Friday, 5 February 2016

ResearchSpeak & PoliticalSpeak: do we need natalizumab to be self-administered?

Surely a self-administered formulation of natalizumab can only be good for the MS community? #PoliticalSpeak #MSResearch #MSBlog #ResearchSpeak

"The interesting study below shows that you can give natalizumab intravenously, subcutaneously and intramuscularly and they do the job almost as well as the intravenous route. This study refers to actual levels of natalizumab in the blood. What an innovation this would be to allow pwMS to administer their own natalizumab to themselves? It would free them up from their monthly infusion visits and free up all those staff in the infusion units across the world to do other things. A subcutaneous or intramuscular preparation of natalizumab would be so much more cost-effective and this would almost certainly feed through the system increasing access for many more pwMS in need of a high efficacy therapy. 
In other words it would improve healthcare efficiency. From my perspective it would make it much easier to use natalizumab in resource poor environments as well."

"So why haven't Biogen developed a self-administration formulation of natalizumab? Rumour has it from an ex-Biogen employee is that when marketing and sales heard about the plans to develop a self-administered formulation of natalizumab  they stopped the programme. Apparently, one of the big drivers of natalizumab prescribing is the income neurologists, and MS centres, make from running infusion units. In the US the heavy prescribers of natalizumab who have large infusion units are called 'Tysabri Millionaires'. The fact that pharma marketing and sales divisions have such an influence in holding back technological innovation is quite shocking, but not surprising, their job is too keep the gold geese laying the golden eggs. In short sales and marketing have to maximise profits for themselves and their shareholders. We often forget pharma is big business with their primary responsibility to their shareholders."

"However, every decision that is made has some repercussions. For example, I recall an email I received from a desperate person with MS from a few years ago. He was living in San Antonio, Texas. He was unemployed, and uninsured, and had highly active MS. Biogen had kindly agreed to give him natalizumab free, as part of their drug-access scheme. However, he couldn't find any infusion unit in San Antonio to give him the infusions at price he could afford to pay. His local unit wanted to charge him $1200 an infusion. Unfortunately, he was unable to start natalizumab. My heart goes out this man. At this moment I have two visions of him. Firstly, of him sitting in a wheelchair doubly incontinent the victim of uncontrolled active MS. Then a more pleasant second vision, of him self-injecting with a new formulation of natalizumab on the first Monday of each month before he leaves his home and walks to work. Since starting subcutaneous natalizumab 3 years ago he has no evident disease activity and has noticed a marked improvement in all his symptoms and disabilities. In fact he improved so much that he was able to get a job and return to full-time employment. There is little doubt that natalizumab is a transformational drug it is a great pity that it is only the privileged few who have access to it. I sincerely hope Biogen reconsider their decision not to develop a new self-administered formulation of natalizumab; who is really more important, pwMS who need access to highly effective therapies or the business people who prescribe natalizumab to keep their infusion units running smoothly and profitably?"


Epub: Plavina et al. A Randomized Trial Evaluating Various Administration Routes of Natalizumab in Multiple Sclerosis. J Clin Pharmacol. 2016 Feb 2. doi: 10.1002/jcph.707.

Background & Objectives: The primary objective was to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of single subcutaneous (SC) or intramuscular (IM) 300-mg doses of natalizumab with IV 300-mg doses of natalizumab in patients with multiple sclerosis (MS). Secondary objectives included investigation of the safety, tolerability, and immunogenicity of repeated SC and IM natalizumab doses. 


Methods: DELIVER was a 32-week, open-label, multicenter study of natalizumab-naive patients with relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS) randomized to receive 300 mg natalizumab by SC injection, IM injection, or IV infusion. PK and PD were evaluated over 8 weeks after the first natalizumab treatment (Part 1) and over 24 weeks with repeated dosing every 4 weeks, beginning at Week 8 (Part 2). Seventy-six patients (24 with RRMS and 52 with SPMS) were enrolled in DELIVER. 

Results: Following SC or IM administration of natalizumab, peak serum concentrations were approximately 40% of those observed with IV administration and showed no major differences in elimination characteristics. Mean bioavailability relative to IV administration was 57.1-71.3% with SC administration and 48.7% with IM administration; mean trough serum concentrations were similar with SC or IV administration and lower with IM administration. Following single or multiple doses of natalizumab, PD response was comparable across administration routes and disease stages. 

Conclusions: No meaningful differences were observed across administration groups in the incidence or nature of overall adverse events, serious adverse events, administration site reactions, hypersensitivity reactions, or anti-natalizumab antibodies. These findings support the comparability of PD measures of natalizumab administered IV, SC, or IM.

CoI: multiple

22 comments:

  1. Subcutaneous cladribine..you don't need them infusion units, is this why there is resistance to it :-)

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    1. More than a hint of truth in that I suspect. Resistance overcome with a brown envelope full of cash?

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  2. What about PLM if you don't see anyone

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    1. You would still need to be monitored for JC virus status regularly, which again as MD suggests, Cladribine is a much better alternative.

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  3. "Apparently, one of the big drivers of natalizumab prescribing is the income neurologists, and MS centres, make from running infusion units. In the US the heavy prescribers of natalizumab who have large infusion units are called 'Tysabri Millionaires'."

    Follows from the legendary Interferon millionaires, its disgusting and if it stops the development of a better more convenient delivery method, it is even more so.

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  4. You mean like?

    Adverse events of subcutaneous natalizumab may include:

    A. NBAS Suppression (Neurologist bank account suppression)
    B. S.S.W.S Syndrome (Starbucks & Sushi Withdrawal Syndrome)
    C. High risk of becoming an "NPO" (No Porsche Owned)

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  5. If you let the patients self administer Tysabri the perceived effectiveness is going to go down.

    This is because of the fact that many of the patients are going to become non-adherent while still reporting that they are taking it as directed.

    The infusion eliminates this problem.

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    1. I can relate to this. I'm not on Tysabri, I'm on a tablet.

      I make assumptions that because Tysabri is an infusion administered at a clinic it must be more effective than the tablets and injectables.

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  6. Unfortunately, cladribine at the de-risked doses we are using is unlikely to be as effective as natalizumab. This is based on indirect comparison of end-organ damage, i.e. brain volume loss data, between the agents. In addition, the improvement in quality of life on natalizumab is some of the best published. As easy as subcutaneous cladribine is to use it is not the necessarily the panacea we need; pwMS may still want the higher efficacy natalizumab offers and not everyone is sold on the induction paradigm (yet). A lot of people have concerns about long-term safety, in particular the delayed risk of secondary malignancies. These are due to reduced immune surveillance as a result of premature immunosenescence and not due to possible carcinogenic effects of cladribine, which cause an earlier secondary malignancy signal. However, subcutaneous cladribine is still by far our best option of getting DMTs to pwMS in resource poor environments.

    If only we could have gone higher with the cladribine dosing! What we really need is a cladribine-like small molecule that targets B cells only; and agent like this will give us the the efficacy we so desire and will come without the risk profile associated with T-cell depletion, particularly long-term effects of T-cell depletion and premature immunosenescence.

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  7. But what about the side effects of Tysabri? I had an anaphylactic reaction to it during an infusion. I definitely couldn't have have handled it at home.

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    1. Fair point but you could sub cutaneous injection under medical supervision without having to hang around for an infusion

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    2. Then these medical supervisors will become millionaires :p. Perhaps, Tysabri administration should be left to experienced professionals after all. It's a wondeful yet complicated drug!

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    3. Why do they infuse if it isn't necessary? Just administer a shot and have the patient wait an hour before leaving. Is there a medical reason to infuse?

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    4. I suspect slow infusion rather than a bolus means it is less likely that the protein clump...whichw ould increase there potential to induce allergic reactions however with subcutaneous injections it is a bolus via a sensitizing route so I am probably just talking mushroom food

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  8. Where I live, I have seen a number of infusion centers close. Our centers are forced to buy the tysabri prior to infusing the patients. They were left with med doses they could not use of sell back when the patients insurance failed to pay. So while I agree, that too many neuros are getting rich on the centers, adhering to the schedule and monitoring for PML are very important.

    Due to my JC Virus conversion, I have been put on extended dosing. This seems the perfect solution to me. My costs go down and my time spent infusing is manageable.

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  9. I know that MS economics is a subject requiring suspension of logic but I believe that the rate at my previous center in NYC was less than $1200. It would be interesting to see a plot of infusion cost across the U.S.

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  10. In addition, Biogen rethink on the issue of Natalizumab self-injectable she could focus on discovering the mechanism of JCV.
    I see JCV the main torment for those who are about to use or for those who already use Natalizumab. Talk to several pwMS in Brazil and some abroad and the greatest fear of all is the PML.
    Worst thing is that I know the case of two neurologists in Brazil who also has MS and developed PML associated with Natalizumab ...

    If Cladribine might cause cancer (which is a risk, not a certainty) Natalizumab has 10x more likely enabling the action of JCV in the CNS, and lead to PML ...

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  11. Thought I would share a couple of thoughts with a monthly self injection.

    Training: Self injecting once per month is not sufficient to train people how to inject. It will not go into muscle memory. In my work we have to explain to the users ever month how to run the monthly report. These are smart people with Ivy/Oxbridge degrees. I could see patients being uncomfortable holding and using such an expensive product too.

    Distribution: Challenging to get a refrigerated item to a home address and then into the fridge. Someone might have to pick it up at the hospital, but then you're at an infusion site anyway.

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    1. I self injected Avonex (weekly IM) and then Rebif (3x/week s.q.)for over 16 years until I slipped into SPMS and these DMTs were of no use. I went to a clinic for a quick tutorial on self-injection and then was on my own. It became part of a normal routine and any anxiety soon dissipated. Delivery was on cold packs in thermal packaging and was never an issue. Later on the interferon was lyophilized which was more tolerant of temperature fluctuations.

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  12. I agree with training. You need more practice than just once a month.

    Distribution is not do much of an issue. I used to get 3 month supply of Copaxone through overnight in a styrofoam box which was packed with ice packs. The mailman would leave the box outside my house. I would move all the injections into the fridge as soon as I came home.

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