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Overview
CU-40101 is an investigational topical liniment to treat androgenetic alopecia. It contains
a potent small molecule hormone receptor agonist that binds to thyroid receptor in hair follicle
cells and induces hair growth. CU-40101 is to be applied to the scalp directly, reducing
systemic exposure to the drug and the associated adverse effects. CU-40101 is differentiated
from current available androgenetic alopecia treatment in its innovative mechanism of action
and the potential to be used in both male and female patients. We are currently running a Phase
I dose escalation trial in China to evaluate the safety and tolerability of CU-40101 as an
innovative therapeutic agent effective in promoting hair growth in patients with androgenetic
alopecia. We enrolled the first patient in a Phase I clinical trial to treat androgenetic alopecia
in September 2022 in China, and we expect to complete the Phase I clinical trial in the second
quarter of 2024.
Mechanism of Action
CU-40101 is a potent small molecule thyroid hormone receptor agonist. CU-40101 binds
to thyroid hormone receptor in hair follicle cells and induces hair growth by promoting hair
follicle stem cell to initiate hair growth, a programmed regeneration process that runs
automatically once initiated. The skin is a recognized target of thyroid hormones. The
biological activity of thyroid hormones is mediated through the nuclear thyroid hormone
receptor. These effects are mediated in part through ligand-specific interactions of the thyroid
hormone receptor with its partner retinoid X receptor and the binding of these transcription
factors to specific promoter regions of the thyroid hormone response gene. The expression of
thyroid hormone receptor is localized in the nuclei of human hair follicle outer hair root sheath
and dermal papilla cells, suggesting a role for thyroid hormones in hair growth. Thyroid
hormones have been shown to stimulate epidermal proliferation and hair growth in animals. On
the other hand, hypothyroidism causes hair loss, with symptoms of lusterless, brittle hairs and
increased percentage of resting hair follicles. Therefore, CU-40101 may be a novel, effective
and safe therapeutic agent for the androgenetic alopecia.
Competitive Advantages
We believe that CU-40101 has the following advantages:
Stimulating Growth of Hair Follicles in Resting Phase
The pre-clinical in vivo efficacy studies in C3H mice have shown that CU-40101 is
effective in stimulating growth of hair in resting phase in a dose-dependent manner when
applied topically. Such results demonstrated the efficacy of CU-40101 in promoting the
transition of dormant hair follicles from resting phase to growing phase. In the in vivo hair
growth model in C3H mice, the hairs on the dorsal skin of C3H mice are in resting phase from
about 6-14 weeks after birth. In the pre-clinical in vivo efficacy studies, the hairs cycle phase
on the dorsal skin of C3H mice at about 7 weeks of age is in the resting phase, characterized
by pink skin, and the hair on the lower back of the mice is shaved to prepare the skin for
administration. The vehicle (propylene glycol/ethanol, 30/70, negative control) or test
compounds, including CU-40101 and minoxidil, is applied to an area near the base of the tail.
The figure below shows the gross appearance of representative mice in each group on the day
21 of treatment with the red asterisks indicating the center of the treated area. Application of
CU-40101 to the dorsal skin of C3H mice induced hair growth prior to the next natural growth
phase, presumably by activating hair follicles in resting phase into the growth phase. No
significant treatment-related abnormalities were observed during the treatment. In comparison,
hair growth was not observed in any mice in the vehicle control or minoxidil groups,
suggesting that minoxidil had no effect at all on the hair follicles in resting phase of the mice
experimental model.
Furthermore, treatment for hairs in resting phase of C3H mice with three different
concentrations (0.005%, 0.01%, 0.05% w/v) of CU-40101 showed that both 0.01% and 0.05%
CU-40101 treatment groups started to grow hair after 3-5 days of administration. In contrast,
0.005% CU-40101 did not show signs of hair growth until 12 days after administration,
a delay in reaching full hair. Thus, topical administration of CU-40101 to C3H mice was able
to effectively stimulate hair growth in resting phase in a dose-dependent manner, suggesting a
potentially novel, effective and safe therapeutic agent for androgenetic alopecia.
Favorable Safety Profile and Low Systemic Drug Exposure
Pre-clinical studies showed that topical administration of CU-40101 solution at doses of
0.28 and 1.4 mg/kg (0.05% and 0.25%) in British guinea pigs caused no skin or systemic
allergic reactions. The in vitro and in vivo genotoxicity studies further showed negative results,
sufficient to demonstrate that the compound does not pose a significant risk of genotoxicity. In
addition, with a topical liniment formulation, CU-40101 is applied to the scalp directly and is
poorly absorbed systematically with a short elimination half-life to reduce the systemic adverse
effects or drug-drug interaction. The pre-clinical pharmacokinetic studies showed that after a
single topical application of CU-40101 at 0.001-0.02 mg/mouse or 0.11-2.2 mg/pig, plasma
CU-40101 concentrations were below the limit of quantification by 0.1 ng/mL. With such
extremely low systemic exposure following topical application, the risk of CU-40101 to cause
clinical drug-drug interaction is expected to be very low. It is an important advantage for
patients to use CU-40101 in combination with other therapeutic drugs concomitantly.
clinicaltrials.gov
folliclethought.com
ichgcp.net
