Date: 2016-07-09
Type of information: Publication of results in a medical journal
phase: 1-2
Announcement: publication of results in The Lancet HIV
Company: Bionor Pharma (Norway) Celgene (USA - NJ)
Product: Vacc-4x and Istodax® (romidepsin)
Action
mechanism: peptide/immunotherapy product/histone deacetylase inhibitor. Vacc-4x is a therapeutic HIV-vaccine based on four, slightly modified peptides (building blocks of proteins) from conserved parts of the HIV-virus. Endocine is an adjuvant shown to enhance the immune response to vaccine antigens delivered nasally. This investigational HIV vaccine Vacc-4x has already completed a large exploratory phase II randomized, multinational (USA and 4 European countries), double-blind, placebo-controlled trial. It has shown that patients achieved a statistical significantly lower viral load compared to the placebo group. Romidepsin is a histone deacetylase (HDAC) inhibitor. HDACs catalyze the removal of acetyl groups from acetylated lysine residues in histones, resulting in the modulation of gene expression. HDACs also deacetylate non-histone proteins, such as transcription factors.
Disease: HIV infection
Therapeutic area: Infectious diseases
Country: Denmark
Trial
details: The REDUC ("Kick and Kill") trial's objective is to address one of the core issues with the treatment of HIV, which is that some HIV infected cells hide in so-called latent reservoirs. The reservoirs are unaffected by conventional HIV medication and invisible to the immune system. HDACi have the potential to activate ("Kick") these latently infected cells. This will make the HIV infected cells visible to the immune system; the immune response generate by Vacc-4x will be able to attack and eliminate ("Kill") the infected cells. The REDUC trial's objective was to address one of the core issues with clinical management of HIV infection, which is that some HIV infected cells remain hidden in latent reservoirs. The reservoirs are unaffected by conventional HIV medication and invisible to the immune system. Histone deacetylase inhibitors (HDACi) have the potential to activate (‘Shock’) these latently infected cells to produce virus. This ‘shock’ will make the HIV infected cells visible to the immune system; the immune responses generated by Vacc-4x will be able to attack and eliminate (‘Kill’) these infected cells. REDUC (‘Safety and Efficacy of the Histone Deacetylase Inhibitor Romidepsin and the Therapeutic Vaccine Vacc-4x for Reduction of the Latent HIV-1 Reservoir’ (NCT02092116)) was an open Phase Ib/IIa clinical trial to evaluate the safety and effect of therapeutic HIV immunization, using Vacc-4x (administered with GM-CSF as adjuvant) and HIV reactivation using romidepsin, on the viral reservoir in virologically suppressed, HIV infected adults on cART. The trial was conducted as a single center clinical trial at the Aarhus University Hospital in Denmark. In total, 26 patients were enrolled from March 2014, six of whom participated in REDUC Part A, and 20 patients participated in REDUC Part B. REDUC Part A reported with positive results in May 2014, and was presented and attracted significant attention in July 2014 at the International AIDS Society (IAS) conference in Melbourne, Australia. Part A was published in the peer-reviewed journal PLOS Pathogens in September 2015. In REDUC Part B, 20 patients received Vacc-4x immunizations (administered with GM-CSF as adjuvant). Three weeks after the last immunization, treatment with romidepsin was initiated as three courses of 5 mg/m2 given over three weeks. After an eight-week follow-up period, a treatment interruption of cART up to 16 weeks was planned to evaluate the efficacy of the treatment regimen for control of viral load in the absence of cART. Data on viral load were obtained from 17 patients and 16 patients completed the trial. (NCT02092116)
Latest
news: * On July 9, 2016, Bionor Pharma announced that the positive results from the clinical trial REDUC Part B has been published for the first time in The Lancet HIV. The manuscript is entitled “Combined effect of Vacc-4x, recombinant human granulocyte macrophage colony-stimulating factor vaccination, and romidepsin on the HIV-1 reservoir (REDUC): a single-arm, phase 1B/2A trial”. The manuscript concludes that the REDUC trial was safe and provided the first evidence for the feasibility of a combined Shock & Kill strategy, but also emphasizes that further optimization of this strategy is needed to achieve a sizeable effect on the latent reservoir that will translate into clinically measurable benefits for people living with HIV. The REDUC Part B trial resulted in the following important findings: Latent HIV reservoir was significantly reduced by approximately 40% measured by Total HIV DNA and qVOA. Measured by Integrated HIV DNA, a statistical non-significant decrease of 19% was observed. * On June 9, 2016, Bionor Pharma announced that results from the clinical trial REDUC Part B (BPC01-001) will be published in The Lancet HIV. The manuscript, entitled “The combined effect of Vacc-4x/rhuGM-CSF vaccination and romidepsin on the HIV-1 reservoir: a phase Ib/IIa, single group, clinical trial”, will be published online. Ole Schmeltz Søgaard from Aarhus University Hospital in Denmark is corresponding author of the manuscript. Top line results from REDUC Part B were announced by Bionor on 21 December 2015. The REDUC Part B trial resulted in important signals, which provide the first evidence for the feasibility of a Shock & Kill strategy for achieving a functional cure for HIV infection. Viral load (Plasma HIV-1 RNA) remained below the limit of detection (20 copies/ml) in 11 of 17 patients throughout the trial while on cART despite a documented viral reactivation in CD4+ T cells following romidepsin infusions. Of the six patients with detectable viral load, four patients had measureable but low HIV in the blood after one of the three romidepsin infusions. Importantly, only two of 17 patients had detectable viral load after each of the three romidepsin infusions. The results also emphasize that further optimization of the Shock & Kill strategy is needed to achieve a sizeable impact on the latent reservoir that will translate into clinically measureable benefits for persons living with HIV, as the combined intervention did not prolong median time to viral rebound during ART interruption. Bionor anticipates that a third agent capable of further strengthening immune reactivity is needed as part of a combination treatment in addition to Vacc-4x and a latency reversing agent. These considerations have previously been described in the company’s announced clinical strategy and are being addressed in the BIONAB clinical trial. Based on the REDUC data, Bionor is currently also planning BIOSKILL, a multicenter placebo-controlled proof of concept Phase II clinical trial, which is intended to document the potential of Vacc-4x as a core component of a HIV cure strategy. * On February 23, 2016, Bionor Pharma announced that the third and final assay for measuring latent HIV reservoir size, the primary endpoint in the REDUC Part B trial, supports that the combination of Vacc-4x and the latency reversing agent romidepsin (Istodax®, Celgene) leads to a reduction in latent viral reservoir. The REDUC Part B results were presented at an oral presentation at the prestigious Conference on Retroviruses and Opportunistic Infections (CROI), in Boston, MA (USA). The presentation, entitled “Effect of Sequential Vacc-4x/GM-CSF Immunization and Romidepsin on the HIV Reservoir” was delivered by Dr. Ole Schmeltz Søgaard from Aarhus University Hospital in Denmark. In REDUC Part B, three different assays were selected to measure the effect on latent reservoir size due to ongoing discussions in the scientific HIV community on how best to estimate the true size of the reservoir and the effects of treatments. As reported on 21 December 2015, the first two assays demonstrated a significant reduction in the latent HIV reservoir (by 40% in Total HIV DNA and qVOA assays). Bionor reports results from the third assay of latent HIV reservoir by measuring levels of integrated HIV DNA. With the results of this assay showing a mean 13% non-statistically significant (p=0.271) reduction, the direction of all three assays is consistent. The technological differences between these assays in view of sample sizes allows no further comparison of absolute numbers. As previously communicated, Bionor expects to initiate the international and controlled BIOSKILL clinical trial when funding has been secured to execute and complete the full scope of the trial. To date, Bionor has received approval of its clinical trial applications for BIOSKILL in the United Kingdom and Denmark. * On December 21, 2015, Bionor Pharma announced successful results of the REDUC Part B clinical trial. In the REDUC trial, the combination of Vacc-4x and romidepsin leads to control of reactivated HIV and reduction in latent viral reservoir, and the trial results confirm and extend the positive and compelling findings of the interim analysis announced 4 May 2015. REDUC Part B enrolled 20 patients. Data on viral load were obtained from 17 patients and 16 patients completed the trial. The headline results are: The latent HIV reservoir was significantly reduced by 40% (Total HIV DNA and qVOA) A consistent result in reduction of the latent reservoir was observed. Measured by Total HIV DNA, a significant reduction of 40% (p=0.012) was achieved, and likewise, a 40% (p=0.019) reduction in latent HIV reservoir size was measured by qVOA. In REDUC Part A, in which the patients received romidepsin infusions without preceding vaccination with Vacc-4x, the size of the latent reservoir was not affected. Analysis of samples for Integrated HIV DNA by an external clinical research partner is still ongoing, and will be presented in a follow up statement from the company in the first quarter of 2016. Bionor expects that the data will support the conclusions presented in this announcement, since it has previously been demonstrated that the results of the Integrated HIV DNA and Total HIV DNA assays are positively correlated (Eriksson et al (2013) ‘Comparative Analysis of Measures of Viral Reservoirs in HIV-1 Eradication Studies’,PLOS Pathogens, February 2013, volume 9, 2). In REDUC Part A, romidepsin induced HIV-1 transcription resulting in a significant increase in viral load that was readily detected in five out of six patients. Comparing the results of REDUC Part A and REDUC Part B shows that vaccinations with Vacc-4x enabled control of reactivated virus. Bionor anticipates that a third agent capable of further strengthening immune reactivity is needed as part of a combination treatment in addition to Vacc-4x and a latency reversing agent. These considerations have previously been described in the company’s announced development strategy. In total, 141 adverse events were registered of which 43 adverse events were considered related to Vacc-4x administered with GM-CSF and 57 to romidepsin. Forty-one adverse events were non-related and 133 of the adverse events were mild (grade 1) and resolved spontaneously within a few days. There were a few grade 2 adverse events, and no observed drug related grade 3 adverse events. Other secondary virological and immunological endpoints Long-term development plan and next steps Bionor is currently planning BIOSKILL, a Phase II, randomized, double blind, placebo controlled clinical trial as the next step in developing a functional cure for HIV. The primary endpoint will be viral load during cART after each of three romidepsin infusions in Vacc-4x treated patients compared to placebo controlled patients. Secondary virological and immunological endpoints will include measurements of the size of the latent reservoir, CD4+ and CD8+ T cell counts, and other immunological parameters. The correlation between patients’ levels of anti-C5/gp41 antibodies and the ability to control virus in the blood will also be assessed. The BIOSKILL trial will not include cART treatment interruption. As part of its clinical program, Bionor intends to conduct two exploratory clinical trials in parallel with BIOSKILL to select the optimal components in a combination regimen, including 1) an evaluation of an appropriate third agent, intended to further improve the immune response towards HIV, and 2) a latency reversing agent with a more convenient route of administration than what is currently possible with romidepsin (intravenous infusion). The company expects that the completion of the BIOSKILL proof of concept clinical trial and the two smaller exploratory clinical trials will provide the basis for the execution of a subsequent Phase II clinical trial of a triple regimen for a functional HIV cure with Vacc-4x as its core. A successful completion of this clinical trial would be expected by the company to lead to initiation of a clinical Phase III program and regulatory approvable product. * On September 18, 2015, Bionor Pharma, a peptide vaccine company advancing a potential first therapeutic vaccine towards a functional cure for HIV, announced the publication of the manuscript “The Depsipeptide Romidepsin Reverses HIV-1 Latency in vivo” in PLOS Pathogens. Ole Schmeltz Søgaard from Aarhus University Hospital in Denmark is corresponding author of the manuscript, which describes the results from Part A of the Bionor sponsored REDUC study presented at the IAS 2014 conference in Melbourne. Until now, approaches to kick HIV out of latent reservoirs in humans have yielded mixed results. This manuscript reports Part A of a proof-of-concept phase Ib/IIa clinical trial where 6 HIV infected adults, well controlled on antiretroviral therapy, received intravenous doses (5 mg/m2) of Celgene’s HDAC inhibitor, romidepsin (Istodax®), once weekly for 3 weeks. Romidepsin safely increased the level of virus measured in the blood stream such that it became readily detectable using standard commercial assays. * On May 4, 2015, Bionor Pharma announced results from an interim analysis of Part B of the REDUC study. In the study, Bionor’s vaccine candidate Vacc-4x and romidepsin (Istodax®, Celgene) are explored as a possible treatment regimen to reduce the persistent latent viral reservoir in HIV infected patients on anti-retroviral treatment. In previous clinical trials, Vacc-4x demonstrated a significant reduction of HIV viral load set point and a long-term immune response in infected patients, supporting the company’s strategy to take Vacc-4x forward as a cure regimen for HIV. Vacc-4x has been designed to elicit a cell-based immune response by generating T-cells which can recognize and destroy infected HIV cells. In Part B of the REDUC study, Bionor combined Vacc-4x with romidepsin, which can reactivate and “kick awake” latent viral reservoirs. The interim analysis announced re-confirms that administration of romidepsin leads to activation of the virus in infected CD4+ T cells. Further, the results suggest that administration of Vacc-4x prior to an HDAC inhibitor enables killing of re-activated virus, as virus in plasma after reactivation is low or undetectable. Finally, results indicate a reduction of total HIV DNA levels in CD4+ cells, a measure used as surrogate for the size of the latent viral reservoir. The interim analysis shows: Next results will be in H2 2015 with the final report in January 2016 and are expected to be published in a peer-review journal.
Viral load (Plasma HIV-1 RNA) remained below the limit of detection (20 copies/ml) after each romidepsin infusion in 11 of 17 patients while on cART despite a documented viral reactivation in CD4+ T cells. Of the six patients with detectable viral load, four patients had measureable but low HIV in the blood after one of the three romidepsin infusions. Importantly, only two of 17 patients had detectable viral load after each of the three romidepsin infusions.
The treatment of Vacc-4x/rhuGM-CSF and romidepsin (Istodax®, supplied by Celgene Corporation) was safe and well tolerated. All adverse reactions were consistent with the known side effects of either romidepsin or Vacc-4x/rhuGM-CSF.
These results are encouraging and show that Vacc-4x, administered with rhuGM-CSF, is capable of priming the immune system to control HIV in the blood after the virus has been ‘shocked’ out of its dormant state by a latency reversing agent. The trial results are supported by previous data, demonstrating that Vacc-4x/rhuGM-CSF reduced the viral load set-point during antiretroviral treatment interruption in a placebo-controlled trial (CT BI-Vacc-4x 2007/1).
The treatment of Vacc-4x/rhuGM-CSF and romidepsin (Istodax®, supplied by Celgene Corporation) was safe and well tolerated. All adverse reactions were consistent with the known side effects of either romidepsin or Vacc-4x/rhuGM-CSF.
These results are crucial in showing that Vacc-4x administered with rhuGM-CSF is capable of priming the immune system to control HIV in the blood after the virus has been ‘shocked’ out of its dormant state by a latency reversing agent. The trial results are supported by previous data, demonstrating that Vacc-4x/rhuGM-CSF reduced the viral load set-point during antiretroviral treatment interruption in a placebo-controlled trial (CT BI-Vacc-4x 2007/1).
Viral load remained below the level of detection in 11 out of 17 patients on combination antiretroviral therapy (cART) despite reservoir reactivation. Four patients had measureable but low viral load and only at one of the three romidepsin infusions. The pharmacodynamic effect of romidepsin, i.e., reactivation of the latent HIV reservoir, was confirmed by increases in histone acetylation levels and viral expression
The combination of Vacc-4x and romidepsin was safe and well tolerated.
The results create a strong foundation for further advancement of Vacc-4x as a core component in a functional cure for HIV. As previously communicated, Bionor expects to initiate the BIOSKILL clinical trial when funding has been secured to execute and complete the full scope of the trial. To date, Bionor has filed clinical trial applications for BIOSKILL in the United Kingdom, Germany, and Denmark.
Viral load (Plasma HIV-1 RNA) remained below the limit of detection (20 copies/ml) in 11 of 17 patients throughout the trial while on cART despite a documented viral reactivation in CD4+ T cells following romidepsin infusions. Of the six patients with detectable viral load, four patients had measureable but low HIV in the blood after one of the three romidepsin infusions, and only 21-59 copies/ml. Importantly, only two of 17 patients had detectable viral load after each of the three romidepsin infusions.
The median time to re-initiation of cART following treatment interruption was 24.5 days, which is similar to what would be expected without an intervention. The results are aligned with a consensus in the HIV scientific community that a combination of more than two different compound classes is likely required to achieve a long-lasting viral control in the absence of cART.
The treatment of Vacc-4x and romidepsin was safe and well tolerated. All adverse reactions were consistent with the known side effects of either romidepsin (i.e., fatigue, nausea, and constipation) or Vacc-4x administered with GM-CSF (local skin reactions, fatigue, and headache).
Additional secondary virological and immunological endpoints, such as ELISPOT, proliferation, antibody titer to Vacc-4x peptides and to p24, and change in antibody titer to C5 are still being analyzed, and will be presented in the final study report.
It is encouraging and supportive of Bionor’s clinical ‘Shock & Kill’ approach that latent reservoir was reduced by 40% while patients were on cART, and that viral load remained below the level of detection in the majority of patients. While the observed reduction in latent reservoir may not be sufficient to maintain long-term viral control in the absence of cART, the novel findings in the REDUC trial are considered by the company as well as by the investigators as an important clinical advancement in the search for a functional cure for HIV.
• viral load remained below the level of quantification in 7 out of 9 patients
• increases in histone acetylation levels correlating to the time of romidepsin-infusions, demonstrating the pharmacodynamic effect of romidepsin
• a rapid and temporary viral reactivation in CD4+ T cells following romidepsin-infusions
• the combination of Vacc-4x and romidepsin was safe and well tolerated
