UPDATED 18.11.2010:

After further analyses of the international, randomized, double-blind, placebo-controlled multi-center phase IIb study of Bionor Pharma's therapeutic HIV-vaccine candidate, Vacc-4x, the Company reports an unexpected statistically significant reduction in viral load (amount of HIV virus) at the end of the study period for patients on the vaccine compared to the placebo group.

The study was designed to test HIV-patients' ability to stay off anti-retroviral therapy (ART) after having been immunized with Vacc-4x. Although the study did not meet its primary endpoints, as announced October 1, the findings from the additional analysis discovered that treatment difference with regard to viral load was statistically significant both within the study period and when compared to the viral load prior to ever starting ART. In patients who received immunization, viral load never returned to its pre-ART level, which normally happens when being taken off ART.

Due to the new findings, the Company has reversed its decision to stop development of Vacc-4x. Along with upcoming immunological data, these findings are expected to become the basis for the future positioning of Vacc-4x as a viable therapeutic HIV-vaccine.

Clinical Development of Vacc-4x

Vacc-4x has undergone several pre-clinical and clinical studies:

Pre-Clinical

The non-clinical toxicology programme was designed to characterise the acute and repeated-dose toxicology of Vacc-4x when administered alone and in combination with the GM-CSF adjuvant. Vacc-4x was shown to be free of acute toxicities that would preclude its development. The toxicology of Vacc-4x has been investigated using study designs that have mimicked proposed clinical study administration with administration intradermally on an intermittent (Weeks 1, 2, 3, 4, 12, 16, 18 and 22) and (Weeks 1, 2, 3 and 4) weekly treatment schedule. Relevant immunological measures and a full histopathological evaluation were incorporated into the designs. The effect of Vacc-4x in these studies was evaluated in the presence of concomitant GM-CSF. The studies showed no evidence of adverse systemic effects but there were signs of redness and swelling local to the injection, regardless of administration of Vacc-4x, and additional local reaction associated with the higher dose of Vacc-4x with GM-CSF. In a further study different GM-CSF products have been compared with similar results for each. Overall the data indicate that Vacc-4x has shown no limiting toxicology.

Phase I

Study CTN B-HIV-1/99 was a Phase I single-centre, open-label study at Haukeland University Hospital, designed to evaluate the safety and toxicity of the Vacc-4x therapeutic vaccine in HIV-positive subjects. The study enrolled 11 chronically HIV-infected subjects, including nine subjects on HAART, all of whom were treated with  up to 12 vaccinations with Vacc-4x, at a dose of 0.4mg/injection, over a period of 26 weeks. Immunizations were performed following injection of GM-CSF (Leucomax® [molgramostim]) as adjuvant. The results demonstrated that Vacc-4x at a dose of 0.4mg per immunization after injection of GM-CSF (Leucomax® [molgramostim]) at the same injection site was well tolerated. Adverse reactions reported were of mild or moderate severity except for local reactions graded as severe in one subject. No subjects were withdrawn due to treatment-related adverse events or toxicological reactions; no serious adverse events occurred.

Phase IIa – “Drug holiday” 

The Vacc-4x Phase IIa trial was a single centre, open-label study at Oslo University Hospital, designed to evaluate the response to two dose levels of the Vacc-4x therapeutic vaccine (with GM-CSF) and to evaluate safety and tolerability in HIV-positive subjects who had complete suppression of HIV-1 by ART. The study enrolled and treated 40 chronically HIV-infected subjects (infected for 5-9.5 years). The trial commenced in March 2002 and was completed in December 2003, with patient follow-up through August of 2006. The patients had been on ART for between 1.2 and 10.8 years, and at the time of entry into the study had CD4+ T cell levels of more than 300 cells per mm3 and less than 400 copies of HIV RNA per ml of peripheral blood. Patients were maintained on ART and treated with 10 immunizations at a dose of 0.4mg (20 patients) or 1.2mg (20 patients) per Vacc-4x injection, over a period of 26 weeks. The intradermal injections were co-administered with a small dose of GM-CSF, the adjuvant that is used to activate local dendritic cells which then efficiently stimulate T-cells. ART was interrupted from Week 26 to Week 30 to allow exposure to the subject’s own virus (autologous immunization). ART was resumed from Week 30 to Week 38 to allow maturation of immune responses to the Vacc-4x peptides and to the subject’s own virus. ART was discontinued from Week 38 to Week 52 when the study was formally concluded. As the majority of subjects were doing well at the conclusion of the study, the subjects were allowed to be monitored ART-free under the care of their personal physician until they resumed ART according to standard clinical practice.

The primary objective was to study immunogenicity to Vacc-4x, which included post-vaccination in vitro antigen specific T-cell responses and a delayed-type hypersensitivity skin test (DTH). The results of the study showed that Vacc-4x at both doses was well tolerated. No serious adverse events were reported during the period of immunization. Patients that responded well to Vacc-4x had significantly reduced viral loads compared to low responders and better preserved CD4+ T-cell counts at the end of a three month ART-free period. Although CD4+ counts decline during ART free periods, the majority of patients remained off ART on completion of the study, and the duration of treatment interruption was related to immune responsiveness to the peptides. The median treatment interruption achieved was 31 months when ART was resumed based on clinical practice.

Patients experienced a significant increase in CD4+ levels while on ART during the immunization phase. The potential for a clinically significant increase was shown in several of the enrolled patients with low CD4+ levels. This is corroborated by the aggregated results from this study and the Phase I study showing that CD4+ levels increased about 25% for those patients with CD4+ levels below 500 cells per mm3. This clinical result substantially exceeds what clinicians consider as the benchmark for a significant therapeutic increase; i.e., in patients with CD4+ counts at or below 300 cells per mm3, an increase of 8- 15% or 25-50 CD4+ cells per mm3. Additionally, patients experienced a very slow CD4+ decline while off ART.

The results, when compared by an independent academic research group to 52 similar patients selected from a Dutch academic Observational Cohort (called Athena), showed that while 25% of the patients from the Athena study remained off ART at 48 weeks, 75% of the patients in the Phase IIa trial remained off ART at 48 weeks. The difference between the groups is significant and illustrated on the graph below. The median time off ART for the 38 patients who completed the Phase IIa trial was 31 months, compared to 4 months in the Athena study. For 13 patients (34%) this benefit continued considerably longer with a median value of 44 months off ART. A few patients within the Phase IIa group continued to remain off ART over five years. As of June 2010 all patients, except two patients  were back on ART.

Phase IIa “Re-vaccination” study

Trial conducted during first half of 2010 at Oslo University Hospital to re-immunize 26 study volunteers from the original Phase IIa study conducted in 2002/2003.

In about half of the blood samples from the volunteers prior to re-vaccination, it was found retained memory to Vacc-4x seven years after their initial immunization. The following re-vaccination showed that this memory can be safely reactivated following re-immunization resulting in improved anti-viral responses.

Two thirds of study volunteers responded to Vacc-4x, and these responses were found to be cross-reactive with the virus itself.  The study also showed that Vacc-4x is capable of triggering the specific T-cells of the immune system that  function to seek out and kill infected cells (CD8+ killer T-cells) which is the objective of a successful T-cell vaccine.  Bionor Pharma believe these findings demonstrate the ability to safely and effectively “re-vaccinate” patients that previously have had an extended break in their daily HIV-medication (ART).

The complete study results are being prepared for publication in an international peer reviewed journal.

Phase IIb - Drug Holiday

The ongoing Phase IIb study of Vacc-4x is a randomized, double-blind, placebo-controlled, international, multi-center Phase II clinical study in HIV-positive subjects who are clinically stable on ART. Patients from USA, UK, Germany, Italy and Spain were randomly enrolled in a 2:1 ratio into one of two treatment groups receiving either Vacc-4x immunization while on ART or placebo injections while on ART.

The study recruited 135 HIV-positive patients who had been clinically stable on ART for the last six months with a viral load less than 50 copies/mL for the last six months and a CD4+ cell count of more than 400 cells per mm3. Patients received initial immunizations of 1.2mg Vacc-4x + 0.06mg Leukine (GM-CSF) at Weeks 1, 2, 3 and 4 followed by booster immunizations at Weeks 16 and 18. At Week 28, eligible subjects whose CD4+ count is at least 350 cells per mm3 were removed from ART and followed for an additional 24 weeks.

The primary efficacy endpoint is the proportion of subjects who require resumption of ART between the interruption of ART at Week 28 and the end of the study at Week 52. The criteria for resumption of ART has been defined as: CD4+ count falls below 350 cells per mm3 or decreases by >50% on two consecutive tests or whose viral load increases above 300,000 copies/mL on three consecutive tests (each re-test should be within two weeks of the last test).

In addition there are several secondary efficacy endpoints, including CD4 counts, CD8 counts and HIV-1 RNA and immunological responses.

The safety endpoints include the proportion of subjects who experience similar virologic suppression after reinitiation of ART as before ART interruption, in addition to vital signs (heart rate, blood pressure), clinical laboratory evaluations (serum chemistry, hematology) and physical examinations, etc.

The study was initiated under a US IND and commenced recruitment in 2008. Results are expected in September/October 2010, with immunological data being submitted primo November. 

Planned Phase IIa - Immune Reconstitution (“Low CD4+”)

The Company has decided to pursue an indication for patients with low CD4+ counts due to an insufficient immune reconstitution (poor regain of CD4+ counts) following the initiation of ART. The support for this new indication comes from the completed Phase IIa trial study data, which demonstrated increases in the CD4+ count, which were more marked in patients with low initial CD4+ counts than in other HIV-patients.

The Company plans to initiate a 20 or 24 patient Phase IIa trial in Q4 2010 to study the effect of Vacc-4x in conjunction with ART for patients with low CD4+ counts, i.e. baseline CD4+ level less than 300 cells per mm3 and an insufficient regain of CD4+ counts. The trial will measure immunogenicity, the number of patients with CD4+ levels above 200, immune cell subsets supporting T-cell functionality and the number of patients who develop an opportunistic infection. Data from the study is expected to be available in 2011.

Further studies

The company is evaluating its development program to include other indications and possible combinations with ART or various other immune therapies.

The development program will be revised following the completion of the phase IIb study.