Dual bNAbs in children: dose-finding and safety data on VRC01LS and 10-1074 in the Tatelo study 

Treatment with dual broadly neutralising monoclonal antibodies (bNAbs) was safe and well-tolerated in children receiving ART. [1]

Initial dose-finding and safety data from the Tatelo study was published ahead of print in JAIDS, 9 June 2022.

Trough levels exceeded minimal targets with four-weekly administration of 10-1074 dosed at 30 mg/kg and VRC01LS at 15 mg/kg.

The Tatelo study (A clinical trial to evaluate the impact of broadly neutralising antibodies VRC01LS and 10-1074 on maintenance of HIV-1 suppression in a cohort of early-treated children in Botswana) is an ongoing phase 1/2, multi-site clinical trial in virally suppressed children with HIV.

The overall aim is to evaluate dual bNAb treatment as an alternative to ART for up to 24 weeks.

The JAIDS manuscript covered the first two phases of the study (phases A and B) for dose-finding and safety. Data recently presented at virtual CROI 2022, showed treatment with dual bNAbs maintained viral suppression in 44% of children (n=25) for 24 weeks without ART. [2]

In the first pharmacokinetic (PK) and safety phase (phase A), 6 children on suppressive ART were given 3 intravenous (IV) doses (every 4 weeks) of 10-1074, and 6 received 3 (IV) doses (every 4 weeks) of VRC01LS and received safety and PK testing for 12 weeks.

These data were reviewed by a Safety Monitoring Committee before continuing the second phase of the study (phase B). In phase B, the children continued ART and 6 received both bNAbs every 4 weeks, with PK evaluation of dual bNAb dosing for 8 weeks, and safety evaluations for 32 weeks.

Eligible children had started ART before they were 7 days old and continued for at least 96 weeks, with viral load <40 copies/mL for at least 24 weeks before enrollment.

In phase A, 6 children received 10-1074 (30 mg/kg on day 0, 28, and 56) and 6 VRC01LS (30mg/kg on day 0, 10mg/kg on days 28 and 56).

Their median age at baseline was 3.1 years (range 2.1 to 4.1). Nine of 12 (75%) were girls.

All children were treated with lopinavir/ritonavir (LPVr) plus zidovudine (AZT) and lamivudine (3TC); one child also received abacavir. All started phase A on the LPVr liquid formulation; 7 switched to solid formulations (granules and/or tablets) during the study.

In phase B, 6 children received dual bNAb treatment (with higher VRC01LS maintenance dose, 15 mg/kg) every 4 weeks for 32 weeks with PK evaluations over 8 weeks.

At the start of phase B, median age was 4.5 years (range 3.4 to 4.9). All children sustained an undetectable viral load, while continuing LPVr/AZT/3TC.

The investigators developed population PK models to predict steady-state concentrations.

The study found the bNAbs to be well-tolerated in both phases. There were no infusion reactions or any bNAb-related grade 3⁄4 adverse events.

The first dose median Cmax and trough (day 28) for 10-1074 were: 1,405 mcg/mL (range 876 to1,999) and 133 mcg/mL (84 to 319). These values for VRC01LS were: 776 mcg/mL (range 559 to 846) and 230 mcg/mL (range 158 to 294).

The investigators noted that these concentrations were similar with single or dual bNAbs. They also reported little accumulation of 10-1074 Cmax with repeated doses of 30 mg/kg in both phases. Cmax after the second dose (10–15 mg/kg) of VRC01LS was lower than the Cmax after the first dose of 30 mg/kg.

10-1074 trough concentrations increased with each 30 mg/kg dose and the median 10-1074 day 84 concentration in phase B was 258 mcg/mL (range 122 to 467).

Based on adult data, the steady-state VRC01LS concentrations were expected to be 200 mcg/mL or more with 10 mg/kg IV every 4 weeks. But the median VRC01LS day 84 concentration in phase A was 156.9 mcg/mL (range 125.8 to 201.4). So the investigators increased the VRC01LS maintenance dose to 15 mg/kg for phase B.

The median first dose Cmax and trough combined from both phases were: 1,405 (range 876 to 1,999) mcg/mL and 133 (range 84 to 319) mcg/mL for 10-1074 and 776 (range 559 to 846) mcg/mL and 230 (158 to 294) mcg/mL for VRC01LS.

The investigators reported less Cmax/trough fluctuation and higher steady-state troughs with VRC01LS than 10-1074, despite the lower maintenance dose of VRC01LS. They noted this was to be expected because of slower elimination associated with the LS modification.

The predicted median steady-state troughs with phase B dosing for 10-1074 and VRC01LS were 261 mcg/mL and 266 mcg/mL, respectively. Both met the pre-specified targets for phase B and this dosing was approved for the final phase of the Tatelo Study, using dual bNAbs without ART.

comment

These initial PK and safety data from the Tatelo Study provide the first information to guide IV use of dual bNAbs in children, and the first data on 10-1074 use in this population. The findings support further evaluation of these two agents as paediatric treatment strategy.

Further proof-of-concept data from Tatelo, presented at CROI [2], went on to show dual bNAb treatment with VRC01LS and 10-1074 maintained viral suppression for 24 weeks in the absence of ART.

Four-weekly IV dosing is not without complications and longer acting LS formulations (including 10-1074-LS) might enable less frequent dosing intervals (3 to 6 montly) that could potentially make bNAb use easier for both adults and children.

References

1. Capparelli EV et al. Safety and pharmacokinetics of intravenous 10-1074 and VRC01LS in young children. JAIDS Journal of Acquired Immune Deficiency Syndromes. Volume 10. Issue 1097. 9 June 2022.
   https://journals.lww.com/jaids/pages/articleviewer.aspx?year=9900&issue=00000&article=00064&type=Abstract
2. Clayden P. Dual bNAb treatment maintains undetectable viral load off-ART in 44% of children in the Tatelo Study. HTB. 1 March 2022.
   https://i-base.info/htb/42175

This report was first posted on 24 June 2022.