Viamet Pharmaceuticals (United States)

VT-1161 and VT-1598 are promising investigational tetrazole antifungals that have shown in vitro and in vivo activity against Candida and other fungi. Candida glabrata is a problematic opportunistic pathogen that is associated with high mortality in invasive infection, as well as both intrinsic and rapidly acquired antifungal resistance. The MICs of VT-1161 and VT-1598 were determined by CLSI methodology to evaluate their in vitro activities against clinical C. glabrata isolates and strains containing individual deletions of the zinc cluster transcription factor genes PDR1 and UPC2A as well as the efflux transporter genes CDR1, PDH1, and SNQ2 Overall, both tetrazoles demonstrated relative activities comparable to those of the tested triazole antifungals against clinical C. glabrata isolates (MIC range, 0.25 to 2 mg/liter and 0.5 to 2 μg/ml for VT-1161 and VT-1598, respectively). Deletion of the PDR1 gene in fluconazole-resistant matched clinical isolate SM3 abolished the decreased susceptibility phenotype completely for both VT-1161 and VT-1598, similarly to the triazoles. UPC2A deletion also increased susceptibility to both triazoles and tetrazoles but to a lesser extent than PDR1 deletion. Of the three major transporter genes regulated by Pdr1, CDR1 deletion resulted in the largest MIC reductions for all agents tested, while PDH1 and SNQ2 deletion individually impacted MICs very little. Overall, both VT-1161 and VT-1598 have comparable activities to those of the available triazoles, and decreased susceptibility to these tetrazoles in C. glabrata is driven by many of the same known resistance mechanisms.

Annual global deaths from cryptococcal meningitis (CM) are estimated at 180 000 and mortality is as high as 30%, even with optimal therapy. VT-1598 is a novel fungal CYP51 inhibitor with potent intrinsic antifungal activity against Cryptococcus. We report here VT-1598's in vivo antifungal activity in a murine model of CM. Single-dose plasma and brain pharmacokinetics in mice and MIC for Cryptococcus neoformans H99 were determined prior to efficacy studies. Short-course monotherapy and combination doses were explored with the endpoint of brain fungal burden. A survival study was also conducted using monotherapy treatment with fungal burden measured after a 6 day drug washout. Oral doses of VT-1598 had good plasma and brain exposure and resulted in significant (P < 0.0001) and dose-dependent reductions in brain fungal burden, reaching a 6 log10 reduction. Unlike either positive drug control (fluconazole or liposomal amphotericin B), both mid and high doses of VT-1598 reduced fungal burden to below levels measured at the start of treatment. When VT-1598 was dosed in the survival study, no VT-1598-treated animal succumbed to the infection. Whereas fluconazole showed a 2.5 log10 increase in fungal burden after the 6 day washout, the VT-1598 mid- and high-dose animals showed almost no regrowth (<0.5 log10). In a separate fungal burden study using suboptimal doses of VT-1598 and liposomal amphotericin B to probe for combination effects, each combination had a positive effect relative to corresponding monotherapies. These pre-clinical in vivo data strongly support clinical investigation of VT-1598 as a novel therapy for this lethal infection.

Coccidioidal meningitis can cause significant morbidity, and lifelong antifungal therapy is often required. VT-1598 is a fungus-specific Cyp51 inhibitor that has potent in vitro activity against Coccidioides species. We evaluated the in vivo efficacy of VT-1598 in murine models of central nervous system coccidioidomycosis caused by C. posadasii and C. immitis Infection was introduced via intracranial inoculation, and therapy began 48 h postinoculation. Oral treatments consisted of vehicle control, VT-1598, and positive controls of fluconazole in the C. immitis study and VT-1161 in the C. posadasii study. Treatment continued for 7 and 14 days in the fungal-burden and survival studies, respectively. Fungal burden was assessed in brain tissue collected 24 to 48 h posttreatment in the fungal-burden studies, on the days the mice succumbed to infection, or at prespecified endpoints in the survival studies. VT-1598 plasma concentrations were also measured in the C. posadasii study. VT-1598 resulted in significant improvements in survival in mice infected with either species. In addition, the fungal burden was significantly reduced in the fungal-burden studies. Plasma concentrations 48 h after dosing stopped remained above the VT-1598 MIC against the C. posadasii isolate, although levels were undetectable in the survival study after a 4-week washout. Whereas fungal burden remained suppressed after a 2-week washout in the C. immitis model, a higher fungal burden was observed in the survival arm of the C. posadasii model. This in vivo efficacy supports human studies to establish the utility of VT-1598 for the treatment of coccidioidomycosis.

Coccidioidomycosis can be a chronic, systemic fungal infection requiring long-term to lifetime medication. Thus, there is a need for improved antifungal agents with greater efficacy and reduced toxicity. VT-1161 has a low affinity for mammalian cytochromes and potently inhibits fungal CYP51 with proven efficacy in murine models of central nervous system (CNS) and respiratory coccidioidomycosis. Dogs experience coccidioidomycosis similar to humans and are a useful preclinical model for naturally occurring disease. Twenty-four client-owned dogs diagnosed with respiratory coccidioidomycosis based on radiography, serology, clinical signs, and clinicopathologic abnormalities were treated with a loading dose of VT-1161 for 14 days, followed by 46 days of a lower maintenance dose. Twelve dogs received a high dose (29 mg/kg loading, 6 mg/kg maintenance) and 12 received a low dose (10 mg/kg loading, 1.6 mg/kg maintenance). Response to treatment was assessed by calculating the reduction in disease scores at exit compared to disease scores at enrollment. Overall, 20 of 24 (83%) dogs had ≥50% reduction in enrollment disease scores at exit (P < 0.001), with no difference between the high- and low-dose groups (P = 0.66). Time-weighted average plasma concentrations for the high- and low-dose groups were 39 ± 5 μg/ml and 19 ± 2 μg/ml, respectively. In this open-label study, VT-1161 was efficacious for the treatment of respiratory coccidioidomycosis in naturally infected dogs. Combined with previously reported murine data, this finding supports the further development of VT-1161 for the treatment of coccidioidomycosis in humans.

187 Background: VT-464 is an oral, non-steroidal inhibitor of CYP17-L and an antagonist of androgen receptor (AR) variants F876L and T877A which are associated with resistance to enzalutamide (ENZ) and abiraterone/prednisone (AA), respectively. INO-VT-464-CL-001 is a Phase (Ph) 1/2 study of VT-464 in treatment-naïve (TN) and treatment-failure (TF) patients with CRPC. Results are reported for Ph 1 (TN patients) and early results from Ph 2 patients. Methods: Phase 1: safety, tolerability, PK and initial efficacy (PSA and steroid concentrations) in M0 and M1 TN patients in escalated dose-cohorts from 50 to 600 mg bid in 28-day continuous dosing cycles. Phase 2: preliminary efficacy in M0 and M1 TN and TF (post-AA, -ENZ, and/or CHEMO) patients at 450 mg bid. Results: In Ph 1, 26 TN patients received VT-464 at 50 mg bid (n=1), 100 mg bid (n=1), 200 mg bid (n=4), 300 mg bid (n=8), 450 mg bid (n=9) and 600 mg bid (n=3) with 2 patients currently on study (15 and 29 months). Another 10 TN patients received VT-464 in Ph 2 at 450 mg bid. Most Ph 1 adverse events (AEs) were grade 1 or 2 and not considered drug related. There were 18 grade 3 AEs and 1 grade 5 AE considered not related to study drug, plus 4 grade 3 AEs (vasovagal/syncope) considered at least possibly related. For a single oral 450 mg dose, t½ was 6.8±0.8h (mean±SEM), Cmax was 8.6±1.2uM and Tmax was 3.4±0.7h. 19 of 26 Ph 1 and Ph 2 TN patients who received from 300 to 600 mg bid had PSA responses (6 PSA30%, 2 PSA50% and 1 PSA90% response). Preliminary PSA responses in Ph 2 TF patients included a PSA90% response in a prior-ENZ pre-chemo patient and a PSA50% response in a prior-ENZ and -chemo patient. No mineralocorticoid excess syndrome (MES) or changes in ACTH response or LFTs were observed. Plasma testosterone concentrations were reduced to near or below the limit of quantification in most patients at ≥ 450 mg bid, with normal progesterone and cortisol concentrations. No supplemental steroids were used. Conclusions: Clinical results at the doses evaluated support VT-464 CYP17 L-selectivity. The PSA50% and PSA90% responses in 2 of 7 prior Xtandi patients, combined with a lack of MES despite no supplemental steroids, warrants further investigation in the ongoing Ph 2 study, particularly in prior ENZ and AA patients. Clinical trial information: NCT02012920.

4671 Background: With the FDA approval of abiraterone acetate, inhibition of CYP17 (17α hydroxylase/C17, 20-lyase) is now a validated approach to the treatment of castration-resistant prostate cancer. VT-464 is a novel, selective CYP17-lyase inhibitor with decreased activity against CYP17 hydroxylase (less mineralcocorticoid and glucocorticoid effects). The study objectives were to observe the effects of VT-464 in a prostate cancer xenograft model and to compare its activity to abiraterone acetate and surgical castration. Methods: SCID mice were implanted subcutaneously with LNCaP cells. When tumors reached 100 mm3, mice were randomized to receive vehicle (0.5% CMC in saline, 5 mL/kg), VT-464 at 15, 50, or 100 mg/kg p.o. b.i.d. A second cohort of LNCaP tumor-bearing mice received vehicle, surgical castration, or VT-464, or abiraterone acetate at 100 mg/kg p.o. b.i.d. for 28 days. Terminal blood and tumor concentrations were analyzed on day 28, four hours after the last dose. Results: In the first LNCaP xenograft cohort, percent growth inhibition (± S.E.) of 9.6 (±15.6), 38.5 (±12.4), and 73.9 (±13.2) was observed on day 21 of treatment for VT-464 doses of 15, 50, and 100 mg/kg, respectively. Growth reduction at 100 mg/kg was statistically significant compared to vehicle control from day 7 to 28. VT-464 was well tolerated with insignificant weight loss at all doses. In the second cohort, VT-464-treated (100 mg/kg) mice had significantly reduced tumor volumes on day 28 compared to control and abiraterone acetate (p&lt;0.05, p&lt;0.01, respectively). Reduction in tumor volumes were similar between VT-464-treated (100 mg/kg) and castrate animals. Plasma and tumor analyses revealed much greater plasma and tumor exposure of VT-464 compared to abiraterone acetate. Conclusions: VT-464 exhibited dose-dependent growth inhibition with significantly reduced tumor volumes at the highest dose compared to abiraterone acetate. The activity in VT-464-treated animals was similar to that of castrate animals. These preclinical results show promising activity of VT-464 in the treatment of prostate cancer.

198 Background: CYP17 is a single protein with two distinct enzyme activities, 17 α-hydroxylase (hydroxylase) and 17,20-lyase (lyase). Reduction of extragonadal androgen production through CYP17 inhibition is a validated CRPC treatment paradigm. While treatment with the recently-approved CYP17 inhibitor, abiraterone acetate (AA), increases overall survival in post-docetaxel CRPC patients (de Bono et al, N Engl J Med 2011; 364:1995–2005), it is also associated with cortisol (F) suppression and increased steroid concentrations up-stream of CYP17 hydroxylase. The clinical candidate VT-464 is an oral, non-steroidal, lyase-selective CYP17 inhibitor. The study objectives were to compare VT-464 to abiraterone in regards to in vitro selectivity and to compare VT-464 to AA in regards to in vivo primate endocrine response. Methods: Human CYP17 hydroxylase and lyase IC50 values were determined for VT-464 and abiraterone in vitro. Plasma progesterone (P), F, and testosterone (T) responses were measured 0-24 hours after single subcutaneous doses of AA (12.5 mg/kg), VT-464 (6.25 and 12.5 mg/kg), or vehicle in adult, castrate, male rhesus monkeys. Results: Human lyase and hydroxylase IC50 values were 69nM and 670nM for VT-464 and 15nM and 2.5nM for abiraterone, respectively. AA and both dose levels of VT-464 produced a similar overall reduction in plasma T, compared to vehicle (p ≤ 0.009). AA treatment resulted in an elevated plasma P (peak increase &gt;9,000%; p ≤ 0.05), compared to both VT-464 treatments and vehicle. F was not affected by either VT-464 dose, whereas AA resulted in F suppression (p ≤ 0.005) compared to vehicle. Conclusions: VT-464 was 10-fold more selective for human CYP17 lyase vs. hydroxylase inhibition. This selectivity was associated with androgen suppression, but not increases of up-stream steroids or F suppression in male monkeys. In contrast, abiraterone was 6-fold more selective for hydroxylase vs. lyase inhibition resulting in associations with increased up-stream steroids and F suppression in AA-treated male monkeys, consistent with clinical observations in CRPC. VT-464 may thus provide a more lyase-selective alternative to AA for extra-gonadal androgen suppression in CRPC.