Bionor announces that the HIV 'Shock & Kill' trial REDUC with Vacc-4x and romidepsin meets its primary endpoint by significantly reducing latent HIV reservoir and demonstrates control of viral load

BIONOR PHARMA ASA

STOCK EXCHANGE ANNOUNCEMENT

Bionor announces that the HIV 'Shock & Kill' trial REDUC with Vacc-4x and romidepsin meets its primary endpoint by significantly reducing latent HIV reservoir and demonstrates control of viral load

(Oslo, Norway, 21 December 2015) Bionor Pharma ASA (OSE:BIONOR), a biopharmaceutical company focused on advancing a functional cure for HIV announces successful results of the REDUC Part B clinical trial. In the REDUC trial, the combination of Vacc-4x and the latency reversing agent romidepsin (Istodax^®, Celgene) 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.

Bionor will host a conference call today with CEO David Horn Solomon who will present the results and conclusions. Please see dial-in details at the back of this announcement.

The headline results are:

• 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 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.

Dr. David Horn Solomon, President and CEO commented:
"I am very excited about the results announced today. The findings of the REDUC trial convey a clear and unequivocal message that it is highly relevant to further advance the combination of Vacc-4x and romidepsin in clinical development. I am especially encouraged by the significant reduction in latent reservoir combined with the fact that a majority of patients were able to control viral load after latency activation. Based on our pioneering work and robust clinical development experience, I am confident that the international, controlled and adequately powered BIOSKILL trial can confirm the role of Vacc-4x as a therapeutic HIV vaccine, and that Bionor is on the right track to develop a functional cure for HIV."

The Principal Investigator of the REDUC trial, Professor Lars Østergaard, Head of the Department of Infectious Diseases, Aarhus University Hospital Center in Denmark, also expressed enthusiasm for the trial outcome:
"The results of the REDUC trial are highly encouraging and confirm that we are on the right track toward a cure for HIV. There are several highlights of the study, namely, the statistically significant decrease of the viral reservoir as measured by Total HIV DNA, and of utmost importance is the highly acceptable short-term safety data. It is also very positive that we see consistency with the interim results reported earlier in 2015. While no patient is yet cured as a consequence of the REDUC trial, it is a step on the way to a cure for HIV, and further research and development based on the Shock & Kill principle is urgently needed."

Study design
In Part B of the REDUC trial, Bionor's proprietary therapeutic vaccine Vacc-4x and the latency reversing agent romidepsin were explored as a possible treatment regimen to reduce the size of the latent viral reservoir in HIV infected patients on anti-retroviral treatment, which could significantly contribute to a functional HIV cure. In addition, the ability to control viral load during a treatment interruption of cART was investigated.

The primary endpoint was the latent reservoir size measured in CD4+ T cells by three assays:

• Total HIV DNA (copies per 10⁶ CD4+ T cells);
• HIV quantitative viral outgrowth assay (qVOA) (infectious units per 10⁶ resting memory CD4+ T immune cells (IUPM)); and
• Integrated HIV DNA (copies per 10⁶ CD4+ T cells).

Secondary endpoints were:

• Plasma HIV-1 RNA (viral load);
• Time to re-initiation of cART following treatment interruption; and
• Other secondary virological, immunological, safety and tolerability endpoints.

Latent reservoir size
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.

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.

Total HIV DNA is the most widely used assay for estimation of reservoir size (Rouzioux, C & Richman, D (2013) 'How to best measure HIV reservoirs?' Current Opinion in HIV and AIDS 8, 170-175). The application of qVOA in clinical trial settings is challenging, and in this study, data above the limit of detection were achieved for six patients.

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).

Viral load
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.

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.

These results are crucial in demonstrating that Vacc-4x 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.

Time to rebound
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.

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.

Safety and tolerability
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).

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
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.

Long-term development plan and next steps
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.

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.

Background information
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.

Vacc-4x is the company's proprietary therapeutic vaccine, which contains four synthetic HIV p24 peptide analogs. 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. Vacc-4x has been designed to elicit a cell-based immune response by generating T cells that can recognize and destroy infected HIV cells.

In 2012, the global HIV market generated sales of roughly $12 billion from the sale of anti-retroviral therapies. HIV patients treated with antiretrovirals face a lifetime of daily pills, often with side effects and long-term health implications including cardiovascular disease, kidney, liver and bone problems.

This information is subject of the disclosure requirements pursuant to section 5-12 of the Norwegian Securities Trading Act.

Teleconference 21 December 2015 at 12:00 CET
Bionor will host a conference call today with CEO David Horn Solomon who will present the results and conclusions. To attend the call, please use the participant code 3751489.

Norway: +47 2316 2771
Denmark: +45 32 71 16 59
United Kingdom: +44 20 3427 1916
USA: +1 212 444 0412
Sweden: +46 850 653 936

A presentation will be available on our website prior to the call. A webcast of the conference call will be available during and after the event.
Link to webcast: http://edge.media-server.com/m/p/ppbqccqh

Further information
David H. Solomon, President and CEO, +45 22 20 63 00, dhs@bionorpharma.com
Jørgen F. Ravn, VP Investor Relations & Communications, +45 20 30 39 03, jfr@bionorpharma.com

About Bionor
Bionor Pharma is a Norwegian biopharmaceutical company focused on advancing its proprietary therapeutic vaccine Vacc-4x in combination with other medicines toward a functional HIV cure. The company believes it has first mover potential based on clinical results to date and early adoption of now recognized clinical strategy. In December 2015, Bionor reported successful completion of the REDUC clinical trial and is currently planning BIOSKILL, a proof-of-concept Phase II trial, which may lead to a major value inflection point and partnering opportunities. Bionor currently retains full ownership rights to Vacc-4x, i.e., the upside potential from partnering or licensing remains with the company. Bionor is based in Oslo, Norway, and also has offices in Copenhagen, Denmark and New York, USA. Bionor is listed on Oslo Børs (OSE:BIONOR). More information about Bionor is available at www.bionorpharma.com.