Friday, 22 July 2016

ClinicSpeak: pregnancy the new DMT battle ground

What type of patient would choose daclizumab as a treatment for MS? #ClinicSpeak #MSBlog #MSResearch

"I am often asked if there a place for daclizumab in the treatment of MS and what profile of patients would I recommend daclizumab for. Yes, there is a place for daclizumab in the treatment of MS and the profile of patients I would recommend daclizumab for is very wide, i.e. within the EU label."

"Given daclizumab's efficacy and safety profile there is definitely a place for daclizumab in the treatment of MS in 2016. As you are aware daclizumab has a very liberal first-line label in the EU for use in 'adults with relapsing forms of MS'. This means it can be used first-, second- and even third-line. The good news is that alongside alemtuzumab, daclizumab is the second monoclonal that can be offered as a first-line treatment. Some of you will be saying '.... but so can natalizumab be offered first-line'. I agree that natalizumab can be used first-line, but only in patients with rapidly-evolving severe MS (two disabling attacks in a 12 month period with objective evidence on MRI of disease activity, i.e. new T2-lesions or Gd-enhancing lesions); this group of patients represents a relatively small group of patients." 

"I envisage well-educated patients, who want a high-efficacy monoclonal therapy first-line, choosing between daclizumab and alemtuzumab. Patients who want a treatment that has a reversible mode of action, is not associated with infusion reactions, who can't take time-off work for infusions, and don't want transient immunosuppression will possibly choose daclizumab over alemtuzumab. When it comes to second-line therapies daclizumab's attributes will differentiate it from fingolimod, natalizumab and alemtuzumab. Although patients on daclizumab require monthly blood monitoring the fact that the drug is administered subcutaneously monthly, by self-injection, will appeal to some MSers. Finally third-line, I suspect it will become the agent of choice post-natalizumab in patients who are JCV+ve. Reasons for this are that daclizumab has a rapid onset of action, which should prevent rebound disease activity, daclizumab is not immunosuppressive so if there is carry-over PML you should be able to mount a robust immune response to the virus and finally daclizumab expands the population of natural-killer cells (NK-cells) that have anti-viral properties."

"Many commentators state that the immune-mediated adverse events due to daclizumab (skin reactions and liver function abnormalities) are too risky to justify prescribing daclizumab. Too risky for whom? The neurologist prescribing the drug or the patient receiving the drug? The important thing to stress is that the immune-mediated adverse events of daclizumab, similar to those that occur post-alemtuzumab, can be detected early and managed. I don't think we should assume that because daclizumab will come bungled with a monitoring programme that patients will necessarily be put off being treated with daclizumab. As I have said many times before patient-engagement is the name of the game and I think we need to  be open and honest with our patients; if they are eligible for treatment with daclizumab we should be obliged to provide them with information about daclizumab so that they can make an informed decision. Some patients may not want to make a choice and will ask you to do it for them, but that is still engaging them in the decision-making process."

"What is becoming increasingly clear that decisions about DMTs and how to use them is not simply based on the risks and benefits of the drug, but other attributes. A very important attribute is pregnancy. The majority of people with MS are women who may be wanting to start, or extend, their families. The safety of these treatments in pregnancy and how they are used in, and around, pregnancy is becoming a new marketing battle ground. The paper below describes the latest pregnancy data on daclizumab; although the data is reassuring there is too little data to be confident of daclizumab's safety in pregnancy. The good news is  that there is no obvious teratogenic (causing foetal abnormalities) signal. If over time daclizumab is shown to be safe in pregnancy then I see it being used more widely."



INTRODUCTION: Multiple sclerosis (MS) is more common in women and can occur during childbearing years; thus, information on outcomes following exposure to MS therapy during pregnancy is important. No formal studies of daclizumab have been conducted in pregnant women. Here, we report available nonclinical and clinical data on pregnancy outcomes from the daclizumab clinical study program.


METHODS: Reproductive and developmental toxicity studies were conducted in cynomolgus monkeys. Reports of pregnancies that occurred during the daclizumab clinical study program through March 9, 2015 were collated and summarized. In the event of pregnancy, daclizumab was discontinued and safety monitoring continued.

RESULTS: Studies in cynomolgus monkeys showed no daclizumab-related effects on maternal well-being, embryo-fetal development, indirect fertility end points, and pre- and postnatal development and growth. Across the clinical study program, 38 pregnancies were reported in 36 daclizumab-exposed women (on treatment ≤6 months from last dose); 20 resulted in live births and four (11%) in spontaneous abortions or miscarriages. One congenital heart defect (complex transposition of great vessels) occurred in one live birth (considered unrelated to daclizumab); daclizumab had been discontinued and intramuscular interferon beta-1a and lisinopril were used at conception. Eight women had an elective termination, two had an ectopic pregnancy, and two were lost to follow-up; two pregnancy outcomes are pending. Six additional pregnancies occurred in five women >6 months after their last daclizumab dose; in one additional pregnancy, exposure was unknown.

CONCLUSION: Spontaneous abortion rate in daclizumab-exposed women was consistent with early pregnancy loss in the general population (12%-26%). Data on pregnancies exposed to daclizumab do not suggest an increased risk of adverse fetal or maternal outcomes, although the numbers are too small for definitive conclusions.

CoI: multiple

5 comments:

  1. I know that my comment is off-topic, but I'd like to ask ProfG about his statement "Some of you will be saying '.... but so can natalizumab be offered first-line'. I agree that natalizumab can be used first-line, but only in patients with rapidly-evolving severe MS". Besides cost-effectiveness, is there any other reason not to use natalizumab as 1st-line drug, while alemtuzumab can be used so?

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    1. Re: "Besides cost-effectiveness, is there any other reason not to use natalizumab as 1st-line drug, while alemtuzumab can be used so?"

      It is not really cost-effectiveness, but safety. When the EMA licensed natalizumab Biogen had not yet derisked the drug with its anti-JCV antibody assay. Now that we know the risk of PML in JCV-ve subjects is extremely rare the EMA should rethink its position and give it a broad first-line label for active MS. I sincerely hope that Biogen will try and get a first-line label for natalizumab. However, the cynic in me says they won't they have so many drugs licensed for MS they don't want to cannibalise their own market.

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    2. That is first-line for JCV-ve pwMS. It is hard to sanction starting natalizumab in JCV+ve subjects when we now have so many other options at hand.

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  2. If you are jc virus positive which 50% are then you have to think about it as you will probably need to switch by year two.

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  3. If you have recently become JCV positive after 7 years on Natalizumab, would you suggest a switch to Fingolimod now or keep on with Natalizumab until nice hopefully approve Daclizumab very soon?

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