Yesterday I heard the news that Tokai Pharmaceuticals has filed a $75 million IPO. Pieper Droppert (Biotech Strategy Blog) said that 75 million is a pretty small. I can’t agree with it any more. Just look back on J&J’s $1 billion acquisition of Aragon Pharmaceuticals for ARN-509, a phase III me-better drug of enzalutamide.
Tokai’s galeterone (TOK-001, VN/124-1) is an analog of abiraterone, also a C-17 heteroarylsteroid, but not just a me-too drug (Tokai believes it is first-in-class, but I think “me-better follower” is suitable.). Galeterone disrupts androgen receptor (AR) signaling via three distinct mechanisms of action, specifically, CYP17 inhibition, AR antagonism, and AR degradation.
Galeterone combines the mechanisms of action of abiraterone and enzalutamide with a third, unique mechanism—-AR degradation. Thereby galeterone’s multi-targeted treatment may reduce the risk of drug resistance and may translate to better outcomes, sounds so good.
Galeterone can down-regulate the AR protein by 89% at a concentration of 15 μmol/L in LNCaP cells, possibly due to the increasing AR degradation. Down-regulation of the AR may decrease the sensitivity of cancer cells to androgens, reducing resistance to CYP17 inhibitors and AR antagonists.
According to Tokai, there are no other drugs for the treatment of prostate cancer either in clinical development or on the market that act to degrade AR protein. However, AECC’s article demonstrated that both galeterone and abiraterone can target the cell’s own translational machinery to reduce AR protein levels.
Another advantage of galeterone is the good selectivity for CYP17 hydroxylase and CYP17 lyase.
CYP17 has both 17 α-hydroxylase and 17,20-lyase catalytic functions. CYP17 lyase inhibition reduces the biosynthesis of testosterone and dihydrotestosterone. That is what we want. However, hydroxylase inhibition elevates progestogens and mineralocorticoids, resulting in secondary mineralocorticoid excess (ME). Galeterone is more selective for lyase than hydroxylase (IC50: 23 nM vs 73 nM), whereas abiraterone more selectively inhibits hydroxylase (IC50: 12 nM vs 7 nM).
Abiraterone has been shown to cause ME syndrome characterized by hypokalemia (88%), hypertension (40%), and fluid overload (31%). This is treated clinically with concomitant prednisone. However, abiraterone induced-ME can’t be rescued completely by prednisone. Fluid retention/edema (31% vs 22%), hypertension (10% vs 8%), and hypokalemia (17% vs 8%) were more frequently reported in the abiraterone/prednisone group than in the placebo/prednisone group.
Galeterone is a selective CYP17 lyase inhibitor, thereby may have no influence on mineralocorticoids. According to the phase II clinical data presented at ASCO2014 GU, galeterone is well tolerated with no reported cases of ME, confirming previous observations.
Tokai announced positive interim results from the phase II ARMOR2 study in June 2014. Among 51 treatment-naïve CRPC patients, 82% achieved PSA30 and 75% achieved PSA50. It should be noted that 27% of abiraterone-refractory patients had a PSA decline.
Tokai has received the FDA’s Fast Track designation for galeterone. Maybe galeterone and ARN-509 are the next generation prostate cancer therapies.
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