, specifically aimed on the macrophages that are activated in ALS. The study included a total of no less than 136 pALS, with smaller groups in each category; there was a placebo arm and both in high as in low doses. According to the analysis of McGrath and his team of the dates, 10% of the placebo pALS in this study did not make any progress during the clinical study, 19% of those with a low dose remained stable and 27% of those who tolerated and finished a high dose had an unaltered ALSFRS-R measurement. It was a small study and was not intended to measure the effectiveness. However, McGrath presented encouraging dates about the target of NP001, the activated macrophages.

The amount of these cells in the blood flow can be measured by using a number of different markers, including the lipopolysaccharides (LPS). McGrath reported that pALS in the trial with higher levels of LPS reacted more positively on the treatment with NP001. McGrath proposed that, although the amount of pALS was small in this category, it might be a clinical inclusion criterion for bigger and maybe crucial clinical studies with NP001.

When he was asked during this follow-up session whether he would only enclose pALS with high levels of LPS in these potential future studies, McGrath said that that is something he and his scientific advisory committee relatively debate about. It is important to notice that no timeline was reported for a following clinical trial with this product during the meeting, but during informal conversations it turned out that discussions are on about financing these follow-up trials and that more information is expected this year.

Slow Vital Capacity as primary end point for Tirasemtiv on Fast Track?

Several other presentations were given during the session, including an overview of the most recent dates of the Tirasemtiv Phase 2 clinical trial. With ALS, the motor axon moves away from the muscle, which might cause the possibility for the muscle to contract voluntarily. In time, the axons will detach temselves (a process that is also known as “denervation”) from separate muscles (since there are a lot of connections per muscle), and the muscle will atrophy. Tirasemtiv is a troponin activator of the quick skeletal muscle and strengthens the power of the muscle contraction.

Like it was already mentioned, this substance statistically did not give any significant results for the primary end point, the ALSFRS-R. However, the effect on the clinical measurement of the slow vital lung capacity (Slow Vital Capacity) was interesting and Cytokinetics takes in a strong role to defend SVC as a potential primary end point in the future studies.

Jinsey Andrews, M.D., gave an overview during the session, in which she reported that the SVC improvement was statistically significant at each moment of the study (week 5, 10 and 15). This was particularly interesting because the final measurement point after the intake was over, suggesting that Tirasemtiv might have had a permanent effect. Andrews suggested that SVC probably is a more sensitive measurement method for the effects of Tirasemtiv, because troponins might be better to increase the muscle contraction in a submaximal way. 

Session 5B: PRACTICE IN CARE

Presentation C29: T Meyer Berlin: the role of e-health in ALS: the digital agenda

At this moment, most data about ALS care come from clinical studies. However, the e-health revolution might also benefit ALS care. This requires the digitalization of:

1) Information from a) electronic medical files b) telemedicine c) new kinds of data, for example patient reported outcomes, e.g. PatientsLikeMe
2) Processes: link the complex care like nutrition, ventilation and palliation, like in Berlin through Internet or Services
3) Tools: become more mobile, smarter and more interactive like communication systems like in Berlin through Internet or Things

Digitalization involves several problems:

1) Secure data and legal problems, especially on international level
2) Access to digital services by pALS and care takers: technical, social and emotional thresholds
3) Costs and compensations are a big problem for innovation.

Conclusion: the advantages of digitalization are bigger than the challenges and risks. Digitalization makes it possible to make ALS care more accessible, interactive, patient-oriented, faster and safer. That is why ALS care takers and pALS should fulfill an active and creative role with the introduction of the digital agenda and the result that is necessary. 

Presentation C30: McDermott Sheffield: the impact of neck weakness and experiences with neck supports

The current neck supports often do not meet the needs of pALS. A new neck support (orthosis) has been developed by studying experiences with current models and the impact of neck weakness of MND patients. Data about daily experiences were gathered, for example about pain, nutrition, communication and hypersalivation, from 26 users by means of a questionnaire and interviews.

A model that was developed by this group (head-up SSS) was discussed.

Conclusion and discussion: the results indicate the important impact of neck weakness during the daily functioning; pALS state that neck support should receive more priority. At the moment, there are not enough good supports, and therefore pALS often have to choose whether to use or not to use a non-ideal support.

Presentation C31: H. Stephens, Harrisburg: pain with ALS

Even though ALS is considered to be painless, recent studies show that pain is often underestimated, especially in later stages, but little research has been conducted.

Therefore, an electronic questionnaire was sent to 319 pALS; 87 patients reacted and more than 50% of them reported pain.

Discussion and conclusion: Pain is an important component of ALS. More than half of the participating pALS reported a moderate pain that interferes daily life. More than 80% uses pain medication. Other treatments (like relaxation therapy) were often used against the pain. 

Presentation C32: A. Seeber, Amsterdam: advance care planning in a Dutch tertiary ALS centre, an evaluation of the Dutch care approach (organization)

People become more and more aware of the need for an integrated approach of palliative care, including advance care planning (APC), with decisions made by the patient before this becomes impossible for him/her. Even though this is a very difficult matter for both the doctors and the patients, discussions are held standard in an early stage in this centre.

It has been investigated when and what has been discussed about future care during consultations in the centre and how MND patients experienced this. This happened by observing 28 patients and interviewing 21 patients for six months.

Results: Shortly after the diagnosis the specialist gave an overall picture of the future with progressive physical deterioration, needs and options in care, unless serious physical restrictions were already present. As soon as concrete problems appeared, more detailed information was given. The patients appreciated this gradual approach and the repeated discussions.

Discussion: The content of the conversations go together with the course of a disease: it starts shortly after the diagnosis and then later on is discussed step by step according to the needs and wishes of the patient. A good start and good habits give the patients the strength and control in discussions about the future and the end of life. If the patient does not start this conversation, the doctor should.

Session 6B: EPIDEMOLOGY

Presentation C43: M. ELAMIN, Dublin: the prognosis in predicting ALS: a simple algorithm

A simple predicting model is needed to plan tailor-made aid. An index was composed out of four components that can be measured easily during a consultation and patients were divided into 3 risk groups (high, average and low risk). This index was tested on two national ALS registers, namely on 204 Irish and 122 Italian pALS.

Discussion and conclusion: these data suggest that an index that can be determined during the first consultation is a simple model for the prognosis. 

Presentation C44: C. Lunetta: Validation of a simple ALS survival score (ALS-SS)

Patients and clinical trials need a better understanding of prognostic factors.

Therefore, 298 Italian pALS (without tracheotomy) were analyzed in a study.

Discussion and conclusion: ALS has a very variable course and it is hard to determine prognostic factors. This group succeeded in validating and reproducing a simple score, the ALS-SS, based on family history, age, aspartate lab tests and ALSFRS-R. This can be used both on consultations as for clinical trials.

 

Translation: Annemie