Not at lot of information out there on the trials, but it doesn't look to competitive against leronlimab. How much is Gilead going to spend on a drug combo that's already outclassed?
Patients were screened for sensitivity to 3BNC117 and 10-1074. 67% for 3BNC117 and 58% for 10-1074 and 40% for both. Which leaves a lot of patients out of the loop. That 2 patients had mutations occur that were not initially detected may mean resistance developed.
http://www.natap.org/2018/HIV/s41586-018-0531-2.pdf
Patients were screened for sensitivity to 3BNC117 and 10-1074. 67% for 3BNC117 and 58% for 10-1074 and 40% for both. Which leaves a lot of patients out of the loop. That 2 patients had mutations occur that were not initially detected may mean resistance developed.
Quote:Participant 91C33, who failed to respond to antibody infusions, had preexisting circulating viruses that were resistant to both antibodies . These viruses carried mutations in 3BNC117 contact sites (N280S and A281H) and in 10-1074 contact sites (N332T and S334N. Two individuals, 91C35 and 9341, responded to antibody therapy with a decrease in viremia of -1.58 and -1.32 log10 copies per ml but HIV-1 RNA levels returned to baseline within 3 and 4 weeks, respectively. 91C35 was found to have pre-infusion circulating viruses with reduced sensitivity to 3BNC117, and carried a CD4 contact residue mutation (A281T) that was associated with viral escape from 3BNC11720. Pre-infusion viruses derived from bulk CD4+ T cell outgrowth cultures of 9341 showed a 10-1074 IC80 that was 1.3 log10 higher than the geometric mean IC80 of all other enrolled viremic individuals (Supplementary Table 1). In both of these cases, rebounding viruses were resistant to both antibodies and carried mutations resulting in the loss of the potential N-linked glycosylation site at position 332 that is critical for 10-1074 binding. In addition, rebound viruses from 91C35 and 9341 contained G471E and N276D mutations, respectively, that are associated with increased resistance to 3BNC117. These mutations were not found in the pre-infusion circulating viruses described above or in the additional 113 pre-infusion env sequences that were analyzed from these two participants
Quote:However, HIV-1 is a highly diverse virus with varying levels of sensitivity to specific bNAbs. As a result, maintenance therapy with just the combination of 3BNC117 and 10-1074 would only be possible for the approximately 50% of clade B-infected individuals that are sensitive to both antibodies. This problem may be overcome by addition of or substitution with other antibodies or long-acting small-molecule antiretroviral drugs.
Quote:For the 11 individuals who had complete viral suppression (HIV-1 RNA <20 copies per ml) during the screening period and at day 0, combination antibody therapy was associated with maintenance of viral suppression for between 5 and more than 30 weeks. The median time to rebound was 21 weeks compared to 2.3 weeks for historical controls who participated in previous non-interventional ATI studies 10 and 6-10 weeks for monotherapy with 3BNC1179. Together, 9 of the 11 participants maintained viral suppression for at least 15 weeks, although two rebounded at weeks 5 and 7 ......Quantitative and qualitative viral outgrowth assays (Q2VOA) were used to retrospectively analyse the replication-competent latent viral reservoir in all individuals. Phylogenetic analysis showed that the trial participants were infected with epidemiologically distinct clade B viruses. Q2VOA analysis revealed that the pre-infusion latent reservoir in the two individuals who rebounded early, 9245 and 9251, harboured 10-1074- or 3BNC117-resistant viruses, respectively. Therefore, these two individuals were effectively subjected to antibody monotherapy, because there was pre-existing resistance in the reservoir of these individuals to one of the two bNAbs. Consistent with this idea, the delay in rebound in these two participants was within the anticipated range of antibody monotherapy. In addition, all four of the individuals excluded from the analysis due to incomplete viral suppression showed pre-existing resistance or viruses that were not fully neutralized by one or both of the antibodies and these individuals rebounded before week 12
http://www.natap.org/2018/HIV/s41586-018-0531-2.pdf
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