The European Union and its Institutions have been heavily criticised as part of the Brexit debate as been undemocratic and unaccountable to the man or woman on the street. However, it is only when their decisions impact on you, or your patients, that you realise that these critics have a valid point.
Last week the European Medicine Agency’s safety committee (PRAC or Pharmacovigilance Risk Assessment Committee) did something that makes me despair. They railroaded through changes to alemtuzumab’s SmPC (summary of product characteristics) against the advice of experts and without data to support their position. Their advice is therefore not evidence-based and as a result, it is likely to deny many pwMS access to one of our most effective DMTs.
The PRAC states “Alemtuzumab should no longer be used in patients …. who have autoimmune disorders other than multiple sclerosis”. There is no evidence to support this statement. PwMS who have a pre-existing autoimmune disease are not at an increased risk of developing complications from alemtuzumab or secondary autoimmune disease when compared to pwMS who don’t have a pre-existing autoimmune disease.
The problem I have is that the PRAC made this decision despite robust evidence to the contrary being presented by Genzyme and advice from experts in the field. I even co-signed a letter that Prof. Alasdair Coles penned to the PRAC, CHMP and MHRA, which clearly fell on deaf ears.
The behaviour of the PRAC reminds me of the Michael Gove interview with Faisal Islam on Sky News that took place on the 3rd June 2016 in the run-up to the Leave-Remain EU referendum:
Gove: I think the people in this country have had enough of experts, with organizations from acronyms, saying—
Faisal Islam: They’ve had enough of experts? The people have had enough of experts? What do you mean by that?
Gove: People from organizations with acronyms saying that they know what is best and getting it consistently wrong.
Faisal Islam: The people of this country have had enough of experts?
Gove: Because these people are the same ones who got consistently wrong what was happening.
Faisal Islam: This is proper Trump politics this, isn’t it?
Gove: No it’s actually a faith in the —
Faisal Islam: It’s Oxbridge Trump.
Gove: It’s a faith, Faisal, in the British people to make the right decision.
Does the EMA expect us to have faith in their decision-making?
As an MSologist looking after pwMS this upsets me and worries me immensely. The implications of ignoring experts is one thing, but what are the implications for my patients? What impact will this PRAC decision have in practice?
I estimate that about a third of pwMS will have a comorbid autoimmune disease and may even be more than a third. The latter depends on how you define autoimmunity. This means many people with MS will be denied access to alemtuzumab because of EU officials who ignored the evidence presented to them and without any transparency around their thought processes and why they made this decision. This is no way for EU officials to be acting when we are trying to argue the case for Britain staying in the EU.
Lack of transparency with the EMA is not new. I have been involved with many EMA-CHMP decisions and it really depends on the whim of rapporteur or co-rapporteur. Unlike the FDA which holds its meetings in the open, with the EMA and its various sub-committees you have no idea of the decision-making processes that go on behind closed doors. I am often asked why the British voted to leave the EU. The elephant in the room is the EU itself and how it functions; its decisions impact the lives of its citizens and this is another example of very, very, poor decision making with many downstream ramifications.
CoI: multiple
The Time-to-Think DMT
At an MS Masters Forum in Rome yesterday I was teaching MSologists and MS clinical nurse specialists using a recently created board game, which I like to think of as being MS Monopoly. MS monopoly is based on a game of chance that lets you discuss case scenarios and make treatment choices. Then you roll a dice, which determines the outcome of your choice.
Two things emerge from playing the game. Firstly, how choosing an immune reconstitution (IRT) addresses so many of the treatment aims and longterm issues of safety. The question I ask is why aren’t the IRTs dominating the treatment landscape?
Secondly, it became clear how many times natalizumab was considered as a treatment option and discarded because of its PML risk. From yesterday’s discussions it clear to me that natalizumab is the ‘time-to-think’ DMT, i.e. you start someone on natalizumab for 6-12 months whilst you make the necessary long-term decisions. This may be necessary to wait for lymphopaenia to recover, to complete a vaccination programme (e.g. the three-dose HPV polyvalent vaccine), to wait to get the all-clear on a previously-treated malignancy, to prevent rebound on stopping fingolimod so that the woman with MS can fall pregnant, or to complete a diagnostic work-up. The latter indication underpins our #AttackMS trial design.
Another indication for natalizumab is to prevent CNS adverse events associated with cancer immunotherapy. I recently recommended that a patient with MS who had disseminated bowel cancer and was about to start an immune checkpoint inhibitor go onto natalizumab despite being JCV positive to prevent exacerbation of her MS. The rationale being that the polyclonal activation of her T-cells in the periphery, including her autoimmune cells responsible for her MS, would not traffic to the brain and spinal cord and cause an MS relapse. The downside of this strategy is that if she had occult secondaries in her CNS then natalizumab will prevent her T-cells finding and clearing these cells. As bowel cancer rarely metastasizes to the CNS we thought this was a risk worth taking. Last I heard she was doing well from the MS perspective, but not that well in relation to her bowel cancer.
I am sure natalizumab will prevent the CNS complications associated with CAR-T cell therapies. Could this be a repurposing opportunity for natalizumab?
What makes natalizumab so uniquely special as a DMT are the observations that it has the most rapid onset of action of all the DMTs, it has very high efficacy, its mode of action can be reversed with plasma exchange and natalizumab does not cause systemic immunosuppression. The only downside of natalizumab therapy is the long-term PML and other CNS infection risk and the emerging CNS lymphoma risk. These are all due to reduced CNS immune surveillance. The fact that extended interval dosing (EID) reduces the PML risk by over 80% suggests natalizumab may make a resurgence and all these CNS side effects may be preventable. However, for this to happen we need to be able to prescribe natalizumab more liberally as a first-line treatment for active MS. If anyone from Biogen is reading this blog post can you please ask the powers that be in Biogen to consider asking the EMA to reconsider natalizumab’s label? By not doing this you are denying many pwMS access to natalizumab, albeit for a short period of time as highlighted above.
The good news is that the EMA has accepted the EID data and it is now in natalizumab’s summary of product characteristics.
New text in the EMA’s SmPC: In a pre-specified, retrospective analysis of US anti-JCV antibody-positive natalizumab patients (TOUCH registry), the risk of PML was compared between patients treated with the approved dosing interval and patients treated with extended interval dosing as identified in the last 18 months of exposure (EID, average dosing intervals of approximately 6 weeks). The majority (85%) of patients dosed with EID had received the approved dosing for ≥1 year prior to switching to EID. The interim analysis showed a lower risk of PML in patients treated with EID (hazard ratio = 0.06 95% CI of hazard ratio = 0.01- 0.22). The efficacy of natalizumab, when administered with EID, has not been established, and therefore the benefit/risk balance of EID is unknown (see section 4.4).
For those interested, I have included the latest PML figures from Biogen.
CoI: multiple
Hopebird
The debate about what is active and inactive secondary progressive MS will not be settled by the EMA adopting a positive opinion, recommending the granting of a marketing authorisation for siponimod, which is now ‘licensed’ for the treatment of adult patients with secondary progressive multiple sclerosis (SPMS) with active disease. Siponimod reduces disability progression in people with active SPMS. The most common side effects are headache, hypertension and increased liver enzyme levels. The full indication is: “treatment of adult patients with secondary progressive multiple sclerosis (SPMS) with active disease evidenced by relapses or imaging features of inflammatory activity (see section 5.1)”.
This label will disappoint the many pwSPMS who don’t have active scans and therefore won’t be eligible for DMTs. I have commented on what is and is not active SPMS in the past. I think the siponimod label entrenches the MRIcentric worldview of what is active MS. We know that the majority of people dying with SPMS have ongoing inflammation in their brains and spinal cords at post-mortem. Try telling someone with SPMS who is getting worse that they don’t have active MS because they have no enhancing, or new or enlarging T2, lesions on MRI. And what about using CSF and/or peripheral blood neurofilament levels to assess activity? We clearly need to challenge the EMA’s and FDA’s definitions of what is active SPMS.
At least the licensing of siponimod for treating SPMS is a big positive for the field and indicates that we are beginning to address the unmet need in treating more advanced MS.
The impact that this will have on our MS services should not be underestimated. We are now going to have to monitor our SPMS patients with annual MRI scans. Do we have the resources for this? What about the extra follow-up clinic slots? This alongside ocrelizumab for active PPMS is going to put a major strain on our MS services. Will our managers give us more resources?
Siponimod may not be an eagle, phoenix or maven, but rather a hopebird which symbolises the importance of “an optimistic approach to what lies ahead” and why it is important to have a “glass half full” attitude. Less than a decade ago we were telling our patients with a progressive course that they were beyond hope, that has now changed.
CoI: multiple
The Phoenix
Like a phoenix rising from the ashes for the third or fourth time, alemtuzumab is given yet another life. I am sure many neurologists and people living with MS will be grateful, but I don’t agree with its positioning.
EMA’s safety committee or PRAC has handcuffed alemtuzumab and is restricting it for adults with relapsing-remitting multiple sclerosis that is highly active despite adequate treatment with at least one DMT or if the disease is worsening rapidly with at least two disabling relapses in a year and brain-imaging showing activity. The new indication is not too dissimilar to that of natalizumab. Just when we are pushing for natalizumab to get a first-line license to address our #AttackMS concept, alemtuzumab gets yoked to natalizumab.
In my opinion, the contraindication handcuff that alemtuzumab must no longer be used in patients who have auto-immune disorders other than MS is not necessarily correct. I am not aware that having another comorbid autoimmune disease puts you at increased risk of developing another autoimmune disease after being treated with alemtuzumab. I have asked Joanne Jones and Alasdair Coles from Cambridge who have the most experience with alemtuzumab, both clinically and scientifically, and they agree. I think we need to appeal this contraindication as it may deny many pwMS access to one of our most effective DMTs. I suspect that Sanofi-Genzyme will have data from their trial programme to help appeal this contraindication.
Looking at this with from a glass-half-full perspective is the good news that at least we still have alemtuzumab as a treatment option for pwMS with more active disease. However, this will deny many pwMS with active MS from being treated with the most effective DMT first-line.
When will regulators come to the realisation that the decision to take on risks should be taken by the person with the disease guided by their HCP and not the regulators? By moving alemtuzumab to a predominantly 2nd-line position means pwMS will now have to wait several years to access the most effective DMT. I am not sure the new positioning of alemtuzumab in the therapeutic hierarchy will stop the more educated and determined people with MS seeking HSCT abroad or in the private sector.
I am curious to know if my letter to the EMA (below) helped. But having alemtuzumab back on the treatment landscape as predominantly 2nd-line therapy means we will at least be able to offer alemtuzumab as a realistic option before, or alongside, HSCT in London. This also means we can go ahead with our head-2-head comparison of alemtuzumab vs. HSCT to assess HSCT’s relative efficacy and safety against a licensed DMT.
Open letter the EMA sent on the 20th August 2019
European Medicines Agency
Amsterdam
Dear Sir/Madam
Alemtuzumab has transformed the MS treatment landscape. It not only provides superior short term efficacy, but a significant number of patients treated with alemtuzumab note improvement in disability. However, its main advantage over other DMTs is that a large proportion of patients go into longterm remission and normalise the rate of their brain volume loss. In regard to the latter, this is unprecedented in comparison to other licensed MS disease-modifying therapies, with the possible exception of haemopoietic stem cell transplantation (HSCT), which is not licensed and hence not widely available to treat patients with MS in Europe. Alemtuzumab, therefore, is the only realistic alternative to HSCT, which has become a very popular treatment choice amongst people with multiple sclerosis, in particular, ‘digital natives’ who get their information online. As with all DMTs the earlier you use them the more effective they are and the greater the benefit to the individual patient. Alemtuzumab is, therefore, an important treatment option for people with MS; being able to offer alemtuzumab early as a treatment option is an important factor in my clinical practice to dissuade many Britsih patients from travelling abroad for HSCT.
At our centre, Barts Health NHS Trust, we have now treated over 250 patients with alemtuzumab with over 40% being treated with alemtuzumab first-line. Patients receiving alemtuzumab first-line tend to have more active disease and less favourable baseline prognostic profile. Despite its side effect profile and the need for monthly monitoring, many patients are willing to take on the risks and the burden of monitoring to be treated with the most effective licensed DMT first-line. All our patients are extensively counselled about the risks and benefits of alemtuzumab treatment and sign an informed consent and a patient contract agreeing to the mandatory monitoring programme. We feel the use of alemtuzumab in the correct environment is relatively safe and the adverse events manageable. Not having alemtuzumab for use in early active disease would mean patients having to wait to fail several other, less effective, licensed DMTs prior to accessing alemtuzumab. I firmly believe in the concept that ‘time is brain and spinal cord’ in MS and delaying access to the most effective treatment would limit our ability to optimise the management of MS in patients with more active disease and in those with a poor prognostic profile. In addition, shifting the use of alemtuzumab to a population of patients with more advanced disease would unfavourably change the benefit-risk profile of alemtuzumab and make it less appealing as a treatment option.
The real-life data of alemtuzumab clearly supports it as being the most effective DMT on the market and its other attributes in relation to its posology make it a very appealing therapy; for example in women wanting to start or extend their families.
In summary, limiting alemtuzumab to a third-line, last resort DMT, will severely limit our treatment options for managing this devastating disease. Alemtuzumab offers many patients with MS a real hope of living as normal a life as possible, however, this option does depend on using alemtuzumab early in the course of the disease. I, therefore, appeal to the MS community and the European Medicine Agency to consider these factors when reviewing the benefits and risks of alemtuzumab as a treatment for MS.
Yours faithfully
GAVIN GIOVANNONI
CoI: multiple
Short- or long-sighted
I saw three patients 9-and-half-years after starting treatment with alemtuzumab as first-line therapy, yesterday. It was a remarkable experience. Only one of the three patients had needed a third cycle of alemtuzumab. All are in long-term remission; i.e. flat-lining on the EDSS, relapse-free and with no MRI activity (NEDA-3). Their EDSS scores yesterday were 1.0, 1.5 and 2.0. All of them are fully functional, with no physical and cognitive restrictions and described themselves as being well. One patient suggested to me she doesn’t have MS anymore. One patient has had ITP and recovered from it. All three patients have normally functioning immune systems with normal total lymphocyte counts. None of them is concerned about infections, travel, vaccinations or secondary malignancies. This is why treating MS with an immune reconstitution therapy, such as alemtuzumab, is so appealing.
I have a dream that this will be the new normal and all people with MS in future will have similar experiences. I sincerely hope the EMA allows people with MS to be treated and managed the same way as these three patients of mine have. I still have had no response from the EMA to my letter below. Maybe they don’t care?
Can anybody tell me from testing their vision if they are short- or long-sighted?
Open letter the EMA sent on the 20th August 2019
European Medicines Agency
Amsterdam
Dear Sir/Madam
Alemtuzumab has transformed the MS treatment landscape. It not only provides superior short term efficacy, but a significant number of patients treated with alemtuzumab note improvement in disability. However, its main advantage over other DMTs is that a large proportion of patients go into longterm remission and normalise the rate of their brain volume loss. In regard to the latter, this is unprecedented in comparison to other licensed MS disease-modifying therapies, with the possible exception of haemopoietic stem cell transplantation (HSCT), which is not licensed and hence not widely available to treat patients with MS in Europe. Alemtuzumab, therefore, is the only realistic alternative to HSCT, which has become a very popular treatment choice amongst people with multiple sclerosis, in particular, ‘digital natives’ who get their information online. As with all DMTs the earlier you use them the more effective they are and the greater the benefit to the individual patient. Alemtuzumab is, therefore, an important treatment option for people with MS; being able to offer alemtuzumab early as a treatment option is an important factor in my clinical practice to dissuade many Britsih patients from travelling abroad for HSCT.
At our centre, Barts Health NHS Trust, we have now treated over 250 patients with alemtuzumab with over 40% being treated with alemtuzumab first-line. Patients receiving alemtuzumab first-line tend to have more active disease and less favourable baseline prognostic profile. Despite its side effect profile and the need for monthly monitoring, many patients are willing to take on the risks and the burden of monitoring to be treated with the most effective licensed DMT first-line. All our patients are extensively counselled about the risks and benefits of alemtuzumab treatment and sign an informed consent and a patient contract agreeing to the mandatory monitoring programme. We feel the use of alemtuzumab in the correct environment is relatively safe and the adverse events manageable. Not having alemtuzumab for use in early active disease would mean patients having to wait to fail several other, less effective, licensed DMTs prior to accessing alemtuzumab. I firmly believe in the concept that ‘time is brain and spinal cord’ in MS and delaying access to the most effective treatment would limit our ability to optimise the management of MS in patients with more active disease and in those with a poor prognostic profile. In addition, shifting the use of alemtuzumab to a population of patients with more advanced disease would unfavourably change the benefit-risk profile of alemtuzumab and make it less appealing as a treatment option.
The real-life data of alemtuzumab clearly supports it as being the most effective DMT on the market and its other attributes in relation to its posology make it a very appealing therapy; for example in women wanting to start or extend their families.
In summary, limiting alemtuzumab to a third-line, last resort DMT, will severely limit our treatment options for managing this devastating disease. Alemtuzumab offers many patients with MS a real hope of living as normal a life as possible, however, this option does depend on using alemtuzumab early in the course of the disease. I, therefore, appeal to the MS community and the European Medicine Agency to consider these factors when reviewing the benefits and risks of alemtuzumab as a treatment for MS.
Yours faithfully
GAVIN GIOVANNONI
CoI: multiple
Hepatitis post-alemtuzumab
Another alemtuzumab-related post, this time in relation to alemtuzumab-associated liver injury, which has been also been included as a complication of alemtuzumab treatment in the EMA’s SmPC (summary of product characteristics).
Liver or hepatic injury can occur as part of a drug-induced injury as seen in case 2 below or as a delayed, presumably autoimmune, condition as in case 1 below. Please be aware autoimmune hepatitis has been described in association with all licensed MS DMTs including the original injectable therapies, i.e. interferon beta and glatiramer acetate. I have always considered this to be a simple association, i.e. pwMS are at risk of developing comorbid autoimmune hepatitis.
Again I think autoimmune hepatitis is a rare complication if it is a complication, of alemtuzumab treatment. You need to be vigilant of any new symptoms and get medical help immediately if you experience any of the following:
- Yellow skin or eyes
- Dark urine
- Bleeding or bruising more easily than normal
El Sankari et al. Auto-immune hepatitis in a patient with multiple sclerosis treated with alemtuzumab. Acta Neurol Belg. 2018 Jun;118(2):331-333.
Case 1
25-year-old female patient was diagnosed with RR-MS in September 2011. The patient received two courses of ATZ in November 2014 and 2015 successively. She remained stable with an EDSS score of 4 and no recurrence of disease activity on brain MRI. Eleven months following the last ATZ course, laboratory assessments revealed hyperthyroidism attributed to Grave’s disease. l-thyroxin and thiamazol were initiated.
An increase in liver enzymes occurred 1 month later, while thyroid function was normalized. Despite the interruption of thiamazol, liver dysfunction persisted.
Liver biopsy showed a diffuse, severe and mixed inflammatory infiltrate, composed of lymphocytes, eosinophils and neutrophils, infiltrating the limiting plate, surrounding the portal triad, and sparing the biliary tract. A diagnosis of type 1 autoimmune hepatitis (AIH) was made.
Standard treatment, consisting of 1 mg/kg/day of prednisolone, was initiated, with a transient episode of encephalopathy, resolving after corticosteroid dose reduction (to 0.5 mg/kg/day). 1 month later, the patient improved clinically and her laboratory abnormalities resolved; prednisolone doses were then slowly decreased, and immunosuppressive treatment with azathioprine was introduced.
Beattie e al. Acute severe hepatitis with alemtuzumab and rechallenge after a year. J Clin Neurosci. 2019 Feb;60:158-160
Case 2
This patient developed severe hepatitis within two days of starting alemtuzumab, both initially and upon rechallenge. The alanine aminotransferase peaked at 577 units per litre and 426 units per litre after the initial dose of alemtuzumab and rechallenge respectively. The patient’s liver function tests improved significantly between doses of alemtuzumab and again normalised within three months of the second dose, with no clinical manifestations of acute hepatic failure.
CoI: multiple