ACARIZAX 12SQ-HDM Sublingual lyophilisate

Pharmacotherapeutic group: Allergen extracts, house dust mites ATC code: V01AA03 Mechanism of action ACARIZAX is an allergen immunotherapy product.‍‍‍‍‍‍​​​‍​​​​​​ Allergen immunotherapy with allergen products involves repeated administration of allergens to allergic patients in order to modify the immunological response to allergen exposure. The pharmacodynamic effect of allergen immunotherapy targets the immune system, but the complete and precise mechanism of action underlying the clinical effect is not yet fully understood. Treatment with ACARIZAX has been shown to increase house dust mite-specific IgG4 and to induce a systemic antibody response that competes with IgE for binding to house dust mite allergens. This effect can be observed as early as 4 weeks after initiation of treatment. The effect of ACARIZAX targets the underlying cause of house dust mite-induced respiratory disease, and clinical efficacy has been demonstrated for both the upper and lower airways. ACARIZAX provides sustained protection, leading to improved disease control, better quality of life manifested by symptom relief, reduced need for additional medications, and reduced risk of disease exacerbation. Clinical efficacy in adults The efficacy of ACARIZAX 12 SQ-HDM treatment in house dust mite-induced allergic respiratory disease was evaluated in two double-blind, randomised, placebo-controlled trials with different endpoints and different patient populations. Two-thirds of subjects were sensitised to additional allergens besides house dust mite allergens. Sensitisation to house dust mites alone or to house dust mites together with one or more additional allergens did not affect trial results. Supporting evidence from an allergen challenge chamber study and from a study conducted with lower doses was also presented. Allergic rhinitis: MERIT study (MT-06) The MERIT study included 992 adults with moderate-to-severe house dust mite-induced allergic rhinitis who were using rhinitis medication. Subjects were randomised to receive 12 SQ-HDM, 6 SQ-HDM, or placebo daily for one year, and all had access to standard rhinitis pharmacotherapy. Throughout the trial, subjects attended specialist assessment visits approximately every 2 months. The primary endpoint was the average daily total combined rhinitis score (TCRS) assessed during the last 8 weeks of treatment. TCRS was the sum of the rhinitis symptom score and rhinitis medication score. For the rhinitis symptom score, 4 nasal symptoms (runny nose, blocked nose, nasal itching, sneezing) were assessed daily on a scale of 0–3 (none, mild, moderate, severe symptoms), i.e. the scale range was 0–12. The rhinitis medication score was the sum of nasal corticosteroids administered (2 points per puff, max. 4 puffs daily) and oral antihistamines (4 points per tablet, max. 1 tablet daily), i.e. range: 0–12. Thus the TCRS scale range was: 0–24. Additional pre-defined key secondary endpoints included total combined rhinoconjunctivitis score and rhinoconjunctivitis quality of life (RQLQ). Post-hoc analyses of rhinitis exacerbation days were also performed to illustrate the clinical relevance of the results. Rhinitis exacerbation was defined as a day when the subject returned to such a high level of symptoms that met the entry criterion for inclusion in the study: a rhinitis symptom score of at least 6 or at least 5, with one symptom rated as severe. weeks of treatment Placebo (adjusted mean +1/2 width of the 95% CI for the difference in adjusted means) 12 SQ-HDM (adjusted mean +1/2 width of the 95% CI for the difference in adjusted means) TCRS – total combined rhinitis score MERIT study: total combined rhinitis score over time TCRS: total combined rhinitis score (symptoms + medication score). The primary endpoint was the average daily TCRS during approximately the last 8 weeks of treatment (week ~44–52). Adjusted mean values of TCRS over time with error bars for the difference in adjusted means. Non-overlapping intervals indicate a statistically significant difference. MERIT study results 12 SQ-HDM Placebo Treatment effect Primary endpoint N Score N Score Absolute difference c Relative difference d p-value Total combined rhinitis score FAS-MI a (adjusted mean) 318 5.71 338 6.81 1.09[0.35;1.84] - 0.004 FAS b (adjusted mean) 284 5.53 298 6.76 1.22[0.49;1.96] 18% 0.001 FAS b (median) 284 5.88 298 7.54 1.66 22% - Pre-defined key secondary endpoints N Score N Score Absolute difference c Relative difference d p-value Rhinitis symptom score FAS b (adjusted mean) 284 2.76 298 3.30 0.54[0.18;0.89] 16% 0.003 FAS b (median) 284 2.98 298 3.98 1.00 25% - Rhinitis medication score FAS b (adjusted mean) 284 2.22 298 2.83 0.60[0.08;1.13] 21% 0.024 FAS b (median) 284 2.83 298 4.00 1.17 29% - Total combined rhinoconjunctivitis score FAS b (adjusted mean) 241 7.91 257 9.12 1.21[0.13;2.28] 13% 0.029 FAS b (median) 241 8.38 257 10.05 1.67 17% - Rhinoconjunctivitis Quality of Life Questionnaire score (RQLQ(S)) FAS b (adjusted mean) 229 1.38 240 1.58 0.19 e [0.02;0.37] 12% 0.031 FAS b (median) 229 1.25 240 1.46 0.21 14% - MERIT study results 12 SQ-HDM Placebo Treatment effect Post-hoc endpoints N Proportion N Proportion Odds ratio f [95% CI] p-value Probability of a rhinitis exacerbation day FAS (estimate) b 284 5.33% 298 11.14% 0.45 [0.28;0.72] 0.001 Probability of a rhinitis exacerbation day despite pharmacotherapy FAS (estimate) b 284 3.43% 298 6.50% 0.51 [0.32;0.81] 0.005 N: number of subjects in the treatment group with data available for analysis. CI: confidence interval a FAS-MI: full analysis set with multiple imputations. Subjects who discontinued treatment during the trial before efficacy assessment were allocated to the placebo group in the analysis. For the primary analysis (FAS-MI), only the absolute difference was pre-specified. b FAS: full analysis set. All available data used to the maximum extent, i.e. subjects who provided data during the efficacy assessment period. c Absolute difference: placebo minus 12 SQ-HDM, 95% confidence interval. d Relative difference versus placebo: placebo minus 12 SQ-HDM divided by placebo. e The difference between 12 SQ-HDM and placebo was primarily driven by differences in three domains: sleep problems, problems with everyday activities, and nasal symptoms. f Odds ratio for rhinitis exacerbation: 12 SQ-HDM versus placebo. Supporting evidence – allergic rhinitis In a randomised, double-blind, placebo-controlled phase II study, 124 adults with house dust mite-induced allergic rhinitis were exposed to allergen in an allergen challenge chamber. Prior to each allergen exposure in the chamber, subjects underwent a wash-out period of all allergic pharmacotherapy. After the last allergen exposure in the study at 24 weeks of treatment with 12 SQ-HDM, 6 SQ-HDM, or placebo, the mean rhinitis symptom score was 7.45 [6.57; 8.33] in the placebo group and 3.83 [2.94; 4.72] in the 12 SQ-HDM group, corresponding to an absolute difference of 3.62 and a relative difference of 49% (95% confidence interval [35%; 60%], p < 0.001). The difference between 12 SQ-HDM and placebo was also statistically significant at week 16 (mean scores 4.82 and 6.90, difference of 2.08 corresponding to 30%, 95% CI [17%; 42%], p < 0.001) and at week 8 (mean scores 5.34 and 6.71, difference of 1.37 corresponding to 20%, 95% CI [7%; 33%], p = 0.007). Allergic asthma: MITRA study (MT-04) The MITRA study enrolled 834 adults with house dust mite-induced allergic asthma that was not well controlled on daily inhaled corticosteroids (ICS) at a dose equivalent to 400–1200 µg budesonide. Before ICS dose reduction, all subjects received 12 SQ-HDM, 6 SQ-HDM, or placebo in addition to their existing ICS and short-acting beta-agonist therapy for a period of 7–12 months. No titration phase to establish the lowest maintenance ICS dose was conducted prior to randomisation. Efficacy was assessed by time to first moderate-to-severe asthma exacerbation during ICS reduction over the last 6 months of the 13–18-month treatment period. The definition of a moderate asthma exacerbation was met if the subject experienced one or more of the following 4 criteria, resulting in a change in therapy: Nocturnal awakening or symptom deterioration: nocturnal awakening requiring short-acting β2 agonists (SABA) for two consecutive nights or increase in daily symptom score by ≥ 0.75 from baseline for two consecutive days. Increased SABA use: increase in baseline SABA doses for two consecutive days (minimum increase: 4 puffs/day). Decline in lung function: ≥ 20% decrease in PEF from baseline for at least two consecutive mornings/evenings or ≥ 20% decrease in FEV1 from baseline. Physician visit: emergency/study centre visit for asthma treatment not requiring systemic corticosteroids. A severe asthma exacerbation was defined by the occurrence of at least one of the following two situations: Need for systemic corticosteroids for ≥ 3 days Emergency visit requiring systemic corticosteroids or hospitalisation for ≥ 12 hours. MITRA study Illustration of primary efficacy data: Time course of risk of moderate or severe asthma exacerbation during ICS reduction/withdrawal. In the graph, time = 0 on the time axis represents the time at which ICS was reduced by 50%. After approximately 3 months, i.e. at time = 90 days, ICS was completely withdrawn in subjects who had not experienced an exacerbation. MITRA study results 12 SQ-HDM Placebo Efficacy 12 SQ-HDM versus placebo p-value N n (%) N n (%) Hazard ratio [95% CI] Risk reduction a Primary endpoint Any exacerbation, moderate or severe (FAS-MI) b 282 59 (21%) 277 83 (30%) 0.69[0.50;0.96] 31% 0.027 Any exacerbation, moderate or severe (FAS) c 248 59 (24%) 257 83 (32%) 0.66[0.47;0.93] 34% 0.017 Pre-defined component analyses of primary endpoints Nocturnal awakening or symptom deterioration c 248 39 (16%) 257 57 (22%) 0.64[0.42;0.96] 36% 0.031 Increased SABA use c 248 18 (7%) 257 32 (12%) 0.52[0.29;0.94] 48% 0.029 Decline in lung function c 248 30 (12%) 257 45 (18%) 0.58[0.36;0.93] 42% 0.022 Severe exacerbation c 248 10 (4%) 257 18 (7%) 0.49[0.23;1.08] 51% 0.076 N: number of subjects in the treatment group with data available for analysis. n (%): number and percentage of subjects in the treatment group who met the criteria CI: confidence interval a estimated by the hazard ratio b FAS-MI: full analysis set with multiple imputations. Subjects who discontinued treatment during the trial before efficacy assessment were allocated to the placebo group in the analysis. c FAS: full analysis set. All available data used to the maximum extent, i.e. subjects who provided data during the efficacy assessment period. Post-hoc analyses of asthma symptoms and symptomatic treatment used during the last 4 weeks of therapy before ICS dose reduction were also performed to investigate the effect of ACARIZAX as add-on therapy to inhaled corticosteroids. The analyses focused on daytime and night-time asthma symptom scores, nocturnal awakenings, and SABA use. Post-hoc analyses showed numerical differences consistently in favour of 12 SQ-HDM over placebo for all parameters studied during the last 4 weeks of treatment before ICS reduction. Differences were statistically significant only for daytime asthma symptom score (p=0.0450) and probability of no nocturnal awakenings (p=0.0409). Supporting evidence – allergic asthma In a double-blind, randomised, placebo-controlled phase II study, 604 subjects aged ≥ 14 years with house dust mite-induced allergic asthma controlled with inhaled corticosteroids (100–800 µg budesonide) and with a clinical history of house dust mite-induced allergic rhinitis were randomised to approximately one year of treatment with 1, 3, or 6 SQ-HDM or placebo. In week 4 of the last evaluation phase of the study, the mean difference from baseline in daily ICS dose was 207.6 µg budesonide in the 6 SQ-HDM group and 126.3 µg in the placebo group, corresponding to an absolute difference of 81 µg budesonide daily (95% confidence interval [27; 136], p = 0.004). The relative mean and median reduction in ICS use from baseline was 42% and 50% for 6 SQ-HDM and 15% and 25% for placebo. In a post-hoc analysis of a subgroup of subjects (N = 108) with lower asthma control and ICS use ≥ 400 µg budesonide, the mean difference from baseline in daily ICS dose was 384.4 µg budesonide in the 6 SQ-HDM group and 57.8 µg in the placebo group, corresponding to an absolute difference of 327 µg budesonide daily between 6 SQ-HDM and placebo (95% CI [182; 471], p < 0.0001, post-hoc analysis). Paediatric population Clinical efficacy in children The efficacy of ACARIZAX 12 SQ-HDM treatment in house dust mite-induced allergic respiratory disease in children was evaluated in two double-blind, randomised, placebo-controlled trials. The primary objective was to evaluate efficacy in allergic rhinitis in trial MT-12 and to evaluate efficacy in allergic asthma in trial MT-11. Allergic rhinitis: Children aged 5–11 years MATIC trial (MT-12) The efficacy of ACARIZAX 12 SQ-HDM treatment in house dust mite-induced allergic rhinitis in children aged 5–11 years was evaluated in a double-blind, randomised, placebo-controlled trial (MATIC trial (MT-12)). The MATIC trial (MT-12) included 1,458 children (aged 5–11 years) with moderate-to-severe house dust mite-induced allergic rhinitis/rhinoconjunctivitis (baseline mean total combined rhinitis score (TCRS) 18.3). Approximately 40% of the trial population reported concomitant asthma at baseline. Subjects were randomised to receive 12 SQ-HDM or placebo daily for approximately one year and had access to standard rhinitis and conjunctivitis pharmacotherapy. The primary endpoint was the average daily total combined rhinitis score (TCRS) assessed during the last 8 weeks of treatment. The daily TCRS was the sum of the daily rhinitis symptom score (DSS) and the rhinitis daily medication score (DMS). For the rhinitis symptom score, 4 nasal symptoms (runny nose, blocked nose, sneezing, nasal itching) were assessed daily on a scale of 0–3 (none, mild, moderate, severe symptoms), i.e. the scale range was 0–12. The rhinitis medication score was the sum of nasal corticosteroids administered (max. 8 points daily) and oral antihistamines (max. 4 points daily), i.e. range: 0–12. Thus the TCRS scale range was: 0–24. After one year of treatment with 12 SQ-HDM, an absolute difference in adjusted means of 0.97 (95% confidence interval [0.50;1.44]) and a relative difference of 22% (p<0.0001) compared to placebo was observed. The treatment effect may vary between individual patients depending on their allergic disease status. Onset of clinical effect was observed after 8 weeks of treatment (p=0.01). MATIC trial: Total combined rhinitis score over time TCRS: total combined rhinitis score (symptoms + medication score). TCRS measured as the average over 2-week assessment periods starting at week 8 and week 16. The primary endpoint was the average daily TCRS during approximately the last 8 weeks of treatment (week ~44–52). Adjusted mean values of TCRS over time with error bars for the difference in adjusted means. Non-overlapping intervals indicate a statistically significant difference between groups. MATIC study results 12 SQ-HDM Placebo Treatment effect Primary endpoint n Score n Score Absolute difference b Relative difference c p-value Total combined rhinitis score FAS a (adjusted mean) 693 3.44 706 4.41 0.97[0.50; 1.44] 22.0% <0.0001 Sensitivity estimate 1 e 727 f 3.45 731 f 4.42 0.97[0.49; 1.44] 21.9% <0.0001 Pre-defined key secondary endpoints n Score n Score Absolute difference b Relative difference c p-value Rhinitis symptom score FAS (adjusted mean) 693 1.50 706 1.92 0.43[0.23; 0.62] 22.2% <0.0001 Rhinitis medication score FAS (adjusted mean) 693 1.44 706 1.94 0.49[0.18; 0.80] 25.3% 0.0016 Total combined rhinoconjunctivitis score FAS (adjusted mean) 693 4.01 706 5.16 1.15[0.58; 1.71] 22.2 <0.0001 Pre-defined secondary endpoints n Score n Score Absolute difference b Relative difference c p-value Paediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ) FAS (adjusted mean) 695 0.84 690 1.01 0.17[0.08; 0.25] 16.6% <0.0001 Pre-defined secondary endpoints n Proportion n Proportion Odds ratio d [95% CI] p-value Rhinitis exacerbation days FAS (estimate) 693 0.025 706 0.044 0.56 [0.42; 0.74] <0.0001 Mild rhinitis days FAS (estimate) 693 0.318 706 0.209 1.77 [1.27; 2.47] 0.0008 Pre-defined exploratory endpoints n Proportion n Proportion Odds ratio d [95% CI] p-value Rhinitis symptom-free days FAS (estimate) 693 0.200 706 0.116 1.90 [1.37; 2.66] 0.0002 n: number of subjects with observations contributing to the analysis. CI: confidence interval a FAS: full analysis set. All available data used to the maximum extent, i.e. subjects who provided data during the efficacy assessment period. b Absolute difference: placebo minus 12 SQ-HDM, 95% confidence interval. c Relative difference versus placebo: placebo minus 12 SQ-HDM divided by placebo. d Odds ratio for rhinitis exacerbation, mild rhinitis days, and rhinitis symptom-free days: 12 SQ-HDM versus placebo. Rhinitis exacerbation days (days with rhinitis DSS of 6 or 5 with one individual symptom score of 3 (symptom that is difficult to bear; causes impairment of activities of daily living and/or sleep)). e Clinical effect sensitivity estimate: For subjects who discontinued treatment due to lack of efficacy or treatment-related adverse events, missing endpoints were imputed from the placebo group. For discontinuations due to other reasons, missing endpoints were imputed from their own treatment group. f For sensitivity estimate 1, n includes subjects with imputed observations. Subgroup analysis of the primary endpoint (TCRS) by baseline asthma status showed an absolute difference in adjusted means of 1.26 (95% confidence interval [0.46; 2.06]) in children with concomitant asthma and 0.77 (95% confidence interval [0.19; 1.36]) in children without concomitant asthma. A pooled analysis of TCRS across 5 phase III trials in patients with house dust mite-induced allergic rhinitis treated with 12 SQ-HDM or placebo showed an absolute difference in adjusted means of 1.27 (95% confidence interval [0.82; 1.72]) in patients with concomitant asthma (n = 1,450) and 0.81 (95% confidence interval [0.49; 1.13]) in patients without concomitant asthma (n = 2,595). In favour of placebo difference with 95% CI p-value Absolute Absolute treatment difference (95% CI) In favour of 12 SQ-HDM Baseline asthma status Without asthma With asthma MATIC trial: Forest plot of treatment difference in average daily TCRS in subgroups by baseline asthma status – observed case (FAS) CI = confidence interval, FAS = full analysis set, n = number of subjects with observations contributing to the analysis, TCRS = total combined rhinitis score Pre-specified analyses of asthma-related endpoints assessed daily asthma symptom score, SABA use, SABA-free days, and nocturnal awakenings requiring SABA use. Results showed numerical differences consistently in favour of 12 SQ-HDM over placebo for all 4 parameters. Differences were statistically significant for daily asthma symptom score (p=0.0259) and nocturnal awakenings requiring SABA use (p=0.0279). Children aged 5–17 years MAPIT trial (MT-11) The primary objective was to demonstrate the efficacy of ACARIZAX 12 SQ-HDM versus placebo in children and adolescents (5–17 years) with house dust mite-induced allergic asthma based on clinically relevant asthma exacerbations after at least 4 months of treatment. ACARIZAX 12 SQ-HDM was administered as add-on therapy to background asthma treatment (low-dose ICS and long-acting β2-agonists [LABA] or medium/high-dose ICS with or without LABA). The trial population also had a clinical history of house dust mite-induced allergic rhinitis of any severity (total combined rhinitis score (TCRS) >0 at baseline; baseline mean TCRS 9.0). Study MT-11 was not designed to assess the clinical effect on allergic rhinitis. Results for the rhinitis endpoints TCRS, rhinitis DSS, and rhinitis DMS are presented in the table below. MAPIT study results 12 SQ-HDM Placebo Treatment effect Pre-defined additional secondary endpoints a n Score n Score Absolute difference b Relative difference c p-value d Total combined rhinitis score 0.30 FAS e (adjusted mean) 253 2.16 259 2.46 [-0.22; 12.1% 0.2597 0.81] Rhinitis symptom score 0.12 FAS (adjusted mean) 253 0.55 259 0.67 [-0.04; 18.2% 0.1349 0.28] Rhinitis medication score 0.12 FAS (adjusted mean) 253 1.27 259 1.40 [-0.24; 8.8% 0.5071 0.48] FAS: full analysis set. n: number of subjects with observations contributing to the analysis. a Rhinitis endpoints b Absolute difference: placebo minus 12 SQ-HDM, 95% confidence interval. c Relative difference versus placebo: placebo minus 12 SQ-HDM divided by placebo. d p-values were not adjusted for multiplicity. Therefore, the analyses should be considered exploratory. e All available data used to the maximum extent, i.e. subjects who provided data during the efficacy assessment period. Adolescents aged 12–17 years The efficacy of ACARIZAX 12 SQ-HDM treatment in house dust mite-induced allergic rhinitis in adolescents was evaluated in two double-blind, randomised, placebo-controlled studies (P001 and TO-203-3-2). In these studies, adolescents formed part of the study population. Study P001 included 189 adolescents (out of a total of 1,482 subjects) with moderate-to-severe house dust mite-induced allergic rhinitis/rhinoconjunctivitis, with or without asthma. Subjects were randomised to receive 12 SQ-HDM or placebo daily for approximately one year, and all had free access to standard rhinitis pharmacotherapy. The primary endpoint was the average daily total combined rhinitis score (TCRS) assessed during the last 8 weeks of treatment. After one year of treatment with 12 SQ-HDM, the adolescent subgroup showed an absolute difference in medians of 1.0 (95% confidence interval [0.1; 2.0]) and a relative difference of 22% (p=0.024) compared to placebo. Study TO-203-3-2 included 278 adolescents (out of a total of 851 randomised subjects) with moderate-to-severe persistent house dust mite-induced allergic rhinitis. Subjects were randomised to receive 12 SQ-HDM, 6 SQ-HDM, or placebo daily for approximately one year, and all had free access to standard rhinitis pharmacotherapy. The primary endpoint was the average daily total combined rhinitis score (TCRS) assessed during the last 8 weeks of treatment. At the end of the study, after one year of treatment with 12 SQ-HDM, the adolescent subgroup showed an absolute difference in medians of 1.0 (95% confidence interval [0.1; 1.9], p = 0.037) and a relative difference of 20% compared to placebo. Adolescent subgroups 12 SQ-HDM Placebo Treatment effect Primary endpoint: TCRS N Score N Score Absolute difference Relative difference d p-value P001 FAS (adjusted mean) 76 3.6 84 4.8 1.2 a [0.1; 2.3] 25% < 0.05 FAS (median) 76 3.3 84 4.3 1.0 b [0.1; 2.0] 22% 0.024 TO-203-3-2 FAS (adjusted mean) 99 4.1 92 5.1 1.0 c [0.1; 1.9] 20% 0.037 FAS (median) 99 4.2 92 5.2 1.0 19% - TCRS: total combined rhinitis score a: ANCOVA b: Hodges-Lehmann estimate with 95% confidence intervals (primary analysis in study P001) c: Linear mixed-effects model (primary analysis in study TO-203-3-2) d: Relative difference versus placebo: placebo minus 12 SQ-HDM divided by placebo Allergic asthma: Children aged 5–17 years The MAPIT trial (MT-11) included 533 children and adolescents (5–17 years) with house dust mite-induced allergic asthma. Subjects had a history of recent asthma exacerbations while on preventive anti-asthma medication (low-dose ICS and LABA or medium/high-dose ICS with or without LABA). Subjects were randomised to approximately 24–30 months of daily treatment with 12 SQ-HDM or placebo as add-on therapy to preventive anti-asthma medication. The primary endpoint was the annualised rate of clinically relevant asthma exacerbations calculated as the number of exacerbations per year per subject during the efficacy assessment period. The adjusted rate ratio (12 SQ-HDM divided by placebo) was in favour of 12 SQ-HDM, but there was no statistically significant difference in treatment effect between treatment groups (rate ratio = 0.89, 95% CI [0.60; 1.31], p=0.54). Among subjects included in the MAPIT trial (MT-11), the asthma exacerbation rate during the trial was generally low in both treatment groups and decreased by approximately 67% during the COVID-19 pandemic compared to the pre-COVID-19 pandemic level, which may have contributed to the inability to detect a statistically significant difference (for information on use in children, see section 4.2). The European Medicines Agency has waived the obligation to submit the results of studies with ACARIZAX in children aged below 5 years with house dust mite-induced respiratory allergy (treatment of allergic rhinitis, treatment of asthma). Elderly population ACARIZAX is not intended for patients over 65 years of age (see section 4.2). There are limited safety and tolerability data in patients over 65 years of age. Long-term treatment International treatment guidelines recommend a 3-year course of treatment for allergen immunotherapy to achieve disease modification. Efficacy data are available for 18 months of treatment with ACARIZAX from the MITRA study. Long-term efficacy has not been established.