AAN2022 Natalizumab and the Me-Too

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Natalizumab is being used by ProfK in the AttackMS trial, which is to treat at first sign to prevent subsequent attacks, whilst diagnostic work-up is done and getting people onto highly effective treatment quickly. This is going to use standard monthly intravenous dosing. This is relatively safe to use for a couple of years and it gives people breathing-space to decide how best to move forward and it is easy to transition onto something else.. At present people who are John Cunningham virus positive switch to something else within 2 years because of the risk of progressive multifocal leucoencephalopathy (PML), which is a damaging brain disease.

However there have been attempts to de-risk the drug

Indeed, there is a suggestion that if you extend the dosing interval you can reduce the risks of PML. This has been shown in a study reported at the AAN

Lana Zhovtis Ryerson et al. Natalizumab Extended Interval Dosing (EID) is Associated with a Reduced Risk of Progressive Multifocal Leukoencephalopathy (PML) Compared With Every-4-Week (Q4W) Dosing: Updated Analysis of the TOUCH® Prescribing Program Database

Objective:To update the assessment of PML risk with natalizumab EID in comparison with Q4W dosing using TOUCH data as of June 30, 2021.

Background:Natalizumab treatment is associated with PML risk. Previous analyses of patient data in the TOUCH database have demonstrated that EID is associated with lower risk of PML than is Q4W dosing.Design/Methods:TOUCH data were used to determine whether EID is associated with lower PML risk in comparison with Q4W dosing in anti–JC virus antibody-positive patients using three prespecified analyses: primary analysis (EID defined by the last 18 months of treatment), secondary analysis (EID defined as any prolonged period of EID at any time during treatment), and tertiary analysis (EID defined as a dosing history consisting primarily of EID). Patients with any dosing interval of <3 or >12 weeks were excluded. Hazard ratios (HRs) of PML with EID versus Q4W dosing were estimated using adjusted Cox regression models.

Results:Compared with the June, 2020 analysis, patient numbers increased for all three analyses (16.0%–21.0% increase for EID; 3.0%–4.0% increase for Q4W). The mean number of natalizumab infusions (primary: 63.9 vs 55.5 infusions; secondary: 60.6 vs 39.5 infusions; tertiary: 41.1 vs 40.7 infusions) and mean natalizumab treatment duration (primary: 73.1 vs 54.1 months; secondary: 66.8 vs 37.8 months; tertiary: 55.0 vs 40.3 months) were greater with EID than with Q4W dosing. All three analyses showed reduced risks of PML for EID vs Q4W (primary: 87% [HR =0.127]; secondary: 81% [HR =0.195]; tertiary: 96% [HR = 0.042]; all P ≤0.0003).

Conclusions: This analysis is consistent with all previous annual analyses of TOUCH patient data and demonstrates that natalizumab EID is associated with a significantly lower PML risk than Q4W dosing. Continued follow-up will further quantitate the amount of risk reduction with EID.

It has been reported by others too

García-Estévez DA, Pérez-Lorenzo G, Fernández-Pérez MJ, Cid-Rodríguez C, Ozaita-Arteche G. Clinical and radiological effectiveness of natalizumab extended dosage interval in patients with relapsing multiple sclerosis]. Rev Neurol. 2022;74(8):265-268

Introduction: Natalizumab (NTZ) is a very effective treatment approved for highly active multiple sclerosis. The main risk of treatment with NTZ is the possibility of developing progressive multifocal leukoencephalopathy, which is related to JC virus positivity and the number of NTZ infusions. This risk decreases with the extended dosage interval (EDI), which involves 9 or fewer infusions/year. However, it is a matter of controversy as to whether EDI remains effective in reducing recurrences and the presence of new lesions in magnetic resonance imaging (MRI).

Patients and methods: A prospective observational study was conducted from 1 April 2019 to 30 June 2021, following up patients on NTZ treatment who switched to EDI. Patients should have at least one MRI six months after the start of EDI. The presence of attacks or MRI activity (new lesions in T2) during the EDI was recorded.

Results: Twenty-three patients with a mean age of 43.5 ± 9.4 years were included. The median number of NTZ infusions was 68 (minimum, 25; maximum, 127). The median interval between the start of the EDI and the last MRI was 14 months (minimum, 6; maximum, 25), and 23 months from the last medical follow-up visit (minimum, 7; maximum, 28). Two patients (8.7%) presented with attacks and two others (8.7%) showed MRI activity.

Conclusions: EDI with NTZ maintains high clinical and activity effectiveness in MRI.

This delay is safe with regards to controling MS

John Foley, Gilles Defer, Lana Zhovtis Ryerson, Jeffrey A. Cohen, Doug L. Arnold, Helmut Butzkueven, Gary Cutter, Gavin Giovannoni, Joep Killestein, Heinz Wiendl, Karen Smirnakis, Shan Xiao, George Kong, Robert Kuhelj, Nolan Campbell. Primary Results of NOVA: a Randomized Controlled Study of the Efficacy of 6‑Week Dosing of Natalizumab Versus Continued 4-Week Treatment for Multiple Sclerosis

Objective:Evaluate the efficacy of natalizumab Q6W in patients previously treated with natalizumab Q4W for ≥12 months compared with continuation of Q4W over 72 weeks.

Background:Natalizumab 4-week dosing (Q4W) with 300 mg is approved for treatment of relapsing-remitting multiple sclerosis. Dosing frequency of approximately 6 weeks (Q6W) is associated with lower progressive multifocal leukoencephalopathy (PML) risk in retrospective analyses. NOVA is the first randomized trial to assess Q6W efficacy.

Design/Methods:NOVA is a randomized, controlled, open-label, rater-blinded phase 3b trial. Included patients were treated with natalizumab Q4W without relapse for ≥12 months and had no enhancing lesions at screening. Patients were randomized 1:1 to Q6W or Q4W. The primary endpoint was new/newly enlarging T2 (N/NET2) lesions. Secondary endpoints included relapses and 24-week confirmed disability worsening (CDW). Primary estimand used all observed data; secondary estimand treated post-intercurrent event data as missing. Missing data were imputed by worst value on treatment or multiple imputation depending on discontinuation reason.

Results:195/248 (79%) Q4W patients and 207/251 (82%) Q6W patients completed NOVA. Proportions of patients with N/NET2 lesions were low in both arms (Q4W:4.1%; Q6W:4.3%). Mean N/NET2 lesions in the Q4W and Q6W arms with the primary estimand were 0.05 and 0.20 (P=0.0755) and 0.06 and 0.31 (P=0.0437) with the secondary estimand. Differences were mainly due to 2 Q6W patients with high values (≥25 lesions); otherwise the distributions of N/NET2 lesions were similar with no other patient having >2. Relapse occurred in 2.1% and 2.8% (P=0.64) and CDW occurred in 8% and 10% (P=0.40) of patients in the Q4W and Q6W arms, respectively. Safety data were similar between groups.

Conclusions: Despite a small difference in efficacy between arms, NOVA data suggest the vast majority of patients stable on Q4W dosing can switch to Q6W dosing with no clinically meaningful loss of efficacy.

This tells us something about MS. Natalizumab blocks MS for 6 weeks but blocks what controls PML for 4 weeks so what does it keep out of the brain for those extra two weeks?

Answer The cells that cause the relapse in MS.

I think I know the answer to this because I saw the science to explain this two years ago. You take 4 week blood from someone treated with natalizumab and ask which immune subsets does it stop penetrating through layers of brain blood vessel cells in an experiment you can do in cell culture…..

.Answer essentailly all are stopped and then do the same with 6 week blood from someone treated with natalizumab and there are differences…..Why have we not seen this data?

Maybe they are desperately trying to show it is Th17 cells and until they do it wont see the light of day, but Iwas happy when I say te data because it didnt disprovemy views 😉

Anyway back to the AAN 2022 and further dat shows that natalizumab works well when used early so this supports the appproach in ATTACKMS

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Maria-Chiara Bellomo et al. High Efficacy Agents as First Line Treatment of Relapsing Forms of MS

Background: Clinical trials of natalizumab and B-cell depleting therapies (ocrelizumab, rituximab, ofatumumab) have demonstrated that these drugs are highly effective in preventing relapses and new MRI lesions and moderately effective in slowing down disease progression over a two-year period.  
Design/Methods:

This was an IRB approved retrospective chart review from The Brown Neurology Multiple Sclerosis Center between 2007-2021. 

Results: This study included 162 patients (N=75, B=87) with an average age of 38.5 years. Patients were followed for an average of 2.4 years (range:0.1-9.5). 14 (8.6%) patients had a confirmed relapse (N= 10, B=4) with an annualized relapse rate of 0.03. 17 (10.5%) patients had changes on MRI when compared to baseline MRI (N=14, B= 3). 6 had symptoms corresponding to MRI changes while 11 were asymptomatic. The average baseline EDSS score was 2.47 (range: 0-7) which decreased to an average EDSS of 1.97 (range: 0-6.5) after treatment. The EDSS score remained stable or improved in 144 patients (88.8%). The NEDA rate was 45.1%% (73 patients, N=30, B=43). 19 natalizumab patients (25.3%) discontinued treatment while all ocrelizumab patients remained on treatment. 11 (14.7%) natalizumab patients seroconverted to JCV antibody positivity. Of these, 9 of 11 patients switched to other therapies. 4 natalizumab patients developed anti-natalizumab antibodies. There were no serious adverse events.
Conclusions:

As first line therapies, both natalizumab and B-cell depleting therapies are highly effective in preventing relapses, MRI lesions and slowing disability progression with no significant or serious adverse events. B-cell depleting therapy treated patients are more likely to remain on treatment when compared to natalizumab treated patients. 

It works when it is the first drug or the subsequent drug, further supporting the concept of ATTACKMS

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Jai Perumal et al. Effectiveness of Natalizumab Treatment Inpatients With Early Relapsing-Remitting Multiple Sclerosis (RRMS) who were Treatment-Naive Versus Those Who Had Prior Disease-Modifying Therapy (DMT) Use

Objective:To describe the real-world effectiveness of natalizumab in patients with early RRMS who were treatment-naive versus those who had prior DMT use at natalizumab initiation.

Background:STRIVE was a 4-year observational study of natalizumab-treated anti–JC virus antibody negative patients with early RRMS (disease duration ≤3 years).

Conclusions: Results confirm natalizumab’s effectiveness regardless of prior DMT use. However, treatment-naïve patients receiving natalizumab early in their disease course had improved clinical outcomes over the long term. 

So use early. But in future you may not have to use the original natalizumab as alternatives are appearing as the patent life of natalizumab has expired. There is nothing special about natalizumab as you could use the Me-Too (biosimilar)

Bernhard Hemmer et al. Efficacy and safety of proposed natalizumab biosimilar PB006 versus Tysabri® in patients with relapsing remitting multiple sclerosis: Primary data from the Phase III Antelope study

Objective: The Phase III Antelope study (NCT04115488) was designed to confirm the equivalent efficacy and similarity in safety and immunogenicity of Biosim-NTZ compared to Ref-NTZ in relapsing remitting multiple sclerosis (RRMS) patients.

Background:Biosimilars are medicines developed to match approved biologics, in terms of analytical comparability, clinical efficacy and safety, aiming to support a sustainable healthcare system by improving access to biologics while reducing healthcare spend. Proposed biosimilar natalizumab (PB006; Biosim-NTZ) was developed to match reference natalizumab (Tysabri®, Biogen; Ref-NTZ), an anti-α4 integrin monoclonal antibody treatment for active RRMS and Crohn’s Disease (US only).Design/Methods:

This multicenter, double-blind, active-controlled, parallel-group study randomized participants to receive either 300 mg intravenous Biosim-NTZ (n=131), or 300 mg intravenous Ref-NTZ (n=133) every 4 weeks for a total of 48 weeks. The primary objective was to assess equivalent efficacy, using the difference in cumulative combined unique active (CUA) lesions (new gadolinium-enhanced T1-weighted lesions and new/enlarging T2-weighted lesions) from baseline to Week-24. For immunogenicity assessment, a subset of patients initially randomized to Ref-NTZ were switched to Biosim-NTZ after 24 weeks of treatment (n=30), for the final 24 weeks. 

Results: The primary efficacy analysis demonstrated comparable efficacy for cumulative CUA lesions between Biosim-NTZ (n=126) and Ref-NTZ (n=130). The point estimate for difference of cumulative CUA lesions between Biosim-NTZ and Ref-NTZ was 0.17, and the corresponding 95% CI (-0.613 to 0.944) at Week-24 was well within the pre-defined margins (±2.1). The mean of cumulative CUA lesions at Week-24 was 1.4 for Biosim-NTZ [SD: 3.62; range: 0-30] versus 1.9 for Ref-NTZ [3.94; 0-29]. Safety profiles and incidence rate of adverse events were comparable. No cases of progressive multifocal leukoencephalopathy or deaths were reported for either group.

Conclusions:Analysis of the primary endpoint and safety data suggest that Biosim-NTZ matches Ref-NTZ for efficacy and safety. No new safety signals were observed in the Biosim-NTZ group.

So this is all good news except there is a move to use subcutaneous natalizumab and not infusions, but one can say it offers benefits to you as it may save time and possibly to others because the patent is expiring/expired. However, the subcutaneous dosing has only been tested at 4 weekly dosing so trials would need to done for extended dosing intervals to show it is safe.

However the biology looked good for ATTACK MS, so lets hope a speedy recruitment to the studies that have started.

COI Multiple but I am involved in the ATTACKMS trial and proud to be part of it.

Disclaimer. This is a view of the authour/

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MouseDoctor

4 comments

  • I have been receiving treatment of Tysabri 6 weekly (IV) since about Jan 2020 (when New Zealand was starting to get clusters of covid), before that I was on 4weekly doses since being diagnosed in Dec 2018. I have had no relapses since starting treatment, and 6 weekly appears to make no difference to disease progression; that is, I don’t have much disability (RR MS). I have blood sent to Denmark for JC testing 6 monthly. I am also eating keto diet to further reduce risks. So far, so good. No relapses, no disease activity on my yearly MRIs and still JC virus negative!

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