A platform with many opportunities
The estrogen receptor (ER) is activated by the hormone estrogen and regulates a number of functions in the body. Estrogen has a number of positive effects, but its use as a medical treatment has been limited by the associated risk for uterine and breast cancer as well as an increases risk of thrombosis. These risks are mainly linked to the ER-alpha receptor, while the ER-beta receptor, which Karo Bio co-discovered in the 1990’s, seems to mediate many of the positive effects of estrogen.
Indication areas
Multiple sclerosis- Potential for neuroprotection and remyelination
Since 2011, multiple sclerosis is Karo Bio’s main focus area. The reason for focusing on MS is that ER-beta agonists in preclinical models have demonstrated high efficacy in the repair processes and reconstruction of the myelin sheaths that surround and insulate nerves and are necessary for efficient conduction of nerve impulses. If treatment with ER-beta agonists proves capable of repairing damaged myelin in patients this will represent a significant breakthrough in the care of MS patients, where damaged myelin leads to symptoms of the illness and disability. We believe that ER-beta agonists offer a new way to halt or reverse disease progression and treat the progressive forms of MS. They may also have beneficial effects on non-core symptoms of MS such as improvement in cognition and sleep disturbances and also positive effects on mood. We have demonstrated proof-of-concept in the EAE animal model of MS. The results demonstrate a significant reduction of clinical scores in severe sick animals and histology analysis show that our compound has neuroprotective effects. The project is in late lead optimization and we plan to start preclinical development in 2013. Our compounds have also shown good efficacy in animal models of depression and hot flashes.
Cancer- New possibility to treat multiple types of cancer
Our most advanced compound within the ER-beta program is KB9520, which is in preclinical development. The compound have shown good efficacy in four different forms of cancer; cholangiocarcinoma, T- and B-cells lymphoma and mesothelioma. Xenograft models in mesothelioma and lymphoma demonstrate good efficacy in slowing tumor progression. Treatment with KB9520 leads to a significant reduction in tumor size due to anti-proliferative and pro-apoptotic effects. Our development strategy is to focus on a rare form of cancer with the later possibility to expand to other cancer forms.
Urology
ER-beta is also expressed in various urogenital tissue and ER-beta selective agonists have shown positive effects on both reducing prostate size and have an effect in prostate cancer. ER-beta agonists have the possibility to be a faster acting therapy with an improved side-effects profile for the treatment of benign prostate hyperplasia, compared to existing therapy. Our compounds have positive effects on decreasing prostate size in an animal model of BPH.
Collaboration with Merck
Karo Bio has also collaborated with Merck (“MSD” outside the U.S. and Canada) on estrogen receptors since 1997. In 2002, Merck assumed full responsibility for the development work. The aim of the partnership is to develop drugs in the area of women’s health. In September 2010, Merck discontinued a phase II study of the leading drug candidate MK-6913 for the treatment of hot flashes in menopausal women after an interim analysis of data showed that the predefined efficacy criteria were not met. Merck is evaluating alternatives for future studies of MK-6913. Karo Bio has the right to milestone payments from Merck based on successful clinical development and drug registration, as well as royalties on the future sale of drugs developed within the framework of the partnership.
