NP001: Dr Brian Dickie’s comments…

I’m sure many of you who follow our blog have also been following the discussion on our forum about the Neuraltus trial for a drug called NP001. First of all, thanks to ‘Matt J’ for initially raising this issue on our forum. It highlights the power of the forums in facilitating information spread and getting new news out to the community quickly. I also appreciate his initial trepidation in posting as it illustrates some of the ‘messier’ aspects of forum-based communication, such as the difficulty in following threads and in separating the ‘wheat’ from the ‘chaff ‘in terms of evidence.

Secondly, the disclaimer. It is not the Association’s role to provide medical advice. We’re not clinicians. Where possible, we’ll try to present the facts as we understand them, throwing in a few assumptions or speculation where it’s unavoidable.

This relates to a third point. NP001 is a North American trial. If it were a UK trial we would undoubtedly know much more about it and be in closer contact with the company. The downside of a closer relationship is that Patient Organisations have to sign a Confidentiality Disclosure Agreement (CDA) with the company, which restricts the amount of information that can be disseminated. I suspect this is probably the case for some of our North American counterparts. So this means that while our information is more limited that we would like, we are at least in a position to communicate something.

At the moment we simply don’t know whether NP001 is working or not. I appreciate the frustration that statement will generate, but there are some issues that have to be discounted before any conclusions can start to be drawn and these form a large part of the rest of this blog.

I’m going to spend some time on the underlying biology of MND as it is highly relevant to this issue. I’ve tried to make it accessible and not cut too many corners, but given the different degrees of knowledge among our readership, it can be difficult to pitch at the right level, so I hope it is understandable to all, but does not come across as simplistic or even patronising to some. That is certainly not my intention. Neuroscience and Immunology are arguably the two most complex subjects in medical science and drug trial design in MND is a ‘dark art’ in itself. I can’t claim to be speaking with authority on every aspect.

How do we think NP001 works?

From what we know, NP001 affects the activity of modified white blood cells called macrophages, which are an important part of the immune system and, among other roles, are involved in inflammation. Macrophage activity and proliferation increases alongside disease progression in MND. Neuraltus are seeking to prove that reducing macrophage activation with NP001 has a beneficial effect on disease progression. They have not stated clearly how they expect lower numbers of activated macrophages to achieve this. However, the mechanism probably involves cells called microglia.

Microglia are macrophages that have infiltrated the central nervous system (CNS). Unlike the rest of the body, the CNS does not have an immune system, so it relies on microglia as a key part of the ‘defence system’ here. Previous research, mainly based on SOD1 mouse models of MND, has shown that microglia play an important role in influencing the progression of MND but they do not appear to be involved in triggering the disease in the first place. Instead, they form part of a specialised inflammatory response which aggravates the initial problem. We know that MND is not primarily an immune system disorder because treatments like immunoglobulin, which impact significantly to depress immune system, responses, have no effect on the disease.  Controlling microglia activity more selectively is a valid strategy which may help slow the progression of MND but as it is probably addressing a secondary pathology rather than the primary pathology, the strategy is aimed at slowing disease progression rather than stopping or reversing it.  

Neuraltus may believe that, because macrophages give rise to microglia, a reduction in macrophage activity and numbers in the blood will be paralleled by a reduction in microglia activity in the CNS. However, macrophages also produce lots of chemical messengers that act to promote inflammation in general – within the CNS it’s microglia that respond to these messages. It may be that Neuraltus scientists are working on the theory that reducing the production of these inflammatory messengers may limit inflammation in the central nervous system, at least in part through decreased stimulation of microglia. Whatever the precise mechanism, they intend to measure macrophage levels and activity as a ‘biomarker’, to demonstrate that the drug is at least hitting its intended target.

Could NP001 have an instant effect?

One of the members of our forum commented that the reported changes within a few hours were surely too fast to be drug related? I’d tend to agree.

The CNS has an amazing capacity for compensation – this is particularly the case in Parkinson’s disease, where up to 80% of the vulnerable neurones have degenerated before the first appearance of symptoms. Even in MND it’s estimated that by the time a muscle group is affected, it will already have lost up to 50% of its neuronal connections.   

The compensation occurs by a process called collateral innervation (or compensatory innervation). In a nutshell, if a motor neurone cell dies back from its target muscle, the muscle releases neurotrophic factors that attract a neighbouring, healthier, neurone to literally ‘sprout’ a new connection, but this will take place over a longer timecourse than a few hours. A really good example of this process in action comes from looking at polio patients.

Polio is caused by a virus (poliovirus) that wipes out a large number of motor neurones in an instant, causing paralysis.  However, people can often recover partial or complete function, caused by the compensatory innervation by the surviving motor neurones. This process takes a long time, as many people who contracted the virus in childhood in the 1940s/50s and spent many months, even longer, in ‘iron lungs’, will testify. 

So, the first point is the rapidly reported changes are too rapid. This doesn’t discount, for example, a drug effect directly on the muscles rather than the nerves themselves, perhaps reducing peripheral inflammation, or some other metabolic ‘pick me up’. However, as outlined above, that doesn’t appear to be the mechanism of action of NP001 and certainly not the mechanism by which restoration of function is most likely to occur. 

It’s important to remember that in MND, compensatory innervation is occurring even after the disease symptoms appear. This can explain why any individual can have a plateau phase or even slight transient improvements in muscle function.  So, the second point is that loss of muscle function in any single individual cannot be viewed simply as a straight line, a constant decline.

For a moment, let’s assume that the drug has a quick acting effect. The question that follows is whether it is a short-term or a long-term effect? It could be transient.

The only way of working that out is through continuing the trial for a longer period. I am less familiar with FDA regulations, but the NP001 trial will have an independent Data Monitoring Committee, which will confidentially review the trial data at various timepoints, with predefined ‘stopping rules’. This is primarily carried out for safety, to ensure the drug is not making things worse. However, such committees are also able to flag up any significant positive deviations due to the drug, but they would need to be convinced that this was not down to the inherent variation in disease progression within and between individuals (some of which has already been discussed) and/or a statistical ‘glitch’ due to the low power of the study (by that I mean not enough participants). I completely understand the need for answers as quickly as possible – this is a disease where time is very much a luxury. It makes my third point that more difficult to state: basically, the trial needs to run its course and calls for the discontinuation of the current NP001 trial are premature.

If the results from the current Phase II trial are outstandingly positive, it is possible that the company could attempt to apply for licensing straight away. In this case, their first port of call would be the FDA in America, which has already granted NP001 ‘fast track’ status. This is a commitment to dealing with the licensing paperwork quickly but is not an endorsement of efficacy. ‘Fast tracking’ does not automatically mean that a Phase III trial will not be necessary – if the data from the Phase II trial are encouraging but not significant enough to be conclusive, then the company would need to proceed to Phase III.

The FDA has no influence over UK licensing. We will investigate whether there is anything we can do to hurry the European licensing authority along in the event that the Phase II trial or a future Phase III trial produces positive results. Ultimately though, while we may be able to try and ‘pull’ things along from this end, it is up to the company to ‘push’ by making the application in the first place.

As has been mentioned elsewhere, information on NP001 will be presented at this year’s International Symposium in Sydney (30 November – 2 December 2011). I believe that the Phase I study data, which was also performed in MND patients, will be presented. That should at least tell us whether any rapid effects were seen in that preliminary study.

This leads to a point which I approach with a great deal of trepidation, but it needs to be raised. With all the discussion on NP001, there hasn’t been much said about the placebo effect but it does offer one explanation for the improvements claimed by some of the participants. I’ll talk firstly from personal experience of 15 years in working in the MND field. In virtually every major trial I can recall (myotrophin, xaliproden, creatine, BDNF, pentoxiffyline, etc) there are invariably a small number of claims of improvements which have unfortunately not been borne out by the trial results. Additionally, in every clinical trial, participants in the placebo group also experience ‘adverse events’ that could be perceived as drug side effects, but are unrelated.

Let me give you an example, which was presented at the symposium several years ago. A pilot randomized, placebo-controlled trial of creatine was performed. Participants were assessed in a variety of ways, including direct objective measures of muscle strength (maximum voluntary isometric contraction). Participants were assessed before their first dose (baseline) then at 1,2,3 weeks, 4 months and 9 months.  When the results were analysed, it showed that those on the creatine arm showed an improvement in muscle strength in the first week and no overall decline from baseline in the first three weeks. However, those on the placebo also showed a subtle increase in the first week and no overall decline from baseline over the first three weeks. At the 4-month timepoint there was a marked decline in both groups, which was much more pronounced at the 9-month timepoint. As we know, the initial excitement of creatine was not supported in larger, more comprehensive trials. Basically, this illustrates another reason why the NP001 trial needs to be performed for longer.

 What about WF-10?

A colleague with extensive experience in drug discovery in the pharmaceutical industry has trawled though numerous patents to try and work out whether WF-10 and NP001 are one and the same, but were unable to reach that conclusion. Patents are legal, not scientific documents, so the scientific detail is often substandard or absent. The proposed mechanisms are certainly similar and the main active component is probably the same but the chemical formulation of NP001 is not available (if anyone can find it, please let me know). On the evidence available, we suspect that the two are different and we can speculate that NP001 is possibly a ‘souped-up’ version of WF-10 – either an improved formulation or a combination of more than one drug acting on inflammation /immunity. Either way, the bottom line is that if NP001 is ineffective, WF-10 probably will be too.

Some of our forum members have asked if we could organise a trial of WF-10. As you will appreciate from the previous paragraphs, there is no such thing as a quick or simple trial so the NP001 results would be known a long time before a WF-10 trial could come to fruition. Besides this, there is no reliable laboratory or clinical evidence to support the use of WF-10 in MND. While Nuvo Research and its subsidiaries have researched WF-10 in relation to a number of other macrophage-associated diseases, they have only hypothesised that it may be helpful in MND. Outside of a mention in a patent document of its short-term administration in two MND patients many years ago, they have not actually studied its effects in neurodegenerative disease.  

As you know, ALS Untangled is going to look into the evidence for WF-10 and have told us it’s next on their list. I don’t think we can pin them down to a date, as each review depends on the quality, quantity and availability of information, but they have at least moved the likely date forward from end of the year. The clinicians who are members of ALS Untangled are the best qualified to review the data and we will forward anything we find to them – including relevant information that our forum members may discover. I know that their objectivity has been questioned, given that some may be involved in the NP001 trial, but any such concerns are unfounded.

Some of you have asked about access to WF10 on a compassionate use basis.  As neither of these drugs is licensed for use in any condition in the UK, the situation is far more complex than for a licensed drug like lithium, which can more simply be prescribed ‘off label’ due to its use in treating other CNS-related conditions for the past 40 years.

The decision to proceed with compassionate use rests entirely with clinicians. In theory, consultants can prescribe unlicensed drugs like WF-10 to a particular individual (or ‘named patient’), provided that they and the NHS Trust they work for are prepared to accept complete responsibility for the consequences. I n the case of WF-10 they would need to do this for a drug that they have no previous experience of and for which there is not yet any evidence of efficacy in MND. Even if a consultant did decide to prescribe WF-10, the Medicines and Healthcare Regulatory Agency (MHRA), which oversees the licensing of medicines in the UK, must still grant permission for the unlicensed drug to be imported into the country for that particular patient. In order to give this permission, the MHRA will need to be satisfied that the patient has a ‘special need’ for the unlicensed drug. Although everyone with MND has a desperate need for effective treatments, the MHRA definition of ‘special need’ means a need that is relatively unique to that individual, such as an allergy to an ingredient in the equivalent licensed drug.

I hope the information provided is helpful.  These are exciting times in MND research – new knowledge about the disease is emerging fast and we are seeing an increasing number of trials emerging around the world – but due to the complexity of MND, these trials move at a speed that appears ‘glacial’ and NP001 is no exception. Only time can tell if we are looking at a genuine ray of hope and not another false dawn.