To challenge the incumbents enzalutamide (Xtandi) and abiraterone (Zytiga), Tokai is investing in galeterone as a challenger in the prostate cancer space. Tokai designed galeterone as a CYP17 inhibitor but has found that the drug also has anti-androgen effects, and more interestingly, that it exhibits a second-order effect of inducing androgen receptor (AR) degradation via a proteasome-mediated pathway. The importance of this multi-prong inhibition is underlined by the utility of abiraterone (a CYP17 inhibitor) and enzalutamide, an AR antagonist. If only for its CYP17 and AR antagonism, the development of galeterone is worth following.
However, the differentiating wildcard for galeterone is its additional ability, in vitro, to promote degradation of the AR. This is particularly relevant in the case of one splice site variant of the AR, termed AR-V7, that truncates the protein after the stretch encoded by exon 3, effectively producing a receptor without the ligand binding domain. This variant is particularly problematic for patients being treated for enzalutamide, as it removes the drug’s target binding domain. The result: presence of the AR-V7 splice variant correlates with lack of response to enzalutamide (and abiraterone) therapy in an AR-V7 expressing patient population. In effect, being able to reduce full length and AR splice variant expression via protein degradation would circumvent the problems caused by mutants and variants of the AR receptor that no longer offer regulation via ligand binding. Therefore, it is worth vetting the data to date to determine if galeterone induces degradation of the AR and if this effect may translate to the clinic.
The preclinical data demonstrating the impact of galeterone on AR degradation has been published in a few studies. The proteasome-dependent degradation of the AR appears valid for both full length as well as the AR-V7 splice variant. What is also consistent from these studies is that the degradation induced by galeterone treatment is not readily evident until concentrations of 10 uM and above, with 15 uM being the typical concentration used*. At concentrations below 5 uM galeterone, degradation is not readily observed. This is worrisome when attempting to translate this in vitro feature to the in vivo setting, as Tokai’s clinical data with the new tablet formulation demonstrates a drug Cmax of ~1 ug/mL, which, for a structure with an Mr of ~400, results in a concentration of 2.5 uM. In effect, Tokai’s preclinical data demonstrate that this concentration of galeterone is not sufficient to induce degradation of the AR in vitro.
These data should be kept in mind when vetting the ARMOR2 data provided by the company. To forward the differentiating claim regarding AR degradation, the company notes that 6 of 7 treatment naive patients with AR splice variants responded to galeterone treatment. The assumption to be made by investors is that these patients are responding to treatment due to the differentiating MOA of galeterone. However, the burden of proof remains on the company, and remains unmet.
First of all, the aforementioned preclinical data regarding the concentration of galeterone required to achieve AR degradation is well above the Cmax of the drug observed in the phase I trial. Therefore, the scientific case for this activity manifesting in vivo is weak. A possible caveat is that there could be significant accumulation of the drug in the tissue in order to reach 3-4x serum levels and therefore support AR degradation. However, that needs to be shown rather than assumed.
The second caveat is that the company did not test specifically for the AR-V7 splice variant. Their assay is a qualitative two-step immunoassay wherein they survey for presence of the AR with an NH2-terminal directed antibody, and then overlay these results with an antibody directed against a COOH-terminal epitope. The presumption here is that the presence of AR variants missing the COOH-terminal region will show differential staining with this two-step assay. It is important to note here that the simple absence of the COOH-terminal does not directly show presence of the AR-V7 splice variant. There are multiple splice variants of the AR, and some may act as dominant negatives rather than ligand-independent constitutively active forms as in the case of AR-V7. Therefore, Tokai’s presentation of this 7 patient cohort does not provide evidence of in vivo activity against the AR-V7 variant.
Questions and comments welcome.
* It should be noted that in the ARMOR2 slide deck, in slide 7 it is shown that 20 uM is not sufficient for ~100% degradation yet in slide 20, it appears that 5 uM is sufficient for ~100% degradation. Therefore, there is significant variability in the numbers shown in this slide deck. As these are not peer reviewed, more weight to the company’s own peer reviewed data is merited. Below, I’ve pasted a few of the relevant figures demonstrating the various effective concentrations demonstrated in Tokai’s own data.