J Allergy Clin Immunol. 2012 May;129(5):1282-1289.

A novel intranasal therapy of azelastine with fluticasone for the treatment of allergic rhinitis.

Carr W, Bernstein J, Lieberman P, Meltzer E, Bachert C, Price D, Munzel U, Bousquet J.

Allergy and Asthma Associates of Southern California, Mission Viejo, CA 92691, USA. wcarr@allergee.com

 

Abstract

BACKGROUND: Moderate-to-severe allergic rhinitis (AR) is a challenge to treat, with many patients using multiple therapies and achieving limited symptom control. More effective therapies must be developed and tested in well-controlled, randomized, prospective studies with a direct comparison to current standards.

OBJECTIVES: The aim of these studies was to investigate the efficacy of MP29-02 (a novel formulation of azelastine and fluticasone propionate [FP]) in patients with moderate-to-severe seasonal allergic rhinitis (SAR) and to compare its efficacy with 2 first-line therapies (ie, intranasal azelastine and intranasal FP) in this population.

METHODS: Three thousand three hundred ninety-eight patients (≥12 years old) with moderate-to-severe SAR were enrolled into 3 multicenter, randomized, double-blind, placebo- and active-controlled, parallel-group trials (MP4002 [NCT00651118], MP4004 [NCT00740792], and MP4006 [NCT00883168]). Each trial was conducted for 14 days during different allergy seasons. The primary efficacy variable was the sum of the morning and evening change from baseline in reflective total nasal symptom score (range, 0-24) over the treatment period. Outcomes for the meta-analysis included efficacy according to disease severity and time to response in relevant responder criteria.

RESULTS: In the meta-analysis MP29-02 reduced the mean reflective total nasal symptom score from baseline (-5.7 [SD, 5.3]) more than FP (-5.1 [SD, 4.9], P < .001), azelastine (-4.4 [SD, 4.8], P < .001), or placebo (-3.0 [SD, 4.2], P < .001). This benefit was observed from the first day of assessment, with improvement in each individual nasal symptom, even in the patients with the most severe disease. MP29-02 achieved response consistently days earlier and showed greater efficacy in patients with moderate-to-severe rhinitis than FP and azelastine.

CONCLUSIONS: MP29-02 represents a novel therapy that demonstrated superiority to 2 first-line therapies for AR. Patients with moderate-to-severe SAR achieved better control, and their symptoms were controlled earlier with MP29-02 than with recommended medications according to guidelines.

Copyright © 2012 American Academy of Allergy, Asthma & Immunology.

PMID: 22418065

 

SUPPLEMENT

Why did we do the study?

The misconception that allergic rhinitis (AR) is simply a nuisance condition is decades old. That sugar-coated perception is one that is contested by those that suffer from AR [1], especially those with uncontrolled disease. The real face of AR is a debilitating and an intrusive one; debilitating in terms of its chronicity and intrusive in terms of its symptom burden and impact on patients’ lives and the lives of their families [1]. However, unlike other chronic diseases such as asthma and diabetes, AR receives significantly less attention. As a result it is trivialised by misconceptions about its severity as well as being under-diagnosed, under-estimated and ultimately under-treated. Today, many moderate/severe AR patients, who comprise the majority of AR patients who visit doctors, still have poorly controlled symptoms [2-4]. This can be due to many factors, but primarily stems from the complexities of its pathology. No single therapy provides complete relief of patients’ symptomatic burden. This leaves patients dissatisfied with their treatment [5]. They will often use multiple therapies in different combinations and permutations in an attempt to achieve better symptom control [2, 6-8]; few achieve it [3,4]. The majority of studies show this to be an ineffective approach [9,10], with patients remaining symptomatic despite use of multiple treatments [3,4].

AR patients need a new medication that can adequately control their symptoms. More specifically, they want two things from their treatment: greater efficacy and a faster substantial response [11]. They are continually looking for something new, ‘something that works’ [12]. There has been no substantial improvement in symptom burden or patient quality of life [13, 14] even though several new AR treatments have come to market in recent years. It is time for AR to be recognised as a disease of significant morbidity, and for patients to be given what they want, a more effective treatment for AR that ticks all of the boxes; effectively relieving all of the symptoms of AR (including ocular ones), in a timely manner and in an uncomplicated way.

The aim of the studies contained within this article was to assess the efficacy of MP29-02 (Dymista®, Meda, Solna, Sweden) versus an intranasal corticosteroid (INS, fluticasone propionate (FP)) and an intranasal anti-histamine (azelastine (AZE)) in patients with moderate/severe seasonal AR (SAR) in a head-to-head manner [15]. Whilst there is no shortage of active versus placebo comparisons in the AR literature, there is a paucity of comparisons with active therapies in a head-to-head fashion. MP29-02’s clinical development programmed aimed to rectify that situation and provide clinically-relevant information to patients and physicians alike, filling an important unmet medical need in AR.

 

An introduction to MP29-02

In Europe, MP29-02 is currently indicated for the symptomatic relief of moderate-to-severe SAR or perennial allergic rhinitis (PAR) in patients 12 years or older where monotherapy with either INS or intranasal anti-histamine is not considered sufficient [16]. In the U.S. it is indicated for SAR only in patients 12 years and older who require treatment with both AZE and FP for symptomatic relief. It is a novel intranasal formulation of AZE and FP in an advanced delivery system, benefiting from the incorporation of a potent intranasal antihistamine and a modern INS in a single spray, constituted in a patented formulation and delivered in an advanced delivery system (vs marketed nasal steroid sprays). MP29-02 is a new class of AR medication. Its formulation and device contribute to its overall effect and are integral components to this new generation AR product.

Methods

This article presents the results of 3 large SAR studies, carried out during different allergy seasons, with results given both individually for each study (in line with good publication practice) and pooled as a meta-analysis [15]. This makes sense as all of the studies used the same active comparators, had the same study design, practically identical patient inclusion/exclusion criteria and assessed efficacy in the same way. In total, 3398 patients were randomized into these double-blind, placebo-controlled trials to 14-days treatment with MP29-02, AZE, FP or placebo, all administered as 1 spray/nostril b.i.d. The daily doses of AZE and FP were 548µg and 200µg, respectively.

It should be noted that AZE and FP used in these studies are NOT commercially available. Rather, they were made up in MP29-02’s formulation and delivered using the MP29-02 device. This was done at the request of the FDA in order to reveal the true pharmacological difference between MP29-02 and two currently considered firstline therapies, and to negate the well-known influence of formulation and/or device on the efficacy of topically-applied medications.

In addition to the standard and regulatory-driven AR efficacy parameters of reflective total nasal symptom score (rTNSS, comprising nasal congestion, itching, rhinorrhea and sneezing), the reflective total ocular symptom score (rTOSS, comprising ocular itching, redness and watering) and individual symptom scores, a panel of key opinion leaders proposed several novel efficacy criteria which were born by asking clinically-relevant questions. For example, physicians often ask the question, ‘will this treatment provide cover even for my most severe patients?’ and patients frequently ask, ‘how much better will I feel on this treatment compared to what I’ve been on in the past, and how soon will I feel better?’. By measuring the efficacy of MP29-02 by patient severity and responder analyses (and head-to-head versus currently considered firstline therapies) it was possible to answer those questions.

Results

In each of the studies, patients treated with MP29-02 experienced significantly better overall nasal symptom relief than those treated with FP or AZE; a consistent superiority across different seasons (Figure 1)[15]. The meta-analysis showed that over the entire 14-day treatment period MP29-02 reduced patients’ overall nasal symptom score from baseline (-5.7±5.3), significantly more than FP
(-5.1±4.9, p<.001), AZE (-4.4±4.8, p<.001), or placebo (-3.0 [SD, 4.2], p<.001) (Figure 1). This superiority was not driven by one particular symptom over another; a reduction in each of the 4 main nasal symptoms of congestion, itching, rhinorrhea and sneezing contributed to MP29-02’s superiority over FP and AZE [15].

There have been varied and inconsistent reports of INS efficacy in relieving ocular symptoms. MP29-02 showed a considerable advantage over FP here, reducing patients’ overall ocular symptom burden from baseline by -3.2 points [SD, 4.0]), significantly more than either FP (-2.8 [SD, 3.6]; p≤0.022), or placebo (-1.8 [SD, 3.4]; p≤0.001) and numerically more than azelastine (-2.9 [SD, 3.8]).

But what about patients with the most severe disease? These patients are the most challenging to treat but have the greatest potential to benefit from a new treatment for AR. In our article patients were categorized into more and less severe groups based on their baseline rTNSS or overall rhinitis quality of life questionnaire (RQLQ) score. Those with median baseline rTNSS ≤18.9 or RQLQ ≤3.9 were defined as less severe. Conversely those with values of >18.9 and >3.9, respectively, were defined as more severe. As seen in Figure 2, MP29-02 provided superior relief for all patients vs AZE, FP and placebo, but those with more severe symptoms achieved even greater relief with MP29-02 than those receiving monotherapy [15].

Time to response analyse were used to answer the questions, ‘will I feel a real effect, and how long do I have to wait to feel better?’. Response was defined as a 50% reduction in rTNSS (substantial response) or a rating of at most ‘mild’ for each and every nasal symptom (complete/near-to-complete symptom control). More MP29-02-treated patients achieved both responses, and did so many days faster than FP, AZE or PLA (Figure 3). 1 in 2 MP29-02-patients achieved a substantial response, up to 3 and 5 days earlier than FP or AZE, respectively. Similarly, more MP29-02-patients achieved the stricter uniform response of complete/near-to-complete symptom control, up to 5 days faster than FP and 7 days faster than AZE (Figure 3) [15]. This time advantage, measured in days is clinically relevant since a typical moderate/severe SAR symptom episode lasts just about 12.5 days [6].

MP29-02 was well- tolerated in our studies. The number of treatment-related adverse events was comparable among active groups in all the studies. Dysgeusia was most commonly reported in the MP29-02 (2.1-4.7%) and AZE groups (3.4-7.2%) and headache in the FP group (1.3-2.4%). All were transitory and the vast majority were mild in nature [15].

The importance of the study

To the best of our knowledge, this study comprises the largest and most complete body of evidence directly examining the efficacy of different classes of AR treatment head-to-head. In almost 3,400 patients studied, MP29-02 elicited a faster and more efficacious response than long-established firstline therapies in moderate/severe AR. Consistency of results was achieved across various allergy seasons and for all symptoms, including nasal congestion and ocular symptoms, which are considered the most troublesome of all. This is the first time that the efficacy of an INS has been exceeded, and without any safety repercussion while also providing sound clinical evidence that intranasal anti-histamines and INS have complementary effects on the pathogenesis of AR. The importance of this article was also recognized by the Editors of the J Allergy Clin Immunol who called MP29-02 a major advancement in the treatment of AR [17]. MP29-02 has an even greater treatment difference versus commercially available FP and AZE, as in that case the impact of formulation and device was seen [18]. In fact, in that study MP29-02 was twice as effective as either commercially-available FP or AZE in providing overall nasal and ocular symptom relief, provided substantial and complete symptom relief in more patients and many days faster [18] than shown here [15].

What both patients and clinicians can take from the studies presented in our article [15] is that those previously treated with INS can expect greater symptom relief to what they’ve experienced and will achieve substantial and clinically-relevant symptom control days faster. When assessed together, these results clearly demonstrate that MP29-02 can be considered the firstline, drug of choice for AR treatment because, as patient’s requested, ‘it works’.

 

fig_01_effect_of_mp29_02Figure 1: Effect of MP29-02, Fluticasone propionate (FLU) and azelastine (AZE) on overall rTNSS in patients with moderate/severe SAR. Data are presented change from baseline minus placebo. The precision of these estimates are indicated by the upper bounds of the respective 95% CIs. MP4002: *p=0.034 vs FP, †0.001 vs AZE; Study MP4004: * p=0.038 vs FP, † p=0.032 vs AZE; Study MP4006: * p=0.029 vs FP, †p=0.016 vs AZE; Meta-analysis: * p<0.001 vs FP, † p<0.001 vs AZE. Reprinted with permission from J Allergy Clin Immunol [15].

 

fig_02_effect_of_mp29_02_rtnssFigure 2: Effect of MP29-02, fluticasone propionate (FP), azelastine (AZE) and placebo (PLA) on rTNSS by severity in patients with SAR. Patients were classified as having more or less severe disease based on median baseline rTNSS or baseline RQLQ scores. Data are presented as mean change from baseline for the meta-analysis dataset. The precision of these estimates are indicated by the lower bounds of the 95% CIs. * p≤0.001 vs all active treatments, † p<0.040 vs MP29-02, ‡p≤0.010 vs MP29-02. Reprinted with permission from J Allergy Clin Immunol [15].

 

fig_03_time_response_curveFigure 3: Time response curves showing the percentage of patients exhibiting 50% improvement in rTNSS (A) or a score of ≤1 pt or less (i.e. complete or near-complete resolution) for each nasal symptom (B) by treatment day after treatment with MP29-02, fluticasone propionate (FLU), azelastine (AZE) or placebo (PLA). Data are presented as mean proportion of patients for the meta-analysis dataset. (A) MP29-02 vs FLU: p=0.071; MP29-02 vs AZE: p<0.001; MP29-02 vs PLA: p<0.001. (B): MP29-02 vs FLU p=0.033; MP29-02 vs AZE: p<0.001; MP29-02 vs PLA: p<0.001.  Reprinted with permission from J Allergy Clin Immunol [15].

 

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