Kay Anderson of Alpha1 Advocacy and Action asked me: “Why is Prof Lomas non-approving of therapy for us?“

If you mean “why is he preventing approval of therapy for the whole Alpha community?“, he isn’t. No single doctor is. The Named Patient Program doesn’t work like that, and involves many more people than just individual doctors making decisions on patients use of unlicensed drugs. In terms of licensed drugs, its the Medicines and Healthcare products Regulatory Agency (MHRA) that grants or refuses licenses, and it does so usually on the basis of the drug concerned having proven its efficacy via a number of Randomised Controlled Trials, and having a statistically-significant, positive outcome.

On the other hand, if you mean, “why is Prof Lomas a sceptic about augmentation therapy?“, my understanding is that it simply has not yet successfully completed any Randomised Controlled Trials (RCTs) and shown any statistically-significant results of a positive nature. As far as I am aware, there have only been two RCTs ever conducted (so far) with the express remit of measuring the efficacy of Augmentation Therapy – in the whole world of Alpha – since it was discovered in 1963. Both of those trials (Dirksen 1999 and Stockley/EXACTLE 2009) came back with results that did not show any statistically-significant improvement in FEV1 decline rates of patients with or without AAT therapy.

The 1999 trial showed a (non-significant) trend towards a worsening of FEV1 decline-rates in those patients who had therapy. (The trial focussed on 58 ex-smoker Alphas with FEV1s of 30%–80% predicted at the start of the trial. They were infused with 250 mg per kilogram of body-weight every 4 weeks for a minimum of three years). It is important to remember that this worsening of FEV1 decline was not statistically significant, and may be within the bounds of experimental error. But there was no clear-cut indication that augmentation worked – as you would expect, say, if you measured 58 people for the effects of paracetamol stopping pain, or penicillin stopping bacterial infections. The Dirksen trial did discover a reduction in the rate of decline of lung-tissue density, when measured by CT scan, in the therapy-receiving group. The trial was not designed to measure mortality-rates, so this didn’t feature in the results. Principally, it was measuing FEV1 decline, and on that basis it produced no significant FEV1 result. The ‘hard science’ view is that (on this occasion) there was no evidence to prove that AAT-therapy is any better than doing nothing (and a possibly random trend that suggests that therapy is worse!).

In Stockley’s 2009 EXACTLE trial, FEV1 decline was again the primary measure of efficacy, but again the results showed no significant FEV1 difference with or without AAT-therapy. The patients were never-smokers and ex-smokers, and the dose was 60 mg per kg of bodyweight, weekly, for 2 years minimum. Like Dirksen 1999, EXACTLE also showed a borderline significant result that lung-tissue density degraded less quickly in those patients with therapy, as measured by CT scan. But only when the data was measured in one of four different analytical ways. Initially, exacerbations were not seen to be any different with or without AAT-therapy, but in a later reworking of the data, Stockley saw a marginal improvement in exacerbation reduction in the patients with therapy. Once again, mortality was not a statistic that formed part of the trial’s measurement system or design.

These are the only two Randomised Controlled Trials that have been done on AAT Therapy Efficacy. Virtually all other papers in the Alpha field which reference augmentation (usually as a sideline) are either about measuring something else entirely (quality of measurement techniques, equipment, etc) or have been ‘re-hashes’ (for want of a better word) of the numerical data of both these two RCTs, or other trials that were not RCTs (i.e. they were Observational studies, or Non-Random trials – neither of which are the ‘gold standard’ of science). The infamous Cochrane report was a ‘re-hash’ of the Dirksen & EXACTLE data mixed together (in a way that was never intended, and which was slammed by most experts in the field, including the sceptics), and Stockley’s group themselves ‘revisited’ the EXACTLE data and improved the processing of the lung-density results, and were able to put a statistical figure on them of p = 0.006, which showed the improvement in lung-density was significant. (Without going into massive detail on evidence-based medicine, the lower this ‘p-value’ is the better. A p-value of 0.05 or less is generally regarded as ‘significant’, and is taken to mean that the result which has been measured in the trial is not something that would have happened randomly, if the drug was ineffective. That is to say, the effect seen, is seen because the drug has had some effect, and ‘doing nothing’ (what they call the ‘null hypothesis’) would not have reached this same result within the bounds of accepted randomness (5% of the time)).

The point is, all the stuff most lay-people suggest is ‘proof’ of AAT-therapy value hangs on the results of other trials or studies (or sometimes even just anecdotal or personal observations) which are not deemed by the scientific community as being unequivocal. Methodologies, measurements, objectivity, randomness, placebo-effect and suitability (or lack of similarity) of patients are all features that can be criticised and regarded as introducing some ‘wooliness’ to the results. This is always the case with observational studies and non-random trials, and they will always be regarded as less ‘valid’ than fully randomised, double-blind, placebo-controlled trials which will usually be accepted by the scientific commmunity.

As Prof Lomas said to us in Bristol – the daft thing is that if a Randomised Controlled Trial showed that a certain new drug gave us as little as six weeks extra extension on the life of a cancer patient, that evidence would be accepted by MHRA and the drug would be licensed. Whether it was clinically valid to buy it – especially if it was hideously expensive, or difficult to administer – would not be their remit to determine (the cost issue would be NICE’s problem). Their job is to approve on the basis of efficacy – can it be proven, by an accepted standard, to work? (there are other factors, such as side-effects and dangers, but in terms of the baseline, the drug has to be considered to work, first, above all else).

So, until we see other RCTs which are targeted at the question of ‘is augmentation therapy effective?’, and get a statistically-significant positive result from those trials, the hardcore science community is unlikely to change its viewpoint. That’s what scepticism is all about. They are not ‘disbelievers’, nor are they ‘fans’ (if you want to look at it in emotional terms, which of course, scientists are supposed not to do!). They are ‘on the fence’. Agnostics, if you like; not religous, not atheist… they remain to be convinced, by the approved, agreed method. Randomised Controlled Trials. That is the science industry we have made for society in the 21st Century, and it’s a pretty good one really, generally. Obviously in cases like ours where the disease is still quite ‘new’ (50 years is nothing compared to other diseases), and where the drugs to treat them have been around less than a quarter-century and are still evolving, it’s not always the easiest hurdle to jump our drugs over. Even worse when our sufferer numbers are small, and the disease is rare, because it makes Randomised Controlled Trials so much harder to conduct.

However, Prof Lomas’s comments to Caroline Gillisen indicated that he thinks there are enough Alphas to make up a randomised controlled trial now (but he didn’t say – or maybe I couldn’t hear – whether that would need international co-operation, which is what he indicated would be necessary when talking about patient numbers in his Aug 2011 paper – entitled “Why has it been so difficult to prove the efficacy of alpha-1-antitrypsin replacement therapy?“ ).

It has been commented on that if AAT-therapy was a brand-new drug discovered today, EU regulations would allow it to be used under the ‘orphan drug/orphan disease’ rule (Regulation(EC) No 141/2000) – but as you can see from the date of that regulation, it only came into effect in 2000. The regulation does not allow a drug that has previously been licensed by an EU Member State (via the old rules) to be granted Orphan Drug status retrospectively… which is damned shame. It means that the ‘gold standard’ of testing cannot be lowered for antitrypsin replacement therapy in the UK, to allow it in via the orphan rules, which would not require a full randomised controlled trial. Maybe that’s something we should be campaigning for, too? Orphan status might enable a way in for AAT-therapy, but it still wouldn’t convince the sceptical scientists that it was effective, though. Only a successful RCT will likely achieve that… (but if it’s already in, and being used, perhaps we can let the scientists worry about that, while we’re busy using it!)

Kay said: “I can’t quite remember the whole thing on the polymers – surely this happens regardless? So why would putting in the good AAT make matters worse than it already is?”

Simple answer is, it wouldn’t make matters worse. Not in general.

Of course, if we’re strict, and refer only to the results of the two Randomised Controlled Trials, putting in the ‘good’ AAT won’t make any difference (statistically), and (according to the Dirksen 1999 results) there is a chance we’d follow their (non-significant) trend, and find that it made our FEV1 decline more quickly than if we’d not used AAT therapy! (But as I said, that ‘trend’ was not outside the bounds of ‘experimental error’, so really we should discount that entirely.) All we can really say (by the numbers) is that it won’t make any statistical difference to our FEV1 decline, but it would make a difference to our lung-density decline (as shown by Stockley’s revisit to the 2009 EXACTLE data).

Of course, that’s just if we look at the RCTs – which is what the hardcore scientists are supposed to do. If we go by the observational and non-randomised studies (which the scientists and regulators discount) then we can probably expect benefits – but exactly what they will be, and to what degree, is hard to be certain of (so I won’t even speculate). We’re almost back to ‘belief’ and the ‘power of placebo’ and self will, but plenty of people we know, say that they feel it’s extended their life, so, well, maybe there’s more to it than the RCTs have been able to show. So far, anyway.

But one of the RCTs (and some of the non-random trials) did show that if you give AAT therapy to someone who is above the 80% predicted FEV1 mark (and one suggested even above the 65% mark) you will cause them to have a faster rate of FEV1 decline than if you’d given them nothing. That, sadly, is a pretty convincing incidence of where ‘putting in the good AAT’ clearly can ‘make matters worse’. The ‘sweet spot’ where benefits have been shown to lie, in observed and non-random trials, is those sufferers with 30-65% predicted FEV1 levels at the start of the treatment. Below 30%, I have been told conflicting stories, and haven’t found any definitive papers to suggest whether they’d benefit at all, or whether it would make matters worse. I think the general consensus is that sub-30%, it’d be a waste, but I am quite prepared to re-evaluate my opinion on that if someone can point me at a medical report on that sector of the Alpha population.

There are also a few people who suffer from allergies to AAT (and other similar conditions), and of course, they could be harmed or endangered (or at least experience discomfort and pain) by taking the treatment – but that’s not really a ‘fault’ of AAT; it’s a sensitivity of some unfortunate people, so I won’t dwell on that. But it is worth bearing in mind.

The other side to your question is about polymerisation, and the fact that it’s going on all the time (in Z, S, Mmalton and Siiyama Alpha patients) to varying degrees. That’s going to be happening whether or not the patient is receiving ‘good’ M-antitrypsin. There is no question that the mix is somehow ‘bad’ – that’s not an issue (as far as I’m aware); but there is a situation where it can render some types of trial – which rely on the measurement of inflammation in the lungs – completely unreliable. Pre 2004, nobody was aware that the lungs themselves dispense AAT directly into the lungs. Nor were they aware that Z-AAT can polymerise right there in the lungs, as well as the liver (which they did know about). Any trial which relied on pumping in M-AAT and measuring to see whether the lungs became less-inflamed, was actually being messed up – because the Z-AAT coming from the lungs was itself causing inflammation. The thinking (pre-2004) was that all the polymerisation happens in the liver – but that’s not the case; it can polymerise in the lungs, too. At best, it might just mean that trials based on inflammation measurements were biased (in such a way that would make M-AAT’s effects look less good, or perhaps unstable or inconsistent). Worst case, it might mean that because the Z-AAT polymerisation is going on in the lungs themselves, it is potentially causing direct tissue damage itself (as well as the effect of the elastase that is the main cause of lung damage; the thing that ‘good’ AAT is supposed to stop). If that’s the case, it means that M-AAT therapy is only really addressing half the problem – the damage caused by elastase – while the damage caused by polymerisation in the lungs is still continuing unabated.

Of course, from that knowledge, the question arises: “isn’t it still better to have some protection than none? Some M-AAT addressing half the problem is better than no good AAT, not addressing any of the problem, surely?”  Yes, it probably is – but again, only for the right people – the 30-65 percenters, the non allergics, and of course, only the Alphas with emphysema! No kind of AAT therapy is going to benefit an Alpha who isn’t suffering from any kind of emphysema, but is instead suffering liver damage from chronic polymerisation! That might seem obvious, but if I had a penny for every time I’ve read “All Alphas are entitled to Augmentation Therapy and should have it!” or “AAT-therapy benefits all Alphas”, I’d be a rich man. Tell that to the liver-Alpha who’s never smoked a day in his life and whose lungs are as sound as a bell, but whose liver is shot, and you’ll get a derisory response, I’m sure!

So – for the right people, maybe good AAT is a worthwhile ‘stab in the dark’; a ‘better than nothing’. Yup, I would agree it’s worth a shot. I’d have it in an instant, if I didn’t have to pay for it. And therein lies the next problem. Someone’s got to pay for it, and in this country, it’s the State. That’s why they seek to prove efficacy by the highest standard before they’ll cough up the cash for something so hideously expensive. Even if we could prove by that RCT gold standard that it made a few weeks difference to life-extension or quality, we’d stand a better chance (we might at least be able to get it on BUPA or something, if it was licensed). But at the moment, no way. We’re stymied by MHRA due to lack of convincing RCT results, and that in itself stops us even getting as far as the NICE committee table where they’d argue the toss about the cost aspect, and whether it was worth spending out that much in order to gain the extra life-value offered by the (what would be now proven) treatment. It’s hurdle after hurdle – and although I know it seems unfair, it’s actually not. We’re just on the wrong side of a safeguard that’s been put in place to avoid squandering the majority’s healthcare cash. It doesn’t mean that they’re wasting any less on admin, dealing with society’s alcohol problem, drug-addicts being propped up by the state, or even the side-effects of failing to keep the wards clean and giving us all super-bugs… that stuff is all still happening, and it’s all still questionable, wrong, annoying as hell, and all that. But they’re not doing that to spite us. We’re just in a tricky corner, right now.

As far as I can tell, the only way out of this, and on to the next hurdle (NICE and the purse-strings) is to have a drug company grow some balls, step up to the plate, and PROVE their drug works, in a proper Randomised Controlled Trial that no sceptical scientist could deny is ‘proper’. And, of course, it would need to have a good outcome (or else we’d be totally screwed, and you’d probably see AAT-therapy disappearing off the treatment-lists of all the other nations where it was licensed, quicker than you could say ‘oops’… And maybe thereby hangs a tale? Perhaps that is why we’re not seeing a big rush to do RCTs to prove AAT works, once and for all. What drug company in its right mind would want to risk upsetting their worldwide moneyspinner, just for the sake of getting in to li’l ol’ Britain? The cost of preparing and conducting such an RCT would itself be humungous – imagine the damage to their worldwide reputation and sales if it came back as a perfectly accurate, ‘gold standard’ NEGATIVE result? It’s almost better for them not to look under that stone at all, isn’t it?

If they can be sure of the quality and efficacy of their drug beforehand, however, we might yet see some proof in the for of an RCT. I believe one is currently ongoing, using mortality as a measurement. Maybe this will improve things. If not, I’m not going to let it worry me. There are bigger fish to fry than these (currently) half-proven ‘holding pattern’ and ‘time-buying’ AAT therapies that may not even hold or buy time. There are cures to be had. Real answers to chase. Beta-sheet holes in antitrypsin molecules to block, stem-cells to tweak and ‘set right’, and perhaps even lucky breaks to be had with ‘old’ drugs like Carbamazepine (CBZ), the epilepsy drug that’s been shown to ‘clear’ the polymerisation of Z-AAT, and make our AAT useful again. I can’t see that its wise to focus all our fight and energy on AAT therapy, if it takes as long as it looks like taking, to get that in the UK. By the time it’s here, and coursing through our veins, we might well all have been ‘flushed’ by CBZ, or had our genes stitched back to working versions, or be jacking up on stuff which blocks the tiny holes in our antitrypsin that makes it so ‘hooky’. Who can tell? All these other rolling dice need watching and fighting for too, I believe.