RINTEGA® (rindopepimut) is an investigational immunotherapy that targets the tumor specific oncogene EGFRvIII (also known as EGFRv3), a functional and permanently activated mutation of the epidermal growth factor receptor (EGFR), a protein that has been well validated as a target for cancer therapy. Expression of EGFRvIII correlates with increased tumorigenicity in mouse models and poor long term survival in clinical studies of glioblastoma patients. In addition, EGFRvIII positive cells are believed to stimulate proliferation of non-EGFRvIII cells through IL-6 cell-to-cell signaling and to release microvesicles containing EGFRvIII, which can merge with neighboring cells, transferring tumor-promoting activity. EGFRvIII expression may also be associated with tumor stem cells that have been identified in GBM. These stem cells contribute to resistance to cytotoxic therapy and tumor recurrence. EGFRvIII is expressed in tumors in about 30% of glioblastoma patients. It has not been detected at a significant level in normal tissues; therefore, targeting of this tumor-specific molecule is not likely to impact healthy tissues.

RINTEGA is administered via intradermal injection and consists of the EGFRvIII-specific peptide sequence conjugated to keyhole limpet hemocyanin (KLH), a carrier protein. RINTEGA stimulates the patient’s immune system, inducing pronounced EGFRvIII-specific humoral and cellular responses.

The Phase 3 ACT IV Study of RINTEGA in Newly Diagnosed Glioblastoma (discontinued)

ACT IVA Phase 3 study called ACT IV was conducted in newly diagnosed EGFRvIII-positive glioblastoma patients. The 745-patient study was a randomized, double-blind, controlled study of RINTEGA plus granulocyte-macrophage colony-stimulating factor (GM-CSF) added to standard of care temozolomide. The control arm regimen included standard of care temozolomide plus injections of keyhole limpet hemocyanin (KLH). KLH is a component of RINTEGA and was selected due to its ability to generate an injection site reaction similar to that observed with the RINTEGA vaccine, which improves the blinding of the study. The ACT IV study was discontinued in March 2016 based on the recommendation of the independent Data Safety and Monitoring Board that the study was unlikely to meet its primary overall survival endpoint in patients with minimal residual disease as both the RINTEGA arm and the control arm were performing on par with each other. In the ACT IV study, RINTEGA performed consistently with prior Phase 2 studies (ACTIVATE, ACT II, ACT III) but the control arm significantly outperformed expectations (Hazard ratio = 0.99; median OS: RINTEGA 20.4 months vs. control 21.1 months). All patients on the RINTEGA arm of the ACT IV study, prior Phase 2 studies and existing compassionate use recipients are being offered ongoing access to RINTEGA on a compassionate use basis. Across all studies, RINTEGA has been generally well tolerated. The most common adverse events are injection site reactions, fatigue, rash, nausea and pruritus.

The Phase 2 ReACT Study of RINTEGA in Recurrent Glioblastoma

ReActThe ReACT study was a randomized, Phase 2 trial of RINTEGA in combination with bevacizumab (Avastin®) in patients with recurrent EGFRvIII-positive glioblastoma. The study enrolled 125 patients in a first or second relapse of glioblastoma following receipt of standard therapy and was conducted at approximately 20 sites across the United States. Group 1 enrolled 73 bevacizumab-naïve patients randomized to receive either RINTEGA or a control injection of KLH in a blinded fashion; all patients also received bevacizumab. Additionally, group 2 included 25 patients refractory to bevacizumab (received bevacizumab in either the newly diagnosed or recurrent setting with subsequent progression) who received RINTEGA plus bevacizumab in a single treatment arm. In August 2013, we reported that an expansion cohort (group 2C) of patients refractory to bevacizumab was added to better characterize the potential activity of RINTEGA in the refractory patient population. 28 patients were enrolled into this group. All patients were evaluated for the progression rate at six months, objective response rate, overall survival (OS) and progression free survival (PFS).

In November 2014, the Company reported interim data from the ReACT study at the Annual Scientific Meeting of the Society for Neuro-Oncology (SNO). Across both group 1 and group 2, RINTEGA plus bevacizumab was very well tolerated, and the results demonstrated promising signs of clinical activity in advanced patient populations.

At the Annual Meeting of the American Society of Clinical Oncology (ASCO) in May 2015, the Company reported that the ReACT Study’s (group 1) primary endpoint of progression-free survival at six months (PFS6) was met, and a clear advantage was demonstrated across multiple, clinically important endpoints including overall survival (OS), long-term progression-free survival, objective response rate (ORR) and need for steroids.

At the Annual Scientific Meeting of the Society for Neuro-Oncology in November 2015, the Company reported mature, long-term survival data from the ReACT Study (group 1). Mature OS data continued to show a marked benefit with a long-term survival benefit clearly seen in the RINTEGA arm of the study. At two years, the survival rate was 25% for patients in the RINTEGA arm versus 0% for patients in the control arm. The advantage across multiple endpoints continued to be demonstrated.

For more information on the RINTEGA program, view recent scientific presentations and publications.