RINTEGA Product ShotRINTEGA® (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. 85% of patients in clinical trials evaluating RINTEGA developed significant anti-EGFRvIII antibody titers, which increased with time on study. The majority (67%) of these patients developed titers above 1:12,800. Such immune responses may contribute to the direct destruction of tumor cells expressing EGFRvIII.

Three Phase 2 trials of RINTEGA have been completed in newly diagnosed EGFRvIII-positive glioblastoma patients with consistent results—ACTIVATE, ACT II, ACT III —and patients continue to be followed for survival. Across all three studies, RINTEGA has been generally well tolerated with generation of robust, specific and durable immune responses. The most common adverse events for RINTEGA include injection site reactions, fatigue, rash, nausea and pruritus.

Pipeline - Rindopepimut

RINTEGA is currently being studied in two clinical trials—an international Phase 3 study called ACT IV in newly diagnosed GBM and a Phase 2 study called ReACT in recurrent GBM.

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

ACT IV

The ACT IV study is a randomized, double-blind, controlled study of RINTEGA plus granulocyte-macrophage colony-stimulating factor (GM-CSF) added to standard of care temozolomide in patients with newly diagnosed, surgically resected, EGFRvIII-positive glioblastoma. 745 patients were enrolled at over 200 centers worldwide to recruit 374 patients with minimal residual disease (assessed by central review) to be included in the primary analysis. Patients were randomized, one-to-one, into a treatment or control arm after the completion of surgery and standard chemoradiation.

The treatment arm regimen includes a vaccine priming phase post-radiation, followed by an adjuvant temozolomide and vaccine maintenance therapy phase. Patients are treated until disease progression. The control arm regimen includes 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 primary objective of the study is to determine whether RINTEGA plus GM-CSF improves the overall survival of patients with newly diagnosed EGFRvIII-positive glioblastoma after gross total resection (GTR) when compared to treatment with the current standard of care, temozolomide. Secondary endpoints include progression free survival, safety and tolerability of RINTEGA and GM-CSF in combination with temozolomide, neurologic status and quality of life.

The Phase 2 ReACT Study of RINTEGA in Recurrent Glioblastoma

ReAct
The ReACT study is 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 is being 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 keyhole limpet hemocyanin (KLH) in a blinded fashion; all patients are also receiving Avastin. Additionally, group 2 includes 25 patients refractory to bevacizumab (received bevacizumab in either the newly diagnosed or recurrent setting with subsequent progression) who are receiving 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 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 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. Mature OS data continue 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 is 25% for patients in the RINTEGA arm versus 0% for patients in the control arm. The advantage across multiple endpoints continues to be demonstrated.

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