
==== Front
Neurol Ther
Neurol Ther
Neurology and Therapy
2193-8253
2193-6536
Springer Healthcare Cheshire

39046635
647
10.1007/s40120-024-00647-0
Original Research
Patient Preference for Subcutaneous Versus Intravenous Administration with Every-6-Week Natalizumab (Tysabri®) Dosing: NOVA Phase IIIb Extension Study (Part 2)
Wiendl Heinz heinz.wiendl@ukmuenster.de

1
Foley John 2
Defer Gilles 3
Zhovtis Ryerson Lana 4
Cohen Jeffrey A. 5
Arnold Douglas L. 6
Butzkueven Helmut 7
Cutter Gary R. 8
Giovannoni Gavin 9
Killestein Joep 10
Domingo-Horne Rose 11
Toukam Marie 11
Nunn Aimie 12
Maghzi Amir-Hadi 11
Kuhelj Robert 13
Lasky Tyler 11
1 https://ror.org/00pd74e08 grid.5949.1 0000 0001 2172 9288 Department of Neurology with Institute of Translational Neurology, University of Münster, Albert-Schweitzer-Campus 1, Building A1, 48149 Münster, Germany
2 https://ror.org/015dsp568 grid.490358.3 Rocky Mountain MS Clinic, Salt Lake City, UT USA
3 https://ror.org/027arzy69 grid.411149.8 0000 0004 0472 0160 Centre Hospitalier Universitaire de Caen, Caen, France
4 https://ror.org/04p5zd128 grid.429392.7 0000 0004 6010 5947 Hackensack Meridian Health Jersey Shore University Medical Center, Neptune City, NJ USA
5 https://ror.org/03xjacd83 grid.239578.2 0000 0001 0675 4725 Cleveland Clinic, Cleveland, OH USA
6 grid.14709.3b 0000 0004 1936 8649 Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada
7 https://ror.org/02bfwt286 grid.1002.3 0000 0004 1936 7857 Central Clinic School, Monash University, Melbourne, Australia
8 https://ror.org/03xrrjk67 grid.411015.0 0000 0001 0727 7545 University of Alabama, Birmingham, AL USA
9 grid.4868.2 0000 0001 2171 1133 Blizard Institute, London, UK
10 MS Centre Amsterdam, Amsterdam, The Netherlands
11 https://ror.org/02jqkb192 grid.417832.b 0000 0004 0384 8146 Biogen, Cambridge, MA USA
12 Cytel, London, UK
13 Biogen, Baar, Switzerland
24 7 2024
24 7 2024
10 2024
13 5 13851401
3 4 2024
4 7 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
Introduction

Following NOVA (part 1) and the approval of the subcutaneous (SC) route of administration of natalizumab by the European Medicines Agency, an extension phase of the NOVA phase IIIb study (part 2) was initiated to collect patient preference data for SC versus intravenous (IV) dosing in patients receiving every-6-week (Q6W) dosing of natalizumab. This study was performed to evaluate patient preference for SC versus IV natalizumab administration and explore the efficacy, safety, and pharmacology characteristics of both routes of administration.

Methods

In part 2, participants received natalizumab (Tysabri®) 300 mg via IV infusion Q6W for 36 weeks and then were randomized to 48 weeks of crossover treatment (24 weeks SC Q6W and 24 weeks IV Q6W, or vice versa). The primary endpoint was the proportion of participants who indicated a preference for natalizumab SC administration on the Patient Preference Questionnaire.

Results

A total of 153 participants were randomized in NOVA part 2. Of 123 with patient preference data, 108 (87.8%) preferred the SC route of administration for natalizumab over the IV route; 102 (82.9%) specified “requires less time in the clinic” as the reason for the SC preference.

Conclusion

In NOVA (part 2), most participants on Q6W dosing of natalizumab preferred SC administration versus IV administration.

ClinicalTrials.gov

NCT03689972.

Infographic

Supplementary Information

The online version contains supplementary material available at 10.1007/s40120-024-00647-0.

Keywords

Extended interval dosing
Intravenous
Multiple sclerosis
Natalizumab
NOVA
Patient preference
Subcutaneous
http://dx.doi.org/10.13039/100005614 Biogen issue-copyright-statement© Springer Healthcare Ltd., part of Springer Nature 2024
==== Body
pmcKey Summary Points

The NOVA (part 1) study provided the first randomized, controlled efficacy and safety data for patients who switch to Q6W IV dosing with natalizumab (Tysabri®) after at least 1 year of disease stability on Q4W IV dosing	
The extension phase of the NOVA study (part 2) was initiated to provide patient preference data for SC versus IV dosing in those receiving Q6W dosing and secondary/exploratory clinical data to support the understanding of Q6W usage with natalizumab SC	
NOVA study (part 2) showed that the majority of participants (87.8%) on Q6W dosing preferred SC administration versus IV administration	
There was a trend of lower trough serum concentration and α4 integrin saturation on SC Q6W dosing versus IV Q6W dosing	
Regardless of SC or IV route of administration of Q6W dosing, disease activity was low overall during the crossover period of the study	

Digital Features

This article is published with digital features, including an infographic to facilitate understanding of the article. To view digital features for this article, go to 10.6084/m9.figshare.26159224.

Introduction

Natalizumab (TYSABRI®, Biogen), a humanized immunoglobulin G4 antibody against the adhesion molecule α4-integrin, is the first high-efficacy disease-modifying therapy approved for treatment of relapsing forms of multiple sclerosis (MS) [1–4]. Natalizumab is available as an intravenous (IV) infusion and a subcutaneous (SC) injection [2, 5]. For the IV infusion, the approved dosing is 300 mg administered intravenously over 1 h every 4 weeks; for the SC injection, the approved dosing is 300 mg using two 150-mg pre-filled syringes consecutively (administered within 30 min of each other) every 4 weeks. As of 31 December 2023, 269,687 patients had been treated with natalizumab, representing 1,159,827 patient-years of experience, based on clinical trials and prescription data.

Natalizumab is only available in the US through a prescribing program called Tysabri Outreach Unified Commitment to Health (TOUCH™) [6]. TOUCH™ is the largest dataset in the world that can provide safety information associated with alternative dosing intervals of natalizumab [7]. A retrospective cohort study using the TOUCH™ database showed that once every 6 weeks (Q6W) IV dosing frequency was associated with clinically and statistically significantly lower progressive multifocal leukoencephalopathy (PML) risk than once every 4 weeks (Q4W) dosing frequency [7].

The NOVA study (NCT03689972) is the first randomized, controlled, phase III clinical trial to compare the efficacy of Q4W and Q6W IV dosing of natalizumab in patients with relapsing-remitting MS (RRMS) [8]. NOVA part 1 demonstrated that, in participants who switched to Q6W IV dosing after ≥ 1 year of disease stability on Q4W IV dosing, Q6W IV dosing provided a high level of efficacy in controlling MS disease activity in clinically stable patients [8].

Following NOVA part 1, and the subsequent approval of the SC route of administration of natalizumab by the European Medicines Agency [9], the NOVA phase IIIb extension study (part 2) was initiated to provide patient preference data for SC versus IV dosing in those receiving Q6W dosing and secondary/exploratory clinical data to support the understanding of Q6W usage with natalizumab SC.

Here, we evaluate patient preference for SC versus IV natalizumab Q6W administration, explore efficacy and safety of Q6W administration and patient-reported outcomes (PROs), and characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of natalizumab SC versus IV dosing.

Methods

Study Design and Participants

NOVA part 2 was a randomized, open-label, two-treatment (SC Q6W vs. IV Q6W), crossover, multicenter study. It was a 108-week open-label extension for rollover participants who completed their treatment in part 1 and new participants who satisfied the inclusion and exclusion criteria and eligibility requirements of part 1.

Inclusion criteria for enrollment to part 2 were the same as for part 1 [8]. In brief, participants were aged 18–60 years with a diagnosis of RRMS and an Expanded Disability Status Scale (EDSS) score of ≤ 5.5 and had received ≥ 11 doses of natalizumab monotherapy per the approved dosing schedule (natalizumab [Tysabri®, Biogen] 300 mg via IV infusion Q4W) ≥ 12 months before randomization, with no missed doses in the preceding 3 months. Participants were excluded if they had a diagnosis of primary progressive or secondary progressive MS and if gadolinium-enhancing (Gd+) lesions were present on magnetic resonance imaging (MRI) at screening. Written consent was provided by all participants before screening. This study was performed in accordance with the International Council for Harmonisation Guidelines on Good Clinical Practice and the Declaration of Helsinki. The study protocol was approved by each center’s ethics committee or institutional review board (Table S1 in the electronic supplementary material).

In part 2, participants received natalizumab 300 mg via IV infusion Q6W for 36 weeks and were then randomized to an additional 48 weeks of natalizumab crossover treatment, comprising 24 weeks SC Q6W (300 mg using two 150 mg pre-filled syringes, consecutively, administered within 30 min of each other) and 24 weeks IV Q6W, or vice versa (Fig. 1). The route of administration (SC or IV) for the final dose in the study at week 156 was selected by the participant. Twelve weeks after the final dose of natalizumab, participants reported for a follow-up safety visit, and 12 weeks thereafter (i.e., 24 weeks after the last natalizumab dose) participants received a follow-up safety phone call before study completion.Fig. 1 NOVA part 2 study design. IV intravenous, Q4W every 4 weeks dosing, Q6W every 6 weeks dosing, SC subcutaneous

Assessments and Study Endpoints

The primary endpoint was the proportion of participants who indicated a preference for natalizumab SC administration on the Patient Preference Questionnaire (PPQ) at the end of part 2. The PPQ was administered during crossover period 2, at weeks 138 and 150. Key secondary efficacy endpoints included mean time for drug preparation and administration, brain MRI outcomes, and number of relapses. Secondary safety endpoints included the proportion of treatment-emergent adverse events (TEAEs) and proportion of participants who developed anti-natalizumab antibodies. TEAEs were defined as having an onset date on or after the first randomized dose during the crossover, up to and including 84 days after the last dose of study drug, or up to and including 168 days after the last dose for PML events. All endpoints were assessed by comparing 6 months of SC and 6 months IV in the randomized crossover period (total duration of 48 weeks–24 weeks each for SC and IV dosing).

PROs between natalizumab SC and IV routes of administration were evaluated (Table S2 in the electronic supplementary material). PK and PD parameters for natalizumab dosing routes were assessed by trough concentration (Ctrough) and trough α4-integrin saturation on mononuclear cells (MNC).

Details of the part 2 schedule of activities are shown in Table S2 in the electronic supplementary material.

Statistical Methods

The protocol-defined modified intention-to-treat (mITT; N = 131) population included participants who received at least one dose of SC natalizumab after randomization in part 2 and who completed at least the first question in the PPQ on one occasion. The mITT population was used for analyses of the primary endpoint. The proportion of participants preferring natalizumab SC at the end of the randomized crossover phase was estimated (and 95% confidence interval [CI] calculated) using the exact binomial method. In the absence of Q6W SC natalizumab data at the initiation of part 2, it was assumed that the proportion of participants who would prefer SC natalizumab would be 75%, with a 7.5% margin of error. Therefore, a sample size of 130 participants was selected for the 95% CIs to be within 67.5% and 82.5%.

Analyses for key secondary endpoints (including brain MRI, relapses, EDSS, Treatment Satisfaction Questionnaire for Medication [TSQM], PROs) were performed in the full analysis set (FAS; N = 141). The FAS included randomized participants who received at least one dose of study treatment during at least one study period and had at least one baseline clinical assessment (i.e., specified secondary endpoint). The safety population (n = 141) included randomized participants who received at least one dose of study treatment during the crossover phase. The PK and PD populations included participants who received at least one dose of SC or IV natalizumab and had at least one assessment of serum trough natalizumab concentration (PK; N = 141) or at least one assessment of trough α4 integrin saturation (PD; N = 140) during the crossover phase. For PK and PD analyses, summary statistics were presented by treatment sequence and by route of administration at each timepoint. Subgroup analyses were performed for PK and PD for participants with baseline weight ≤ 80 kg and > 80 kg. For EDSS, TSQM, and PRO analyses, change from baseline over the treatment period was analyzed using a linear mixed effect model to estimate the mean difference (including 95% CI and P value) between routes of administration (IV vs. SC) after 24 weeks of treatment.

Results

Participants

The first participant for part 2 of the study was enrolled on November 24, 2020, and the last participant was enrolled on June 20, 2021. The last participant completed the end-of-study visit on July 24, 2023.

A total of 153 participants were randomized in NOVA part 2, including 86 who did not participate in part 1 (Table 1). Of the 67 participants who completed part 1, natalizumab 300 mg was administered intravenously Q6W (n = 38) or Q4W (n = 29). One hundred forty-one and 127 participants were dosed in periods 1 and 2, respectively. Baseline characteristics were similar between the randomization groups, as shown in Table 1. Overall, participants had a mean (SD) age of 38.8 (10.1) years, with most being female and weighing ≤ 80 kg. Mean (SD) duration of natalizumab exposure at baseline was 6.7 (3.4) years; most (131 [92.9%]) participants reported > 3 years of drug exposure.Table 1 Accounting of participants, baseline demographics, and clinical characteristics

	IV/SC	SC/IV	Total	
No. of participants randomized, n (%)	75 (100)	78 (100)	153 (100)a	
 Q4W in part 1	14 (18.7)	15 (19.2)	29 (19.0)	
 Q6W in part 1	18 (24.0)	20 (25.6)	38 (24.8)	
 New participants in part 2	43 (57.3)	43 (55.1)	86 (56.2)	
No. of participants dosed in period 1, n (%)	75 (100)	66 (84.6)	141 (92.2)	
No. of participants dosed in period 2, n (%)	66 (88.0)	61 (78.2)	127 (83.0)	
No. of participants dosed in periods 1 and 2, n (%)	66 (88.0)	61 (78.2)	127 (83.0)	
Baseline demographics and clinical characteristics, N	75	66	141b	
Age, years, mean (SD)	38.7 (10.4)	39.0 (9.9)	38.8 (10.1)	
Female, n (%)	47 (62.7)	48 (72.7)	95 (67.4)	
Ethnicity	
 Hispanic or Latino	2 (2.7)	1 (1.5)	3 (2.1)	
 Not Hispanic or Latino	60 (80.0)	54 (81.8)	114 (80.9)	
 Not reportedc	13 (17.3)	11 (16.7)	24 (17.0)	
Race	
 American Indian or Alaska Native	1 (1.3)	0	1 (0.7)	
 Asian	0	0	0	
 Black or African American	0	0	0	
 Native Hawaiian or Other Pacific Islander	0	0	0	
 White	65 (86.7)	55 (83.3)	120 (85.1)	
 Not reported	9 (12.0)	10 (15.2)	19 (13.5)	
 Other	0	1 (1.5)	1 (0.7)	
Weight categories (kg), mean (SD)	
 ≤ 80	47 (62.7)	44 (66.7)	91 (64.5)	
 > 80	28 (37.3)	20 (30.3)	48 (34.0)	
Duration of natalizumab exposure at baseline (years)	6.29 (3.09)	7.17 (3.75)	6.70 (3.43)	
Duration of natalizumab exposure at baseline categories (years)	
 ≤ 3	6 (8.0)	4 (6.1)	10 (7.1)	
 > 3	69 (92.0)	62 (93.9)	131 (92.9)	
IV intravenous, IV/SC crossover from IV to SC, Q4W, every 4 weeks dosing, Q6W, every 6 weeks dosing, SC subcutaneous, SC/IV crossover from SC to IV, SD standard deviation

aNumber of participants enrolled in part 2 and dosed during the run-in period: 158

bTwelve participants withdrew after randomization and did not receive a dose of SC natalizumab

cNot reported because of confidentiality regulations

Patient Preferences

Of 123 participants with available patient preference data at the end of the crossover period, 108 (87.8%) preferred the SC route for natalizumab administration (Fig. 2). Among participants, 81.3% selected SC administration for the last natalizumab dose of the study at week 156 after the crossover period. Participants were able to choose two or fewer options on the PPQ for reasoning behind their dosing preference, with 102 (82.9%) preferring SC over IV administration mainly because it “requires less time in the clinic.” In 53 (43.1%) of participants, the main reason for participant preference for SC was “feels more comfortable during administration” (Table S3 in the electronic supplementary material). No significant differences in least squares (LS) mean change from baseline were reported for SC versus IV administration in TSQM global satisfaction score during the crossover period (LS mean: 0.64; difference for SC vs. IV: 0.47; 95% CI of estimated difference: − 2.61 to 3.54; P = 0.764).Fig. 2 Proportion of participants indicating preference for SC administration of natalizumab in part 2. IV intravenous, IV/SC crossover from IV to SC, SC subcutaneous, SC/IV crossover from SC to IV

Drug Preparation and Administration Time

The mean (SD) total preparation and administration time of natalizumab was 65.8 (5.9) min for the IV dosing regimen and 4.3 (5.1) min for the SC dosing regimen. Mean preparation time for IV dosing was 4.9 (3.9) min [5]; there was no preparation time for the SC dosing regimen due to the pre-filled syringe formulation.

Efficacy

For ten participants, the investigators reported a clinical relapse during NOVA part 2 (Table 2); unlike part 1 of the study, relapses were not confirmed by an Independent Neurology Evaluation Committee in part 2, which may have influenced the number of reported relapses. Seven (5.0%) participants relapsed during the 36-week run-in period but were not associated with MRI disease activity; five of these seven participants remained on study without further disease activity. The remaining two participants discontinued from the study for reasons unrelated to disease activity. One discontinued because of positive John Cunningham virus serology and the other because of withdrawn consent.Table 2 Summary of relapses during NOVA part 2

	IV/SC (N = 75)	SC/IV (N = 66)	
Relapse versus relapse-free, n (%)	
 Relapsed	5 (6.7)	3 (4.5)	
 Relapse-free	70 (93.3)	63 (95.5)	
Relapse during run-in period	4 (5.3)	3 (4.5)	
Relapse during period 1	0	0	
Relapse during period 2	1 (1.3)	0	
Relapse during follow-up safety period	1 (1.3)	1 (1.5)	
IV intravenous, SC subcutaneous

During the crossover period, one patient missed a SC Q6W dose with a subsequent report of relapse and a new/newly enlarging (N/NE) T2 lesion. In addition to this patient, N/NE T2 lesions were reported by two patients after 24 weeks of SC Q6W dosing and in one patient after 24 weeks of IV Q6W dosing (Table 3). One new T1 hypointense lesion was observed in one participant after receiving IV Q6W dosing; no new or newly enlarging Gd+ lesions were observed throughout the study.Table 3 Comparison of brain MRI lesions by treatment sequence

	From baseline to week 24	From 24 to 48 weeks	
IV/SC (N = 75)	SC/IV (N = 66)	IV/SC (N = 75)	SC/IV (N = 66)	
T2 hyperintense lesionsa,b	
 No. of N/NE T2 lesions, n (%)	
  0	73 (97.3)	63 (95.5)	62 (82.7)	57 (86.4)	
  1	0	0	2 (2.7)	1 (1.5)	
  2	0	1 (1.5)	0	0	
  ≥ 3	0	0	0	0	
 Mean (SD), n	0.0 (0.0), 73	0.0 (0.25), 64	0.0 (0.18), 64	0.0 (0.13), 58	
T1 hypointense lesionsa,c	
 No. of N/NE T1 lesions, n (%)	
  0	72 (96.0)	64 (97.0)	64 (85.3)	58 (87.9)	
  1	1 (1.3)	0	0	0	
  ≥ 2	0	0	0	0	
 Mean (SD), n	0.0 (0.12), 73	0.0 (0.00), 64	0.0 (0.0), 64	0.0 (0.0), 58	
New Gd + lesionsa	
 No. of N/NE Gd + lesions, n (%)	
  0	73 (97.3)	64 (97.0)	64 (85.3)	58 (87.9)	
  ≥ 1	0	0	0	0	
 Mean (SD), n	0.0 (0.0), 73	0.0 (0.0), 64	0.0 (0.0), 64	0.0 (0.0), 58	
Gd + Gd-enhancing, N/NE new/newly enlarging lesions, SC subcutaneous, SD standard deviation

aNeither negative binomial nor Poisson model was considered as the total number of lesions across the two arms were < 15 for each visit

bThe N/NE T2 lesions at each post-baseline visit were calculated cumulatively over time

cThe new T1 lesions at each post-baseline visit were calculated cumulatively over time

For two participants, clinical relapses were reported during the follow-up period after completion of study treatment (one participant was in the IV/SC treatment group and one participant was in the SC/IV treatment group). Both participants selected SC administration for the last dose of the study after the crossover period.

Change from baseline in EDSS score was minimal during the crossover period for IV and SC dosing, with no significant difference reported between groups (LS mean: 0.10; difference for SC vs. IV: 0.08; 95% CI of estimated difference: − 0.09 to 0.25; P = 0.357).

Safety

The safety of natalizumab administered SC or IV with Q6W extended interval dosing in NOVA part 2 was consistent with the known safety profiles of SC and IV natalizumab, respectively (Table 4).Table 4 Overall summary of treatment-emergent AEs—safety population

	IV/SC (N = 75)	SC/IV (N = 66)	IV (N = 136)	SC (N = 132)	Total (N = 141)	
No. of participants with any event, n (%)	63 (84.0)	49 (74.2)	78 (57.4)	83 (62.9)	112 (79.4)	
No. of participants with any moderate or severe event	20 (26.7)	22 (33.3)	23 (16.9)	30 (22.7)	42 (29.8)	
No. of participants with any severe event	2 (2.7)	1 (1.5)	2 (1.5)	1 (0.8)	3 (2.1)	
No. of participants with any related event	14 (18.7)	14 (21.2)	12 (8.8)	19 (14.4)	28 (19.9)	
No. of participants with any SAE	3 (4.0)	3 (4.5)	2 (1.5)	4 (3.0)	6 (4.3)	
No. of participants with any related SAE	1 (1.3)	0	0	1 (0.8)	1 (0.7)	
No. of participants with any event leading to discontinuation of study treatment	1 (1.3)	0	0	1 (0.8)	1 (0.7)	
No. of participants with any event leading to withdrawal from study	1 (1.3)	0	0	1 (0.8)	1 (0.7)	
No. of participants with any event of special interesta	2 (2.7)	3 (4.5)	3 (2.2)	2 (1.5)	5 (3.5)	
No. of participants with any other event of interestb	43 (57.3)	36 (54.5)	43 (31.6)	48 (36.4)	79 (56.0)	
No. of participants who died	0	0	0	0	0	
AE adverse event, IV intravenous, IV/SC crossover from IV to SC, PML progressive multifocal leukoencephalopathy, SAE serious adverse event, SC subcutaneous, SC/IV crossover from SC to IV

Numbers in parentheses are percentages based on the number of participants in the safety population

aDefined as events of PML, serious herpes infections, malignancies, and immunogenicity of SC dosing

bDefined as infusion and injection reactions, infusion and injection site reactions, injection site reactions upon switching to SC, injection site pain, opportunistic infections (excluding PML), hepatic injury, drug-induced liver injury, and hypersensitivity reactions

The incidence of TEAEs (62.9%; 57.4%) was similar between the SC Q6W and IV Q6W groups, respectively (Table 4). Most TEAEs were mild or moderate in severity, and the most common TEAEs (occurring in ≥ 5% of participants, or in ≥ 5% with either route of administration) were labeled events or attributable to the global coronavirus disease-2019 pandemic (Table S4 in the electronic supplementary material). The higher incidence of related TEAEs reported during SC (14.4%) versus IV (8.8%) administration was primarily due to (mild) injection site pain, which was reported in six participants (4.3%), all during SC treatment (Table 4), and consistent with previous natalizumab studies [10, 11].

A total of six (4.3%) participants reported a treatment-emergent serious adverse event (SAE), one (0.7%) of which was considered related to study drug per investigator assessment; none led to study withdrawal or change in dose. The incidence of related treatment-emergent SAEs was similar between the SC (0.8%) and IV (0.0%) treatment groups (Table 4). The incidence of related treatment-emergent SAEs during SC administration in the present study (0.8%) was consistent with previous studies of SC administration [10, 11]. Reasons for discontinuation that were unrelated to any adverse event included consent withdrawn (8 [5.7%]), investigator decision (4 [2.8%]), pregnancy (1 [0.7%]), and other (3 [2.1%]).

There were no deaths, no events of PML, no development of anti-drug antibodies, and no events meeting the search criteria for immunogenicity reported in part 2 of the study.

PROs

After 24 weeks in the crossover period, there were no significant differences between natalizumab SC and IV administration in LS mean change from baseline in NeuroQoL fatigue score, MSIS-29 physical score, or MSIS-29 psychological score (Table S5 in the electronic supplementary material). There was a small but significant difference between SC and IV administration in LS mean change from baseline in the EQ-5D-5L score after 24 weeks in the crossover period (− 0.05 [95% CI − 0.08 to − 0.02]; P = 0.002).

PK and PD

PK findings indicate that, over the 24-week treatment period for each route of administration, there was a trend of lower serum Ctrough in participants on SC Q6W dosing (9.2–10.4 µg/ml) compared with participants on IV Q6W dosing (10.7–12.9 µg/ml; Fig. 3a). PD results suggest that, over the 24-week treatment period for each route of administration, there was a trend of lower α4 integrin saturation on MNC in participants on SC Q6W dosing (65.5–67.2%) versus participants on IV Q6W dosing (70.7–73.0%; Fig. 3b).Fig. 3 Mean (± SE) serum trough natalizumab concentration over time in A PK population and mean value of trough α4 integrin saturation (on MNC) over time in B PD population. IV intravenous, MNC mononuclear cells, PD pharmacodynamic, PK pharmacokinetic, SC subcutaneous, IV/SC crossover from IV to SC, SC/IV crossover from SC to IV, SE standard error. PK population: all participants who received one or more doses of SC or IV natalizumab and had one or more post-baseline concentration of natalizumab in serum. PD population: all participants who received one or more dose of SC or IV natalizumab after randomization in part 2 and have one or more post-baseline assessment of the PD parameter. Week 0: the last value taken prior to the first dose of the crossover period. The dotted lines represent the randomization visit and the beginning of period 2, respectively

In the FAS, 91 participants (64.5%) were ≤ 80 kg; 50 participants (35.5%) were > 80 kg at screening. In patients with body weight ≤ 80 kg, mean Ctrough across all time points ranged from 10.8–16.0 mg/l and 12.7–18.4 mg/l for SC and IV, respectively. Mean α4 integrin saturation in patients ≤ 80 kg ranged from 67.6–72.4% and 72.2–78.3% for SC and IV, respectively. In patients with body weight > 80 kg, mean Ctrough across all time points ranged from 3.1–5.7 mg/l and 5.6–7.1 mg/l for SC and IV, respectively. Mean α4 integrin saturation across all time points ranged from 54.1–63.3% and 61.8–74.3% for SC and IV, respectively. However, lower α4 integrin saturation on SC natalizumab was not associated with disease activity in the NOVA study, and Ctrough and α4 integrin saturation in patients with disease activity did not differ significantly from the rest of the study population without disease activity.

Discussion

Based on the PPQ, nearly 90% of participants in this study preferred the SC method of administration of natalizumab at the end of the crossover period, mainly because it “requires less time in the clinic.” IV natalizumab took about 15 times longer to prepare and administer than SC natalizumab. Other observational studies comparing these two modes of administration of natalizumab support our findings. Interim results from SISTER, a 12-month prospective, German multicenter, open-label study (n = 166) evaluating patient preference for SC or IV administration of natalizumab, also showed that nearly 90% of patients preferred SC administration of natalizumab; the most frequent reason for selecting SC over IV administration was the shorter duration of administration and convenience [12]. The EASIER study [13], a multicenter, observational, cross-sectional study aimed at evaluating the economic impact associated with the use of natalizumab SC versus IV in patients with RRMS, found that the SC route of administration would result in 50% reduction in patient time and 55% reduction in active working time of healthcare providers.

The second most common reason for the preference for the SC route of administration in our study was that this method “feels more comfortable during administration.” This finding is consistent with previously reported patient preference studies reporting that, compared with the IV route of administration, SC administration of biotherapeutics is a safe, efficacious, and convenient dosing alternative that is generally valued by patients and healthcare professionals [14, 15].

Notably, when the 14-item TSQM scale was administered to participants in our study, there were no significant differences between SC and IV administration in LS mean change from baseline in the TSQM global satisfaction score during the crossover period. This may be attributed to the several assessment domains of the TSQM encompassing effectiveness, side effects, convenience, and global satisfaction. With the exception of EQ-5D-5L, there were no significant differences between SC and IV administration on PROs including NeuroQoL fatigue and MSIS-29 Physical and Psychological, with no clinically meaningful changes from baseline on any PROs.

Overall, disease activity was low during the crossover period, when participants on Q6W dosing switched between SC and IV routes of administration. The clinical relapses during the run-in period were not associated with MRI disease activity; no participants had Gd+ during the study. The maintenance of low disease activity during the extension study for the few participants from part 1 who switched to Q6W from the Q4W dosing schedule of natalizumab is consistent with findings from previous studies [16–19], suggesting that the efficacy of natalizumab is maintained with a Q6W dosing schedule. Stable clinical and disease activity after switching from IV to SC routes of administration have also been demonstrated with other biologics [15, 20].

NOVA part 2 participants tended to have lower Ctrough and lower target engagement at the SC versus IV crossover periods, which is in line with the estimated 82% median relative bioavailability following SC administration of natalizumab [21]. Another study had also shown a decrease in natalizumab trough levels after switching from IV to SC dosing, though this was not associated with any radiological or clinical disease [22]. Both trough serum concentrations and trough α4 integrin saturations on MNC over time were higher in participants with lower baseline body weight (≤ 80 kg) compared with those who had higher baseline body weight (> 80 kg). N/NE T2 lesions were observed in three participants receiving SC administration versus one participant receiving IV administration; however, it is difficult to establish an association between Ctrough and trough α4-integrin saturation level with efficacy in this study for the following reasons: (1) One participant (> 80 kg) had very low α4 integrin saturation (3.4%) at week 150 after missing a dose of SC at week 144. Although this patient’s body weight may have contributed to lower drug exposure at steady state [21], the importance of treatment adherence with Q6W dosing should be emphasized, as this participant’s drop in α4 integrin was likely driven by a missed dose rather than the SC route of administration; (2) two participants with T2 lesions had variable α4 integrin saturation over the course of the study, whereas others maintained high saturation on both SC and IV. Previous studies have differed on the minimal level of α4-integrin saturation required to suppress disease activity [23, 24]. Future analyses will explore the impact of body mass index on SC trough levels and concentration.

Safety findings were consistent with the known safety profiles of SC and IV natalizumab [10, 11]. The incidence of TEAEs was similar between the SC Q6W and IV Q6W groups, respectively [10, 11]. There were no deaths and no treatment-emergent events of PML, recognizing that the size and duration of the study were insufficient to be informative on rare adverse events such as PML. There was no development of anti-natalizumab antibodies, and no events met the search criteria for immunogenicity.

While the NOVA part 2 crossover study was designed to remove any timing bias for patient preference and to allow for assessment of steady-state PK/PD switching to and from the SC route of administration, the crossover design has limitations. First, it is difficult to make direct comparisons between the SC and IV routes of administration. Second, because there was no washout period between SC and IV in the crossover periods, there could potentially have been carryover effects between the two routes of administration. Third, conclusions regarding the efficacy and safety of SC compared with IV Q6W dosing may be limited by the short follow-up duration of either route during the crossover period.

In conclusion, in the extension phase of the phase IIIb NOVA study (part 2), most participants on Q6W dosing preferred SC administration versus IV administration. There was a trend of lower trough serum concentration and α4 integrin saturation on SC Q6W dosing versus IV Q6W dosing. Both Ctrough and α4 integrin saturation were inversely related to body weight, although lower α4 integrin saturation on SC Q6W dosing was not associated with MS disease activity. Regardless of SC or IV route of administration of Q6W dosing, disease activity was low overall during the crossover period of the study.

Supplementary Information

Below is the link to the electronic supplementary material.Supplementary file1 (PDF 476 KB)

Acknowledgements

The authors thank the NOVA study patients, investigators, and study staff for their contribution to the research presented in this article. We thank Susie Sinks, PhD, for her contributions toward the development of this manuscript.

Medical Writing and Editorial Assistance

Suzanne Douthwaite, CMPP, and Bess Reinoso, PhD, of Excel Scientific Solutions co-wrote the first draft with input from authors, and Cara Farrell of Excel Scientific Solutions (Fairfield, CT, USA) provided editorial support for the preparation of this manuscript; funding was provided by Biogen. The authors provided final approval of all content.

Author Contributions

Conceptualization, Methodology, Investigation, Writing, Review, and Editing: Gilles Defer, Helmut Butzkueven, Gavin Giovannoni, and Joep Killestein. Conceptualization, Methodology, Writing, Review, and Editing: Douglas L. Arnold, Heinz Wiendl, Gary R. Cutter, Lana Zhovtis Ryerson, Jeffrey A. Cohen, John Foley, Rose Domingo-Horne, Marie Toukam, Amir-Hadi Maghzi, Robert Kuhelj, and Tyler Lasky. Conceptualization, Methodology, Formal Analysis, Data Curation, Writing, Review, and Editing: Aimie Nunn.

Funding

This study was sponsored by Biogen (Cambridge, MA, USA), and funded the Rapid Service Fee. The author(s) received no financial support for the research, authorship, and/or publication of this research.

Data Availability

Individual participant data collected during the trial may be shared after anonymization and on approval of the research proposal. Biogen commits to sharing patient-level data, study-level data, clinical study reports, and protocols with qualified scientific researchers who provide a methodologically sound proposal. Biogen reviews all data requests internally based on the review criteria and in accordance with our Clinical Trial Transparency and Data Sharing Policy. Deidentified data and documents will be shared under agreements that further protect against participant reidentification. To request access to data, please visit https://vivli.org/.

Declarations

Conflict of Interest

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Heinz Wiendl has received honoraria for consulting or speaking from AbbVie, Actelion, Alexion, Argenx, Biogen, Bristol Myers Squibb, Cognomed, EMD Serono, Evgen, F. Hoffmann-La Roche, Idorsia, IGES, Immunic, Immunovant, Janssen, Johnson & Johnson, MedDay, Merck Serono, Novartis, Roche, Sanofi Genzyme, Teva Pharmaceuticals, and UCB Pharma. John Foley has received speakers’ and consultant honoraria from Biogen, EMD Serono, Genentech, Genzyme, and Novartis. Gilles Defer has received personal compensation for scientific advisory boards or speaker honoraria from Biogen, Bristol Myers Squibb, Merck Serono, Novartis, Sanofi Genzyme, and Teva Pharmaceuticals. Lana Zhovtis Ryerson has received personal compensation for advisory board activities from Biogen, Genentech, and Novartis; and research support from Biogen, Celgene, and Genentech. Jeffrey A. Cohen has received personal compensation for consulting from Biogen, Bristol Myers Squibb, Convelo, Genentech, Janssen, NervGen, Novartis, and PSI, and for serving as an editor of Multiple Sclerosis Journal. Douglas L. Arnold has received consulting fees from Albert Charitable Trust, Alexion Pharma, Biogen, Celgene, Frequency Therapeutics, Genentech, Med-Ex Learning, Merck, Novartis, Population Council, Receptos, Roche, and Sanofi Aventis; and equity interest in NeuroRx. Helmut Butzkueven has received compensation for advisory board membership or speaker bureaus from Biogen, Merck, Novartis, Roche, and UCB Pharma; and honorarium for serving on the NOVA trial steering committee. Gary R. Cutter has participated on consulting or advisory boards for Biodelivery Sciences International, Biogen, Click Therapeutics, Genzyme, Genentech, GW Pharmaceuticals, Immunic, Klein Buendel, MedDay, MedImmune, Neurogenesis, Novartis, Osmotica, Perception Neurosciences, Recursion-Cerexis, Rekover, Roche, and TG Therapeutics. Gavin Giovannoni has received consulting or speaker fees from AbbVie, Aslan, Atara Biotherapeutics, Biogen, Bristol Myers Squibb–Celgene, GlaxoSmithKline, GW Pharma, Janssen-Actelion, Jazz Pharmaceuticals, LIFNano, Merck KGaA-EMD Serono, Novartis, Roche-Genentech, Sanofi Genzyme, and Teva Pharmaceuticals. Joep Killestein has received speaker and consulting fees from Biogen, Genzyme, Merck Serono, Novartis, Roche, and Teva Pharmaceuticals. Aimie Nunn is an employee of Cytel. Rose Domingo-Horne, Marie Toukam, Amir-Hadi Maghzi, Robert Kuhelj, Tyler Lasky are employees of and hold stock/stock options in Biogen.

Ethical Approval

This study was performed in accordance with the International Council for Harmonisation Guidelines on Good Clinical Practice and the Declaration of Helsinki. The study protocol was approved by each center’s ethics committee or institutional review board (Table S1 in the electronic supplementary material).

Prior Presentation: The data in this manuscript have been presented at ECTRIMS 2023 [Wiendl H, Foley J, Defer G, et al. Results from the NOVA Extension Study Evaluating Patient Preference for Subcutaneous Versus Intravenous Administration with Natalizumab Q6W Dosing. Poster presented at 39th Congress of the European Committee for Treatment & Research in Multiple Sclerosis (ECTRIMS); October 11–13, 2023; Milan, Italy; P1657].
==== Refs
References

1. Jackson Y Janssen E Fischer R The evolving role of patient preference studies in health-care decision-making, from clinical drug development to clinical care management Expert Rev Pharmacoecon Outcomes Res 2019 19 4 383 396 10.1080/14737167.2019.1612242 31070048
Jackson Y, Janssen E, Fischer R, et al. The evolving role of patient preference studies in health-care decision-making, from clinical drug development to clinical care management. Expert Rev Pharmacoecon Outcomes Res. 2019;19(4):383–96.31070048 10.1080/14737167.2019.1612242
2. Tysabri (natalizumab) [prescribing information]. Biogen Inc. Cambridge.
3. FDA approves Tysabri. 2004. https://www.drugs.com/newdrugs/tysabri-approved-multiple-sclerosis-162.html. Accessed 31 Oct 2023
4. Simonsen CS Flemmen H Broch L Early high efficacy treatment in multiple sclerosis is the best predictor of future disease activity over 1 and 2 years in a Norwegian population-based registry Front Neurol 2021 12 693017 10.3389/fneur.2021.693017 34220694
Simonsen CS, Flemmen H, Broch L, et al. Early high efficacy treatment in multiple sclerosis is the best predictor of future disease activity over 1 and 2 years in a Norwegian population-based registry. Front Neurol. 2021;12: 693017.34220694 10.3389/fneur.2021.693017
5. Tysabri: EPAR—product information. 2022. https://www.ema.europa.eu/en/medicines/human/EPAR/tysabri#product-information-section. Accessed 1 Nov 2023
6. FDA Drug Safety Communication: risk of progressive multifocal leukoencephalopathy (PML) with the use of Tysabri (natalizumab). 2010. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/fda-drug-safety-communication-risk-progressive-multifocal-leukoencephalopathy-pml-use-tysabri. Accessed 31 Oct 2023
7. Zhovtis Ryerson L Foley J Chang I Risk of natalizumab-associated PML in patients with MS is reduced with extended interval dosing Neurology 2019 93 15 e1452 e1462 31515290
Zhovtis Ryerson L, Foley J, Chang I, et al. Risk of natalizumab-associated PML in patients with MS is reduced with extended interval dosing. Neurology. 2019;93(15):e1452–62.31515290
8. Foley JF Defer G Ryerson LZ Comparison of switching to 6-week dosing of natalizumab versus continuing with 4-week dosing in patients with relapsing-remitting multiple sclerosis (NOVA): a randomised, controlled, open-label, phase 3b trial Lancet Neurol 2022 21 7 608 619 10.1016/S1474-4422(22)00143-0 35483387
Foley JF, Defer G, Ryerson LZ, et al. Comparison of switching to 6-week dosing of natalizumab versus continuing with 4-week dosing in patients with relapsing-remitting multiple sclerosis (NOVA): a randomised, controlled, open-label, phase 3b trial. Lancet Neurol. 2022;21(7):608–19.35483387 10.1016/S1474-4422(22)00143-0
9. Tysabri (natalizumab). 2021. https://www.ema.europa.eu/en/documents/smop/chmp-post-authorisation-summary-positive-opinion-tysabri-x-116_en.pdf. Accessed 1 Nov 2023
10. Plavina T Fox EJ Lucas N Muralidharan KK Mikol D A randomized trial evaluating various administration routes of natalizumab in multiple sclerosis J Clin Pharmacol 2016 56 10 1254 1262 10.1002/jcph.707 26835603
Plavina T, Fox EJ, Lucas N, Muralidharan KK, Mikol D. A randomized trial evaluating various administration routes of natalizumab in multiple sclerosis. J Clin Pharmacol. 2016;56(10):1254–62.26835603 10.1002/jcph.707
11. Trojano M Ramió-Torrentà L Grimaldi LM A randomized study of natalizumab dosing regimens for relapsing-remitting multiple sclerosis Mult Scler 2021 27 14 2240 2253 10.1177/13524585211003020 33821693
Trojano M, Ramió-Torrentà L, Grimaldi LM, et al. A randomized study of natalizumab dosing regimens for relapsing-remitting multiple sclerosis. Mult Scler. 2021;27(14):2240–53.33821693 10.1177/13524585211003020
12. Gold R, Schmidt S, Motte J, et al. SISTER—subcutaneous: non-interventional, observational, prospective, German multi-center, open label study over 12 months for Tysabri patient preference. In: 38th Congress of the European Committee for treatment and research in multiple sclerosis (ECTRIMS 2022) 2022 26th–28th October, 2022; Amsterdam, Netherlands; 2022.
13. Filippi M Grimaldi L Conte A Intravenous or subcutaneous natalizumab in patients with relapsing-remitting multiple sclerosis: investigation on efficiency and savings – the EASIER study J Neurol 2024 271 1 340 354 10.1007/s00415-023-11955-0 37715789
Filippi M, Grimaldi L, Conte A, et al. Intravenous or subcutaneous natalizumab in patients with relapsing-remitting multiple sclerosis: investigation on efficiency and savings – the EASIER study. J Neurol. 2024;271(1):340–54.37715789 10.1007/s00415-023-11955-0
14. Bittner B Richter W Schmidt J Subcutaneous administration of biotherapeutics: an overview of current challenges and opportunities BioDrugs 2018 32 5 425 440 10.1007/s40259-018-0295-0 30043229
Bittner B, Richter W, Schmidt J. Subcutaneous administration of biotherapeutics: an overview of current challenges and opportunities. BioDrugs. 2018;32(5):425–40.30043229 10.1007/s40259-018-0295-0
15. Alten R An Y Kim DH Yoon S Peyrin-Biroulet L Re-routing infliximab therapy: subcutaneous infliximab opens a path towards greater convenience and clinical benefit Clin Drug Investig 2022 42 6 477 489 10.1007/s40261-022-01162-6 35657560
Alten R, An Y, Kim DH, Yoon S, Peyrin-Biroulet L. Re-routing infliximab therapy: subcutaneous infliximab opens a path towards greater convenience and clinical benefit. Clin Drug Investig. 2022;42(6):477–89.35657560 10.1007/s40261-022-01162-6
16. Zhovtis Ryerson L Frohman TC Foley J Extended interval dosing of natalizumab in multiple sclerosis J Neurol Neurosurg Psychiatry 2016 87 8 885 889 10.1136/jnnp-2015-312940 26917698
Zhovtis Ryerson L, Frohman TC, Foley J, et al. Extended interval dosing of natalizumab in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016;87(8):885–9.26917698 10.1136/jnnp-2015-312940
17. Clerico M De Mercanti SF Signori A Extending the interval of natalizumab dosing: is efficacy preserved? Neurotherapeutics 2020 17 1 200 207 10.1007/s13311-019-00776-7 31452081
Clerico M, De Mercanti SF, Signori A, et al. Extending the interval of natalizumab dosing: is efficacy preserved? Neurotherapeutics. 2020;17(1):200–7.31452081 10.1007/s13311-019-00776-7
18. Zhovtis Ryerson L Naismith RT Krupp LB No difference in radiologic outcomes for natalizumab patients treated with extended interval dosing compared with standard interval dosing: real-world evidence from MS PATHS Mult Scler Relat Disord 2022 58 103480 10.1016/j.msard.2021.103480 35051898
Zhovtis Ryerson L, Naismith RT, Krupp LB, et al. No difference in radiologic outcomes for natalizumab patients treated with extended interval dosing compared with standard interval dosing: real-world evidence from MS PATHS. Mult Scler Relat Disord. 2022;58: 103480.35051898 10.1016/j.msard.2021.103480
19. Zhovtis Ryerson L Foley JF Defer G Exploratory clinical efficacy and patient-reported outcomes from NOVA: a randomized controlled study of intravenous natalizumab 6-week dosing versus continued 4-week dosing for relapsing-remitting multiple sclerosis Mult Scler Relat Disord 2023 72 104561 10.1016/j.msard.2023.104561 36931078
Zhovtis Ryerson L, Foley JF, Defer G, et al. Exploratory clinical efficacy and patient-reported outcomes from NOVA: a randomized controlled study of intravenous natalizumab 6-week dosing versus continued 4-week dosing for relapsing-remitting multiple sclerosis. Mult Scler Relat Disord. 2023;72: 104561.36931078 10.1016/j.msard.2023.104561
20. Volkers A Straatmijer T Duijvestein M Real-world experience of switching from intravenous to subcutaneous vedolizumab maintenance treatment for inflammatory bowel diseases Aliment Pharmacol Ther 2022 56 6 1044 1054 10.1111/apt.17153 35869807
Volkers A, Straatmijer T, Duijvestein M, et al. Real-world experience of switching from intravenous to subcutaneous vedolizumab maintenance treatment for inflammatory bowel diseases. Aliment Pharmacol Ther. 2022;56(6):1044–54.35869807 10.1111/apt.17153
21. Muralidharan KK Kuesters G Plavina T Population pharmacokinetics and target engagement of natalizumab in patients with multiple sclerosis J Clin Pharmacol 2017 57 8 1017 1030 10.1002/jcph.894 28398628
Muralidharan KK, Kuesters G, Plavina T, et al. Population pharmacokinetics and target engagement of natalizumab in patients with multiple sclerosis. J Clin Pharmacol. 2017;57(8):1017–30.28398628 10.1002/jcph.894
22. Toorop AA van Kempen ZLE Steenhuis M Decrease of natalizumab drug levels after switching from intravenous to subcutaneous administration in patients with multiple sclerosis J Neurol Neurosurg Psychiatry 2023 94 6 482 486 10.1136/jnnp-2022-330467 36639226
Toorop AA, van Kempen ZLE, Steenhuis M, et al. Decrease of natalizumab drug levels after switching from intravenous to subcutaneous administration in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2023;94(6):482–6.36639226 10.1136/jnnp-2022-330467
23. Fox RJ Cree BA De Sèze J MS disease activity in RESTORE: a randomized 24-week natalizumab treatment interruption study Neurology 2014 82 17 1491 1498 10.1212/WNL.0000000000000355 24682966
Fox RJ, Cree BA, De Sèze J, et al. MS disease activity in RESTORE: a randomized 24-week natalizumab treatment interruption study. Neurology. 2014;82(17):1491–8.24682966 10.1212/WNL.0000000000000355
24. Derfuss T Kovarik JM Kappos L α4-integrin receptor desaturation and disease activity return after natalizumab cessation Neurol Neuroimmunol Neuroinflamm 2017 4 5 e388 10.1212/NXI.0000000000000388 28856176
Derfuss T, Kovarik JM, Kappos L, et al. α4-integrin receptor desaturation and disease activity return after natalizumab cessation. Neurol Neuroimmunol Neuroinflamm. 2017;4(5): e388.28856176 10.1212/NXI.0000000000000388
