The current Standard of Care does not satisfy the medical need. Approximately 15% of all diabetic patients will develop an ulcer in their lifetime. DFU is the most common reason for hospitalization and the most frequent cause of lower-extremity amputations. Every 30 seconds, a lower limb is lost due to diabetes somewhere in the world. While there is no cure for scleroderma, few treatments can ease symptoms and improve quality of life. Curative therapies are limited to intravenous iloprost, a synthetic analogue of prostacyclin PGI2 and oral PDE5 inhibitors, while prevention can be achieved with endothelin receptor antagonists.

A locally applied, locally acting hybrid molecule was designed to activate cGMP-Enzyme Regulation system. Microcirculation to the wound tissue is restored and the insufficient cell-cell communication is repaired by increasing cGMP levels based on the simultaneous stimulation of sGC and inhibition of PDE5 enzyme activities. In scleroderma, rational, pathophysiology-driven treatment should address both the vasospasms and the architectural remodeling of the digital arterioles. In this context, endothelial dysfunction with impaired endothelial NO production is considered a characteristic feature of vasculopathy in scleroderma.

TOP-N53 is designed to increase local microcirculation and to induce the formation of new blood vessels. This should result in increased oxygen and nutrient supply to the wound tissue to enable the healing of chronic wounds. Its unprecedented potency and efficacy has been demonstrated in animal models of wound healing. The drug was well tolerated and no side effects have been observed. TOP-N53 entered clinical trial phase 1 in Q3 2020. The unique profile of potency, efficacy and tolerability results in an enormous breakthrough potential with life-saving opportunities for patients and a huge cost benefit for society.

Corticosteroids are the mainstay in the treatment of keloids and hypertrophic scars. However, treatments are long and the outcomes of limited success. Despite the importance of scar prevention, there is a lack of studies in this field, and no FDA approved therapy is available for burn scar prevention.

Therapies based on TOP-N44 are expected to reduce inflammation and fibroblast activation and consequently to inhibit scar formation.

TOP-N44 is a new hybrid molecule for topical treatment, designed to suppress inflammation and fibroblast activation to prevent scar formation. Preclinical data showed that TOP-N44 inhibits uncontrolled scarring of human skin fibroblasts, therefore, preventing the formation of hypertrophic scars and keloid.

AMD and DR share several key pathophysiologic aspects, including neovascularization, vascular permeability, and inflammation. The neovascularization that develops in the wet AMD with growth of abnormal blood vessels leads to hemorrhaging and leakage of fluid/blood in the retinal tissue, ultimately causing fibrosis and permanent vision loss. Anti-vascular endothelial growth factor (VEGF) intravitreal injections are used to manage advanced forms of AMD. However, some patients never respond to anti-VEGF therapy, while others still stop responding after initial success, highlighting that the pathobiology of wet AMD development and progression is still unknown. The dry AMD is characterized by atrophic changes that occur due to loss of outer retinal tissue and the surrounding vascular network, specifically the retinal pigment epithelial layer, Bruch membrane, and the capillaries in the choroid. Advanced dry AMD is thought to result from inflammatory and degenerative insults that lead to subsequent photoreceptor loss. These atrophic lesions do not respond to anti-VEGF therapy and currently there is no treatment for dry AMD.  In the non-proliferative DR, the blood vessels in the retina are weakened, and the formation of bulges, called micro aneurysms, induces fluid leakage into the retina leading to swelling of the macula. Similarly, the proliferative DR is characterized by the growth of abnormal, new, fragile blood vessels in the retina. These vessels can leak, causing sudden and severe vision loss. Furthermore, abnormal new blood vessels can press on retinal veins, blocking blood flow. While treatment with intravitreal injection of anti-VEGF and laser photocoagulation can slow or stop the progression of DR, a cure does not exist.

To restore ocular blood flow, promote neuroprotection and inhibit hypoxia by re-establishing optimal intracellular cGMP levels and correcting the insufficient cell-cell communication.

Our approach with TOP-V122 is to target ocular blood flow. Our novel dual mode-of-action drug combines the potent and selective inhibition of the PDE enzyme with the release of NO. Consequently, the intracellular levels of cGMP are restored. The stimulation of microcirculation and healthy angiogenesis should lead to neuroprotection, inhibition of hypoxia, and ultimately the prevention of vision loss. We envisage a monotherapy with eye drops of TOP-V122 to treat dry AMD and non-proliferative DR where inhibiting vascular leakage and reducing hypoxia will stop the disease progression. Moreover, in severe cases which are treated with anti-VEFG drugs, an injectable sustained-release formulation for TOP-V122 will be developed. This will be given in addition to the anti-VEGF drugs mainly to reduce the anti-VEGF side effects, inhibit vascular leakage, and reduce hypoxia for wet AMD and proliferative DR.

Epidemiologic data shows that 80 % of Caucasian men and 40–50 % of Caucasian women are affected by AGA during their life, with prevalence increasing with age. Besides hair transplant, only two drug products are FDA-approved for the treatment of hair loss. The efficacy of these two drugs varies between 30% and 60%, and hair growth is not maintained after treatment discontinuation. The high cost of therapies, low adherence to the needed daily treatment, and possible side effects/allergic reactions are acting as a critical barrier for the hair growth market. Additionally, more advanced cases may be resistant or unresponsive to medical therapy. Also, individuals with hair loss show a decline in self-esteem or a psychosocial impact of the condition.

Decreased microcirculation in the scalp aggravates hair loss. Stimulation of blood circulation in the resting hair follicles allows them to reconnect with the dermal papillae. These structures, which are located under the follicle, ensure the blood supply to the hair bulb, so that the hair can regrow.

TOP-M119 and its structurally-related compound TOP-M111 showed to be very potent hair growth promoters in a predictive animal model for alopecia. The hybrid molecules designed to activate cGMP-Enzyme Regulatory System have the potential to increase blood flow by restoring optimal intracellular cGMP levels. The increase of blood supply to the hair bulb allows the hair to regrow. TOP-M119 was also effective in a  chemotherapy-induced hair loss model.

It has been shown that CRC develops from adenomatous polyps that grow slowly before becoming malignant. By early detection and early removal of polyps and cancerous tissue, colorectal cancer is curable in most cases. Chemoprevention in high-risk patients could be an important and effective strategy in the fight against colorectal cancer.

It has been shown that PDE5 inhibition eliminates cancer stem cells by inducing the PKA signal and that the use of PDE5 inhibitors is associated with a lower risk of colorectal cancer in men with benign colorectal neoplasia.

TOP-V122 with its unique dual mechanism of action is a very powerful and effective cGMP modulator that works locally with a very large therapeutic window. It is expected to be an ideal drug candidate for the prevention of colon polyps, adenoma formation and colon cancer. In addition, it should act on the inhibition of tumor growth and the elimination of cancer stem cells, thus increasing the sensitivity to chemo- and radiotherapy of CRC cells. In the first preclinical proof of concept study in a mouse model of colorectal cancer, the high efficacy of TOP-V122 for the prevention of polyps formation could be demonstrated. Based on the promising results, it could be expected that the drug candidate would have an attractive therapeutic potential for additional indications related to colorectal health.

Although significant progress has been made in recent years, PAH remains an incurable disease. The long-term survival rate of PAH patients remains unsatisfactory and mortality is high. Effective therapies target endothelial dysfunction (epoprostenol and its derivatives, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors). These drugs enable clinical, functional and hemodynamic improvements, but do not prevent disease progression. New drugs that can stop or even reverse disease progression are a major unmet medical need.

The NO-sGC-cGMP signaling pathway is a critical factor in the development of PAH. Dysregulation of this signaling pathway leads to pulmonary vasculitis, thrombosis and constriction and ultimately to the development of PAH. Local, inhaled drug delivery should be able to stop the progressive fibrotic and proliferative aspects of PAH disease and thus provide a new therapy that is causally effective.

TOP-V122 will have the potential to increase NO production and to restore the levels of cGMP. This should enable the formation of new blood vessels resulting in increased oxygen and restored pulmonary arterial pressure. We are confident that TOP-V122 can be used for the treatment of other pulmonary fibrosis diseases, namely idiopathic pulmonary fibrosis.