Recent moves by Roche and Genentech could expand the reach of Herceptin in Europe and the United States.
Genentech last week submitted a supplemental Biologics License Application to the US Food and Drug Administration to enable the drug to be used as an adjuvant to treat early-stage Her2-positive breast cancer, while Roche Pharmaceuticals in Switzerland submitted a Marketing Authorization application to the European Medicines Agency for the same indication.
The drug is currently indicated only for metastatic or stage IV breast cancer, either in combination with paclitaxel or as a stand-alone treatment for women who have had chemotherapy.
Should the companies be granted the new indication, manufacturers of Her2 diagnostics stand to gain, the drug that helped pave the way for pharmacogenomics may gain even more visibility, and it may overcome reimbursement difficulties it has experienced in the UK.
"Obviously, there are more opportunities in early, rather than later-stage breast cancer, and that is clearly what Roche and Genentech are targeting," Sreten Bogdanovich, managing partner of UK consultancy BioPhoenix, told Pharmacogenomics Reporter this week.
Genentech, which was acquired by Roche in 1990, markets Herceptin in the United States while Roche sells the drug in Europe. Herceptin is sold in Japan by Chugai, which Roche purchased in 2002.
"Obviously, there are more opportunities in early, rather than later-stage breast cancer, and that is clearly what Roche and Genentech are targeting."
Genentech has asked the FDA for a priority review designation for its BLA, which would require the agency's response within six months.
After the FDA approved Herceptin in September 1998, the addition of a Her2 IHC diagnostic to the drug's indication arguably led to a more favorable view of pharmacogenomic treatments by showing it was possible and cost effective to identify patients most likely to respond.
In its annual report for 2005, Roche reported worldwide Herceptin sales of CHF 2.15 billion ($1.64 million), up from CHF 1.44 billion ($1.10 million) in 2004. Sales in 2005 were driven by longer average treatment duration and increased first-line penetration, said Roche.
There are already signs that an early-stage indication would be welcomed by the market, which has already been using the drug for this indication off-label. "Clinical data showing significant efficacy in adjuvant breast cancer has led to growing adoption in this unapproved area," said Roche in its 2005 year-end financial report, which it released last month.
A Genentech spokesperson declined to disclose how much an early-stage breast cancer indication might expand Herceptin's market, but breast cancer incidence statistics suggest it would grow significantly. When asked in an e-mail exchange whether there was any information about often the drug is currently used as an off-label adjuvant therapy, the spokesperson said, "Unfortunately, no."
The World Health Organization estimates that 201,000 of the 223,000 cases of breast cancer diagnosed in the United States annually will be early stage stages I, II, or III. The remaining cases are either very early stage 0 tumors or stage IV metastatic tumors, with a large majority falling into the metastatic category. Of early-stage tumors, about 44,000 are likely to test positive for Her2, and 35,000 will be treated with chemotherapy, according to Genentech.
Under its current indication, Genentech's 2005 US sales of Herceptin amounted to $747.2 million, up 56 percent from $479 million in 2004, according to documents Genentech filed last month with the US Securities and Exchange Commission.
Also standing to directly gain from an increase in the drug's market are Her2 diagnostics companies Dako Cytomation, Ventana Medical Systems, BioGenex, and Abbott subsidiary Vysis. Of these companies, only Vysis makes a FISH Her2 test. The rest sell IHC diagnostics. All of the tests are FDA cleared.
In the United States, the market for Her2 diagnostics is not terribly large yet. Promila Rastogi, product manager for reagents at San Ramon, Calif.-based BioGenex, told Pharmacogenomics Reporter last year that the market for Her2 tests amounted to "at least" $5 million in the US.
"I don't think the market is all that accustomed to this sort of testing yet, and my feeling is that a lot of ladies [in the UK] who should receive tests don't get them, and are not considered at all" or prescribed Herceptin partly because clinicians may not be familiar with the treatment, and because of the lack of approval for early-stage disease, said Bogdanovich, the BioPhoenix consultant.
The lack of approval for the use of Herceptin with early-stage cancer has caused a controversy in the UK that culminated in a court verdict last week. The High Court in London refused to overturn a National Health Service affiliate's refusal to pay for a woman's Herceptin prescription for treatment of her early-stage cancer, because of the £26,000 ($45,000) cost of treatment. Had the drug been approved through the correct process for that indication, all affiliates of the NHS would be required to reimburse for it, rather than those who elect to do so due to special circumstances.
In the UK, Herceptin prescriptions are reimbursed by the NHS for early-stage breast cancer only for a patchwork of geographical areas because the drug has not been appraised for by the National Institute for Clinical Excellence. "They're insisting that these ladies [with early-stage breast cancer] have to fail on other treatments before they can have Herceptin, which many people obviously feel is unreasonable," said Bogdanovich.
But should the EMEA approve Herceptin for the new indication, "NICE will have to fall in line with the European regulatory agencies," Bogdanovich said. "NICE might drag its feet," he said, but added that the drug would likely be reimbursed for early-stage disease in the UK within about "a year or two of EMEA approval."
The Clinical Trial Data
Roche based its EMEA application on data from an international Herceptin Adjuvant, or HERA, study conducted by Roche and the Breast International Group. Genentech's is based on data gathered during two clinical trials sponsored by the US National Cancer Institute, NSABP-B31 and NCCTG-N9831, and published in the Oct. 20 issue of the New England Journal of Medicine.
The HERA study enrolled approximately 5,100 patients who were put through standard radiotherapy and a variety of chemotherapy regimens, with and without Herceptin, in a 12-month arm and a 24-month arm. An interim analysis demonstrated that the study had reached statistically significant improvement in disease-free survival in the 12-month arm, its primary efficacy endpoint. The study still has not reached its secondary endpoint, statistically significant overall survival, but the trial is ongoing.
The two NCI trials triggered an interim analysis when patients in the trials experienced a certain number of recurrent cancers, second primary cancers, or deaths, according to a Genentech spokesperson. The researchers released the results of the interim analyses after the patients in the study showed a 49-percent improvement in overall disease-free survival over 24 months when they took Herceptin as adjuvant therapy.
After three years in the study, 13 percent of women treated with Herceptin and chemotherapy experienced disease recurrence, compared to 25 percent of women treated with chemotherapy alone, Genentech said in a statement. Investigators are still continuing to monitor patients involved in the studies.
Chris Womack ([email protected])