Comparative effectiveness of different Natalizumab dosing schedules in real world life: a retrospective Italian multicentre study

Prof. Maria Trojano Dipartimento di Scienze mediche di base, neuroscienze e organi di senso, University of Bari, Italy. maria.trojano@uniba.it

Introduction and aims
Natalizumab (NTZ; Tysabri) is a humanized anti-α4 integrin monoclonal antibody that blocks lymphocyte adhesion to endothelial cells, thereby preventing their migration to the central nervous system (CNS) and reducing inflammation. The NTZ safety and efficacy in relapsing-remitting multiple sclerosis study (Safety and Efficacy of Natalizumab in the Treatment of Multiple Sclerosis- AFFIRM study) showed that NTZ, compared with placebo, was able to reduce the annualized relapse rate (ARR) by 68% relative to placebo, the accumulation of new or enlarging hyper intense lesions b 83%, 12-week sustained disability progression by 42% and 24-week sustained disability progression by 54% over 2 years. Since its approval in 2006/2007, NTZ has demonstrated higher efficacy in reducing the progression of MS compared with second-line drugs, although safety issues have imposed a strict clinical surveillance. The potential occurrence of progressive multifocal leukoencephalopathy (PML) in NTZ-treated patients has prompted an intense search for the best strategy to reduce such a serious complication and to prevent the clinical and radiological relapses associated to NTZ discontinuation, in particular the risk of a clinical rebound. In this regard, an early study has proved that a progressive return of subclinical MRI activity may occur after approximately 7 weeks from the last NTZ infusion in patients with MS, suggesting that the therapeutic window of NTZ could be larger than that approved based on clinical trials. Thus, a reasonable delay of time between infusions could provide advantages in terms of safety (i.e., reduced risk of PML), likely without exposing patients to a risk of MS relapse. Therefore, in real-world clinical practice, the neurologists of Italian MS centers across the country have begun to treat patients with MS using various extended interval dosing schedules.
This multicenter retrospective observational study aims to provide additional information on NTZ effectiveness in the real-world clinical practice and to evaluate the therapeutic durability of different extended dosing strategies (standard interval dosing [SID] versus extended interval dosing [EID]) in a large Italian population of patients with MS.

Results
At the extraction date, 5231 patients with relapsing-remitting MS (RR-MS) who had received NTZ from 1 June 2012 to 15 May 2018 in 30 Italian MS centers were recruited. A total of 2092 patients (mean age of 43.2±12.0 years, 60.6% were women) met the inclusion criteria and were finally enrolled. The remaining 3139 patients were excluded because of missing data. We found that 1254 (59.9%) patients received NTZ according to SID and 838 (40.1%) according to EID. EID patients had longer disease duration and higher EDSS before starting NTZ compared with SID. Moreover, the percentages of patients drug-naïve and of patients treated with immunosuppressant drugs before starting NTZ treatment were higher in the EID compared with the SID group.
At 12 and 24 months after start of NTZ, no differences in terms of annualized relapse rate (ARR) and of expanded disability status scale (EDSS) were found between the two groups. No statistically significant differences in terms of percentage of patients reaching NEDA-2, progression index (PI) and confirmed disability improvement (CDI) were found between the two groups.
Overall, at 24 months, the percentage of patients positive to the John Cunningham virus (JCV) slightly increased from 26.9% to 29.5% (p=0.14), with a significant higher JCV index compared with baseline (p<0.001). Stratifying according to the two different administrations schedules, after 24 months, both SID and EID groups showed a significant increase of JCV index values compared with baseline (1.1±1.4 vs 1.4±1.1, p<0.001 and 2.0±0.9 vs 2.2±1.5, p<0.001, respectively).
At 24 months, in the patients with baseline EDSS scores available (n=1651, 78.9% of 2092), the cumulative probabilities of 12-month and 24-month confirmed EDSS worsening (CEW) were 14.3% and 11.6%, respectively, with worsening defined as an increase in EDSS score of ≥1.0 point. When worsening was defined as an increase of ≥2.0 points, the cumulative probabilities were 8.1% and 6.1%, respectively. No differences in terms of CEW were found between SID and EID. In the overall population, 689 (41.7% of 1651) patients had a baseline EDSS score 0.0–2.0, 432 (41.5% of 1040) in SID and 257 (41.6% of 611) in EID. Among these patients, the cumulative risk of confirmed transition to an EDSS score ≥3.0 was 7.3% at 12 months and 8.1% at 24 months. Among the 643 (38.9% of 1651) patients with a baseline EDSS score of 2.5–3.0, 402 (38.7% of 1,040) in SID and 241 in EID (39.4% of 611), the cumulative risk of confirmed transition to an EDSS score of ≥4.0 was 12.4% at 12 months and 13.2% at 24 months with a trend towards a higher probability to proceed from 2.0 to 3.0 to >4.0 EDSS score in the EID (16.9% at 12 months and 16.9% at 24 months) versus the SID (12.4% at 12 months and 13.6% at 24 months) group. For the 319 (19.3% of 1,651) patients with a baseline EDSS score of ≥4.0, 206 (19.8% of 1040) in SID and 113 (18.5% of 611) patients in EID, the cumulative risk of confirmed transition to an EDSS score of ≥6.0 was 18.4% at 12 months and 23.6% at 24 months with no differences between SID and EID patients. Moreover, Kaplan-Meier estimates for the first relapse occurrence, CEW of 1 point and CEW of 2 points showed no statistically significant differences between the two groups.

Conclusions
The use of NTZ with an extended interval schedule showed similar effectiveness compared with SID. Unchanged clinical efficacy of EID schedule may raise the question of a possible advantage in terms of tolerability and safety.

Pubblicazioni e Comunicazioni a Congressi/ Publications and Congress Presentations
Chisari CG, Grimaldi LM, Salemi G, Ragonese P, Iaffaldano P, Bonavita S, Sparaco M, Rovaris M, D'Arma A, Lugaresi A, Ferrò MT, Grossi P, Di Sapio A, Cocco E, Granella F, Curti E, Lepore V, Trojano M, Patti F; Italian MS Register Study Group. Clinical effectiveness of different natalizumab interval dosing schedules in a large Italian population of patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2020 Dec;91(12):1297-1303. doi: 10.1136/jnnp-2020-323472.

Chisari CG, Grimaldi LM, Salemi G, Ragonese P, Iaffaldano P, Bonavita S, Sparaco M, Rovaris M, D'Arma A, Lugaresi A, Ferrò MT, Grossi P, Di Sapio A, Cocco E, Granella F, Curti E, Lepore V, Trojano M, Patti F; Italian MS Register Study Group. Clinical effectiveness of different natalizumab interval dosing schedules in a large Italian population of patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2020 Dec;91(12):1297-1303. doi: 10.1136/jnnp-2020-323472. Epub 2020 Oct 14.PMID: 33055141

Chisari CG, Comi G, Filippi M, Paolicelli D, Iaffaldano P, Zaffaroni M, Brescia Morra V, Cocco E, Marfia GA, Grimaldi LM, Inglese M, Bonavita S, Lugaresi A, Salemi G, De Luca G, Cottone S, Conte A, Sola P, Aguglia U, Maniscalco GT, Gasperini C, Ferrò MT, Pesci I, Amato MP, Rovaris M, Solaro C, Lus G, Maimone D, Bergamaschi R, Granella F, Di Sapio A, Bertolotto A, Totaro R, Vianello M, Cavalla P, Bellantonio P, Lepore V, Patti F; Italian MS Register Study Group. PML risk is the main factor driving the choice of discontinuing natalizumab in a large multiple sclerosis population: results from an Italian multicenter retrospective study.J Neurol. 2022 Feb;269(2):933-944. doi: 10.1007/s00415-021-10676-6. Epub 2021 Jun 28. PMID: 34181077