A core component in a possible functional HIV cure - Vacc-4x

Vacc-4x is developed to guide the immune system to seek out and kill HIV-infected cells. The treatment aims to induce sustained immune responses to conserved domains (regions of the virus common to all strains of HIV), which do not change despite mutations in other parts of the virus.

A core component in a possible functional HIV cure - Vacc-4x
Vacc-4x: A unique, antigen-specific, anti-HIV Therapy

 Vacc-4x is designed to induce CD4+ and CD8+ T cell responses that will remove HIV-infected cells, which should contribute to reduction of the latent reservoir following re-activation by latency reversing agents, such as romidepsin.

The REDUC trial

Bionor completed the REDUC clinical trial in December 2015 evaluating whether priming the immune system with Vacc-4x to attack HIV infected CD4+ T cells upon activation of the latent reservoir can improve viral control after administration of the latency reversing agent, romidepsin. REDUC with Vacc-4x and romidepsin successfully met its primary endpoint by significantly reducing latent HIV reservoir and demonstrated control of viral load.

The headline results in REDUC were:

  • The latent HIV reservoir was significantly reduced by 40% (Total HIV DNA and qVOA)
  • 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 following findings from Phase I and Phase II clinical trials of Vacc-4x provide the rationale for the company’s development program (ref. to clinical studies):

  • It has been shown to reduce viral load (level of virus in the blood) and viral load setpoint indicating that Vacc-4x can induce an immune response to HIV (CT BI-Vacc-4x 2007/1 clinical trial)
  • Vacc-4x has been shown to induce long term Vacc-4x specific T immune-cell memory indicating that Vacc-4x can induce durable immune responses (CTN BI-Vacc-4x/2009/1 and CT-BI Vacc-4x 2012/1 clinical trials)
  • Immune responses to Vacc-4x have been shown to be safely re-stimulated indicating that periodic booster immunizations can be done to maintain immune effect as for vaccines in general (CTN BI-Vacc-4x/2009/1 and CT-BI Vacc-4x 2012/1 clinical trials)
  • It has been shown to reduce viral pro-viral DNA, a measure of reservoir size, in cART treated patients, indicating that HIV infected latent reservoir cells are killed, also in the presence of cART (CT-BI Vacc-4x 2012/1 clinical trials)
  • Vacc-4x has demonstrated reduction of plasma HIV-RNA after reactivation of latent reservoir, indicating immune-based killing of HIV containing CD4+ T cells (BPC01-001 clinical trial (REDUC))
  • To date, Vacc-4x has been shown to be safe and well tolerated, also in combination with other treatments (cART, romidepsin, lenalidomide) (BPC01-001 clinical trial (REDUC))

Based on the successful completion of the REDUC trial, Bionor is currently planning a multicenter placebo-controlled proof of concept Phase II clinical trial as part of the company’s strategy to significantly contribute to a possible functional cure of HIV infection (BIOSKILL – Bionor Shock and Kill) which may lead to a major value inflection point and partnering opportunities. Bionor currently retains full ownership rights of Vacc-4x.

Vacc-4x description and mode of action

Vacc-4x consists of 4 peptides corresponding to conserved regions on the p24 protein that constitutes the core protein of HIV. These 4 peptides are modified by amino acid substitution, addition and deletion. The vaccine is intended to induce, sustain or recover CD4+ and CD8+ T cell responses to p24, so that the immune cells recognize and remove infected cells presenting the native versions of such p24 peptides. Immune responses to p24 and to Gag proteins (structural proteins that include p24) are associated with slow disease progression and improved viral control.

Conserved regions have low mutation frequency and as such represent functionally critical regions on the virus where mutations that would avoid attack by immune cells are likely to impact virus viability. Using 4 peptides is thought by the company to increase the potential for immune recognition of infected cells in diverse human populations.

Clinical trials

Based on the 7 completed Bionor sponsored Phase I and Phase II clinical trials of Vacc-4x, and the administration of the drug to more than 260 patients, Vacc-4x is considered by Bionor to be safe and well tolerated, including in combination with other treatments (cART, romidepsin, lenalidomide). Vacc-4x treatment is scalable, manufacturing of the peptides is fairly straight forward and it has a patient friendly mode of administration compared to some of the other therapeutic approaches in development. Bionor’s clinical trial results to date indicate that Vacc-4x could become a core component of a functional cure for HIV infection.

In December 2015, Bionor announced that the HIV ’Shock & Kill’ trial REDUC with Vacc-4x and romidepsin met its primary endpoint by significantly reducing latent HIV reservoir and demonstrated control of viral load. The novel findings in the REDUC trial was considered by the company as well as by the investigators as an important clinical advancement in the search for a functional cure for HIV. Based on the successful REDUC trial, Bionor is currently planning BIOSKILL, a multicenter placebo-controlled proof of concept Phase II clinical trial of its strategy for a functional cure of HIV infection.

Overview of completed Bionor-sponsored clinical trials with Vacc-4x

CTN B-HIV-1/99

First in man; 11 patients, 0.4 mg, safety endpoint, Norway

CTN B-HIV-2/2001

Dose finding, 40 patients, 0.4 mg and 1.2 mg, immunogenicity, Norway

CT BI-Vacc-4x 2007/1

Efficacy and safety, 135 patients, 1.2 mg, reduction in viral load
setpoint after treatment interruption, first placebo controlled, randomised, double blind study,  U.S., UK, Germany, Spain, Italy

CTN BI-Vacc-4x/2009/1

Re-boost of 25 of the 38 patients from CTN B-HIV-2/2001, 1.2 mg, Norway

CT-BI Vacc-4x/IMiD-2010/1

Vacc-4x and lenalidomide, 36 patients, randomised, double blind, 1.2 mg Germany

CT-BI Vacc-4x 2012/1

Re-boost of 33 patients from CT BI-Vacc-4x 2007/1, 1.2 mg, U.S., UK, Germany, Spain, Italy

BPC01-001 (REDUC)

Vacc-4x and romidepsin, 26 patients, open label, 1.2 mg, Denmark