The evidence for commercial house dust mite immunotherapy products: A pragmatic systematic review with narrative synthesis

House dust mite (HDM) allergen immunotherapy (AIT) has an established role in the treatment of perennial allergic rhinitis (AR) and allergic asthma (AA) triggered by HDM sensitization. We aimed to identify all double-blind, randomized, placebo-controlled trials of HDM AIT for the treatment of AR and AA in humans and to summarize the evidence for AIT products that are currently manufactured and available for clinical use. A total of 56 eligible double-blind, randomized, placebo-controlled trials of HDM AIT for the treatment of AA and/or AR in humans fit the inclusion criteria and investigated a total of 14 commercial AIT products; together, the 56 studies enrolled a total of 14,619 patients. Of the 56 studies, 39 studies investigated the current manufacturer-recommended maintenance dose (MRMD) of the product, and 17 investigated other doses. We identified 39 studies (12,539 patients randomized) for 8 sublingual immunotherapy (SLIT) products and 17 studies (2,080 patients randomized) for subcutaneous immunotherapy products. For AR, 3 products, the ALK 12 standardized-quality (SQ-HDM) SLIT tablet, the ALK 6 SQ-HDM tablet, and the SG 300 index of reactivity SLIT tablet, had both dose-finding studies (DFSs) and phase III definitive studies (DSs) to demonstrate efficacy of the MRMD of the product. For AA, 2 products, the ALK 12 SQ-HDM SLIT tablet and the ALK 6 SQ-HDM tablet, had both DFSs and DSs for the MRMD. No subcutaneous immunotherapy product had a paired DFS and DS supporting the MRMD. A total of 30 studies of products no longer commercially manufactured were excluded. This study will help to inform clinical care and product selection for the treatment of HDM-induced AR and AA.

Allergic airway diseases are among the most common diseases globally, with allergic rhinitis (AR) and asthma estimated to affect 18% and 12% of adults, respectively. 1,2Approximately half of patients with asthma have allergic asthma (AA). 3Dermatophagoides species, principally Dermatophagoides pteronyssinus (DP) and Dermatophagoides farinae (DF), were identified as the major source of house dust mite (HDM) allergens in 1964 4 and are the major global source of indoor allergens causing perennial AR and AA. 5 The first double-blind, randomized, placebocontrolled trial (DBRPCT) of a commercially prepared HDM allergen immunotherapy (AIT), a subcutaneous immunotherapy (SCIT) product, was published by Smith and Pazzaro in 1972 (see Calderon et al) 6 ; the first DBRPCT of HDM sublingual immunotherapy (SLIT) trial was published by Scadding et al in 1986 (see Larenas-Linnemann et al 7 ); and the DBRPCT of a HDM allergoid AIT product was published by Passalacqua et al in 1998 (see Larenas-Linnemann et al 7 ).
The AIT products used globally vary; the availability of products varies across countries, with a small number of products registered with each country's medical regulation agency and a greater number available on a named patient product basis only. 8The European Medicines Agency (EMA) released guidelines on the regulation of AIT as a medical product in 2008 9 and guidelines on the clinical development of AIT products in 2009. 10Both US and European regulators have advised that newly developed AIT products be evaluated as individual medical products requiring a phase II dose-finding study (DFS) and phase III definitive study (DS) for product registration. 10,11In 2008, the German Paul-Ehrlich-Institut initiated a process known as the Therapeutic Allergen Ordinance to retrospectively evaluate all AIT products for common allergens on the German market, and in doing so, it required a DFS and DS for each product. 12As of 2023, however, no HDM products had completed the therapeutic allergen ordinance process, and several manufacturers had withdrawn from it. 12he clinical performance of dust mite AIT is dependent on several production factors, 10 including method of culturing dust mites, purification and processing of mite bodies and feces into extracts, and posttreatment modification of extracts. 13Consequently, total dust mite protein content and major and minor allergen content vary widely between products. 14The measurement of allergen content is not standardized and varies widely between AIT manufacturers; for this reason and because of their proprietary manufacturing and allergen modification steps, AIT products are not interchangeable, even when their reported major allergen contents are equal. 15Although recent systematic reviews have concluded that HDM SCIT and SLIT are both effective for AR and AA, 16,17 these reviews do not identify which trials refer to currently available commercial AIT products; nor do they summarize the evidence for each AIT product individually.Furthermore, a 2013 review noted that several published DBRPCTs referred to products that were no longer commercially available, and some trials did not state the name of the HDM AIT product investigated or the dose and mite species administered. 6Thus, it is difficult for prescribers of AIT to know of the evidence base for each of the products available for use in the various countries.
To inform clinical care and product selection, our specific aims were to (1) identify all DBRPCTs of HDM AIT for the treatment of AR and AA in humans; (2) determine which studies refer to products that are currently manufactured and available for clinical use; (3) determine the product used in the various trials, the allergen mix, and the maintenance dose (in units) comparable to the current product information statement for each product; and (4) summarize the evidence on a per-product basis, noting specifically whether DFSs and phase III DSs have been performed for the current manufacturer-recommended maintenance dose (MRMD) of the product.For each product, we further aimed to describe whether there were published trials demonstrating shortterm benefits of AIT, long-term benefits of AIT, and sustained symptom relief after cessation of AIT.

METHODS
The systematic review protocol was registered with the International Prospective Register of Systematic Reviews (PROS-PERO) (registration no.CRD42023336291).In May 2022, searches were conducted in Embase, Medline, the European Clinical Trials Database (EudraCT) and the US clinical trials database CliniocalTrials.gov,with searches limited to the previous 22 years (from the year 2000 onward).For a copy of the search strategy, see the Supplementary Information in the Online Repository at www.jaci-global.org.For studies before the year 2000, the reference lists of 3 comprehensive systematic reviews were searched. 6,16,17The risk of bias from noninclusion of studies that have not been published was minimized by searching the European and US clinical trials registries for reports of studies conducted but not published in the searched databases.
The titles and abstracts of the retrieved studies were screened by 1 reviewer to identify studies that potentially met the inclusion criteria, and the same reviewer retrieved and assessed the full text of potentially eligible studies.Studies were included if they were DBRPCTs of HDM AIT for the treatment of AR or AS in humans, had at least 1 eligible treatment arm (see later), included clinical outcomes such as patient scoring systems (eg, combined symptom and/or medication scores) and/or objective measures such as challenge chamber tests, were of at least 12 weeks' duration from initiation of AIT to clinical outcome assessment, had been published as full-length articles in academic journals, had results published to either the US or European clinical trials registries or had been prospectively registered in either the US or European clinical trials registry, and had results that could be obtained from the manufacturer when requested.
Treatment arms were considered eligible if the intervention in the arm was a commercially manufactured HDM AIT product and if the product and extract mix used in the arm was currently commercially available in at least 1 country worldwide.The treatment arms of products developed but not brought to market, noncommercial products, dust mite extracts mixed with other allergens (eg, mixtures of dust mite and grass pollen), and dust mite allergen mixes no longer commercially available were excluded.
After conducting a full-text review, we submitted queries regarding 61 studies to the manufacturers of the AIT products listed in each study to determine the AIT product name, allergen mix, dose used, and current availability of the product.The information obtained is summarized in Table E1 (available in the Online Repository at www.jaci-global.org).A standardized prepiloted form was used to extract data from the included studies for assessment of study quality and study synthesis.A single reviewer extracted the data.The extracted data items are listed in the Supplementary Materials.Risk of bias was not assessed.
Studies were categorized in 4 ways: (1) according to the disease treated (asthma, AR, or both); (2) depending on whether at least 1 arm included the current MRMD of the AIT product under investigation in that article; (3) as DFSs (phase II), DSs (phase III), or exploratory studies (ESs); and (4) as showing (according to the EMA Guidelines 10 ) either short-term benefit (STB), longterm benefit (LTB), or disease-modifying treatment (DMT).We defined DFSs as those studies that included 2 or more intervention arms of the same product at different doses and had prespecified end points for clinical efficacy.We defined DSs as those studies having prespecified outcomes for treatment efficacy on clinical grounds according to the EMA Guidelines, 10 a prespecified power calculation, and at least 100 patients randomized to the active treatment arm.All other studies were considered ESs.According to our definitions, a study could be both a DFS and a DS.Studies were categorized as examining STB if they were designed to demonstrate an improvement in clinical outcomes during AIT treatment and had a duration of less than 24 months (including open-label follow-up).Studies were categorized as examining LTB if they were designed to demonstrate clinical outcomes during AIT treatment and had a duration of 24 months or longer.Studies were categorized as examining DMT if they assessed clinical outcomes following at least 12 months after cessation of AIT.According to our definitions, all studies were categorized as examining either STB or LTB but not both and could be additionally categorized as examining DMT.Long-term follow-up publications were identified during the search process and were incorporated into these analyses.After categorizing all of the studies in these 4 ways, we identified products for which DFSs and/or DSs at the MRMD had been identified.In the case of products for which a paired DFS and DS set had been performed to establish efficacy of the products' MRMDs, we performed descriptive narrative synthesis to summarize the totality of evidence for those products.Because of study heterogeneity and the small number of studies identified for most AIT products, meta-analysis was not possible.We further noted studies categorized as either DFSs or DSs that included long-term outcomes (ie, as examining either LTB or DMT).
During data extraction, it became evident that multiple products do not have a generic name.Because our study aimed to summarize the data for each product, it was important that we be able to identify the product investigated in each study.We therefore created a short name for each AIT product based on its current manufacturer's name; see column 1 of Table I.This was considered preferable to using either the brand name or units of measurement for each product, because both can change over time and vary between countries.

RESULTS
We identified 105 DBRPCTs of HDM AIT for the treatment of AA and/or AR in humans.From among these, we excluded 49 studies: 30 studies of products that are no longer commercially manufactured, 8 studies of noncommercialized extracts or products that were never brought to market, 3 studies that did not report clinical outcomes (eg, laboratory results only), and 8 that were excluded for other reasons.The search strategy is shown in Fig 1 .Notable studies excluded, including the reason for their exclusion, are in listed Table E2 (available in the Online Repository at www.jaci-global.org).
The remaining 56 studies investigated a total of 14 commercial AIT products that are currently available in at least 1 market worldwide; together, these 56 studies randomized a total of 14,619 patients.For SLIT, there were 39 studies that examined 8 products and randomized a total of 12,539 patients.For SCIT, there were 17 studies that examined 6 products and randomized a total of 2080 patients.The products identified and the characteristics thereof are summarized in Table I.Characteristics were obtained from the published studies and the manufacturer's product information for each product.The studies identified for each product, their categorization according to our criteria (DFS, DS, or ES), and the total number of patients investigated for each AIT product are shown in Table II.
Of the 56 studies, 39 included an arm with an AIT dose matching the MRMD of a currently commercially available AIT product, 16 did not include an arm with the current MRMD of any commercially available products, and 1 study examined the US Food and Drug Administration (FDA)-standardized extracts, for which no MRMD is specified. 18

Studies with DFSs and DFs
There were 2 products, namely, the ALK 12 SQ-HDM and ALK 6 SQ-HDM SLIT tablets and the SG 300 IR SLIT tablet, that Studies that enrolled patients with both AR and AA and reported clinical outcomes for both conditions are listed twice.*Formulations of other mite species or mixes of mite species are marketed, but no randomized controlled trials were found for these formulations.
Although companies other than Stallergenes-Greer also manufacture bulk FDA-standardized extracts, the only studies we identified used extract manufactured by Stallergenes-Greer.
had a paired DFS and DS set, hence demonstrating the efficacy of the current MRMD of the AIT product.
The ALK 12 SQ-HDM SLIT tablet and 6 SQ-HDM SLIT tablet For the ALK 12 SQ-HDM SLIT tablet (marketed as Acarizax in Europe and Australia but as Odactra in the United States) and the ALK 6 SQ-HDM SLIT tablet (marketed as Miticure in Japan), we identified a total of 9 studies (in which a total of 6298 patients were randomized).Of these studies (examining a total of 4002 randomized patients), 5 were for the treatment of AR, [19][20][21][22][23] 2 (with a total of 1660 patients randomized) examined AA, 24,25 and 2 (with a total of 636 patients randomized) examined both AA and asthma. 26,27Studies conducted in Japan 20,23,25 describe the dose in Japanese allergy units, with 10,000 Japanese allergy units equating to a dose of 6 SQ-HDM tablets.All of the identified studies included 1 or more MRMD arms (ie, a 6 SQ-HDM arm, 20,27 12 SQ-HDM arm, 22,26 or both 19,21,[23][24][25]. With regard to trials examining AR (including the trials investigating both AR and AA), we identified a total of 7 studies: 1 DFS, 21 2 DSs, 20,22 3 studies that met our criteria for both DFSs and DSs, 19,23,27 and 1 ES. 26][22][23]28 For AA, we identified 4 studies: 2 DSs investigating both the 12 SQ-HDM and 6 SQ-HDM doses, 24,25 1 DFS that included a 6 SQ-HDM dose arm but not a 12 SQ-HDM dose arm, 27 and 1 ES that included a 12 SQ-HDM arm but not a 6 SQ-HDM arm. 26Three studies prespecified their primary outcome; in 2 studies the primary outcome was positive, 24,27 and in 1 study it was negative. 25e SG 300 IR SLIT tablet (Actair and Orylmyte) For the SG 300 index of reactivity (IR) SLIT tablet (marketed as Orylmyte in Germany and Actair elsewhere), we identified 5 studies of the MRMD (300 IR daily dose) in AR. [29][30][31][32][33] The 5 studies of the 300 IR daily dose randomized a total of 3877 patients, of whom 1599 were treated with the 300 IR daily dose.We identified 1 DFS, 32 2 DSs, 31,33 and 2 studies that met our criteria for both a DFS and a DS. 29,30All 5 studies prespecified their primary outcome; in 4 studies the primary outcome was positive, [29][30][31]33 and in 1 study it was negative. 32 n AA, we identified 1 ES of the MRMD, 34 which was reported as negative according to its primary outcome, as well as 2 studies that investigated doses other than the MRMD.35,36 Other products For the remaining products, we found a mixture of DFSs, DSs, and ESs; we did not find a paired DFS and DS set demonstrating the efficacy of the current MRMD of any of these products. Nobly, we identified only 1 study of the FDA-standardized allergen extracts, 18 a small ES that randomized a total of 31   19 Nolte et al, 2015 (DFS) 21 Okubo et al, 2017 (DFS, DS) 23 Studies of 12 SQ-HDM but not 6 SQ-HDM dose Nolte et al, 2016 (DS) 22 Bozek et al, 2022 26 33 Okamoto et al, 2017 (DFS, DS) 30 Okamoto et al, 2019 (DS) 31 Roux et al, 2016 (DFS) 32 Studies of other doses:  65 Guez et al, 2000 66 Mortemousque et al, 2003 67 O'Hehir et al, 2009 68 Potter et al, 2015 69  Studies of MRMD: Chen et al, 2017 74 Luo et al, 2014 75 Wang et al, 2016 76      patients. Acoss these products, 10 studies prespecified their primary outcome, [37][38][39][40][41][42][43][44][45][46] and of these 10 studies, 4 were positive according to their prespecified primary outcome.40,41,43,45 The studies identified are summarized in Tables II to VI and E3.

DISCUSSION
AIT product selection must be individualized to each patient and must consider multiple factors, including evidence, compliance, cost, and convenience. 47We have performed the first systematic review of DBRPCTs of HDM AIT for the treatment of AA and AR that excludes studies of non-commercially available products and groups studies by the AIT product used and the AIT dose use (MRMD vs other).As such, to our knowledge, ours is the first article that allows allergists in a particular country to compare the evidence for the products that are available to them.
The results of our study are notable for several reasons.First, of the 105 DBRPCTs identified, 30 were trials of products that are no longer commercially available and 8 were trials of products that had never been commercially marketed.These studies, therefore, cannot be used to guide AIT product selection and should be regarded as of historic interest only.The oldest study meeting our inclusion criteria, a study of an allergoid SLIT product, was published in 1998. 48The oldest SCIT studies that met our inclusion criteria were published in 2005. 38,49Thus, all of the doubleblind, randomized placebo-controlled studies of HDM SLIT published before 1998 and all of the SCIT studies published before 2005 are of products that are no longer commercially available or were never commercialized and are thus of limited relevance to an allergist working in clinical practice today.
Second, we have shown that only 3 products, the ALK 12 SQ-HDM SLIT tablet, the ALK 6 SQ-HDM tablet, and the SG 300 IR SLIT tablet, have a matched DFS and DS pair demonstrating the efficacy of the MRMD of the AIT product for AR, and 2 products (ie, the ALK 12 SQ-HDM SLIT tablet and the ALK 6 SQ-HDM tablet) have a matched DFS and DS pair for the MRMD dose in AA.
Third, our work demonstrates the relatively small evidence base for SCIT versus for SLIT.The total number of patients enrolled in all of the SLIT trials (N 5 12,418 patients) was 6 times the total number enrolled in the SCIT trials (N 5 2,080).Furthermore, no SCIT product has a DFS and DS pair supporting the MRMD of the product.
Fourth, our work allows comparison of the size of the evidence base for individual products.Notably, the number of patients enrolled in studies of the 6 SQ-HDM SLIT and 12 SQ-HDM SLIT tablets (N 5 6298) is 3 times the total number of patients randomized in all studies of other currently commercially available SCIT products combined (N 5 2080).A single study of the SG 300 IR SLIT tablet in AR enrolled 1607 patients, 33 which is nearly as many as the total number of patients enrolled in all studies of commercially available SCIT products for the treatment of AR (N 5 1621 patients).
Fifth, our analysis of the dose used in each study highlights several products for which the current MRMD is not the dose for which the best evidence is available.For the Allergopharma allergoid SCIT (Acaroid), the only DS identified used an AIT dose that is 3 times greater than the current MRMD (18,000 therapeutic units vs 6,000 therapeutic units). 50Similarly, for the HAL Allergy allergoid SCIT (Purethal Mites), the only DS identified used 2.5 times the current MRMD (25,000 allergenic units [AU]/mL vs 10,000 AU/mL). 51Notably, although the outcomes for both trials have been published to the European Clinical Trials Registry, neither trial has been published in peer-reviewed scientific literature, and the MRMD has not been updated to match the dose used in the DS for either product.For the Lofarma SLIT tablet (Lais Mites), a DFS using more than 5 times the MRMD (3000 AU 7 days per week vs the MRMD of 2000 AU twice weekly according to the Lais product information document) did not show a statistically significant benefit versus placebo. 52hus, although 2 small ESs of the Lofarma SLIT tablet have been published, 48,53 the studies taken together do not support the clinical efficacy of the Lofarma SLIT tablet at any dose.Finally, our study highlights the paucity of evidence for the FDA-standardized allergen extracts, for which we identified only a single ES that randomized 31 patients and showed no improvement in AR symptom or medication scores.Notably, only 2 of the products included in this review are available in the United States: the FDA-standardized allergen extracts and the 12 SQ HDM tablet, which are marketed in the United States as Odactra.
This study included only products for which at least 1 DBRPCT was found.Thus, products for which no such studies were found were excluded from this review.These products may have evidence published in single-arm or open-label studies.However, because of the significant placebo effect of AIT and the product-specific variability of HDM AIT manufacturing, 13,14,54 we argue that these products be regarded as experimental and hence, that their use be constrained to randomized clinical trials in which such trials are available.
Our study has several limitations.First, we excluded retrospective, single-arm, and open-label studies.The placebo effect accounts for up to 77% of the benefit in AIT trials, 54 and both US and European regulators require that new medicinal products be subjected to DBRPCS, thus justifying our decision to include only such studies.Second, our definitions of DFS and DS were arbitrary and were based on the number of treatment arms, trial size, and trial outcomes only, without reference to other trial characteristics required by US and EU regulators.Our study categorization was designed to give a general indication of the size and purpose of each study and, therefore, the overall quality of evidence for each product.An allergist considering using any of these products should review the individual studies for each product.Third, because of the heterogeneity of study outcomes and incomplete data reporting, we were unable to perform metaanalysis.Fourth, we were able to access only study results published in the scientific literature or to the European and US Clinical Trials Registries.There are many studies registered on the European Trials Registry for which no results are available.For products that have undergone assessment by medical regulators, freedom of information requests could be used to obtain results of studies not publicly available 55 ; however, for products available only on a named patient product basis, requests would need to be submitted to individual companies.Fifth, we did not review safety outcomes.

CONCLUSION
We found 3 AIT products, all SLIT products, for which DFS and DS pairs had been performed to demonstrate the efficacy of the MRMD of the product in AR: the ALK 12 SQ-HDM SLIT tablet, the ALK 6 SQ-HDM tablet, and the SG 300 IR SLIT tablet.
Additionally, the ALK 12 SQ-HDM SLIT tablet and ALK 6 SQ-HDM tablet have DFS and DS pairs examining their use in AA.For other products, including all subcutaneous products, the small studies identified generally had significant methodologic problems, and there was insufficient high-quality evidence to satisfy US and European medical regulators.Although the absence of such evidence does not prove that the products are ineffective, better evidence must be gathered, given the high prevalence of dust mite allergy.

DISCLOSURE STATEMENT
Medical writing assistance was funded by Seqirus (Australia) Pty Ltd (CSL Seqirus), the Australian distributors of ALK 6/12 SQ-HDM SLIT tablets.CSL Seqirus had no role in the systematic review, analysis, or data interpretation.
Disclosure of potential conflict of interest: C. H. Katelaris has received honoraria for presentations and fees for advisory board participation from Seqirus, as well as fees for advisory board participation from Stallegenes.T. West has received honoraria for presentations for Seqirus.

TABLE I .
Currently commercially available AIT products for which randomized, double-blind, placebo-controlled trials were identified for the treatment for AR and/or asthma in humans using HDM extracts

Table III (
SLIT for the treatment of AR), TableIV(SLIT for the treatment of AA), Table V (SCIT for the treatment of AR), and Table VI (SCIT for the treatment of AA).

TABLE II .
Summary of studies identified for currently commercially available HDM immunotherapy products for the treatment of AR and/or AA in humans

TABLE II .
(Continued) DF, Dermatophagoides farinae; DP, Dermatophagoides pteronyssinus; PI, product information.*Accordingto our criteria, studies not annotated as DSs or DFSs were ESs.Study recruited patients with both AA and AR.

TABLE III .
DBRPCTs of MRMDs of current commercially available SLIT products for HDM-induced AR

TABLE IV .
DBRPCTs of MRMDs of current commercially available SLIT products for HDM-induced AA

TABLE V .
DBRPCTs of MRMDs of current commercially available SCIT products for HDM-induced AR

TABLE VI .
DBRPCTs of MRMDs of commercially available SCIT products for HDM-induced AA