RAD001 – Anti-Cancer Therapy

RAD001 (everolimus) is a macrolide antibiotic derived from rapamycin that is being investigated by Novartis as a potential treatment for various solid tumours, including advanced kidney cancer.

Rapamycin is an interesting drug because of its diverse clinical applications. Indeed, marketed under the brand name Certican®, Novartis' everolimus is already an approved medication for the prevention of organ rejection in patients undergoing heart and kidney transplantation.

Besides potent immunosuppressant effects, everolimus also inhibits mTOR protein. It is this property that is being exploited in the development of RAD001 (everolimus) as a potential anti-cancer medication.

If the outcome of current trials proves successful Novartis hopes to submit an NDA in 2008 for the use of RAD001 as a treatment for metastatic renal cell carcinoma (RCC).

TARGETING mTOR

Mammalian target of rapamycin, or mTOR, is a protein kinase that regulates cell growth, cell proliferation, cell motility and cell survival, as well as protein synthesis. Studies suggest that the mTOR growth pathway may be hyperactive in some cancers making it a potentially attractive cancer therapy target. Novartis' RAD001 (everolimus) is a serine-threonine kinase inhibitor of mTO that continuously inhibits the mTOR protein and so acts to prevent tumour cell division and blood vessel cell growth.

If approved, RAD001 will join Wyeth's mTOR inhibitor temsirolimus (ToriselÒ), which was approved for the treatment of advanced RCC in 2007. At present it is the only marketed cancer therapy that specifically inhibits mTOR.

RAD001 SHOWS EFFICACY IN RCC

The efficacy and safety of RAD001 (everolimus) has been demonstrated in the phase III RECORD-1 (REnal Cell cancer treatment with Oral RAD001 given Daily) trial, which enrolled more than 400 patients with advanced RCC whose cancer had progressed despite prior treatment with a range of first-line therapies. This included treatment with two of the newest drugs for RCC, sorafenib and sunitinib.

Interim results from RECORD-1, a multicentre randomised, double-blind, placebo-controlled, showed that treatment with RAD001 more than doubled the time to tumour progression after failure of first-line therapy. In fact, the independent data monitoring committee stopped the trial once the interim results were released. Median progression-free survival (primary endpoint) was 4 months for patients in the RAD001 arm compared with 1.9 months in the placebo arm (p<0.0001), a 70% reduction in the risk of cancer progression.

No significant differences were observed with respect to secondary efficacy endpoints, which included overall survival and objective response rate. A central review of the patients evaluable for best percentage change in target lesions showed evidence of tumour shrinkage in 50% of RAD001-treated patients during the double-blind phase, compared with 8% of placebo recipients.

RAD001 appeared generally well tolerated by patients in this study, with 6% prematurely discontinuing because of adverse effects.

POTENTIAL IN OTHER CANCERS

In addition to RCC, RAD001 is also being investigated for its potential to treat other cancers. Studies are ongoing to see whether it can bring therapeutic benefit to patients with pancreatic endocrine tumours, the results for which are expected towards the end of 2008. Other cancers for which RAD001 is being explored include carcinomas of the breast, stomach, and lung.

MARKETING COMMENTARY

RCC, which develops in the renal tubules, is the most common cancer of the kidney. It accounts for about 2–3% of all new cancers. Surgery to remove the tumour is standard treatment and can be effective if the tumour is confined to the kidney. However, if the tumour recurs following surgery prognosis is often poor. Generally resistant to radiotherapy and chemotherapy, RCC has proved one of the more difficult cancers to treat once the disease has spread.

Some important advances have been seen in the treatment of RCC with the arrival of targeted therapies such as the multi-kinase inhibitors sorafenib and sunitinib. Although not curative, they can significantly prolong progression free survival in advanced RCC. As results from the RECORD-1 trial demonstrate, treatment with RAD001 may further extend progression-free survival in patients with metastatic RCC after failure with these newer drugs.