Short ragweed pollen allergen extract(ALK-Abello A/S)

U.S. FDA Approves ALK's RAGWITEK® (Short Ragweed Pollen Allergen Extract) Tablet for Sublingual Use as Immunotherapy for Children and Adolescents With Short Ragweed Pollen-Induced Allergic Rhinitis With or Without Conjunctivitis About ALK ALK is a global allergy solutions company, with a wide range of allergy treatments, products and services that meet the unique needs of allergy sufferers, their families and doctors. Headquartered in Hørsholm, Denmark, the company employs around 2,500 people worldwide and is listed on Nasdaq Copenhagen. To learn more about ALK and allergies, visit . For further information, please contact: ALK: Investor Relations: Per Plotnikof, tel. +45 4574 7527, mobile +45 2261 2525 Media: Stuart Loesch, tel. +1 908 842 8363, mobile +1 267 753 5838 View original content to download multimedia: SOURCE ALK, INC.

*Achoo* Muddling through a stuffy, runny nose and itchy, watery eyes? You aren’t alone - over 17.6 million American adults (about 7.5%) experience allergic rhinitis (also called hay fever or seasonal allergies). Many different substances (called allergens) can trigger allergic rhinitis, such as tree or grass pollen, and each person has their own set of problematic allergens. *Achoo* Muddling through a stuffy, runny nose and itchy, watery eyes? You aren’t alone - over 17.6 million American adults (about 7.5%) experience allergic rhinitis (also called hay fever or seasonal allergies). Many different substances (called allergens) can trigger allergic rhinitis, such as tree or grass pollen, and each person has their own set of problematic allergens. The constant annoying symptoms of seasonal allergies can really be a nuisance to sufferers. Fortunately, there are lots of over-the-counter allergy options in your local pharmacy: decongestants reduce your stuffiness temporarily but shouldn’t be used long-term (Sudafed, Claritin-D, Afrin), antihistamines block histamine, a symptom-causing chemical released after you’re exposed to an antigen (Benadryl, Claritin, Zyrtec), nasal steroids suppress allergy-induced inflammation in the nose (Flonase, Nasacort, Nasonex), and saline nasal rinses clear out mucus and allergens. Unfortunately, those drugs all provide temporary relief by addressing the symptoms and immune system overreaction but don’t address the underlying issue: allergen oversensitivity. Allergen-specific immunotherapy (ASIT) , such as allergy shots, can treat the underlying sensitivity and provide relief long-term. In fact, allergy shots reduce allergy symptoms in about 85% of people with allergic rhinitis. Despite its proven success as a treatment, ASIT is underused. This is due to various unmet needs , such as high out-of-pocket costs due to a lack of insurance coverage and the long-term, often inconvenient nature of the therapy. In this report, we will discuss what ASIT is, FDA-approved drugs, what drugs are in the pipeline, and the outlook of the ASIT field. Although we will focus on the U.S., we will also compare the U.S. to the other major markets (Europe and Japan). Grass and Tree Pollen Allergy The World Health Organization (WHO) estimates that 10-30% of people globally have allergic rhinitis. Grass and tree pollen are among the most common allergy triggers . Top grass pollen allergens in North America include ryegrass, Bermuda grass, Timothy grass, and Kentucky bluegrass. Trees in the birch, cedar, and oak families produce particularly allergenic pollen . For example, Japanese cedar pollen is the most common culprit for seasonal allergic rhinitis in Japan, affecting over one-quarter (26.5%) of Japan’s population. The number of Japanese affected by cedar pollen allergy has been on the rise, prompting Japanese cedar pollen allergy to be considered a “ national affliction .” Each season represents the peak time for various allergens: late winter into early spring is peak tree pollen allergy season followed by late spring into summer being the primary grass pollen allergy season. Allergen-Specific Immunotherapy (ASIT) Allergen-specific immunotherapy is a treatment in which a patient is repeatedly exposed to tiny amounts of an allergen in gradually increasing doses to provoke an immunological response. This ultimately results in increased tolerance to the allergen and reduced allergy symptoms. There are two main types of ASIT: well-known allergy shots and newer allergy tablets/drops. Allergy shots, formally called subcutaneous immunotherapy (SCIT) , inject allergens under the skin of the arm using a needle. According to the American College of Allergy, Asthma, and Immunotherapy (ACAAI) , allergy shots are the “most commonly used and most effective form of allergy immunotherapy” – they have been around for more than 100 years . Injections are given in two phases: the first involving injections a few times each week for about six months with increasing allergen doses, and the second maintenance phase involving injections once or twice a month. Treatment typically lasts 3-5 years but may last longer depending on the type and severity of the allergy. Allergy shots can provide protection from multiple allergens at once and can last a long time after therapy ends; they may even be able to prevent new allergies and asthma from developing! However, the dosing schedule can be burdensome and expensive because you must return to your allergist so often. Side effects such as injection site irritation and allergy symptoms (sneezing, congestion, hives) may occur – this isn’t surprising since you’re exposing yourself to a known allergen. There is also a small risk of a severe allergic reaction called anaphylaxis, so allergy shots are given in an allergist’s office. Allergy tablets or drops, formally called sublingual immunotherapy (SLIT) , involve placing a tablet or liquid containing the allergen under the tongue to dissolve. These have been shown to be just as effective as allergy shots at controlling allergy symptoms and providing long-term protection after treatment stops. However, each tablet only provides protection against one type of allergen. SLIT drops, like allergy shots, can contain multiple allergens, but they are only available off-label in the U.S. Tablets or drops are taken a few times per week (as frequently as daily) for at least three years, if not long-term. Although some people experience long-term relief after three years of treatment, many will have their symptoms return after a few years and will need to go back on treatment. Only SLIT tablets are FDA-approved so far. Mild side effects , such as an itchy mouth or stomach discomfort, may occur, but tablets have a better overall safety pro to shots. This allows the tablets to be given at home (after the first dose is given in a medical setting). However, there is still a small risk for anaphylaxis, so it is recommended that patients are prescribed an at-home epinephrine auto-injector, like an EpiPen, to be used in case of a severe allergic reaction. FDA-Approved ASIT Products for Grass and Tree Pollen Allergies Because allergy shots have been around for so long, there are standardized FDA-approved bulk allergen extracts for nine different types of grasses made by six manufacturers ( ALK-Abello , Inc. , Allergy Laboratories , Allermed Laboratories , Antigen Laboratories , Greer Laboratories , Jubilant HollisterStier ). There are no standardized FDA-approved tree allergen extracts, but non-standardized allergen extracts are licensed for distribution in the U.S. from the same six manufacturers. Allergens are considered standardized when they are compared to a U.S. reference standard for its potency. Rose Joachim , Ph.D., a Senior Healthcare Analyst at GlobalData , told BioSpace, “Only the most prevalent allergens are standardized. Although it would be optimal to have standardized extracts for all allergens, this would neither be feasible nor economical. Non-standardized allergen extracts are still useful in ASIT, but may show some inter-batch variability that allergists need to work around.” SCIT formulation in the U.S. is quite different than it is in Europe. In the US, the injections are formulated directly by allergists in their offices using FDA-approved allergen extracts purchased in bulk. In Europe, pre-formulated SCIT products are purchased from manufacturers and used as-is. Companies like Allergy Therapeutics are beginning to try to introduce these pre-formulated products into the U.S. market. In Japan, unstandardized bulk grass pollen allergens and standardized bulk Japanese Cedar pollen allergens are available, however, SCIT is not very commonly used in that country. “In the U.S., allergists create patient-specific ASIT formulations that can include one to over 15 allergens at concentrations that are matched to the patient’s level of sensitivity,” Joachim explained. “The ability to tailor therapy directly to the needs of a particular patient is a huge benefit. However, the specific efficacy and safety of these combinations have not been studied directly in clinical trials.” There are four FDA-approved SLIT tablets for allergic rhinitis, two of which are for grass pollen: Oralair ( Stallergenes Greer ), which contains extracts from 5 different grass pollens and Grastek [Grazax in Europe] ( Merck /ALK-Abello ), which contains Timothy grass pollen. (The other two approved SLIT tablets are for short ragweed pollen, Ragwitek [Ragwizax in Europe] ( ALK-Abello ) and dust mite allergen, Odactra [Acarizax in Europe, Miticure in Japan] ( Merck/ALK-Abello ).) Cedarcure ( ALK-Abello/ Torii Pharmaceutical ) is the only formally approved SLIT tablet for tree pollen allergy but is only marketed in Japan for the treatment of Japanese cedar pollen allergy. Because SLIT tablets are newer, long-term safety and efficacy are not fully understood yet . No SLIT drops are approved currently in the U.S., but they still may be prescribed by some doctors for off-label use. “Although SLIT has been around a much shorter time than SCIT, it has been experiencing a big uptake in Europe and Japan,” Joachim said. “Patients in these regions like the ease of use as well as the improved safety. While SLIT tablets have been very successful in Japan and Europe, their uptake in the U.S. has been far less than anticipated. This is mainly due to poor insurance coverage as well as a continued focus on the use of multi-allergen SCIT. Interestingly, the heavily ingrained culture of in-house ASIT formulation has even led to an increased usage of off-label SLIT drops that are formulated in a similar manner to SCIT treatments.” Allergic Rhinitis Immunotherapy Pipeline While there are many grass and tree pollen ASIT products in development in various countries, we wanted to focus on some of the major candidates, broken down by allergen. Grass Pollen SCITs Pollinex Quattro Grass ( Allergy Therapeutics ) contains multiple modified grass pollen allergens (called allergoids) that can provoke the same immunological response as the original allergens but cause less of an allergic reaction. It also contains the adjuvant monophosphoryl lipid A (MPL) to enhance the immune response. The benefit of this SCIT product is its very short treatment course – only four injections (or six injections for the newest version). “Although the four-injection formulation of Pollinex Quattro Grass has been available in Europe for about twenty years, the version of the therapy currently undergoing formal clinical development is quite different,” Joachim commented. “The new formulation will consist of six injections delivering a cumulative dose between five and seven times higher than the original product. This new dosing paradigm is the product of recent Phase II dose-finding studies and may result in an even more effective product than that currently being used in Europe.” While Pollinex Quattro Grass is already available in European countries, the company has been working on filing a Biologics License Application (BLA) for FDA approval. The FDA placed holds on the US clinical development for multiple Pollinex Quattro programs in 2007; the hold was lifted for Pollinex Quattro Grass in 2012. Allergy Therapeutics resumed US clinical trials in 2015 , including a Phase 2 dosing trial in 265 adults. In a 2016 presentation , the company expected to submit a BLA in 2020 and launch the product commercially in 2020-21. “If Allergy Therapeutics’ Pollinex Quattro Grass is approved by the FDA and launched in the US, the product would be completely one-of-a-kind,” Joachim elaborated. “Not only would it be the first available off-the-shelf, pre-formulated SCIT product, it would be the first ASIT product to contain modified allergen polymers called allergoids, the first ASIT product to utilize adjuvant to stimulate the immune system and, most importantly, the first ASIT product to require only six injections total to protect a patient from grass pollen allergies within the same year. Limiting patients’ required visits to only six times a year would be a game-changer and would likely increase the number of patients interested in the therapy. However, it is important to note that although Pollinex Quattro Grass would be quite a novel product in the US, there is uncertainty as to how likely US allergists would be to adopt it. Compared to allergen mixtures formulated in-house, Pollinex Quattro Grass only targets a single allergen. Additionally, if priced similarly to marketed SLIT tablet products, it is unclear whether Pollinex Quattro Grass would face similar issues in regards to insurance coverage and consumer costs.” gp-ASIT+ ( ASIT Biotech ) contains only small fragments of ryegrass antigens (rather than both small and large fragments), which allows the immune system to develop a response against the antigens without initiating an allergic reaction. This formulation allows for a very short 3-week treatment schedule with only four treatments involving two injections each. gp-ASIT+ has been tested in five clinical trials with one being a Phase 3 trial in 554 adults, where the drug’s mechanism of action via B- and T-cell modulation was determined. In response to stipulations made by the German regulatory authorities, this year, ASIT biotech launched a second Phase 3 trial in Europe in 650 adults. Topline results, which were expected in December 2019 , were released early . Although the trial did not meet its primary endpoint (absolute reduction of the symptom and medication use score by 0.30, correlating to a 20% treatment effect), the SCIT did significantly reduce the symptom and medication score by 0.15 (p = 0.05, 7.4% treatment effect) during the peak grass pollen allergy season and 0.18 (p = 0.005, 9.8% treatment effect) during the entire allergy season. “ASIT Biotech has published detailed data on gp-ASIT’s specific mechanism of action and it has been looking like a very promising ultra-short course option for patients with grass pollen allergy,” Joachim said. “Unfortunately, it was just recently announced that gp-ASIT failed to meet the primary endpoint in its latest Phase III trial. Although statistically significant, the treatment effect during the peak pollen season and did not reach the expected value of 20%; in fact, it was about 5 percentage points less than that seen in the first Phase III trial. In light of this news, it is unclear what the future for the therapy will be.” BM32 ( Biomay ) is a “peptide carrier fusion vaccine” created using Biomay’s unique technology. It contains four different grass pollen antigens attached to a carrier molecule and an adjuvant (aluminum hydroxide) to stimulate the immune system. BM32 has been tested in four clinical trials with the most recent being a Phase 2b trial in Europe in 130 adults where five pre-season treatments with BM32 over five months (January to May) were determined to give the optimal protection against allergy symptoms during the allergy season (May to July). In a 2017 press release , the company said it was working towards a pivotal Phase 3 trial and it expected the product to be registered by 2021, but there has been no updates since. “Similar to ASIT Biotech’s gp-ASIT, Biomay’s BM-32 uses hypoallergenic allergen peptides,” Joachim explained. “However, while gp-ASIT uses natural, hydrolyzed peptide fragments, BM-32 uses a fusion protein consisting of recombinant peptides targeting key B-cell epitopes for grass pollen. The recombinant peptides are fused to a carrier protein derived from hepatitis B, which helps to enhance immune recognition and response. However, since Biomay’s publication of Phase 2b data for BM-32 in February 2018, there has been no new word on the start of Phase 3 clinical development. Thus, it is unlikely that the product will be registered in Europe by 2021.” Dupilumab ( Regeneron / Sanofi Genzyme ) is a monoclonal antibody against the interleukin 4 (IL-4) receptor that inhibits pro-inflammatory IL-4 and IL-13 signaling, which reduces cytokine-induced inflammation by limiting the release of cytokines, chemokines, nitric oxide, and immunoglobulin E (IgE). Dupilumab (brand name Dupixent ) is currently FDA-approved for atopic dermatitis, asthma, and chronic sinus infections (chronic rhinosinusitis with nasal polyps, CRSwNP). It is also being studied for peanut allergy, chronic obstructive pulmonary disease (COPD), and eosinophilic esophagitis. While Dupilumab itself is not an ASIT, it is being paired with a grass pollen SCIT to study if the antibody can enhance the patient’s response to the SCIT. A Phase 2 trial was recently completed with 103 participants in the US and Canada studying Dupilumab alone and as an adjunct therapy to Timothy Grass SCIT. After 16 weeks of treatment, patients’ allergic rhinitis symptoms were measured after nasal allergen challenge. There has been no word from the company of when a Phase 3 trial is expected. “It will be interesting to see if dupilumab can improve the efficacy and safety of grass pollen SCIT,” Joachim added. “In particular, if dupilumab treatment was able to speed up the up-dosing phase of treatment, allowing patients to reach higher concentrations of allergen more rapidly without negative side effects, this could really help to improve the convenience of the therapy and potentially allow patients to experience relief more quickly.” Tree pollen SLIT tablets Itulazax ( ALK-Abello ) contains a birch ( Betula Verrucosa ) allergen extract that protects against pollen from the “birch homologous family of trees,” including alder, beech, hazel, hornbeam, and oak. A Phase 3 trial in 634 participants ages 12 to 65 showed that the tablet significantly reduced allergy symptoms (via patient-reported symptoms and use of symptom-relieving medication) compared to placebo. Itulazax tablets were recently approved in 17 European countries for adults with birch allergies. ALK-Abello manufactures three of the four FDA-approved SLITs (Grastek/Grazax, Ragwitek/Ragwizax, and Odactra/Acarizax). “Itulazax was approved in Europe in June 2019 and was launched, beginning in Germany, in September 2019,” Joachim said. “Approval of Itulazax in Europe represents the final step in completing ALK-Abello’s ambitious tablet portfolio, which covers the top five allergens worldwide. The therapy showed excellent efficacy in clinical trials and will likely see strong uptake in European markets. Based on GlobalData’s discussions with key opinion leaders, it is doubtful that clinical development of Itulazax will be pursued in the US, considering the mediocre uptake other SLIT tablet products have been receiving.” STAGR120 ( Stallergenes Greer’s/Shionogi’s ), also called S-525606, contains multiple Japanese cedar pollen extracts. It is currently in Phase 2 clinical trials in Japan . The drug significantly reduced patient-reported allergy symptoms in treated participants compared to those who took a placebo. A total of 330 participants ages 12 to 49 received treatment or placebo for four months. “Although Japan already has an approved Japanese Cedar pollen SLIT tablet on the market, with market trends showing steadily increasing demand for ASIT, there will likely be room in the market for a competing tablet product,” Joachim commented. “There is not yet enough clinical data to evaluate whether one product is better than the other. However, differentiating factors to look for include improved efficacy as well as more tolerable side effects such as mouth itching and stomach upset. ” Outlook GlobalData predicts the ASIT market for allergic rhinitis will grow modestly from $901 million in 2018 to $1.14 billion in 2028. This predicted growth is based off the anticipated approval and launch of three grass pollen SCIT products ( Allergy Therapeutics’ Pollinex Quattro Grass, ASIT Biotech’s gp-ASIT+, and Biomay’s BM32) and two tree pollen SLIT products ( ALK-Abello’s Itulazax and Stallergenes Greer’s/ Shionogi ’s STAGR120/S-525606) in various global markets. “Despite a long history of use and it being the only truly disease-modifying therapy for the treatment of allergic rhinitis, ASIT remains underused,” Joachim explained. “Key opinion leaders interviewed by GlobalData suggested that this is in large part due to persisting unmet needs acting as barriers to uptake. Barriers in the US center on inadequate access to therapy as well as low treatment compliance and persistence. In regards to access, with effective and inexpensive over the counter drugs readily available, private and public insurance providers are often less willing to pay for ASIT, making it difficult for patients to afford treatment.” Joachim concluded, “When it comes to compliance and persistence, SCIT and SLIT both have their issues. While the regularly scheduled physician visits are thought to improve compliance and persistence with SCIT, the required high frequency of these injections can be a big hindrance to long-term treatment. Likewise, although patients receiving SLIT can take the therapy at home, without any regular physician check-ins, the patient may forget to take their doses or lose interest in the therapy altogether. Thus, along with potentially increasing the availability of more convenient, short-course SCIT products in the future, key opinion leaders interviewed by GlobalData noted that improving relationships between patients and their doctors could be a helpful move in promoting better usage of SLIT.”