Immunology

Autoreactive immune disorders

Building upon our powerful Marinosolv® platform and our deep know-how in immunology, we will now focus on autoreactive immune disorders that are characterized by an exaggerated adaptive or innate immune system.

Herpetic stromal keratitis

Description of the disease incl. burden of disease

Herpetic stromal keratitis (HSK) is based on the latent infection with herpes viruses. It is a rare ophthalmological indication affecting the stromal layer of the cornea. It is the most abundant cause for infectious severe visual impairment and blindness.

HSK is thought to occur more commonly in recurrences. Much of the morbidity in stromal disease is thought to result from CD4+ T-cell-mediated destruction in the inflammatory response to the virus, in addition to direct viral effects. The severity of disease may increase with each subsequent episode, and inflammatory changes may be seen long after viral activity is no longer detected. Non-necrotizing stromal keratitis presents with localized corneal edema, whereas necrotizing stromal keratitis has a rapid progression with stromal infiltrates and widespread inflammation. Both can lead to corneal neovascularization and scarring, with blindness as an ultimate result.

Incidence / prevalence

Herpetic stromal keratitis is regarded as a rare disease. According to available epidemiological data, the pooled incidence of any keratitis induced by herpes virus infection is 24.0 cases per 100,000 person-years. Among those cases, the incidence for HSK lies at 4.9 per 100,000 person-years, pooling new and recurrent cases. Applying this incidence to the global population of 2020, this results in an estimate of 430,000 cases of HSK worldwide, about 140,000 of those newly experienced some degree of unilateral vision impairment.

Herpes simplex virus induced ocular disease incidence strongly correlates with rates of HSV-1 infection. Therefore, the available epidemiological figures are expected to be underestimates as they are based on a limited number of studies only performed in USA and Europe where the overall prevalence of HSV-1 infection is lower and better access to treatment is available than in other regions of the world.

Current standard of therapy

A topical corticosteroid treatment with an oral antiviral agent for at least ten weeks is the preferred treatment of herpetic stromal keratitis. The balance between antiviral and corticosteroid therapy should be adjusted depending on the presence of absence of epithelial ulceration.

Unmet medical need

Management of HSK requires intense immunosuppression together with a systemic anti-viral treatment. Generally, long-term corticosteroid treatment of the eye can lead to serious and sight-threatening complications such as glaucoma caused by raised intraocular pressure, cataracts, increased susceptibility to infection and corneal melting. Therefore an alternative immunosuppressant therapy replacing the steroids should result in a strongly improved therapy.

Description of product

Tacrosolv/MAM-1003-1 is an eye drop formulation of Tacrolimus. Tacrolimus, a well-known calcineurin inhibitor, is a highly potent immunosuppressant used in the prevention of organ rejection after allogenic transplantation, in the topical treatment of chronic inflammatory conditions of the skin, and as topical treatment of vernal keratoconjunctivitis. Its potency is approximately 100-fold higher compared to cyclosporin A. It is a highly lipophilic substance with a very low water solubility.

Based on proprietary Marinosolv® technology, Marinomed has developed a novel aqueous formulation, which allows the complete solubilization of the compound using a combination of known excipients. It could be demonstrated that the topical application of Tacrosolv results in higher concentrations of Tacrolimus in eyes compared to the marketed product Talymus that contains Tacrolimus in a suspension, even though the concentration of the drug was reduced up to 95%. Thus, the formulation offers a considerable potential as a replacement or add-on therapy for corticosteroid treatments of inflammatory conditions of the anterior of the eye.

A Phase II clinical trial for dose finding was performed in the model indication of allergic rhinoconjunctivitis. In the higher dose group, topline results demonstrated a significant relief of allergic symptoms in the eyes and also in the nose after eight days of treatment. These data strongly support our hypothesis that a fully solubilized Tacrolimus can be developed as an effective therapy for treatment of anterior inflammatory eye disorders.

Recently, an independent clinical study was conducted with subjects suffering from herpetic stromal keratitis. The patients were treated with a 1:10 dilution of Prograf (containing 5 mg/ml Tacrolimus) on top of a steroid treatment. The data showed a strong benefit in the Tacrolimus group already after one week of treatment including the important parameter visual acuity.

Autoimmune gastritis

Description of the disease incl. burden of disease

Autoimmune gastritis (AIG) is a non-self-limiting, autoimmune disease of the stomach lining with subsequent loss of parietal cells causing an increase of pH resulting in strongly reduced iron uptake and symptoms like dyspepsia, bloating, diarrhea, and pain. Late-stage disease is connected to Vitamin B12 deficiency leading to pernicious anemia and neurological symptoms. In addition, patients have an increased risk to develop gastric tumors.

Incidence / prevalence

The prevalence of AIG is strongly variable depending on the tools used for diagnosis. It is estimated that 2-5% of the general population are affected with a higher proportion of women (3:1). In the population older than 60 years the prevalence increases to more than 9%.

Current standard of therapy

Currently, there is no effective anti-inflammatory treatment available. Standard treatment for AIG patients focusses on the repletion of iron and vitamin B12. Additionally, H. pylori eradication therapy is recommended. Endoscopic surveillance is recommended to monitor potential long-term complications.

Unmet medical need

With no adequate therapy currently available on the market, the diagnosis of autoimmune gastritis means a substantial burden and impairment of the quality of life for these patients.
Based on our patented Marinosolv® technology with an excellent track record in mucosal applications, Marinomed Biotech AG is developing a pioneering medicinal product that will focus on the local treatment of the underlying inflammatory processes. By getting the chronic inflammation under control, for the first time, the ground will be prepared for gastric mucosa to heal.

Allergic rhinitis

Description of the disease incl. burden of disease

Allergic rhinitis (AR), either perennial or seasonal, is one manifestation of a type I hypersensitivity reaction caused by an immune reaction to otherwise innocuous agents such as pollen or house dust mites. In the past decades, a globally rising trend of AR has been observed with widely varying prevalence particularly in the developing countries. Up to 30% of the global population may be affected. While allergic rhinitis refers to an inflammatory process of the nasal passages, symptoms involve the nose and may extend beyond to affect the eyes, ears, sinuses and bronchi. Commonly reported nasal symptoms include nasal itching and congestion, runny nose and sneezing. Often, AR will involve the conjunctivae; such patients may experience itching, tearing and red eyes. About 40% of AR patients also suffer from asthmatic symptoms like cough, wheeze and dyspnea. In fact, AR is considered an independent risk factor for subsequent asthma.
Some studies have shown that treatment for AR can reduce healthcare costs and lead to a better asthma control.

Current standard of therapy

Apart from allergen avoidance and physical measures, current therapy of AR comprises two main treatment options: allergen immunotherapy or pharmaceuticals targeting the consequences of mast cell mediator release. While immunotherapy is the only treatment with a long-term sustained effect that is intended to result in a reduced reactivity to the respective allergen, pharmaceutical interventions either block histamine from binding to its receptor (antihistamines), stabilize mast cells (e.g. cromoglycate), or reduce the release of pro-inflammatory mediators such as TNF-alpha. The latter is achieved with the topical application of corticosteroids such as budesonide, fluticasone propionate or others.

Poor solubility and associated poor bioavailability are central challenges faced in many corticosteroid containing liquid formulations which is particularly problematic for compounds intended for local application on sensitive tissues such as the nasal mucosa. As a result, these local treatments for the respiratory tract are often formulated as suspensions of undissolved particles and have a lag time of several days before becoming efficacious.

Revolutionized therapy and unmet medical need

Budesolv/MAM-1004-1 is a nasal spray containing the corticosteroid budesonide to treat allergic rhinitis and has met all endpoints in a phase 3 clinical trial. With a dose that is more than 85% lower than for comparable marketed products, Budesolv led to a noticeable reduction in allergic nasal symptoms and a prominent reduction in symptoms associated with asthma in less than three hours.

The lower dose combined with increased bioavailability ensures high activity of the drug locally. Furthermore, reduction of the amount of active pharmaceutical ingredient contributes to sustainability as less drug substance pollutes the environment, particularly the wastewater.