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Next generation allergen immunotherapy based on specifically modified recombinant hypoallergens

Periodic Reporting for period 2 - AllergyVAX (Next generation allergen immunotherapy based on specifically modified recombinant hypoallergens)

Reporting period: 2020-04-01 to 2021-07-31

Allergy is a rapidly increasing, global problem that already affects 1 billion people and causes significant social and economic burden. In Europe, allergic rhinitis and asthma cause more than 100 million missed work and school days per year. Allergy is usually managed by avoiding the allergen or by medication that temporarily alleviates the symptoms. The only disease-modifying treatment available to date is allergen immunotherapy (AIT) where long-term symptom relief is achieved by training the immune system to tolerate allergens. However, typical AIT takes 3-5 years, involves monthly injections or daily drops/tablets and has the risk of serious allergic reactions during treatment. Thus, the popularity of AIT is still relatively low compared to symptomatic drugs.

The current state-of-the-art allergen immunotherapy is performed with products based on allergen extracts and formulated into injectable suspensions or sublingual tablets. We have developed a platform technology for creating modified hypoallergens to be used in AIT. The goal is to develop safe, effective and reproducible AIT that is convenient for the patients, thus improving treatment compliance and cost-efficiency. The recombinant allergens have a native 3D structure to preserve immunogenicity and contain highly targeted modifications to reduce allergic reactions during treatment. Recombinant production enables reproducibility and standardisation important for regulatory compliance. From the clinically important major birch pollen allergen Bet v 1 we have created DM-101 (rBet v 1 dm) hypoallergen. The aim of AllergyVAX project was to test DM-101 for safety and immunogenicity in a First-in-Human clinical study involving birch-pollen allergic volunteers. The project was expected to facilitate seamless transition to Phase II–III clinical development, establishing a basis for product launch with selected partners and advancing other hypoallergens in the pipeline, including product candidates for grass pollen, peanut, dog and horse allergies.

The main goal of the project was to reach a clinical Proof-of-Concept for the DM-101 birch pollen hypoallergen. The clinical results are expected to facilitate partnering that will allow late-phase clinical development and commercialisation of DM-101. The expected socio-economic impact of the new immunotherapy is setting off a change in allergy management – from treating the symptoms to treating the disease – which is possible with an allergen immunotherapy that goes beyond the state-of-the-art of currently approved AIT in standardisation, safety and efficacy.
A large part of the AllergyVAX project consisted of a First-in-Human (FIH) clinical study of DM-101. During the first half of the project, a regulatory package was compiled for the clinical study. It was submitted to a local regulatory authority and independent ethics committee for evaluation. Preparations for the clinical study were completed and an ethics approval as well as regulatory authorisation was gained. The randomised, double-blinded, placebo-controlled, dose escalation study was designed to evaluate the safety and tolerability of subcutaneous immunotherapy with DM-101 in birch pollen allergic adults. Immunological markers such as allergen-specific IgE and IgG were also analysed. For the study, 27 adults with documented birch pollen allergy were enrolled and randomised into four cohorts. The volunteers received either a single dose or five ascending doses of DM-101 or placebo.

The clinical study was launched in early 2020. In March 2020, the study was temporarily halted due to the Covid-19 pandemic and approaching pollen season. The study was resumed in November 2020, and dosing was completed before the 2021 birch pollen season. The results were analysed and the outcome of the study was positive. The highest of the tested dosing regimens, a biweekly dosing regimen of DM-101 involving five ascending doses was safe and well-tolerated and immunological marker results indicated a favourable change in the markers associated with a protective response.

Desentum's business model is based on performing preclinical product development, taking the product candidates through early clinical trials and partnering with a larger pharmaceutical company to perform late-stage clinical trials and commercialisation. Clinical results are important for partnering negotiations, so the temporary halt of the clinical study that has delayed clinical results, has also prevented full deployment of partnering efforts during the project lifespan. However, activities were still conducted to establish relationships for commercial partnering. Nearly 7 M€ of new capital was also raised for further preclinical and clinical development. With the support from the clinical results, these activities can now be continued and ramped up right after the project conclusion.

Project progress has been communicated to public in press releases and online news updates, and content marketing has been performed to build awareness of the company, especially during the clinical study. Newsletters and presentations have been created for existing and potential new investors and partners.

An unexpected result derived from the project was new information regarding the impact of formulation on the potency of allergens. In parallel to the AllergyVAX project, formulation development work (not funded by the H2020 grant) has been conducted to exploit this information and produce an improved formulation of DM-101 for the next clinical study. Potential new formulations are being tested to select the best one.
At the end of the project, the FIH clinical study has been completed with positive results, although some more data will be required for clinical Proof-of-Concept. An unexpected result that derived from the project was new information regarding the impact of formulation on the potency of allergens. This finding has a potential to bring new properties to the product that can move it further beyond the state-of-the-art. The delayed clinical study unfortunately pushed forward other activities that depend on the study results. Therefore, the full impact of the project will be seen later than expected. Nevertheless, better allergen immunotherapy remains a great need and the market opportunity is only growing as no other breakthrough innovations for this purpose have been launched. The AllergyVAX project enabled Desentum to successfully complete the First-in-Human clinical study, which is a key to reaching other milestones in the coming months and years. The goal is to set off a change in the way allergies are managed – from treating the symptoms to treating the disease.
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