Vaccibody AS today announced positive results from the phase I part of the clinical trial VB C-01. This trial is a first human dose, open-label, multicenter phase I/IIa study of VB10.16 immunotherapy for the treatment of high grade Cervical Intraepithelial Neoplasia (CIN 2/3) caused by human papillomavirus 16 (HPV16).
The phase I enrolled CIN 2 patients in two cohorts of 8 patients each receiving three doses of 3 mg of VB10.16 either at week 0, 3 and 6 (Cohort 1) or week 0, 4 and 12 (Cohort 2). The primary objective of the study is to evaluate the safety and tolerability of three doses of 3 mg VB10.16. The secondary objectives are to assess T cell mediated immune responses in the peripheral blood and to evaluate early signs of efficacy by means of HPV clearance and CIN regression. The vaccine is delivered with a needle-free, pain-less PharmaJet® Stratis Needle-free Injection System.
The treatment with VB10.16 was well tolerated. No serious adverse advents (SAEs) have been reported. The most common AEs were transient mild to moderate local site reactions at the administration site.
Immunological analyses of the peripheral blood demonstrated a strong induction of HPV16-specific T cell immune responses in 12 of 14 patients evaluated. The response was induced against both antigens used in the vaccine (HPV16 E6 and E7). The short interval immunization regimen in Cohort 1 induced a more rapid, stronger and longer-lasting T cell response than seen with the schedule with longer intervals used in Cohort 2. Therefore, and as earlier reported, the immunization regimen in Cohort 1 was chosen for the expansion phase of the study (clinical phase IIa), which was initiated in Q1 2017. Vaccibody will enroll 15-20 additional patients with CIN 2/3 in this expansion phase.
The strength of the immune response correlates directly with reduction in the size of the lesions and shows a clear trend with CIN regression as well as HPV16 clearance. In Cohort 1 reduction in the size of the lesions after 12 months was observed in 4 of 6 patients (two patients chose to be conizated during the course of the study and were thus excluded from the 12-month analysis). Histopathological regression to low grade neoplasia (CIN 1) or no disease was seen in 3 of 6 patients. During the course of the 12-months study/follow up period, however, all 6 of 6 patients at some point in time has shown histopathological regression to CIN 1 or no disease and simultaneously 5 out of 6 presented with reduction in lesion size. Both co-infection with other high-risk HPV infections and a transient upregulation of PD-L1 was observed in the patients without complete long-term responses and may play a role in these findings. The observed HPV16-specific T cell responses peaked after 2 months in Cohort 1 and in order to improve the chances of long-term regression of lesions, the phase IIa immunization scheme will be supplemented with an extra vaccination at 16 weeks to increase and prolong the T cell response that seem to correlate directly with clinical responses.
Vaccibody is currently preparing for a clinical trial application to investigate its neoantigen-based vaccine. In this trial, monthly immunizations are planned throughout the first year of treatment and the patients will be treated with anti-PD-1/PD-L1 (checkpoint inhibitor) immunotherapy. The data from the phase I in VB C-01 serves as a proof of concept for the neoantigen programme both regarding safety, immunogenicity and initial efficacy. The planned trial design with multiple immunizations, 20 targeted neoantigens as well as combination with checkpoint inhibitors are strongly supported by the data observed in VB C-01.
Martin Bonde, CEO of Vaccibody, commented: We are very pleased with the data we have seen so far. The vaccine appears to have an excellent safety profile and the T cell immune responses observed to date indicate that VB10.16 induces a stronger HPV16-specific immune response than what we have seen reported in the literature. While other DNA vaccines developed for this indication require delivery with in vivo electroporation, which requires more investment in equipment and is reported to be quite painful, VB10.16 is delivered by a simple needle-free, painless jet injection which we believe improves patient compliance tremendously and will be a significant asset in further development of this product. The fact that we see lesion size reduction and CIN regression in a high percentage of these patients and see a clear correlation with the vaccine-induced immune responses, is highly encouraging, even if the number of patients evaluated is still low. We look forward to further substantiate the efficacy of VB10.16 in the on-going phase IIa study.
This is the first clinical study utilizing Vaccibody’s Vaccine Platform Technology and the positive results can have a significant impact not only on the development of the company’s lead product, VB10.16, but very importantly also represent a proof of principle for the technology and the potential to use this platform in further indications. We do observe a role of PD-L1 upregulation linked to the clinical responses in this phase I trial. This invites to pursue potential synergistic effects by combining therapeutic Vaccibody cancer vaccines and checkpoint inhibitors, like we have observed in preclinical experiments. We are currently preparing to submit a clinical trial application for our neoantigen programme where we take all data from VB C-01 into consideration in the clinical trial design and we are very excited to get this trial started.
The company’s lead product, VB10.16, is a therapeutic DNA vaccine developed to treat human papillomavirus type 16 (HPV16) induced pre-malignancies and malignancies.
About Cervical Intraepithelial Neoplasia (CIN) and Cervical Cancer
Per year approximately 530,000 women are diagnosed with cervical cancer worldwide and over 275,000 women die of the disease annually. Invasive cervical cancer is preceded by a long phase of pre-invasive disease called Cervical Intraepithelial Neoplasia (CIN). Globally the number of high grade lesions (CIN 2/3), the immediate precursors to malignancy, is estimated to be in the range of 10 million.
Virtually all cervical cancers are caused by high risk HPV types. Among the different high risk HPV types known, HPV16 has been reported to be the most common genotype in high grade cervical intraepithelial neoplasia. It can be detected in up to 60 % of all cervical cancers, especially in younger women and it has also been found to play an essential role in the development of several other cancer types (approximately 90% of anal cancers; 40% of penile, vaginal, and vulvar cancers; 25% of oral cavity cancers and 35% of oropharyngeal cancers).
Current standard therapy for CIN 2/3 varies between countries and regions and often involves surgical removal of the affected tissue. These invasive procedures are associated with bleeding, infection, cervical stenosis, scarring and most importantly pre-term deliveries in subsequent pregnancies. As a result, there is a significant need for an effective therapeutic vaccine to treat existing HPV infection and associated pre-malignancies and malignancies of the cervix and thereby prevent the development of cervical cancer caused by human papillomavirus.
About Vaccibody AS
Vaccibody is a biopharmaceutical company dedicated to the discovery and development of novel immunotherapies. Vaccibody’s lead program is focused on VB10.16, a therapeutic DNA vaccine against HPV16 induced pre-malignancies and malignancies. The first-in-human study will evaluate the safety and immunogenicity of VB10.16 in women with high grade cervical intraepithelial neoplasia (HSIL; CIN 2/3). Vaccibody has also initiated development of neoantigen-based individualized cancer vaccines and is using the Vaccibody technology to generate best-in-class therapeutics to treat cancers with a high unmet medical need.
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