Preclinical pharmacokinetics and clinical exposure prediction for VRDN-003, a next-generation half-life extended antibody to the IGF-1 receptor for thyroid eye disease

Kelly Foster; Brent Dickinson; Vahe Bedian

doi:10.1530/endoabs.92.OP-09-02

OP-09-02

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Endocrine Abstracts (2023) 92 OP09-02 | DOI: 10.1530/endoabs.92.OP-09-02

ETA2023 45th Annual Meeting of the European Thyroid Association ETA 2023 Oral Session 9: Thyroid Eye Disease (5 abstracts)

Preclinical pharmacokinetics and clinical exposure prediction for VRDN-003, a next-generation half-life extended antibody to the IGF-1 receptor for thyroid eye disease

Kelly Foster ¹ , Brent Dickinson ² & Vahe Bedian ²

Err

Author affiliations

¹Viridian Therapeutics Inc, Nonclinical, Waltham, Massachusetts, United States; ²Viridian Therapeutics Inc, Waltham, Massachusetts, United States

Objective: Evidence shows that IGF-1 receptor (IGF-1R) antagonism reduces the inflammation and proptosis that occur in thyroid eye disease (TED). VRDN-001 is a full antagonist to IGF-1R, and VRDN-003 is a next-generation, half-life extended version of VRDN-001 designed to enable subcutaneous (SC) administration. We compared the in vivo pharmacokinetic (PK) parameters of VRDN-001 and VRDN-003 and used a PK model to simulate potential VRDN-003 SC dosing regimens.

Methods: PK parameters were assessed in cynomolgus monkeys, with a single 7.5-mg/kg dose administered via intravenous (IV) infusion or SC injection. PK samples were collected at 12 time points (VRDN-001 group) or 15 time points (VRDN-003 group); non-compartmental PK parameter estimates were calculated using Phoenix WinNonlin v8.3 PK software. A 2-compartment PK model based on VRDN-001 clinical data, with adjusted clearance to reflect the half-life extension of VRDN-003, was developed and potential clinical dose regimens were simulated.

Results: In cynomolgus monkeys, bioavailability was similar for VRDN-001 (70%) and VRDN-003 (71%). For both IV and SC administration, half-life was approximately 2 times as long for VRDN-003 vs VRDN-001, AUC_inf approximately 65% greater, and clearance approximately 40% slower (Table 1). Average serum concentration of VRDN-001 administered IV Q3W was 106 μg/mL for 10 mg/kg and 32 μg/mL for 3 mg/kg. The PK model predictions for average serum concentration of VRDN-003 administered SC (300 mg in 2 mL with a 600-mg loading dose) were 104 μg/mL if given Q2W and 56 μg/mL if given Q4W.

Table 1 IV and SC PK Parameters of VRDN-001 and VRDN-003
Drug	ROA	V_z^a (mL/kg)	CL^a(mL/day/kg)	t_1/2 (days)	*AUC_inf (µgday/mL)**	%F
VRDN-001	IV	78 ± 6	8.5 ± 2.1	6.6 ± 1.3	915 ± 191	70
	SC	112 ± 23	13.1 ± 5.6	6.3 ± 1.4	636 ± 222
VRDN-003	IV	86 ± 17	5.2 ± 0.8	11.9 ± 3.4	1480 ± 223	71
	SC	132 ± 2	7.2 ± 1.2	12.8 ± 2.0	1050 ± 182
^aV_z and CL are V_z/F and CL/F for SC routes of administration. ROA, route of administration; V_z, apparent volume of distribution of the terminal phase; CL, total clearance rate; t_1/2, half-life; AUC_inf, area under curve extrapolated to infinity; %F, bioavailability.

Conclusions: VRDN-003 half-life in cynomolgus monkeys is approximately twice as long as it is for first-generation anti-IGF-1R antibodies. Based on human PK modeling, SC dosing of VRDN-003 either once or twice monthly will produce drug concentrations in the range of those achieved with Q3W IV administration of 3 mg/kg VRDN-001 and 10 mg/kg VRDN-001. These results suggest the potential for VRDN-003 efficacy via self-administered SC injection.