IQYMUNE® IS EFFECTIVE AS MAINTENANCE TREATMENT IN MMN: A RANDOMISED, DOUBLE-BLIND, CROSS-OVER STUDY

VERSUS KIOVIG® - THE LIME STUDY

RESULTS

Patients and treatment

• 23 patients randomized to sequence A (KIOVIG® then IQYMUNE®; N=12) or B (IQYMUNE® then KIOVIG®; N=11)

• Analysis were performed on the ITT* population (N = 22) and on the PPS** (N = 21)

* Intention-To-Treat ** Per Protocol set

Baseline characteristics of patients were similar in the two groups:• Most of the participants were male i 86.4% (cf CSR) • Median age was 48.0 years • All participants were already on stable dose of IVIg therapy for MMN for at least 3 months before inclusion in

the study• Median time from initial diagnosis to study entry was 4.3 years.

CONCLUSION• In summary , this Phase III randomised, comparative, active-control, double-blind study with a crossover design demonstrated the non-inferiority both in efficacy and safety of IQYMUNE®

compared with KIOVIG® in the maintenance treatment of MMN. • To our knowledge, this is the first clinical trial comparing the efficacy and safety of two IVIg brands in the maintenance treatment of MMN.

(1) Van den Bergh PY, Hadden RD, Bouche P, Cornblath DR, Hahn A, Illa I, Koski CL, Léger JM, Nobile-Orazio E, Pollard J, Sommer C, van Doorn PA, van Schaik IN; European Federation of Neurological Societies; Peripheral Nerve Society (2010). European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society - first revision. Eur J Neurol. 17(3):356-63. doi: 10.1111/j.1468-1331.2009.02930.x. - (2) Elovaara I, Apostolski S, van Doorn P, Gilhus NE, Hietaharju A, Honkaniemi J, van Schaik IN, Scolding N, Soelberg Sørensen P, Udd B; EFNS (2008). EFNS guidelines for the use of intravenous immunoglobulin in treatment of neurological diseases: EFNS task force on the use of intravenous immunoglobulin in treatment of neurological diseases. Eur J Neurol. 15(9):893-908. doi: 10.1111/j.1468-1331.2008.02246.x. (3) Cats EA, van der Pol WL, Piepers S, Franssen H, Jacobs BC, van den Berg-Vos RM, Kuks JB, van Doorn PA, van Engelen BG, Verschuuren JJ, Wokke JH, Veldink JH, van den Berg LH (2010). Correlates of outcome and response to IVIg in 88 patients with multifocal motor neuropathy. Neurology. 75:818-825. doi: 10.1212/WNL.0b013e3181f0738e - (4) Cats EA, van der Pol WL, Piepers S, Notermans NC, van den Berg-Vos RM, van den Berg LH (2008). New liquid intravenous immunoglobulin (10 % IVIg) for treatment of multifocal motor neuropathy: a prospective study of efficacy, safety and tolerability. J Neurol. 255(10):1598-9 - (5) Léger JM, Guimaraes-Costa R, Muntean C (2016). Immunotherapy in peripheral neuropathies. Neurotherapeutics. 13(1):96-107. doi: 10.1007/s13311-015-0401-7. - (6) Vanhoutte EK, Faber CG, van Nes SI, Cats EA, Van der Pol WL, Gorson KC, van Doorn PA, Cornblath DR, van den Berg LH, Merkies IS; PeriNomS Study Group (2015). Rasch-built Overall Disability Scale for Multifocal motor neuropathy (MMN-RODS(©) ). J Peripher Nerv Syst. 20(3):296-305. doi: 10.1111/jns.12141.

MATERIAL AND METHODS• Phase III, European, multicentre, randomized, double-blind, active-comparator-controlled, cross-over, non-interiority, efficacy and safety study (NCT01951924).• Patients were randomized in a 1: 1 ratio between the treatment sequences: KIOVIG®/IQYMUNE® or IQYMUNE®/KIOVIG®. • Evaluation period ran from 13 weeks after the initiation of either IQYMUNE® or KIOVIG® until the end of the corresponding period.

Adult men and women (≥ 18 years old) were eligible for inclusion if:• They were diagnosed with probable or definite MMN based on EFNS/PNS 2010 guidelines (1), • They were being treated with stable maintenance dose, within a 15% range, of any brand of IVIg (KIOVIG® excluded during the last six months before enrollment) at a dose between

1 g/kg over 1 to 3 days and 2 g/kg over 2 to 5 days every 4 to 8 weeks (±7 days) for at least three months before enrollment.

KIOVIG®

Randomisation

First cross-over period (P1)21-25 weeks

Second cross-over period (P2)21-25 weeks

Cross-over End of study

Groupe B

Groupe AKIOVIG®

IQYMUNE®

ScreeningPatients under previous IVIG

treatment for at least 3 months

INTRODUCTIONIntravenous immunoglobulins (IVIg) are the gold-standard first-line treatment in multifocal motor neuropathy (MMN) as recommended by both European Federation of Neurological Societies/Peripheral Nerve Society Guidelines for MMN management (1) and EFNS Guidelines for the use of IVIg to treat neurological diseases (2). IQYMUNE® is a highly purified 10% liquid preparation of normal human immunoglobulin for intravenous administration that has been approved in this indication since 2015 in Europe. This study aimed to determine whether IQYMUNE® is non-inferior to KIOVIG® (drug reference), primarily based on efficacy criteria. Investigation of the safety of IQYMUNE® was a secondary objective.

DISCUSSION• The use of MMRC 10-sum score for assessing muscle strength in MMN was approved by the European Medicines Agency. MMRC new 10-sum score focuses more strongly on upper limbs than the original MMRC 10-sum score. Based

on the results obtained in Cats cross-sectional study (3), this scale includes clinically relevant distal upper limbs muscle commonly affected in MMN and excludes irrelevant lower limb muscles not usually affected.• MMRC new 10 sum score yielded lower values by 5-6 points than original MMRC score (difference not tested statistically) so that as anticipated it captured more weakness in a pattern considered to be typical of MMN. • Patients had a mean INCAT disability scale score of 2.5 points on therapy, demonstrating persistent disability despite treatment. Mean grip strength two weeks after last course of each product was higher than that just before the course

concerned, demonstrating ongoing benefit from IVIg treatment. • This study was limited by the absence availability of high quality outcome measures covering all domains of disability, impairment, and quality of life in MMN which need to be simple, valid, reliable, and responsive, and correlate with

disease severity (5).• At the time study protocol was designed, there was no validated functional disability scale for MMN. The Rasch-built overall disability scale for MMN (MMN-RODS®) does overcome the shortcomings of ordinal scales was proposed in

2015 (6) but still needs to be validated in new series.

Efficacy

Secondary efficacy criteria No statistically significant difference between IQYMUNE® and KIOVIG® was detected in all secondary efficacy criteria : • MMRC new 10-sum score, • Rasch-built MMRC 10-sum score, • MMRC 14-sum score, • Total INCAT disability score or normalized grip strength measured during the evaluation period. • Improvement in clinical global impression (CGI) measured at the end of each period was also similar for the

two products, with no specific change observed in more than half of the patients.

Figure 1. Geometric boxplots of MMRC 10-sum scores at baseline and 6 months after each treatment sequence. mITT population

Primary efficacy criterion: mean MMRC sum score• Primary efficacy outcome was the Modified Medical Research Council (MMRC) sum score of 10 predetermined

muscle groups, as described by Cats (4), during the evaluation period. The comparison test was based on a linear mixed model estimating the effect of product, period, and sequence. No sequence or period effect was detected.

• Non-inferiority of IQYMUNE® relative to KIOVIG® was demonstrated : estimated difference between IQYMUNE® and KIOVIG® was - 0.01; 95.0 % CI [-0.51, 0.48] in the mITT population (figure 1) and -0.14 [-0.60, 0.31] in the PPS.

• Associated P-values for non-inferiority were < 0.0001.

Table 1. Primary efficacy outcome – estimated means of MMRC 10-sum score 13 to 26 weeks after the start of administration for each product, linear mixed model – mITT and PPS

Population Covariate Least square means: Estimate [95% CI]

Differences: Estimate [95% CI] P value

mITTN=22

Product IQYMUNE® 94.5 [93.5, 95.6] -0.01 [-0.51, 0.48] 0.96

KIOVIG® 94.5 [93.6, 95.5] Period*

1 94.4 [93.4, 95.4] -0.24 [-0.73, 0.25] 0.322 94.7 [93.7, 95.6]

Sequence* A 95.0 [93.9, 96.0] 0.90 [-0.85, 2.65] 0.30B 94.1 [92.58, 95.61]

Non-inferiority IQYMUNE® versus KIOVIG® <0.001

PPS N=21

Product 100IQYMUNE® 94.4 [93.3, 95.6] -0.14 [-0.60, 0.31] 0.51

KIOVIG® 94.6 [93.6, 95.5] Period*

1 94.3 [93.2, 95.5] -0.37 [-0.83, 0.08] 0.102 94.7 [93.7, 95.6]

Sequence* A 94.9 [93.8, 96.0] 0.80 [-1.06, 2.67] 0.38B 94.1 [92.5, 95.7]

Non-inferiority IQYMUNE® versus KIOVIG® <0.001Range of mean MMRC 10-sum score result: 0 (complete paralysis) to 100 (full strength). *In sequence A, participants were first treated with KIOVIG® for 21-25 weeks (period 1) then with IQYMUNE® for 21-25 weeks (period 2). In sequence B, participants were first treated with IQYMUNE® then with KIOVIG®.Modified-intent-to-treat (mITT), and per protocol set (PPS) populations.

The lower limit of a box represents the 1st quartile, i.e. 25% of data lie below this value; the upper limit of the box represents the 3rd quartile, i.e. 25% of the data lie above this value; the horizontal line within the box indicates the median, i.e. 50% of data lie above this value. The diamond represents the mean value of the distribution, and the dots outside the box represent outliers. This figure shows that the medians after IQYMUNE® treatment and KIOVIG® treatment are similar to the baseline value and that the distributions are not significantly different.

JM. Léger (1), O. Alfa Cissé (2), D. Cocito (3), JM Grouin (4), H. Katifi (5), E. Nobile-Orazio (6), R. Ouaja (2), J. Pouget (7), YA. Rajabally (8), T. Sevilla Mantecon (9), I. Merkies (10)

(1) National Referral Center for Neuromuscular Diseases. University Hospital Pitié-Salpétrière, Paris, France (2) Global medical Affairs unit, LFB BIOMÉDICAMENTS, Les Ulis, France (3) D. Cocito. Department of Neurosciences, Molinette Hospital, Università degli Studi di Torino, Torino, Italy (4) Department of Statistics, Rouen University, Rouen, France

(5) Wessex Neurological Centre, Southampton General Hospital, Southampton, UK (6) Neuromuscular and Neuroimmunology Service, Humanitas Clinical and Research Center, Milan University, Rozzano, Milan, Italy (7) National Referral Center for Neuromuscular Diseases. University Hospital La Timone, Marseille, France (8) YA. Rajabally. School of Life and Health Sciences, Aston Brain Centre, Aston University, Birmingham, United Kingdom

(9) T. Sevilla Mantecon. Neurology Department, La Fe University Hospital, Centro de investigación Biomédica en red de enfermedades raras (CIBERER), University of Valencia, Valencia, Spain (10) Maastricht University Medical Center, Maastricht, the Netherlands & St. Elisabeth Hospital, Willemstad, Curacao

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