January 16, 2016

expert reaction to French drug trial – reports of one patient dying and five others in hospital and of the Paris prosecutor’s office having opened an investigation into what happened

One of the six people who was seriously ill following administration of oral medication in a phase I clinical trial has died.

Prof. Alan Boyd, President of the Faculty of Pharmaceutical Medicine, said:

“It was very sad to have read in the media about the death of the subject who had previously been reported to have suffered severe brain damage as a result of their participation in this clinical trial. In relation to the other five subjects who remain in a stable condition in hospital, some of whom have neurological problems, until we have more information about the possible cause of these events and their specific clinical signs and symptoms, it is not possible to comment on the implications of this subject’s death for the other subjects.”

Prof. Carl Heneghan, Professor of Evidence-Based Medicine, University of Oxford, said:

“With so many other people having received the experimental treatment, and given that similar FAAH1 inhibitors have been tested within this class, there is an urgent need for transparency that transcends the prosecution: detailing what has gone wrong and the nature of the medical complications that the volunteers developed and which led to one individual’s death.”

Prof Sir Munir Pirmohamed, David Weatherall Chair of Medicine, University of Liverpool, and Vice President Clinical, British Pharmacological Society, said:

“Pain medicine is an important area of research and clinicians have a limited number of options for treatment of pain, many of which are associated with their own adverse reactions (as evidenced by withdrawal of COX-2 inhibitors such as rofecoxib (Vioxx) which was associated with heart attacks) and problems with addiction (for example opiates). There is therefore a need for new analgesics.

“Fatty acid amide hydrolase (FAAH) inhibitors are being developed by a number of pharmaceutical companies as novel drugs for the treatment of pain and inflammation.  This is therefore an important area of research which could have major benefits for patients.

“FAAH are enzymes that break down endogenous compounds that act as neurotransmitters via the cannabinoid receptors (CB). The idea behind the development of FAAH inhibitors is to preserve the analgesic effects without having the negative effects of cannabinoids. There are two FAAH enzymes, FAAH1 and FAAH2. The majority of drugs developed inhibit FAAH1 but can also have effects on FAAH2.

“Some FAAH1 inhibitors have already been tested in humans, without the adverse effects seen with BIA 10-2474.  As per the current paradigms for development, the testing programme has included phase I trials – the first one was with PF-04457845 (produced by Pfizer), which was studied in 77 subjects, at different doses (single and multiple), and was well tolerated by the volunteers (British Journal of Clinical Pharmacology; 2011; 73: 706-716).  Indeed PF-0445784 has also been trialled in 74 patients with osteoarthritis and was unfortunately not effective, but was well tolerated and did not have the cannabinoid-type adverse events (Pain. 2012 Sep;153(9):1837-46).

“FAAH inhibitors can be reversible or irreversible. There are reports that BIA 10-2474 was an irreversible inhibitor, but I have not been able to find any scientific publications by searching the literature databases. I presume BIA 10-2474 is a FAAH1 inhibitor, but again unverifiable at present, as nothing has been published.  It is interesting to note that reviews of FAAH inhibitors mention many drugs in development by many companies, but BIA 10-2474 is hardly mentioned. The lack of information on BIA 10-2474 in the peer reviewed scientific literature from the manufacturer is surprising.

“From the information available on websites since the reported incident, BIA 10-2474 has undergone the conventional and regulated process of drug development (including testing in chimpanzees as has been reported by some), and the number of volunteers exposed would be consistent with phase I studies, initially starting at low dose and progressing to higher multiple doses.  There are suggestions that this might have been a contaminated batch, but this would be surprising given the stringent quality control procedures which are utilised in drug manufacturing. Nevertheless it is an important potential reason which needs to be excluded through careful analysis of the batch given to the volunteers.

“It is possible that the serious adverse reactions suffered by the volunteers were an off-target effect of the drug (i.e. it was interacting with another receptor, enzyme or target in the body), but without further information on the drug and its pharmacology, it is difficult to be sure.  It is therefore vitally important that as much information as possible is made available to the scientific community as soon as possible by the manufacturer.  The independent enquiry announced by the French Government is also extremely important – it is vital to identify the reasons behind this tragedy so that lessons are learned for future drug development in this vital area, but also more generally.

“Finally, it is important to state, as many commentators have already done so, that the safety record for drug development is good.  The 2012 ABPI report stated that the overall incidence of serious adverse events in phase I trials is 0.02% (http://www.abpi.org.uk/our-work/library/guidelines/Documents/guidelines_phase1_clinical_trials.pdf).  Phase I trials remain a vital part of the drug development process and without such trials, we would not have any new drugs, which are still very much needed to treat the many diseases and symptoms for which we currently have few choices.”

Prof. Max Parmar, Professor of Medical Statistics and Epidemiology at UCL, and Director of the MRC clinical trials unit at UCL, said:

“We really need more information as to what has happened in this trial, especially in terms of the dose of therapy given to these six volunteers, compared to the 84 or so who have received this treatment and (presumably) have not experienced such side effects.

“I would just re-iterate the points that clinical trials are key if we are going to cure diseases such as cancer and Alzheimer’s. In clinical trials usually every effort is made to minimise the risk to participants, however inevitably some risks are just unavoidable. It is too early to say whether the horrible side effects experienced by these individuals was down to avoidable or unavoidable risks.”

Prof Alan Boyd, President of the Faculty of Pharmaceutical Medicine, said:

What is an FAAH inhibitor, what do they do and how do they work?

“FAAH stands for Fatty Acid Amide Hydrolase and it is an enzyme that is responsible for the degradation of endocannabinoids found in the brain and the peripheral nervous system. The endocannabinoid system (ECS) is a group of endogenous cannabinoid receptors located in the nervous system and other body systems and essentially it is human body’s own “cannabinoid system”. The ECS is involved in a variety of body processes such as appetite, pain-sensation, mood, and memory. It is also involved in the psychoactive effects of cannabis when this drug is taken. Giving drugs that are inhibitors of FAAH, theoretically should lead to an increase in the concentration of the body’s natural endocannabinoids in the brain and hence reduce pain, stimulate appetite and enhance mood and memory.

What kinds of diseases or conditions are they already used to treat or known to be effective at treating?

“There are no approved medicines that are FAAH Inhibitors but compounds that are FAAH Inhibitors have been in development. For example Pfizer have had a clinical development programme for a compound known as PF-04457845 and they have conducted and completed both a human volunteer study and a clinical study in patients with osteoarthritis for pain relief with this product (details can be found on the Clinical Trials.gov website –www.clinicaltrials.gov by searching for the respective study identifiers NCT008360082 and NCT00981357). Other companies are also known to have FAAH inhibitors in their portfolios.

Some media reports suggest the drug was tested in chimpanzees. If the drug in this case had been tested in chimpanzees, what might that mean?

“Chimpanzees are only rarely used these days for animal experiments – this fact, given it has been reported by the media and not by the company, would need confirming by them.

Is it too early to know what might have gone awry with this drug in this group of volunteers?

“Until we have more information about the study it can only be speculation.

Is it possible it may have been a contaminated batch, or more likely to be a problem with the mechanism of the drug?

“Batch contamination could be the issue but the most likely issue is probably a toxic effect of the drug at the dose that has been given to this group of volunteers. Given this was a Phase 1 study and, although the actual design of the study has not been disclosed publically, typically it would have involved the administration of initially single doses of the product in increasing amounts to individual groups of the human volunteers, followed by repeated doses again with increasing amounts to separate groups of volunteers. As you move through these various doses and amounts of drug given to these separate groups you would monitor them closely for side effects – it would appear that this last group have experienced these very severe effects at the does that received. From the press release that the company Bial have issued they have stated that prior to this group of volunteers they have not observed any moderate or severe reactions to date – so what has happened is clearly a surprise to them. (Please note this is speculation on my part in relation to what might have happened).

Now we know that the drug is an FAAH inhibitor, is there any more you can say about why 108 patients were administered the drug (https://www.bial.com/download.php?f=166&key=6a32080107d3edc38d993bb8f930ddeb) and so far five have been reported to have suffered side-effects?

“In my previous comment I have suggested a typical design for the study that has been performed – a figure of 108 volunteers involved in the study has been given by the company – and although this is larger than would normally be exposed, if the study covered several different escalating doses then this number can be accounted for. In addition following what has just happened to these final six volunteers, all the other volunteers who have been treated in the study need to be checked for any clinical issues and it would appear that this is what is happening now.”

Prof. Jackie Hunter, Chief Executive of BBSRC, said:

“FAAH stands for fatty acid amide hydrolase. FAAH is a membrane bound, intracellular, enzyme which belongs to the serine hydrolase superfamily. It is known to regulate the endogenous concentrations of several important and pharmacologically active molecules called fatty acid amides (FAAs). It mediates the breakdown of FAAs such as anandamide (AEA), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). These FAAs are agonists at a range of receptors but AEA for example has been shown to be important as an agonist of cannabinoid (CB) receptors, CB1 and CB2.

“Given that agonists for CB receptors have been shown to be involved in a range of activities including pain, increasing the levels of AEA by blocking its degradation through inhibiting FAAH would be postulated to be analgesic. Pre-clinically FAAH inhibitors have been shown to be active in a range of models of chronic, acute and neuropathic pain. They have also been postulated to be of use in Post-traumatic stress, Parkinson’s disease, depression and inflammation.

“There are no FAAH inhibitors on the market.

“The following table shows that other compounds with this mechanism have been trialled in man over a period of weeks with no adverse effects:

Other compounds that are FAAH inhibitors include:

“In response to suggestions in media reports that this drug had been tested on chimpanzees: companies would normally only test in primates if the compound only worked on a human version of the protein in question – in this case FAAH. Other molecules work on both rodent and human versions although the potency might not be the same so this is odd. Also if one went to primates one would usually test on macaques rather than chimpanzees so it appears to indicate that there is something different about this particular compound if this report is true.

“We have no information as to whether this is a reversible enzyme inhibitor – if it was an irreversible inhibitor then this would be different to the other compounds. We also know nothing of its off-target profile or its metabolic profile.

“The compound was clearly safe in single dose and it appears that the problems arose on multiple dosing. The standard protocol for Phase I is single doses in groups of volunteers with placebo controls, increasing the dose with each cohort until either adverse effects are seen (which could be mild e.g. nausea) or until the exposure limits of the drug in the blood defined by preclinical toxicology are reached. Then cohorts are dosed on multiple days i.e. receive more than one dose of the compound. The duration of dosing and dose amount in this phase is defined by what has been done preclinically i.e. how long animals have been dosed for. This explains why so many people have received the drug as most of these would have been singe doses.

“The fact that side effects are apparent on multiple dosing might be due to an accumulating metabolite that is not present in animals, some off-target action of the molecule or some other mechanistic reasons. The fact that a number of selective FAAH inhibitors have been dosed for weeks in the clinic does suggest that it isn’t due to reversible inhibition of the enzyme.”

Prof. Stephen Alexander, Fellow of the British Pharmacological Society & Associate Professor in Molecular Pharmacology at the University of Nottingham, said:

What is an FAAH inhibitor, what do they do and how do they work?

“FAAH is an enzyme which inactivates a series of naturally-occurring compounds in the body, the most recognisable of which is anandamide. Anandamide acts as an activator of cannabinoid receptors, the same targets as one of the active ingredients of the Cannabis plant, Delta9-tetrahydrocannabinol, THC. Inhibition of FAAH allows accumulation of these compounds, including anandamide.

“The expectation is that these FAAH inhibitors allow an amplification of signalling through the cannabinoid system, which could have subtle but important differences from treating with a direct activator of the cannabinoid system.  THC does have pain-relieving properties, but its other psychoactivity (including acute memory loss, dissociation from the environment, and further effects on chronic usage) limits its usefulness.  In pre-clinical models, THC and other direct activators of the cannabinoid system evoke a characteristic series of symptoms which includes catalepsy (a rigidity or stiffness of posture).  The use of FAAH inhibitors in these same models is not associated with this symptom.

What kinds of diseases or conditions are they already used to treat or known to be effective at treating?

“As yet, there are no diseases or disorders which are treated with FAAH inhibitors.  The most advanced area associated with the use of FAAH inhibitors is in the treatment of chronic pain (currently, things like non-steroidal anti-inflammatory drugs, such as ibuprofen and aspirin, are effective, but they suffer from issues including gastric ulceration, which can be severe.  Opiates, such as morphine and codeine, are effective in many individuals also, but suffer from issues including tolerance and addiction).

“There are numerous studies from many different labs around the world (including US, Europe, Australia) which have shown good pain-relieving properties of FAAH in pre-clinical models.

What other drugs do we already use safely that use the FAAH mechanism?

“At the moment, there are no other drugs in the clinic which directly target this enzyme.”

Is there history of FAAH inhibitors being successfully and without incident taken past the phase 1 stage of clinical trials?

“In 2012, Pfizer published the results of their Phase II clinical trials (small scale, patient-based investigations). This compound was very similar to the BIAL compound in that it was an orally-active, irreversible FAAH inhibitor, PF04457845, which was being investigated for pain relief (in this case, associated with osteoarthritis –http://www.ncbi.nlm.nih.gov/pubmed/?term=22727500). Pfizer ended the trial because the compound lacked efficacy – no difference from the placebo. There were no reports of the unfortunate severe adverse effects described yesterday.

Now we know that the drug is an FAAH inhibitor, is there any more you can say about why 108 patients were administered the drug (https://www.bial.com/download.php?f=166&key=6a32080107d3edc38d993bb8f930ddeb) and so far five have been reported to have suffered side-effects?

“If the report is correct in that the severe adverse effects were only observed in those individuals that received repeated cumulative doses of the compound, there is a possible explanation. While this is just speculation, one possibility that presents itself is that the compound has low level effects at another target very different from FAAH, the primary target. This would need further investigation, but the logic suggests that low doses or short term exposure to the drug would lead to the expected effect of inhibiting FAAH and potentially some benefit. However, with repeated dosing, not only would the primary target, FAAH, be affected, but also some secondary, as yet unidentified target.  Maybe it is this secondary unknown target which is responsible for the unfortunate severe adverse effects which have been reported.  This obviously requires further investigation, and such evidence is only likely to be forthcoming after a number of months of study.”

Prof. David Nutt, Edmond J Safra Chair and Head of the Centre for Neuropsychopharmacology, Imperial College London, said:

What is an FAAH inhibitor, what do they do and how do they work?

“Preventing the breakdown of endogenous cannabinoids such as anandamide to enhance the effect of this widely spread neurotransmitter system.

What kinds of diseases or conditions are they already used to treat or known to be effective at treating?

“No proven indications as yet – Pfizer compound failed in pain control but there are many other possible target indications as cannabis receptors are the most prevalent GABA-protein coupled receptors in the brain (more than dopamine, noradrenaline and serotonin together).

What other drugs do we already use safely that use the FAAH mechanism?

“None as yet but has long been a target – the first research was over 20 years ago.

Is there history of FAAH inhibitors being successfully and without incident taken past the phase 1 stage of clinical trials?

“Yes – Merk and Pfizer have done this and clinical trials I think also. The fact that these didn’t have significant adverse effects and the fact that this occurred only at the highest dose means that it is likely this is an off-target effect i.e. interferes with another enzyme system of maybe brain or more likely vascular system.

Some media reports suggest the drug was tested in chimpanzees. If the drug in this case had been tested in chimpanzees, what might that mean?

“Best way to assess likely safety in humans.

Is it too early to know what might have gone awry with this drug in this group of volunteers?

“Yes, we’ll need proper and detailed pathology studies though it won’t be easy as the patients are still alive so getting brain material will not be easy if possible at all.

Is it possible it may have been a contaminated batch, or is it more likely to be a problem with the mechanism of the drug?

“Could be either though the former is more likely.

Now we know that the drug is an FAAH inhibitor, is there any more you can say about why 108 patients were administered the drug (https://www.bial.com/download.php?f=166&key=6a32080107d3edc38d993bb8f930ddeb) and so far five have been reported to have suffered side-effects?

“This is a standard way of testing the safety of new drugs.”

Prof. David Webb, President, British Pharmacological Society, said, commenting on the information that the drug is an FAAH inhibitor: https://www.bial.com/download.php?f=166&key=6a32080107d3edc38d993bb8f930ddeb

“FAAH (fatty acid amide hydrolase) degrades neurotransmitters that can influence eating, sleep and pain. It is possible FAAH inhibitors, such as BIA 10-2474 using in the clinical study in France, might, therefore, be useful in disorders affecting these functions, as well as in anxiety and neuro-psychiatric disease (including Parkinsonism), though none have yet been developed into treatments.

“Animal studies (which media reports suggest may have included chimpanzees) and studies with single doses of the drug in humans did not appear to raise concerns, and it appears that the study that caused severe and critical illness was the first to use multiple doses of the drug. Levels of the drug, and/or of the neurotransmitters that are degraded by FAAH, may have accumulated with multiple dosing, and potential cumulation of high concentrations of these neurotransmitters may have caused the current problems, which reports suggest appeared after several days of dosing.

“Other companies have also been exploring FAAH inhibitors, but have discontinued their studies. I am not sure whether this was through lack of efficacy (in which case it is possible they did not get to multiple-dosing) or for other reasons.”

Dr Ben Whalley, Professor of Neuropharmacology, University of Reading, and member of the British Pharmacological Society, said, commenting on the information that the drug is an FAAH inhibitor: https://www.bial.com/download.php?f=166&key=6a32080107d3edc38d993bb8f930ddeb

What is an FAAH inhibitor, what do they do and how do they work?

“FAAH inhibitors block the activity of the enzyme in our bodies that is responsible for breaking down endocannabinoids, compounds that our bodies produce naturally and act at the same receptors as some of the components of Cannabis.

What kinds of diseases or conditions are they already used to treat or known to be effective at treating? 

“None. Some went to Phase II trials some years ago without any associated problems but none became medicines.

What other drugs do we already use that use the FAAH mechanism?

“None, other than research compounds used in non-human animal or test tube studies.

Is there history of FAAH inhibitors being successfully and without incident taken past the phase 1 stage of clinical trials?

“Yes, Pfizer took a FAAH inhibitor to Phase II trials some years ago without incident.

Some media reports suggest the drug was tested in chimpanzees. If the drug in this case had been tested in chimpanzees, what might that mean?

“Too early to say since we do not know the doses used, how long they were treated for etc.

Is it too early to know what might have gone awry with this drug in this group of volunteers?

“Given that there have not been previous problems with a FAAH inhibitor in humans, it is possible that the Bial compound has caused its unwanted effects by interacting with a target that is not FAAH (termed an ‘off target effect’). Another option is a dosing accident where patients were given far more than clinicians thought was in the dosage form.

Now we know that the drug is an FAAH inhibitor, is there any more you can say about why 108 patients were administered the drug (https://www.bial.com/download.php?f=166&key=6a32080107d3edc38d993bb8f930ddeb) and so far five have been reported to have suffered side-effects?

“Those who have experienced side effects appear to be the only patients who have received repeated doses of the drug. This may be a factor. Alternatively, the reasons above may also apply”.