ACTRIMS 2021: Natalizumab Coffee Mornings could be coming to an end

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Part of the Joys of natalizumab are not only the impact of having a highly effective treatment but of having monthly (or six weekly) infusions, where you get to meet the same people each month for a bit of a chat. It is like a coffee morning…perhaps without the coffee. OK, you may think my comic genius is not funny and I accept that but, it does mean you have to hang around hospital for a few hours to get your infusion. However what is the difference between intravenous and subcutaneous? Well about a few hours. You can just inject under the skin, the antibody gets to lymph glands and blood and blocks the lymphocytes (and monocytes) entering the brain. So in a few minutes you can be in an out.

Will it be done in a hosptial?

I think so at least initially. No not so your US injection site can charge your insurance a large fee for the visit:-), because one of the advantages of being in hospital is that you are in a safe place if you have an allergic reaction. This can occurred with natalizumab when you make anti-drug antibody responses and as injecting under the skin is a sensitizing route, this may occur….Dr Angray are you preparing?

Amazingly this study has been done by Biogen and they have not added a load of neurologists as authors to give to cudos. However, I suspect it comes with a new patent for the manufacturers and the lawyers will all be rubbing their hands to ask is this obvious and inventive. For natalizumab it it thought to work by blocking VLA-4/CD49d. Because of this it is easy to work out what you need to dose under the skin to get blood cells coated. Simple nice science.

Maybe it will be a time saver and so you can have your injection and then meet with you mates in the an actual CostaBucks for a real Coffee.

Y. Zhao, N. Campbell, Z. Ren, A. Gafson, H. Naik;
Biogen, Cambridge, MA.

P024 / P024 – Pharmacokinetics and Pharmacodynamics of Natalizumab Every 4 Weeks Following Subcutaneous and Intravenous Administration

Background: Natalizumab, a recombinant humanized monoclonal antibody that targets the α4-integrin cell adhesion molecule on mononuclear leukocytes, is an efficacious treatment for patients with relapsing forms of multiple sclerosis and has an approved dosage of 300 mg infused intravenously (IV) every 4 weeks (Q4W). Subcutaneous (SC) natalizumab has been developed and studied in 2 clinical trials, DELIVER (NCT00559702) and REFINE (NCT01405820), with the expectation that SC administration will offer greater convenience and time savings than IV administration. Pharmacokinetic (PK)/pharmacodynamic (PD) model-based analyses can help elucidate relationships among different routes of administration, drug plasma concentrations, and well-characterized PD endpoints.
Objectives: To characterize the PK and PD (alpha-4 integrin saturation) profile of natalizumab after single and multiple doses of SC administration and to support SC dose selection using population PK/PD model-based simulations to achieve steady-state trough PK/PD levels similar to those observed with 300 mg IV dosing.
Methods: In DELIVER, samples for single-dose PK/PD were collected over 8 weeks, with sampling at 4 hours and on days 2, 3, 4, 7, 14, 21, 28, 35, 42, and 56; multi-dose trough PK/PD was collected for an additional 6 doses over 24 weeks. A population PK/PD model was previously developed using clinical data from 11 clinical trials. Steady-state natalizumab trough serum concentration and alpha-4 integrin saturation over time for natalizumab 300, 350, 400, and 450 mg SC Q4W were simulated for 1000 subjects per SC dose and compared with the PK/PD profile of natalizumab 300 mg IV Q4W.
Results: After a single SC dose, natalizumab concentration peaked at approximately 8 days. The elimination phase was similar with SC and IV administration. Alpha-4 integrin saturation occurred rapidly, with greater than 80% saturation achieved within 4 hours. PD was similar with SC and IV dosing at all assessed time points. Over multiple doses, natalizumab trough concentrations and corresponding alpha-4 integrin saturation levels were similar with SC and IV dosing. Simulations showed that 300 mg SC was the lowest dose at which the 5th percentile, median, and 95th percentile steady-state trough serum natalizumab concentration, and alpha-4 integrin saturation were comparable to those observed with the clinically approved 300 mg IV dose. SC doses greater than 300 mg were not associated with additional increases in alpha-4-integrin saturation.
Conclusions: Single- and multi-dose observed PD as well as simulations conducted using population PK/PD modeling indicate that 300 mg SC dosing results in similar alpha-4 integrin saturation as 300 mg IV dosing. These data support 300 mg SC dosing of natalizumab and suggest that it will have similar efficacy to the approved 300 mg IV dosing.

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MouseDoctor

3 comments

Leave a Reply to Debra Singer Cancel reply

  • Amazing, I just read about this yesterday and was going to ask. Any idea how many ml the shot is? Hard to self inject if it is too large. This is exciting. I’ll be curious to see how my insurance tackles this. For 2021 the cost for Tysabri is now $7500. Insane.

    • Biogen have vast experience of subcutanoeus injection with the interferons and daclizumab so I would not worry.. I know the dose is 300mg not sure if this is 2 x 150mg in different sites. Sorry to burst your bubble the cost won’t be less I suspect it is not how drug costs seem to work

  • In India, subcutaneous injections (and oral DMTs) are a problem for MS patients, unless they are very rich. And it can’t be just in India, the same problem is sure to exist elsewhere too.

    The problem is that health insurance does not pay for outpatient treatment. The insurance plans will pay for treatment only if it involves hospitalisation (proper inpatient admission with a discharge summary at the end). Most insurance plans pay only if the admission is for 24 hours or more, though some pay for 12 hours too

    As a result, we (doctors and patients together) have to be rather ‘creative’ about justifying a hospital stay. Hospital charges for the room etc are peanuts compared to the cost of the medication itself.

    With a subcutaneous injection or with tablets, the insurance companies will never pay for a hospital stint! With an infusion too it’s difficult, but it can be done

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