Panobinostat phase 1 trial provides limited advance in HDAC inhibitor pipeline
The first clinical trial of Panobinostat by the Department of Infectious Diseases and Department of Immunology at Aarhus University Hospital, Denmark marks the next step in the development of the histone deactylase (HDAC) inhibitor group of latency reversal agents . Thomas Rasmussen and colleagues describe results from this single-arm phase1/2 clinical trial of the second HDAC in clinical development. This paper was published in October 2014 in a new journal, Lancet HIV, with limited accessibility. It has recently become available on the National Center for Biotechnology Information online library PubMed, making it publicly accessible.
HDACs are cellular enzymes actively involved in gene silencing during HIV latency, and inhibitors of these enzymes can reverse HIV latency in in vitro studies. Clinical studies of the leading HDAC inhibitor, vorinostat [SAHA], have shown that it can induce expression of cell-associated HIV RNA . But controversy shrouds the expectation that this class of drugs may mediate induction of the reservoir, leading to its depletion in the presence of ART, as some latency reversal agents may be ineffective at inducing viral reactivation ex vivo . Panobinostat is a potent HDAC inhibitor that has been in clinical development for treatment of multiple myeloma.
Fifteen patients participated in this trial and were receiving ART with suppressed viral loads (<50 copies/mL) for at least 2 years prior to recruitment and with CD4 counts >500 cell/mm3 blood. 20mg of panobinostat was given orally, three times per week every other week for 8 weeks. Blood samples were taken after all doses and 4 and 24 weeks after the last dose. The study also included an optional analytical ART treatment interruption after completion of panobinostat, during which ART was resumed if the CD4 count fell <350 or there were two consecutive viral load measurements >1000 copies per mL plasma. One key difference between this study and other clinical studies of HDAC inhibitors was the use of a certified commercial transcription-mediated amplification viral load detection assay for quantification of viral RNA in plasma (Procleix Ultrio Plus, Novartis). Unlike other commercial viral load assays, this assay has substantially greater amplification kinetics compared to regular PCR based assays, resulting in 50% sensitivity to detect 3.8 HIV RNA copies per ml plasma and 95% sensitivity to detect 12 copies per mL.
The trial participants had been on ART for 30.5 – 191.7 months, with undetectable viral loads (<50 copies/mL) for 26.3 – 169.6 months with. All patients completed full panobinostat dosing. There was a significant increase in cell-associated unspliced RNA at all time points during panobinostat therapy compared to baseline (p<0.0001). Interpretation of the ability of panobinostat to induce expression of plasma viraemia as measured with the Procleix Ultrio Plus viral load assay is harder to determine given the manner in which the data is presented in summary rather than longitudinal individual plots. Induction of plasma viraemia by latency reversal agents is regarded to be a critical marker of their efficacy in inducing infectious replication competent viruses that can kill host cells and induce immune responses, leading to reservoir depletion in the presence of ART. The researchers report that 30% of baseline plasma samples were positive for HIV RNA using the Procleix Ultrio Plus assay in comparison to 54% of samples during panobinostat. A positive plasma HIV RNA test was more likely on panobinostat than at baseline (odds ratio 10·5, 95% CI 2·2–50·3; p = 0·0002). The probability of detectable plasma viraemia increased from 17·4% at baseline to 68·9% during panobinostat for the average patient. Confoundingly four of the fifteen patients had detectable viraemia with the use of this highly sensitive assay at all time points, including baseline. No data was presented on the change in magnitude of plasma HIV RNA.
Total HIV DNA decreased from baseline to day 14 of panobinostat (p = 0·04). Despite this integrated HIV DNA did not change signiﬁcantly from baseline and there was no change in the proportion of cells carrying replication-competent virus using a viral outgrowth assay.
Nine patients opted to participate in the analytical treatment interruption. The median time from ART interruption to a plasma viral rebound >1000 copies/ml was 17 days (IQR 17–24·5). While there was no correlation between the time to viral rebound during treatment interruption and baseline total or integrated HIV DNA, there was a strong correlation between time to viral rebound and the change in both total and integrated HIV DNA during panobinostat. Four patients had noticeably larger reductions in total HIV DNA from as early as 14 days after starting panobinostat and which were sustained through study (67–84% decrease overall). Of these four patients, three opted to participate in the ART treatment interruption. As a group these three patients had signiﬁcantly delayed time to viral rebound (median 28 days, IQR 21–56) compared with the six other participants in the treatment interruption (17 days, IQR 16–18; p=0·024).
Panobinostat was safe and well tolerated with only minor but reversible changes in leucocyte, neutrophil, monocyte, and thrombocyte counts. Ten patients experienced 16 adverse events presumed to be related to panobinostat and which were all grade 1. Fatigue was the most common drug-related adverse event.
The authors make much of the increased proportion of plasma samples that were positive for HIV RNA during panobinostat and state that “these results provide evidence that Panobinostat can eﬀectively activate HIV from latency in vivo and that it should be further investigated as a curative intervention for HIV”. In contrast clinical studies of vorinostat found no change in plasma viral load using a non-certified single-copy assay , despite induction of cell-associated HIV RNA. However Romidepsin, a third HDAC inhibitor in clinical development, has been shown to significantly increase viral load from undetectable levels at baseline at multiple post-infusion time points in 5 of 6 patients (range 46-103 copies/mL after 2nd infusion, p = 0.007) as well as cellular HIV-1-RNA levels (2.1-3.9 fold after 2nd infusion; p=0.03) .
1) Rasmussen T et al. Panabinostat, a histone deacetylase inhibitor, for latent-virus reactivation in HIV-infected patients on suppressive antiretroviral therapy: a phase 1/2, single group, clinical trial. Lancet HIV. 2014. Vol 1. e13-21.
2) Archin NM et al. HIV-1 expression within resting CD4 T-cells following multiple doses of vorinostat. J Infect Dis 2014; 210: 728–35.
3) Bullen CK et al. New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo. Nat Med. 2014. 20: 425–29.
4) Søgaard OS et al. The HDAC inhibitor romidepsin is safe and effectively reverses HIV-1 latency in vivo as measured by standard clinical assays. Late breaker oral abstract TUAA0106LB. International AIDS Society Conference, Melbourne, 2014.