By Kevin E. Noonan --
In the late 1980's, Dennis Slamon discovered a new oncogene, Her2/neu,that was amplified in 25-33% of human breast cancers. Slamon et al., "Studies of the HER2/neu ProtoOncogene in Human Breast and Ovarian Cancer," Science 244: 707-12 (1989). Following up on this discovery, Dr. Slamon and his collaborators found that a monoclonal antibody against the protein product of this gene, an epidermal growth factor receptor (EGFR) expressed on the cell surface of breast cancer cells, could be used to reduce proliferation of breast cancer cells in vitro and in vivo. This further discovery led to the development of one of the first therapeutic monoclonal antibody therapies, marketed by Genentech as Herceptin® (trastuzumab). Shepard et al., "Monoclonal antibody therapy of human cancer: Taking the HER2 protooncogene to the clinic," J. Clin. Immunol. 11: 117-27 (1991).
Trastuzumab is approved for treatment of epidermal growth factor receptor (HER2)-positive primary and metastatic breast cancer. It is a "recombinant DNA-derived humanized monoclonal immunoglobulin G1 kappa antibody." Today, Herceptin® is the 25th ranked pharmaceutical in the U.S. (February 2014), with $1.879 billion in sales in 2013. Thus, it is an attractive target for biosimilar competition, and Amgen and Allergan have teamed up to produce a bioimilar competitor. Yesterday the companies announced results from a Phase 3 clinical trial on their biosimilar drug, as reported by PRNewswire.
The Phase 3 clinical study was performed to compare branded Heceptin® with Amgen/Allergan's biosimilar candidate (ABP 980). ABP 980 has the same amino acid sequence as Herceptin® and is administered at the same pharmaceutical dosage form and strength as Herceptin®.
The clinical study was randomized, multicenter, double blind, and active-controlled (No. 20120283) for safety and efficacy. Participants were 725 adult female early breast cancer patients, with 364 being given ABP 980 and 361 given Herceptin®. All patients were HER2 positive.
There were two phases of the trial: the neoadjuvant phase and the adjuvant phase. Patients in the neoadjuvant phase received chemotherapy (epirubicin and cyclophosphamide) every three weeks for four cycles. Thereafter, the patient pool was randomized with regard to Herceptin®/ABP 980 treatment which was administered with paclitaxel every three weeks for four cycles. Surgery was then performed 3-7 weeks after the last dose of the antibody products and the patients were then evaluated for pathologic complete response.
In the adjuvant phase, post-surgical patients received either ABP 980 or Herceptin® every three weeks for up to one year from the first administration of the antibody in the neoadjuvant phase. The species of administered antibody remained consistent between the neoadjuvant and adjuvant phases for ABP 980, but the species of antibody administered during the adjuvant phase was randomized during the adjuvant phase.
The study is not complete, and will not be completed until the last patient has completed the adjuvant phase.
Clinical equivalence between ABP 980 and Heceptin® was evaluated based on the "confidence interval of the risk difference and risk ratio of the pathological complete response in breast tissue and axillary lymph nodes with prespecified equivalence margins" – i.e., comparing the results normalized by the extent of disease in individual patients. The top line results (the statistics that show whether clinical trial end points were met or not) reportedly "ruled out inferiority but could not rule out superiority" for ABP 980. The primary endpoint of the study had a "prespecified equivalence margin" of +\- 13%, and the observed upper end of the confidence interval was 13.4%. Observed adverse effects were comparable overall, with more serious adverse events reported for ABP 980 in the neoadjuvant phase compared with Herceptin®, but were unlikely to be related to the antibody. The incidence of adverse events were similar in the adjuvant phase of the study, and overall comparable immunogenicity was found between the reference product and the biosimilar.
Genentech's patents on its Herceptin® product are scheduled to expire in 2019 and 2020.