Alemtuzumab’s unknown-unknowns

I received an email from a patient this morning that needs careful consideration and a response.

“Gavin I have just seen your Tweet about alemtuzumab and article 20. I am due to have my first course of alemtuzumab in May. What does this mean for me?”

It means a lot. If you have not failed two other DMTs and do not have highly active relapsing multiple sclerosis it is likely you will not be receiving alemtuzumab in May. There is one clause in the EMA’s guidance that may allow you a get out; alemtuzumab can be used ‘where other disease-modifying therapies cannot be used’. However, I am finding it hard to think of why other highly-effective DMTs, for example, natalizumab and ocrelizumab can’t be used instead of alemtuzumab. The big issue from the healthcare provider, and the neurologists, perspective is medicolegal. If we prescribe off-label and something goes wrong it puts us at very high-risk legally; in street speak, the risk is being sued for malpractice. This is why neurologists, in general, loathe prescribing drugs off-label and is part of the reason why our essential off-label DMT list has virtually no impact outside of our centre.

The EMAs ruling needs some deep thought and quiet reflection. The following are some of my initial thoughts.

I recall a conversation I had with one of the Pharma medics who was working for Bayer-Schering at the time when they decided to hand the alemtuzumab, or as it was known back then Campath-1h, baton over to Genzyme. They thought the legacy of repurposing an oncology drug for MS would be too difficult to overcome, but they were also concerned about the known-unknowns and the unknown-unknowns of alemtuzumab. In pharma speak alemtuzumab was simply too risky for Bayer-Schering to take forward. This particular medic would almost certainly claim that his risk assessment has been vindicated.

Can I play devil’s advocate and disagree with him?

Although there are new safety concerns highlighted in the EMA’s ruling they are not that new. I have known about all of these issues for some time now and so have the EMA and FDA. What is new is the triggering of an article 20 procedure. Please note that article 20 can be triggered by any one of the EU member states and there is one particular country that has never come to terms with the liberal alemtuzumab label for treating relapsing MS. I would not be surprised if this particular country was behind the triggering of the article 20 procedure.

The question I have asked myself since being informed about the article 20 procedure earlier this week; is it necessary? On this point, I have to agree with the EMA and this is based on the unknown-unknowns.

In addition to the preliminary prescribing restriction, the EMA’s safety committee (PRAC) has recommended an update of the product information for alemtuzumab to inform pwMS and HCPs about cases of:

• immune-mediated conditions, including autoimmune hepatitis (with damage to the liver) and haemophagocytic lymphohistiocytosis (overactivation of the immune system which may affect different parts of the body);
• problems with the heart and blood vessels occurring within 1–3 days of receiving the medicine, including bleeding in the lungs, heart attack, stroke, cervicocephalic arterial dissection (tears in the lining of the arteries in the head and neck);
• severe neutropenia (low levels of neutrophils, a type of white blood cell that fights infections).

Of these new cases the immune-mediated conditions can be classified as known-unknowns, i.e. based on secondary autoimmune complications that have been described with other immune reconstitution therapies, in particular, HSCT and bone marrow transplantation, these are to be expected. More importantly, they can be derisked as part of the monthly blood monitoring and patient education programmes. The severe neutropaenia is a known-known with several case reports in the literature, is probably autoimmune in origin and can be treated.

The more worrying adverse events are the vascular complications. The first questions that come to mind in relation to these are:

1. How common are these events? I suspect they are rare otherwise a signal would have emerged in phase 3 and 4 trials. We need to know how common they are and what is the relative risk to other DMTs and the general population. Patients will need to know this when weighing up the pros and cons of alemtuzumab compared to other DMTs.
2. What is(are) the underlying mechanism(s)? I say mechanisms as it appears that the vascular complications are both thrombotic (clot formation) and endothelial damage or tearing (dissection). There is also recent evidence that acute hypertensive crises may also contribute to at least the haemorrhagic strokes. With so many competing mechanisms it may not be that easy to derisk these events apart from screening for and treating the hypertensive crises. I would assume anti-platelet therapies and anti-coagulants could potentially be dangerous as they make any haemorrhagic complications worse.
3. Can these complications be predicted and are there any strategies to prevent them? We need more information to see if these complications are limited to pwMS with specific risk factors, for example, vascular comorbidities. This would allow HCPs to avoid using alemtuzumab in these populations. I am sure the EMA will want to drill down into the detail of each of the cases.

I have personal experience with article 20 procedures and was intimately involved with daclizumab’s woes. It was clear that the nail in the coffin for daclizumab was the unknown-unknowns and the fact that the post-daclizumab encephalitis could not be derisked.

So we as a community have a large amount of work to do to help keep alemtuzumab on the table as a treatment for MS and preferably as a treatment option that is not 3rd-line. Why I say this is that there are a large number of pwMS who have benefitted from alemtuzumab by being treated with it early in the course of their disease, either as a first or second-line treatment. A large number of these people are in long-term remission, off DMTs, with no evident disease activity and ‘normalised brain volume loss’. Relegating alemtuzumab to a 3rd-line option puts it alongside HSCT as a treatment option and too far along the course of the disease to make a big difference at a population level. Having alemtuzumab 3rd-line will deny pwMS access to potential benefits of alemtuzumab relatively early in the course of their disease.

Recent MSBase data indicates that pwMS spend over 4 years on each tier of DMTs. This would mean that patients with active RRMS would probably take 8+ years to get to a stage when they are eligible for alemtuzumab as a 3rd-line agent. If you look at the health economic data this would be close to the point where 50% of the MS population is unemployed by the consequences of their disease with more than 60% being cognitively impaired. Is the place where we want alemtuzumab to be offered and used? I would say no. There is an increasing number of pwMS pushing for HSCT to be used 1st-line so why couldn’t we offer alemtuzumab with its new updated risk-profile alongside HSCT?

When it comes to shared decision-making and choice the regulators pay lip service to these ideals. What is important to them is patient safety and protecting them at all costs, even if it means disadvantaging the majority to protect the minority. Of all the stakeholders involved in MS, the regulators are the most conservative followed by the neurologists.

All I can say is that I am going to have a large number of very disappointed patients to deal with in the next week or so. But I have no option but to find another treatment solution until the EMA’s article 20 procedure runs its course.

Our vision of a population of pwMS being cured of their MS as a result of adopting a highly-effective 1st-line IRT strategy has potentially just been put on hold.

CoI: multiple