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Preclinical, Clinical, and Translational Sciences

(T1030-02-11) Toxicokinetics of NIDO-361, a Potential Candidate to Treat Spinal and Bulbar Muscular Atrophy (SBMA), in Rats and Monkeys Following Oral Dosing in a 13-or 26-Week Toxicity Study

Tuesday, October 22, 2024
10:30 AM – 11:30 AM MT

    Presenting Author(s)

  • AK

    Ahmed A. Kousba, Ph.D.

    Associate Director, Pharmacokinetics
    Bioagilytix San Diego
    San Diego, California, United States

    • Main Author(s)

  • AK

    Ahmed A. Kousba, Ph.D.

    Associate Director, Pharmacokinetics
    Bioagilytix San Diego
    San Diego, California, United States

    • Co-Author(s)

  • WN

    William Nappier Cherup, MS

    Senior Scientist
    Charles River Laboratories
    Mattawan, Michigan, United States

  • PH

    Panos Hatsis, Ph.D.

    Director Drug Metabolism and Pharmacokinetics
    Nido Biosciences, Inc.
    Cambridge, Massachusetts, United States

  • HT

    Heath Thomas, Ph.D.

    President / Senior Consultant at Aclairo Pharmaceutical Development Group, Inc.
    Aclairo
    Sterling, Virginia, United States

  • CG

    Carleen Gentry, MS

    Senior Director
    Nido Biosciences, Inc.
    Cambridge, Massachusetts, United States

  • VV

    Vissia Viglietta, M.D.

    Chief Medical Officer
    Nido Biosciences, Inc.
    Cambridge, Massachusetts, United States

Purpose: To assess the toxicokinetics (TK) of NIDO-361 following once-daily oral dosing to male Sprague Dawley rats and male Cynomolgus monkeys. NIDO-361 is a novel small molecule that binds to a distinct site on the androgen receptor (AR) and corrects transcriptional dysregulation to restore healthy cell function.  NIDO-361 is currently being investigated in a  Phase 2 clinical study for the treatment of patients suffering from Spinal and Bulbar Muscular Atrophy (SBMA); a rare inherited X-linked neuromuscular disorder caused by a genetic mutation of the AR resulting in the loss of skeletal muscle and motor neuron function. 

Methods: The TK portion of the rat study consisted of 5 subgroups (Group 1, control consisted of 3 animals, and Groups 2 through 5, NIDO-361-treated, consisted of 6 animals each). Groups 1 through 5 were dosed with once-daily oral dosing of NIDO-361 at 0, 10, 30, 100, or 175 mg/kg, respectively for 13-or 26-weeks. The monkey study consisted of five groups (N = 12 animals in Groups 1, 4 and 5, and N = 5 animals in Group 2 and N = 9  animals in Group 3). Four animals/group in Groups 1, 3 and 4 were designated as interim animals (sacrificed on Day 91), 5 animals/group were designated as terminal animals, and 3 animals/group in Groups 1 and 4 were designated as recovery animals. Groups 1 through 5 were dosed with once-daily oral dosing of NIDO-361 at 0, 5, 15, 45 and 150 mg/kg, respectively, for up to 182 consecutive days, however, the Group 5 dose was reduced to 100 mg/kg/day on Day 8 and the dose group was terminated on Day 52, while the Group 4 dose was reduced to 30 mg/kg/day on Day 107 for the animals designated for terminal or recovery sacrifice. Blood samples were collected at predetermined times from 3 rats/timepoint and all surviving monkeys and were used for measuring NIDO-361 plasma concentrations by validated HPLC/MS/MS assays.  The TK parameters were determined by model independent methods (sparse sampling for the rat study and serial sampling for the monkey study) and are presented in Table 1 and Figure 1 for Days 1 and 182 only in the result section.

Results: Day 1 NIDO-361 TK in Rats: Following a single oral administration of NIDO-361 at 10, 30, 100 and 175 mg/kg/day to male rats, NIDO-361 was absorbed into the systemic circulation with Tmax values ranging from 1.00 to 4.00 h postdose. NIDO-361 Cmax values were 1,120, 2,520, 5,310 and 8,790 ng/mL and AUC(0-24) values were 4,220, 17,400, 44,000 and 108,000 ng·h/mL for NIDO-361 doses of 10, 30, 100 and 175 mg/kg/day, respectively (Table 1). NIDO-361 systemic exposure (Cmax and AUC(0-24)) increased with increasing dose (Table 1 and Figure 1). Day 182 NIDO-361 TK in Rats: Day 182 NIDO-361 Cmax values were 1,150, 2,870, 6,110 and 17,900 ng/mL and the AUC(0-24) values were 6,600, 25,500, 84,600 and 266,000 ng·h/mL for doses of 10, 30, 100 and 175 mg/kg/day, respectively (Table 1). NIDO-361 systemic exposure increased with increasing dose (Table 1 and Figure 1). Day 182/Day 1 NIDO-361 Cmax ratios were 1.02, 1.14, 1.15 and 2.04 and the Day 182/Day 1 NIDO-361 AUC(0-24) ratios were 1.56, 1.47, 1.92 and 2.47 for NIDO-361 doses of 10, 30, 100 and 175 mg/kg/day, respectively (Table 1). Day 182 TK exposure (Cmax and AUC(0-24)) to NIDO-361 did not appear to consistently change following repeated administration of NIDO-361, with the possible exception of the Day 182/Day 1 NIDO-361 Cmax and AUC(0-24) ratios at 175 mg/kg/day. Day 1 NIDO-361 TK in Monkeys: Following a single oral administration of NIDO-361 at 5, 15, 45 and 150 mg/kg/day to male monkeys, NIDO-361 was absorbed into the systemic circulation with Tmax values ranging from 2.00 to 24.0 h postdose (Table 1). Mean Cmax values were 718, 3,340, 7,100 and 11,900 ng/mL and the mean AUC(0-24) values were 11,100, 41,900, 125,000 and 230,000 ng·h/mL for NIDO-361 doses of 5, 15, 45 and 150 mg/kg/day, respectively (Table 1). NIDO-361 systemic exposure (Cmax and AUC(0-24)) increased with increasing dose (Table 1 and Figure 2). Day 182 NIDO-361 TK in Monkeys: Day 182 mean Cmax values were 1,150, 4,440 and 8,960 ng/mL and the mean AUC(0-24) values were 17,700, 68,900 and 127,000 ng·h/mL for NIDO-361 doses of 5, 15, and 30 mg/kg/day, respectively (Table 1). Systemic exposure of NIDO-361 increased with dose. Day 182 overall The Day 182 Cmax and AUC(0-24) values of NIDO-361 at 5 and 15 mg/kg/day were similar to Day 1 values. Day 182/Day 1 Cmax ratios were 1.45 at both 5 and 15 mg/kg/day and the corresponding AUC(0-24) ratios were 1.35 and 1.51 at 5 and 15 mg/kg/day, respectively (Table 1).

Conclusion: The pattern of NIDO-361 systemic exposure in NIDO-361-treated animals appeared to be similar in both species, where there was generally no significant accumulation with limited exceptions.

References: A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Safety, Tolerability, and Pharmacokinetic Study of Single and Multiple Ascending Doses of NIDO-361 in Healthy Male Subjects. clinicaltrials.gov ACTRN12622000964718

TK Table

TK Profiles

TK Profiles