ANYARA – the targeted cancer therapy
In the ANYARA project, Active Biotech is developing a method for combating cancer. The body´s own immune defense is stimulated with a targeted immune activator that helps T cells track and kill cancer cells. T cells can be stimulated with different targeted immune activators depending on the type of cancer being treated.
While it may be true that cancer is a complex disease that is often difficult to treat, we also know that there are some aspects of cancer that could provide the key to its elimination – or at least to future treatment methods. One such key is known as 5T4, a molecule generally found on the surface of tumor cells, but uncommon on healthy cells. Active Biotech's ANYARA (TTS) project focuses on using this molecular target to fight cancer.
The origins of the TTS concept are to be found in research performed at the Medeon Science Park in Malmö at the end of the eighties, where Gunnar Hedlund, who is now the project leader for Active Biotech's TTS project, was one of the inventors of the new concept.
"Developing pharmaceuticals to fight cancer requires both purposefulness and patience," he says. "It involves investigating completely new treatment principles. My entire professional life has been devoted to the field of immunology and immunomodulation."
A molecule unique to cancer
The 5T4 target molecule on the surface of tumor cells is a so-called oncofoetal antigen, a target structure that normally appears only during the early development stages of the foetus and that probably has a "positive" function at this stage. In the context of cancer, however, 5T4 is considered to be significant to the tumor's ability to form metastases, or new tumors.
A target-seeking missile
The TTS concept is generally described as a target-seeking missile consisting of:
- the homing device, which is a selected antibody that specifically binds to 5T4
- a superantigen that activates the white blood cells or lymphocytes in the body's own immune system to kill the tumor cells
A superantigen is a protein that is the most powerful lymphocyte activator known. The TTS substance enables the lymphocytes to gain access to the tumor cells, into which they inject proteins that force them to "commit suicide". This function was only recently explained, earning the 2002 Nobel Prize for medicine.
A new weapon
This is the exciting theory behind Active Biotech's TTS project, which focuses on developing a new drug to fight cancer and a new weapon to add to the traditional arsenal used to fight the disease, i.e. chemotherapy, radiation and surgery.
"But there is also a tremendous amount of research and development work involved," says Gunnar Hedlund. "Prior to the clinical studies, we had already been able to show that the TTS substances:
- are delivered to the right place, i.e. home in on the tumor,
- activate the immune system by attracting lymphocytes to the tumor, and
- are effective, in that the tumor either shrinks or disappears.
Focus on ANYARA
Active Biotech has selected to concentrate the development of its TTS project (Tumor Targeted Superantigens) on the latest product generation, ANYARA (previously known as TTS CD3), primarily for the treatment of renal cell cancer (RCC). Renal cancer affects approximately 32,000 people annually in the US (US FDA, December 2005). The most common age of onset of the disease is between 50 and 70 and it affects more men than women. Five-year survival for non-metastatic disease is approximately 55%. If the disease has metastasized to the lymph nodes, five-year survival declines to 5-15 %.
Active Biotech has completed Phase I and Phase II studies for the first generation substance TTS CD2. In the Phase I studies individualized dosing was established. Furthermore, encouraging anti-tumor effects were recorded in patients with NSCLC. As presented in April 2003 the median survival time in this study was 8.1 months, which is fully comparable to treatments currently on the market. Many patients were stabilized in their progressive disease and even though only a few patients responded with a tumor reduction, the results show a surprisingly long survival time for these patients, for whom the survival time is normally short. The final results of a Phase IIa study using CD2 against RCC were presented in December 2003. The results showed that the cancer stabilized in 68 percent of patients in the study following treatment with CD2. In March 2004, promising final results of a Phase IIa study using CD2 against pancreatic cancer were presented. In both studies, treatment with CD2 demonstrated only limited, mild side effects.
In September 2005, positive results were reported from a survival study with renal cancer patients included in a previously concluded Phase II study of TTS CD2. The patients were treated with individualized doses of TTS CD2 and followed for survival for two years. Survival was substantially longer than expected. Median survival for all the patients in the study was 19.7 months. Expected median survival according to Motzer prognostic factors was 14.4 months. Twenty-two patients were included in a high dose group and twenty-one in a low dose group. The group of patients with the highest drug exposure lived almost twice as long as expected, 26.6 months, compared to 15.1 months. The low dose group lived approximately as long as expected, 12.1 months, compared to 13.0 months.
In parallel with the Phase II studies with CD2, Active Biotech began to develop the next generation TTS product, ANYARA. With ANYARA, it has been possible to develop the TTS into an improved product with considerably higher anti-tumor activity, while side effects have been further reduced. Consequently, ANYARA can be given in far higher doses than CD2 and can also be administered in standardized doses.
Ongoing research
A pivotal Phase III study of ANYARA in combination with interferon-alpha, compared with interferon-alpha alone, in patients with advanced renal cancer is ongoing. Approximately 500 patients will be included in the study. The primary endpoint is overall survival.
Current results
In May 2008, an interim analysis was performed in the ongoing Phase II/III clinical study of ANYARA, in patients with advanced renal cell cancer.
The study protocol was reviewed in a protocol assistance procedure by EMEA and the primary as well as all secondary endpoints were endorsed.
In this interim analysis safety, efficacy, as well as certain biomarkers were evaluated in approximately 200 patients. No safety concerns significantly affecting the risk/benefit ratio for ANYARA were identified. Based on the study data, Active Biotech decided to proceed, in accordance with the study protocol into the pivotal Phase III stage of the study to further evaluate the effect of ANYARA for treatment of renal cell carcinoma.
New survival data from the ANYARA Phase I study in renal cancer patients, which was concluded in 2006, confirms the positive data that was achieved in the previous generation of the project. The median survival for the 11 patients who received treatment was 26.2 months.