Glioblastoma Multiforme

About Brain Tumours

Primary malignant brain tumours can arise from any of the different cell types in the central nervous system but the commonest intracranial neoplasms are tumours of an astrocytic lineage which account for over 60% of all primary brain tumours. These tumours are characterised by diffuse infiltration of adjacent and distant brain and can exhibit a varying degree of anaplasia. Brain tumours can usually be staged by WHO guidelines as Grade I, II, III or IV.

Virttu has focused initially on WHO Grade IV brain tumours or glioblastoma multiforme (GBM), the highest-grade of brain tumours.

GBM is the most frequently occurring and most malignant astrocytic tumour, typically affecting adults with peak incidence between 45 and 70 years. GBM accounts for 15% of all intracranial neoplasms and 50 to 60% of all astrocytic tumours. In most European and North American countries, the incidence of GBM is approximately 7 cases per 100,000 population per year.

GBM remains one of the most malignant human tumours and there is a significant unmet need for new treatment options.

SEPREHVIR^®(HSV1716) Clinical Studies in Glioma

Highlights

• 47 patients injected with HSV1716 at site known to support wild-type virus replication with no apparent toxicity
• Well-tolerated with no adverse events attributable to HSV1716
• No shedding of virus was detected
• Proof of Principle
• Evidence of virus replication in tumours
• Evidence that previous exposure to HSV did not stop replication of HSV1716
• Orphan Medicinal Product Designation from the European Medicines Agency

Summaries

The first clinical study of SEPREHVIR^®(HSV1716) involved the stereotactic intratumoural injection of virus at doses of 10³ to 10⁵ plaque-forming units (pfu) administered via a single dose. 9 patients with primary or recurrent malignant glioma underwent treatment; 3 at 10³ pfu, 3 at 10⁴ pfu, and 3 at 10⁵ pfu. No adverse clinical symptoms attributable to HSV1716 were identified. No symptoms of HSV infection were observed (including no HSV infection in the brain nor any recurrence of skin lesions from a patient's latent HSV were observed). Although subjects in this study were immuno-compromised as a result of previous anti-tumour therapy and corticosteroid treatment, none showed evidence of HSV1716 replication within normal brain tissue.

The study was extended further with an additional 12 subjects treated according to the same protocol. 3 subjects in the supplementary group received a dose of 10⁵ pfu while 9 subjects received a dose of 10⁶ pfu on a single occasion. No toxicity associated with the administration of SEPREHVIR^® (HSV1716) was observed.

A second clinical study assessed the potential for efficacy of SEPREHVIR^® (HSV1716) in glioma patients. 12 subjects with biopsy-verified primary or recurrent malignant glioma received a single intratumoural injection of 10⁵ pfu HSV1716. Four to nine days following virus injection, tumours were resected and analysed for evidence of viral replication. In 2 subjects, SEPREHVIR^®(HSV1716) in excess of the input dose was recovered from the injection site. HSV DNA was detected by PCR at the sites of inoculation in 10 subjects and at distal tumour sites in 4 subjects. HSV specific antigen was detected by immunohistochemistry in tumour tissue from 4 subjects. An immunological response to HSV was detected in 5 patients. Again, no adverse clinical symptoms attributable to HSV1716 were identified, nor any induction of encephalitis or latent wild type HSV re-activation. This study offers supporting evidence that SEPREHVIR^®(HSV1716) replicates in high-grade glioma in both seropositive and seronegative subjects without causing toxicity.

In a third clinical study in glioma, SEPREHVIR^®(HSV1716) was injected into the healthy brain tissue surrounding the tumour immediately following tumour resection in both recurrent and de-novo tumours. 12 subjects with recurrent or newly diagnosed high-grade glioma underwent treatment in this study. No subject experienced toxicity and 3 of the subjects lived longer than 15 months. In 1 subject who had extensive recurrent disease pre-procedure, there was imaging evidence of reduction in residual tumour over a 22 month period despite no further medical intervention at that time.

In a fourth clinical study, two further patients with recurrent GBM each received two administrations of SEPREHVIR^® (HSV1716) at 6-week intervals by intratumoural injection. Repeat administration of doses up to 6 x 10⁶ pfu of SEPREHVIR^® were generally well-tolerated and, in the context of the limited patient numbers, the safety results were consistent with previous experience in glioma patients.

Future Efficacy Trials in Glioma

The Phase I results have led to the expansion into efficacy trials in high grade glioma.

VIRTTU is now preparing to initiate 2 new Phase ll clinical studies in adults and a Phase I in paediatric patient populations.