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We have a dual strategy of developing our own IP as well as
in-licensing compounds for clinical development.
EGF PTI MECHANISM OF ACTION
EGF PATHWAY TARGETED IMMUNISATION
EGF PTI induces an immune response to EGF, the natural ligand to EGFR, in order to inhibit the activation of the EGF/EGFR pathway, thus providing PTI.

The existence of EGF/EGFR in NSCLC is comprehensively validated and has been scientifically and clinically confirmed. BVN-NSCLC-002 is a biological compound for EGF Pathway Targeted Immunisation (PTI) in a pivotal Phase III trial for the treatment of NSCLC.

NSCLC is the most frequently diagnosed form of lung cancer, accounting for up to 90% of all cases. Lung cancer itself is the number one cause of cancer death for
both men and women worldwide, with 1.2 million new cases per year and around 920,000 deaths.

The original research technology has been in-licensed from the Centre of Molecular Immunology, Cuba, and has shown encouraging results in earlier Phase II and Phase III trials.

Bioven commenced its Pivitol Phase III study in May 2015, an open label, multicentre, randomised trial to further establish safety and efficacy of EGF PTI in inoperable, late stage NSCLC patients, complying with EGF biomarker parameters and eligible to receive standard treatment and supportive care.


PHASE III TRIAL - BVNSCLC 002
A Phase III, open label, multi-center, randomized trial to establish safety and efficacy of EGF PTI in inoperable, late stage NSCLC patients, complying with EGF biomarker parameters and eligible to receive standard treatment and supportive care.

  The trial is in active recruitment with FPI, May 2015
  Primary endpoint: assess overall survival of EGF PTI compared with control
  Secondary endpoints: survival rate and progression – free survival
  400 randomized patients, enriched through a biomarker and assessment of gene mutations
  Over 60 centers on 4 continents
  The protocol includes all comments received from US FDA at the pre-IND meeting
  50%-60% of patients diagnosed with late stage NSCLC have an over-expression of EGF
  Concentration of serum EGF will be applied as a biomarker
  KRAS and ALK mutations will be assessed in all patients in all centers
  EGF PTI treatment will start prior to chemotherapy
  Immune response and reduction of circulating EGF is obtained early on in treatment, leading to combined effect of chemotherapy and EGF PTI
  Other key inclusion criteria
  From 18 years onwards
  ECOG, parameter for physical fitness, at enrolment of 0 to 1
  Extensive optimisation of patient enrichment by introduction of biomarker and excluding patients with EGFR mutation
  Further exploratory endpoints such as testing of activation of EGFR, testing KRAS mutation as well as CTCs at different time points will provide specific response criteria in the earlier phase of the trial. The exploratory endpoints will also provide data that can lead to an adaptive clinical protocol
  Principal Investigator: Dr. M. Nicolson, Consultant Medical Oncologist and Honorary Senior Lecturer to NHS in Aberdeen, UK and current chair NCRN, Lung Cancer (trial adopted by National Cancer Research Network (NCRN), NHS, UK)
  Bioven obtained approvals in all countries where clinical trial applications were submitted. Active regulatory contacts with US FDA ongoing


Further details of the trial are available at clinicaltrials.gov, a website of the US National Institutes of Health. Please follow this link:

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BIOMARKER DATA
After Phase IIb work in Cuba it became evident that EGF concentration was potentially a marker for the importance of the role of EGFR/EGF pathway in disease progression. As tumor development, also in NSCLC patients is multifactorial, it is of key importance to identify those patients in which the most important pathway involved in their disease corresponds to the specific treatment, in this case EGF targeted treatment.

A biomarker to identify those patients will lead to an enriched the study population with patients that will benefit most from the specific treatment.

As a result, the Centre for Molecular Immunology in Cuba began retrospectively testing the EGF concentration in all patient blood samples available at the time of enrollment in Phase II B trial and correlates these to the outcome of the trial.

Bioven developed all further steps to validate a biomarker.

The key conclusions of this analysis of EGF concentration are:
  There is a wide variation in serum circulation concentration of EGF in patients at enrollment
  The laboratory results were stratified over the entire data population and correlated with hazard ratios (HR), HR being a statistical evaluation of correlate between marker and OS.
  When patients with a serum concentration >250 ng/ml were considered, the HR value was 0.5, and overall survival benefit of six months was reached. This EGF concentration threshold was the only parameter and valid over the entire study population. This level has been set as biomarker in the inclusion criteria of the BV-NSCLC-002 Phase III trial
  The percentage of patients reaching this serum EGF threshold is approximately 50%, or in line with the 40-60% increased EGFR gene expression observed and reported in the scientific literature on NSCLC patients
  From the above it can be concluded that circulating EGF concentration is in line with EGFR gene up-regulation and a prognostic marker for enriching the study population
  The targeted HR of 0.5 in BV-NSCLC-002 is far better han the Proposed HR of 0.8 by ASCO for studies in NSCLC patients

The KM curves hereunder represent the prognostic value of the 250 pg/ml EGF threshold at randomization in Phase IIB trial at CIM.

In the graph below, the effect of introducing EGF at randomization is presented. This data is derived from a Phase IIB trial in Cuba and patients are selected for EGF concentration above the 250ng/ml threshold (n=94).

The information in this graph shows that the KM curves have the features of an enriched study population, that the HR was lower than 0.5 and that the overall survival benefit is statistically significant and, more importantly, medically relevant. This latter point is even more important from the patient’s perspective in the sense that benefit is achieved with a treatment that compares very favorably in its tolerability profile with current treatments.
Outcomes of Clinical Trials with EGF PTI