Idiopathic Pulmonary Fibrosis (IPF)
The lead clinical indication for the exploration of C21 is Idiopathic Pulmonary Fibrosis (IPF). Preclinical data shows that C21 consistently reduces, and in some experimental models, even reverses the established fibrosis typical for IPF.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease of unknown cause. It is characterized by fibrosis of the alveoli and the supporting framework (interstitium) of the lungs. The disease is typically found in people between the ages of 40 and 80 (mean age is 66) and affects more men than women. It is a serious disease with a prognosis worse than many forms of cancer; median survival is around 2-3 years and 5-year mortality rate is 50-70%.
The unmet need for patients with IPF is very high since there is no real effective treatment available for these patients at the moment. Current treatment is typically palliative and includes supplemental oxygen and pulmonary rehabilitation. The only two drugs approved for IPF are Esbriet and Ofev; both slow down the progression of the disease but none of them has this far demonstrated significant improvement in terms of survival.
Frequency: IPF is currently rising with the disease today affecting about 15-20/100 000 individuals. The IPF market is estimated to reach $1 billion in 2020.
Preclinical data shows that C21 consistently reduces, and in some experimental models, even reverses the established fibrosis typical for IPF. The properties of C21 are favourable for treatment of fibrotic diseases as the concept allow to address the condition from a number of different angles, e.g. below;
- AT2 Receptor is upregulated in IPF lungs ( the target of C21)
- Anti-apoptotic effect (prevent apoptosis of alveolar endothelial cells (initiating factor))
- Anti-inflammatory effect (important in early phases)
- Anti-proliferative effect (reduces cancer like proliferation of fibroblasts/myofibroblasts)
- Improvement of vascular remodeling (reduces secondary pulmonary hypertension)
- Anti-cytokine effect (strong effect on e.g. IL-6 of importance for recruitment fibroblasts, differentiation into myofibroblasts and potent local anti-TGFß effect)
- Anti-fibrotic effect (as demonstrated in the lung, heart, kidney, small and large vessels and skin)
- Anti-fibrotic effect (lung: prevents and reverses pulmonary and vascular fibrosis, reverses collagen deposition and ECM accumulation)
Pulmonary Arterial Hypertension
Pulmonary Arterial Hypertension (PAH) is a rare, often fatal, cardiopulmonary disease with an annual mortality rate of about 15% of diagnosed cases.
C21 has demonstrated potent effects on pulmonary arterial hypertension in an animal model where PAH was induced by pre-treatment with monocrotaline, a chemotherapeutic drug with PAH as a typical side effect. C21 demonstrated to reverse the increased blood pressure in the pulmonary system, largely by alleviating the fibrosis in the blood vessels.
PAH has an estimated total patient population in the US, EU5 and Japan ranging between 42 000 – 74 000 diagnosed prevalent patients. The market value of PAH in 2014 based on sales of drugs has been estimated to be between $2.5b to $3.3b.
AT2 receptor agonism (AT2R) is an attractive novel approach with wide therapeutic implications. Below are indications where our lead candidate, C21, has shown promising results in preclinical research.
C21 has shown excellent capability in enhancing repair of damaged myocardial tissue, via anti-inflammatory and antiapoptotic effects. The rapid restoration of heart function, established in preclinical models, is likely to significantly improve prognosis in patients after acute myocardial infarction.
Based on experimental data, C21 is a promising treatment option for patients with acute and chronic heart failure as well as for prevention of cardiac dysfunction in those at high risk. In addition to its cardioprotective properties, C21 has natriuretic -diuretic action and does not lower blood pressure, which are both clinically important for heart failure patients.
Although C21 does not reduce blood pressure as monotherapy, favourable effects of C21 on vascular remodeling have been demonstrated in different animal models including hypertensive models. Thus, collagen content in aorta is reduced after C21 in both spontaneously hypertensive rats and in L-NAME induced hypertension. This effect on extracellular matrix formation is accompanied by improved pulse wave velocity. Since this effect is blood pressure independent, it demonstrates that C21 has a direct protective effect on both vascular function and structure.
Renal protective effects have been demonstrated in different models, including diabetic models. The marked reduction in albuminuria, seen after C21 in these studies result from a direct renal protective action, since this effect is blood pressure independent.
Stimulation of the AT2 receptor seems to be a key factor for brain protection in connection with an acute stroke. Several animal models have shown a clear cut cerebroprotective action of C21 in experimental stroke without any reduction in blood pressure. Taken together, C21 reduces ischemic brain damage with subsequent improved survival.
Stroke / cognitive impairment
Stimulation of the AT2-receptor with C21 protects the brain after stroke, probably by increasing cerebral blood flow and/or by reducing inflammation and oxidative stress in the ischemic area. Furthermore, neuronal differentiation and neurite outgrowth are enhanced after C21. In animal models, C21 has demonstrated enhancement of spatial memory. These effects indicate a role for C21 also as a therapeutic option in patients to prevent vascular dementia and Alzheimer’s disease in the future.
Spinal cord injury
Spinal cord injury occurs as a result of trauma or tumours to the spinal cord. It poses a high burden on society as it affects many young people who may have difficulty in regaining motoric function. C21 has demonstrated strong effects on nerve injury in spinal cord injury in an experimental model in rodents. The animals were exposed to pressure injury and consequent paraplegia. Treatment with C21 demonstrated to allow for the treated animals to regain motor function and mobility compared to a control group. Histological analyses of the nerve tissue could reveal that in the C21 treated group nerve tissue had regrown and organized itself starting at the site of the injury. The estimated incidence of traumatic and non-traumatic spinal cord injury is around 31,500 individuals yearly in the largest markets (US, EU5, Japan).
The pathophysiological mechanisms in rheumatoid arthritis are favorably influenced by C21, providing a novel treatment alternative as a disease-modifying anti-rheumatic drug for oral administration. Initial experimental data is very encouraging and indicate that the effect size on various markers after C21 is comparable with established drug classes and consistent with long-term benefit for rheumatic patients.
Atopic dermatitis (eczema)
Atopice dermatitis is characterized by skin inflammation. Corticosteroids are either applied topically, or in more severe cases, parenterally. The effects of topical application of C21 has been studied in relevant models of atopic dermatitis, with impressive results, confirming the potent anti-inflammatory action of C21. With the well-known shortcomings of currently available treatment options, C21 presents a new option for effective disease-modifying therapy to benefit patient management.
Sickle cell disease
Renal failure due to sickle cell disease (scd) is a rare condition with great unmet clinical needs and few therapeutic options.
In a genetic experimental model of SCD the combination of C21 and an AT1 receptor blocker have demonstrated to both block the general leakage of fluids out of the kidneys and at the same time stop the increased concentration of proteins in the blood due to insufficiency of the kidneys. Frequency is 2.5 in 10 000 in Europe and 1 in 3000 in the US are affected by SCD, and it is not considered a rare disease in many malaria affected areas.