The Src Kinase inhibition platform refers to novel small molecule compounds that have differentiated mechanisms of actions (MOAs) including: (1) the inhibition of the activity of Src Kinase and (2) the inhibition of tubulin polymerization. We believe the combination of the two mechanisms of action provides a broader range of anticancer activity compared to either mechanism of action alone. Our three key clinical product candidates in this platform are tirbanibulin (formerly KX2-391 or KX-01) ointment for actinic keratosis, pre-cancerous lesions and psoriasis; tirbanibulin oral for solid and liquid tumors, and KX2-361 (formerly KX-02) oral for glioblastoma multiforme (GBM).
Tirbanibulin is a small molecule developed under our Src Kinase Inhibition platform that, as a free base, has advantageous physical properties for topical ointment formulations.
Tirbanibulin ointment has shown promising results in actinic keratosis, or AK, a chronic and precancerous skin disease that occurs primarily in areas that have been exposed to ultraviolet (UV) radiation for a long period of time. It is usually found on the face, ears, lips, bald scalp, forearms, the posterior part of the hands, and lower legs. It is not possible to predict which AK lesions will develop into squamous cell carcinoma, so all lesions should be treated by a dermatologist. AK is the most common pre-cancerous dermatological condition and the second most common diagnosis made by dermatologists in the United States. The reported prevalence of AK is between 11% and 25%.
We completed two pivotal, randomized, double-blind, vehicle-controlled Phase III trials (KX01-AK-003 and KX01-AK-004) that evaluated the efficacy and safety of tirbanibulin ointment 1% in 702 adults with actinic keratosis of the face or scalp. The New England Journal of Medicine (NEJM) has published the results from the pivotal Phase III trials in the February 11, 2021 issue.
Tirbanibulin is also being investigated for the treatment of psoriasis. The trial has already yielded positive early signals of clinical activity, as disclosed in June 2019. Preclinical research is underway to identify further indications for tirbanibulin, such as skin cancers and other dermatological hyperproliferative disorders.
Tirbanibulin is also being developed as an oral for the control of cancer and hyper-proliferative disorders. Src plays a demonstrated role in regulating multiple aspects of tumor development, growth, and metastases, and its inhibition limits such tumor activity. Interfering with tubulin polymerization activity is a clinically validated mechanism for treating cancer. For both targets, tirbanibulin binds at a novel binding site. Together, these two MOAs may provide a potent means of treating cancer and other hyper-proliferative disorders.
KX2-361 is a closely related structural analog of tirbanibulin and demonstrates similar dual MOAs of Src and microtubule polymerization inhibition. Although KX2-361 is an analog of tirbanibulin, it has significantly different physical properties. These properties are designed to allow KX2-361 freely cross the BBB such that the concentration in the brain is equal to, or somewhat greater than, that in the plasma. This trait highlights the potential for KX-361 as a novel therapy for unmet medical needs such as brain cancers, including GBM and brain metastases. KX2-361’s multiple MOAs along with its ability to cross the BBB, make it a novel molecule for the treatment of brain tumors. The FDA has granted Orphan Drug Designation to KX2-361 for the treatment of gliomas.
Studies of KX2-361 in preclinical syngeneic mouse GBM models resulted in the complete eradication, without recurrence, of the tumors in an average of approximately 30% of treated mice. KX2-361 produced long-term survival mice, as compared to temozolomide, which extended survival but did not result in any long-term survivors.
KX2-361 is currently in the early stages of clinical development.
 Wilmer, EN, Gustafson CJ, Ahn CS, Davis SA, Feldman SR, Huang WW. Most common dermatologic conditions encountered by dermatologists and non-dermatologists. Cutis. 2014 Dec;94(6):285-92
 Stockfeth, E., Fernandiz, C, Grob JJ, et al., Development of a treatment algorithm for actinic keratoses: a European Consensus. Eur J Dermatol. 2008;18(6):651-659