Research & Development
About the development project
In the development of Dexa ODF the advantages of the often used and well-documented substance dexamethasone and the fast-dissolving film have been combined in a product that is tailored for rapid access and relief in acute situations.
The drug candidate Dexa ODF is regulatory bioequivalent with conventional dexamethasone tablets according to the study AcuCort001 which was carried out in 2013 according to GCP standards at Lund University Hospital, Sweden. The report concluded that Dexa ODF is bioequivalent with the Fortecontin® tablet. Bioequivalence is a term in pharmacokinetics (the study of drug circulation in the body) used to describe equal medical effect of two drugs. Bioequivalence must be demonstrated in controlled and statistically correct studies.
Furthermore, T(max) for the drug candidate Dexa ODF was 23 percent shorter (p=0.0575) than for the Fortecortin tablet, i.e. Dexa ODF reaches its maximum concentration in plasma faster than the tablet. No serious side effects were reported.
The planned studies for regulatory approval in the EU (AcuCort002) and the US (AcuCort003) are repetitions of the AcuCort001 study with product produced at commercial scale. The study populations are planned to consist of 30 healthy volunteers in each study. The test products will be Dexa ODF 8 mg in AcuCort002 and Dexa ODF 6 mg in AcoCort003.
With the aim of rapidly reaching the market AcuCort’s strategy is to base the registration of the product on the comprehensive documentation that is already available for dexamethasone tablets. This means that Dexa ODF would have the same indications, dosages, warnings, etc. as an “ordinary” dexamethasone tablet. In the EU, this process is called a hybrid application. The scope of indications for dexamethasone is wide and covers the potential clinical situations for Dexa ODF well.
In order to gain approval of a hybrid application in EU, AcuCort must demonstrate that Dexa ODF is safe and bioequivalent with a reference product containing the same dose of dexamethasone. AcuCort has identified Fortecortin® 4 mg tablet as a suitable reference product for comparison with Dexa ODF.
The process for EU approval will follow the so-called decentralized procedure with Sweden acting as Reference Member State (RMS) and other interesting markets in the EU being so-called Concerned Member States (CMS). The implementation of approval in all CMS-countries is estimated to take 6-9 months from the date of application and is expected to occur in 2019.
In the US, the corresponding hybrid application is called FDA 505(b)(2). The same principles as in the EU apply, i.e. Dexa ODF shall be evaluated in terms of bioequivalence and safety against a Reference Listed Drug (RLD). Such an RLD has been identified, and as this is not the same product as in Europe a further study, AcuCort003, is planned to be carried out in order to gain US registration.
The estimated time for the US Food and Drug Administration (FDA) approval is 12 months after the date of application and is expected to occur in 2020.
Every year millions of patients the world over use medicines containing glucocorticoids, for example against allergy and croup. But also cancer patients suffering from nausea and vomiting in connection with chemotherapy (CINV) use this type of drug. One big disadvantage is that these drugs are not perceived to be user-friendly, or require medical staff. Vials or blisters with tablets may not be convenient to bring along in all situations. Some glucocorticoids require the intake of several tablets to achieve sufficient dosing. First having to dissolve the tablets in water can be very awkward in an acute situation, for the sufferers as well as for other persons helping them. The sufferer may have difficulties swallowing, and thus a fast-dissolving film to be place on the tongue, with the same effect as the tablet, might be very useful.
Dexamethasone was introduced in the 1950’s and is well established around the world today. Dexamethasone is a synthetic glucocorticoid that is used in a wide range of medical conditions. Today dexamethasone is available as tablets, suspensions, topical creams and ointments, intravenous infusions and as subcutaneous injections. The list of approved indications for dexamethasone is comprehensive, but AcuCort is primarily interested in the anti-inflammatory and immunosuppressive effects.
There are several other glucocorticoids. What distinguishes dexamethasone is its “potency” compared to other glucocorticoids, which means that a smaller dose of the drug is sufficient to reach a certain effect. This has been decisive for the choice, as AcuCort wants to have a full emergency dose per film, so that the patient doesn’t have to use more than one film on each occasion.
Fast-dissolving films have been available in the market for a long time and several pharmaceuticals are available in this administration form, covering a wide range of clinical areas, e.g. pain relief, smoking cessation and fresher breath. A fast-dissolving film has general advantages compared to tablets and solutions, such as rapid uptake of the active substance in the blood, no need for water, etc. The specific advantages of each product relate to the choice of active substance and the disease/condition to be treated.
Events in the project
Within the framework of the PULS project DuoCort, the opportunity to develop a product with fast uptake of the glucocorticoid via the oral cavity is discovered. Market analysis shows that there is an unmet need for such a product in the allergy market.
A patent application is filed.2006AcuCort AB is founded as a subsidiary of DuoCort AB.
The film manufacturer LTS Lohmann is contracted to assist in the development of the product.
The development work continues but with lower priority than DuoCort’s successful core project.2011A new beginning for the project and the company as PULS acquires it from DuoCort AB. AcuCort is provided with approx. MSEK 9 through a new share issue to enable a focused development work and clinical studies.
A meeting with the Swedish Medical Products Agency confirms AcuCort’s proposed development plan with the aim of achieving a European registration. An animal study of local tolerance is carried out with favorable results. Another MSEK 8.5 is raised through a new share issue.
The results from the clinical study AcuCort001 become available and demonstrate bioequivalence with the European reference product Fortecortin® 4 mg tablet. The study furthermore shows that AcuCort Dexa ODF is absorbed 23 percent faster than Fortecortin. A new meeting is held with the Swedish Medical Products Agency to discuss the results and future plans. The Medical Products Agency confirms that only a repetition of a previous clinical study with a larger production batch is needed to apply for EU registration. Croup is identified as a further potential indication. Another MSEK 2.5 is gained through a new share issue.
Market research is carried out for the applications acute allergy and CINV. PharmaVentures (UK) is commissioned to perform business development work. The film manufacturer tesaLabtec replaces LTS as development and manufacturing partner. The first pilot scale batches are successfully produced for 4 mg and 8 mg strengths. Another MSEK 7.3 is raised through a new share issue.
A rights issue in AcuCort amounting MSEK 1. A new patent application protecting the specific and unique formulation of Dexa ODF. Decision to continue product development based on exit discussions with potential partners. New Chairman of the Board strengthens the Board.
A new CEO is appointed to drive the new strategy. A new business plan is developed based on AcuCort commercializing the product in addition to the opportunity to sell the company. Stability studies demonstrate at least 36 months’ shelf life for Dexa ODF. New on-going discussions with companies regarding licensing and exit. Market research in the US indicate high interest in Dexa ODF among physicians and the possibility of a profitable pricing strategy. Another MSEK 6 is raised through a rights issue. Decision made on an IPO and listing on the Swedish AktieTorget during 2017.
The Board is strengthened by the addition of Anna Eriksrud and Sarah Fredriksson (CEO of P.U.L.S. AB). The IPO raised MSEK 14 after financing costs. AcuCort was listed on Swedish stock exchange AktieTorget in April. A contract is signed with French contract manufacturer AdhexPharma (previously by the name Laboratoires Plasto Santé/PlastoPharma) in May regarding development and future product supply of AcuCort’s product Dexa ODF.
The board is strengthened with Ebba Fåhraeus (chairman) and Daniel S. Olsson and Alexandra Johnsson, who better reflect the current needs of skills and experiences that AcuCort require regarding commercialization and stakeholder management. The collaboration with Adhex Pharma results in the production being scaled up from lab scale to commercial size, and that the manufacturing according to Good Manufacturing Practice (GMP) can be initiated. A collaboration agreement is signed with the Czech CRO (Contract Research Organization) Quinta-Analytica to carry out the crucial bioequivalence studies for the application for approval of Dexa ODF in the EU and the US. AcuCort is granted patent approval in the US for ”Acute Glucocorticoid Therapy” which describes medical self-treatment with glucocorticoids in acute situations without access to medical personnel. In addition, the US Patent Office granted AcuCort an extended term of 1,349 days, which means that the patent does not expire until December 30, 2028.