Pipeline

Preclinical

Lead finding
Profiling
In-Vitro PoC
In-Vivo PoC
Toxicology

Clinical

Phase 1
Phase 2 a+b
Phase 3
Wound Healing

Wound Healing

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TOP-N53

Diabetic Foot Ulcer, Digital Ulcer

Clinical: phase-1

Problem

Wound healing is a complex physiological process that is vital to maintain skin function as a protective barrier. Several diseases can impair wound healing leading to chronic, non-healing wounds such as diabetic foot ulcer (DFU) in diabetic patients and digital ulcer (DU) in scleroderma patients. Diabetes mellitus affects 425 million people worldwide, and its occurrence is expected to increase to 629 million in 2045. DFU is a severe complication of diabetes often accompanied by impaired blood circulation. The latter impedes the physiological wound healing process resulting in chronic open-state, non-healing wounds. The annual DFU care amounts to $ 9-13 billion in the US alone in addition to the cost for management of diabetes alone. Scleroderma is a rare, debilitating autoimmune disease of the connective tissue characterized by inflammation, vasculopathy, progressive fibrosis in the skin, joints, internal organs with excessive collagen accumulation. About 95% of patients with scleroderma are afflicted with recurrent episodes of Raynaud´s phenomenon, a painful condition with tissue ischemia/reperfusion cycles due to vasospasms and accumulating structural damage to the digital arterioles from oxidative stress that favours the occurrence of DU. These ischemic ulcers are very painful and often result in impaired hand function.

Need

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.

Rational

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.

Solution

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TOP-N53

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.

Skin Fibrosis

Skin Fibrosis

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TOP-N44

Scar formation, Burn wounds

Preclinical: in-vivo-poc

Problem

Skin fibrosis is due to excessive scarring and is a result of a pathologic wound healing response. It is caused by chronic venous insufficiency that occurs in hypertrophic scars (as a result of burn wounds) and keloids. Keloids are similar to hypertrophic scars, resulting from inflammation and exaggerated wound healing processes in the fibroblast proliferation phase. Unlike hypertrophic scars, keloids extend and grow beyond the original boundaries of the wound. Keloids and hypertrophic scars occur more frequently following thermal injuries and burns. The hallmark of these diseases is an accumulation of collagen and a switch in the cross-linking pattern of collagen molecules which is thought to be responsible for tissue stiffness seen in skin fibrosis. Up to 15% of the population is affected by keloids as a result of wounds, and 70% of patients with burns develop excessive scars. This led to a predictable direct health care cost of $ 12 billion per year.

Need

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.

Rational

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

Solution

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TOP-N44

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.

Ophthalmology

Ophthalmology

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TOP-V122

AMD, Diabetic Retinopathy

Preclinical: in-vivo-poc

Problem

Age-related macular degeneration (AMD) affects 170 million individuals worldwide and it is projected to reach 288 million by 2040 due to the increase of the aging population. There are two main types of AMD, neovascular (wet or exudative) and non-neovascular (dry). Dry and wet AMD are the leading cause of irreversible blindness globally in individuals over 60. The direct US cost of illness associated with AMD is nearly $10 billion annually including the resources consumed by these patients for diagnosis, treatment, follow-up, and management of the disease.  Diabetic Retinopathy (DR) is classified in non-proliferative, proliferative and diabetic macular edema. The number of people with DR will increase from 126.6 million in 2010 to 191.0 million by 2030 globally. If no action is taken it is estimated that individuals with vision-threatening DR will increase from 37.3 million to 56.3 million. 25% of diabetic patients suffer from DR and these people have higher medical expenses than those with otherdiabetic-related conditions such as neuropathy and chronic kidney disease. Diabetes-related blindness can cost more than $500 million per year.

Need

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.

Rational

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

Solution

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TOP-V122

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 to the prevention of vision loss. We envisage a monotherapy with eye drops of TOP-V122to treat dry AMD and non-proliferative DR where the inhibition of vascular leakage and reduction of hypoxia will stop the disease progression. Additionally, an injectable sustained release formulation for TOP-V122 will be developed in combination with anti-VEGF drugs to reduce the anti-VEGF side effects, inhibit vascular leakage and reduce hypoxia for wet AMD and proliferative DR.

Medical cosmetics

Medical cosmetics

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TOP-M119

Alopecia, Skin aging

Preclinical: in-vivo-poc

Problem

Androgenetic alopecia (AGA), is a common form of male and female pattern hair loss. It is characterized by the non-scarring progressive reduction of the hair follicle. AGA develops by a gradual reduction of the anagen phase and increase in the telogen phase, leading to follicle miniaturization. AGA is heterogeneous and highly complex pathophysiology. Combination of genetical factors, endocrine deviations, androgens, drugs, diet and microinflammation in hair follicles of each individual is related to this condition.

Need

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.

Rational

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.

Solution

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TOP-M119

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.

Oncology

Oncology

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TOP-V122

Colorectal Cancer, IBD

Preclinical: in-vivo-poc

Problem

Colorectal cancer (CRC) is the third most prevalent cancer worldwide (10.2% of all cancer cases) and the second leading cause of cancer mortality. In 2018, it accounted for about 9.2% of all cancer deaths. Several risk factors may increase the chance of developing CRC, such as age, familial CRC, lifestyle factors, colorectal polyps and inflammatory bowel diseases. Additionally, CRC cells contain high percentages of cancer stem cells (CSCs), that are involved in metastasis and resistance development, thus affecting anticancer therapy efficacy.

Need

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.

Rational

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.

Solution

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TOP-V122

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.

Lung Fibrosis

Lung Fibrosis

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TOP-V122

IPF, PAH

Preclinical: in-vitro-poc

Problem

Pulmonary arterial hypertension (PAH) is a rare, life-threatening illness characterized by progressive obliteration of small pulmonary arteries that leads to high pulmonary arterial pressure, right heart failure and ultimately death.

Need

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.

Rational

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.

Solution

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TOP-V122

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.