Research & Development
About the development project
In the development of ISICORT®, previously named Dexa ODF (Oral Dissolvable Film), the advantages of the often used and well-documented substance dexamethasone and the patient benefit with the fast-dissolving oral film have been combined for rapid access and relief in acute situations.
The drug (approved in Sweden) ISICORT® is regulatory bioequivalent with a reference product containing conventional dexamethasone tablets according to the study AcuCort001 which was carried out in 2013 according to GCP standards at Lund University Hospital, Sweden, and the study AcuCort002 which was carried out in Prague, Czech Republic. Both reports concluded that ISICORT® 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 ISICORT® was indicatively just over 20 percent shorter than for the Fortecontin® tablet in both studies, i.e. ISICORT® reached its maximum concentration in plasma faster than the tablet. No serious side effects were reported.
AcuCort has conducted three studies for regulatory approval: in the EU (AcuCort002) and in the US (AcuCort003 and AcuCort004). The studies are basically repetitions of the first study, AcuCort001, but with product produced at commercial scale. The study populations consist of 30 healthy volunteers in each study. The test products were ISICORT® 8 mg in AcuCort002 and ISICORT® 6 mg in AcuCort003 and AcuCort004. The US studies differ from the EU studies with a lower strength and another reference product, Hikma Pharmaceuticals Dexamethasone USP 6 mg tablet. AcuCort003 was conducted with fasting participants and AcuCort004 with non-fasting participants.
With the aim of rapidly reaching the market AcuCort’s strategy is to base the registration of the drug candidate on the comprehensive documentation that is already available for dexamethasone tablets. This means that ISICORT® would have indications, dosages, warnings, similar as the reference product Fortecortin®. In the EU, this process is called a hybrid application. The scope of indications for dexamethasone is wide, in our opinion, and covers the potential clinical situations for ISICORT® well.
In order to gain approval of a hybrid application in EU, AcuCort must demonstrate that ISICORT® 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 ISICORT®.
The process for EU approval is planned in a two-step path. The company sent in a national application regarding market approval of ISICORT® in Sweden to the Swedish Medical Products Agency (MPA) in September of 2019. On October 7, 2020, AcuCort received the market approval from the Swedish Medical Products Agency for the drug ISICORT®. The aim is that, as soon as possible after the Swedish approval, extend the application to several EU countries via the so-called reciprocal procedure, Mutual Recognition Process (MRP).
To conduct studies with the purpose of applying for market approval in the United States, companies are recommended to apply for a so-called Pre-IND meeting with the U.S. Food and Drug Administration (FDA). In the fall of 2018, AcuCort received positive feedback on questions regarding the choice of regulatory strategy, study design, choice of reference product etc.
In the US, the corresponding relevant application is called FDA 505(b)(2). The same principles as in the EU apply, i.e. ISICORT® shall be evaluated in terms of bioequivalence and safety against a Reference Listed Drug (RLD). Such an RLD has been used in the studies AcuCort003 and AcuCort004.
Registration of ISICORT® in the United States requires two bioequivalence studies, one with fasting participants and one with non-fasting participants. The first bioequivalence study with fasting participants has shown positive results. The results of the second study (with non-fasting participants) achieved bioequivalence with the reference product at two points out of three. An expert group reviewed the outcome of the study, its possible causes and assessed the potential impact on a registration application in the United States. The conclusion of the work, which has been verified by two independent external regulatory bodies, shows that the outcome does not constitute an obstacle to submitting an application for market approval in the United States.
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 oral film, so that the patient doesn’t have to use more than one oral film on each occasion.
Fast-dissolving oral film
Fast-dissolving oral 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 oral 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 general benefits are described in a study published in 2017 in the scientific journal Drug Delivery, Vol 224:1, 1243-1248, and show a strong preference among patients as well as custodians for fast-dissolving oral films compared to a liquid solution. The specific advantages of each drug relate to the choice of active substance and the disease or 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.
AcuCort 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.
New start for the project and for AcuCort due to P.U.L.S. AB’s purchase of the project from DuoCort AB. AcuCort is financed with approximately MSEK 9 through issues enabling focus on driving development 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 indicates that AcuCort Dexa ODF is absorbed just over 20 percent faster than Fortecortin. A new meeting is held with the Swedish Medical Products Agency (MPS) to discuss the results and future plans. The MPA 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 chemotherapy-induced nausea and vomiting, 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 principal owner of AcuCort 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 (elected 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 market 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. A rights issue with an oversubscription option is implemented and brings in just under MSEK 11 after financing costs.
Positive results are reported from the bioequivalence studies AcuCort002 and AcuCort003, which means that Dexa ODF is assessed as bioequivalent with the selected reference product in each study. The result from AcuCort002 means that the crucial study to compile an application for market approval in the EU has been positive. AcuCort, in collaboration with Sofus Regulatory Affairs AB, now initiates ProPharma Group Sweden to compile an application for market approval in the EU. AcuCort receives registration of the ISICORT® trademark from the European Intellectual Property Office (EUIPO), which means that Dexa ODF changes its name to ISICORT®. The application for market approval of ISICORT® is submitted to the Swedish Medical Product Agency (MPA), after approval, to extend the application to several EU countries. The first of two bioequivalence studies for market approval in the United States reports positive results. The second study, on non-fasting participants, does not achieve bioequivalence and an expert group is appointed. AcuCort carried out a new share issue with preferential rights for the shareholders, which was subscribed to 101.7 percent, and the company received approximately MSEK 41.2 before issue costs.
Interim CEO takes up the position as of January 1. AcuCort’s the expert group announces its positive view, concluding that the outcome of the second bioequivalence study for the US is not considered an obstacle for a market application for US registration of ISICORT®. The company receives the Primary Round Assessment Report from the Swedish Medical Products Agency (MPA), in response to the national Market Authorization Application (MAA) for ISICORT® in September of 2019. AcuCort completes the reply dossier in response to the Primary Round Assessment Report from the Swedish MPA regarding the national MAA for ISICORT® and submits it as planned on May 8th. In August, Jonas Jönmark takes up the position as CEO and the company submits the reply dossier in response to the Second Round Assessment Report according to the schedule. On October 7, 2020, AcuCort receives the market approval from the Swedish Medical Products Agency for ISICORT®.