{"id":43187,"date":"2022-07-01T07:41:25","date_gmt":"2022-07-01T07:41:25","guid":{"rendered":"https:\/\/i-base.info\/htb\/?p=43187"},"modified":"2022-07-01T08:24:40","modified_gmt":"2022-07-01T08:24:40","slug":"dual-bnabs-in-children-dose-finding-and-safety-data-using-vrc01ls-and-10-1074-in-the-tatelo-study","status":"publish","type":"post","link":"https:\/\/i-base.info\/htb\/43187","title":{"rendered":"Dual bNAbs in children: dose-finding and safety data on VRC01LS and 10-1074 in the Tatelo study\u00a0"},"content":{"rendered":"
Polly Clayden, HIV i-Base<\/b><\/div>\n
\n

Treatment with dual broadly neutralising monoclonal antibodies (bNAbs) was safe and well-tolerated in children receiving ART. [1] <\/span><\/b><\/p>\n<\/div>\n

\n

Initial dose-finding and safety data from the Tatelo study was published ahead of print in JAIDS, 9 June 2022. <\/span><\/b><\/p>\n<\/div>\n

\n

Trough levels exceeded minimal targets with four-weekly administration of 10-1074 dosed at 30 mg\/kg and VRC01LS at 15 mg\/kg.<\/span><\/b><\/p>\n<\/div>\n

\n

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.<\/p>\n<\/div>\n

\n

The overall aim is to evaluate dual bNAb treatment as an alternative to ART for up to 24 weeks.<\/p>\n<\/div>\n

\n

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]<\/span><\/p>\n<\/div>\n

\n

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.<\/p>\n<\/div>\n

\n

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.<\/p>\n<\/div>\n

\n

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. <\/span><\/p>\n<\/div>\n

\n

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).<\/p>\n<\/div>\n

\n

Their median age at baseline was 3.1 years (range 2.1 to 4.1). Nine of 12 (75%) were girls. <\/span><\/p>\n<\/div>\n

\n

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. <\/span><\/p>\n<\/div>\n

\n

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.<\/p>\n<\/div>\n

\n

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. <\/span><\/p>\n<\/div>\n

\n

The investigators developed population PK models to predict steady-state concentrations.<\/p>\n<\/div>\n

\n

The study found the bNAbs to be well-tolerated in both phases. There were no infusion reactions or any bNAb-related grade 3\u20444 adverse events.<\/p>\n<\/div>\n

\n

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).<\/span><\/p>\n<\/div>\n

\n

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\u201315 mg\/kg) of VRC01LS was lower than the Cmax after the first dose of 30 mg\/kg. <\/span><\/p>\n<\/div>\n

\n

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). <\/span><\/p>\n<\/div>\n

\n

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.<\/span><\/p>\n<\/div>\n

\n

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.<\/p>\n<\/div>\n

\n

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. <\/span><\/p>\n<\/div>\n

\n

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.<\/span><\/p>\n<\/div>\n

\n

comment<\/span><\/h3>\n<\/div>\n
\n

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.<\/span><\/b><\/p>\n<\/div>\n

\n

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.<\/span><\/b><\/p>\n<\/div>\n

\n

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.<\/span><\/b><\/p>\n<\/div>\n

\n

References<\/span><\/p>\n<\/div>\n

\n
    \n
  1. Capparelli EV et al. Safety and pharmacokinetics of intravenous 10-1074 and VRC01LS in young children.<\/span> JAIDS Journal of Acquired Immune Deficiency Syndromes.\u00a0Volume 10. Issue 1097. 9 June 2022.
    \nhttps:\/\/journals.lww.com\/jaids\/pages\/articleviewer.aspx?year=9900&issue=00000&article=00064&type=Abstract<\/a><\/li>\n
  2. Clayden P. Dual bNAb treatment maintains undetectable viral load off-ART in 44% of children in the Tatelo Study. HTB. 1 March 2022.
    \n    https:\/\/i-base.info\/htb\/42175<\/a><\/li>\n<\/ol>\n

    This report was first posted on 24 June 2022.<\/em><\/p>\n<\/div>\n","protected":false},"excerpt":{"rendered":"

    Polly Clayden, HIV i-Base 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. …<\/p>\n","protected":false},"author":3,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[32],"tags":[],"class_list":["post-43187","post","type-post","status-publish","format-standard","hentry","category-paediatric-care"],"_links":{"self":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/43187","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/comments?post=43187"}],"version-history":[{"count":0,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/43187\/revisions"}],"wp:attachment":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/media?parent=43187"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/categories?post=43187"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/tags?post=43187"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}