On June 20, 2014 Bayer HealthCare reported that the Ministry of Health, Labor and Welfare (MHLW) in Japan has approved the oral multi-kinase inhibitor Nexavar (sorafenib) for the treatment of patients with unresectable differentiated thyroid carcinoma (Press release Bayer, JUN 20, 2014, View Source [SID:1234500591]). The MHLW granted Nexavar orphan drug status for thyroid carcinoma in September 2013.

“The approval of Nexavar in Japan for the treatment of unresectable differentiated thyroid carcinoma fills a significant unmet need for patients who previously lacked therapeutic options for this type of thyroid cancer,” said Dr. Joerg Moeller, Member of the Bayer HealthCare Executive Committee and Head of Global Development. “This is the third indication for Nexavar, which is already approved in more than 100 countries worldwide for hepatocellular carcinoma and advanced renal cell carcinoma, and we are pleased that this cornerstone treatment continues to reach cancer patients across the globe.”

Nexavar was approved for the treatment of progressive, locally advanced or metastatic differentiated thyroid cancer that is refractory to radioactive iodine in the United States in November 2013 and in May 2014 in the European Union.

The approval in Japan is based on data from the Phase III DECISION (stuDy of sorafEnib in loCally advanced or metastatIc patientS with radioactive Iodine refractory thyrOid caNcer) trial. In the study, sorafenib significantly extended progression-free survival (PFS), the primary endpoint of the study, compared to placebo (HR=0.59 [95% CI, 0.46-0.76]; p<0.001), which represents a 41 percent reduction in the risk of disease progression or death for patients who received sorafenib compared to placebo-treated patients. The median PFS was 10.8 months in patients treated with sorafenib, compared to 5.8 months in patients receiving placebo. The safety and tolerability profile of sorafenib in patients in the trial was generally consistent with the known profile of sorafenib. The most common treatment-emergent adverse events in the sorafenib arm were hand-foot skin reaction, diarrhea, alopecia, weight loss, fatigue, hypertension and rash. DECISION Trial Design DECISION was an international, multicenter, placebo-controlled study. A total of 417 patients with locally advanced or metastatic, progressive, RAI-refractory, differentiated thyroid cancer (papillary, follicular, Hurthle cell and poorly differentiated) who had received no prior chemotherapy, tyrosine kinase inhibitors, monoclonal antibodies that target VEGF or VEGF receptor, or other targeted agents for thyroid cancer were randomized to receive 400 mg of oral sorafenib twice daily (207 patients) or matching placebo (210 patients). Ninety-six percent of randomized patients had metastatic disease.

On June 19, 2014 Merrimack Pharmaceuticals reported that it has reached an agreement with Sanofi to regain worldwide rights to develop and commercialize MM-121, a monoclonal antibody designed to block ErbB3 (HER3) activation in patients with heregulin-positive tumors and improve response to standard of care treatments (Press release Merrimack, JUN 19, 2014, View Source [SID:1234500596]).

In partnership with Sanofi, Merrimack completed an extensive Phase 2 program for MM-121 which was designed to assess the role of ErbB3 in a number of cancer indications in both the metastatic and neoadjuvant settings. In advanced settings of ovarian cancer, ER/PR+ HER2 negative breast cancer and non-small cell lung cancer, Merrimack was able to identify that heregulin, the principal ligand that binds to and activates the ErbB3 receptor, is associated with poor response to standard of care therapy and that adding MM-121 may restore sensitivity in these most at-risk patients. Consistent across three metastatic cancer indications with three different standard of care therapies, patients in these trials with heregulin-positive tumors experienced a statistically significant reduction in their risk of progression when they received a combination with MM-121. Heregulin-driven drug resistance pathways were found to be active in approximately 30-50 percent of patients tested. Data from these studies were recently presented at the 2014 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.

“We are grateful for Sanofi’s support over the last five years and believe that the data generated through this partnership validate the potential for MM-121 to help patients most at risk for progression on current therapies. Regaining MM-121 is an opportunity to capitalize on our leadership position among the other oncology companies that are pursuing ErbB3,” said Robert Mulroy, President and CEO at Merrimack. “With these data and the feedback we’ve received from our committed investigators, we believe MM-121 has the potential to be a foundational therapy for use across multiple solid tumor types and we plan to continue its development through subsequent strategic partnerships. Our next step is to discuss our Phase 2 data and potential registration paths with the FDA.”

Sanofi will continue to fund the existing MM-121 Phase 2 program for the next six months. The neoadjuvant cohort of a Phase 2 study testing MM-121 in combination with paclitaxel in patients with triple negative breast cancer is the final study to be completed through this collaboration. Top line results of that study are below.

Results from the Second Cohort of a Phase 2 Study of MM-121 in Combination with Paclitaxel in Neoadjuvant Breast Cancer

Merrimack and Sanofi completed a randomized (2:1), exploratory Phase 2 study testing MM-121 in combination with paclitaxel followed by doxorubicin and cyclophosphamide. The study was conducted in two populations of patients with either ER/PR positive (ER/PR+) HER2 negative breast cancer (n=101) or triple negative breast cancer (TNBC) (n=99). There was no formal quantitative endpoint specified for this study.

In November 2013, Merrimack released initial top line results from the ER/PR+ HER2 negative cohort. Those results demonstrated that patients who received the combination of MM-121 and paclitaxel achieved a pCR rate of 10.6% (95% CI [5.2; 20.3]) compared to 3.3% (95% CI [0.6; 16.7]) for the control arm. Top line results from this second cohort of patients with TNBC showed that patients who received the combination of MM-121 and paclitaxel achieved a pCR rate of 42.9% (95% CI 30.8; 55.9) compared to 51.7 (95% CI 34.4; 68.6) for the control arm. Translational analysis is ongoing for both cohorts and the full data set will be reported at a future medical conference. Preliminary analysis of approximately 50 percent of the pretreatment biopsies suggests a link between heregulin levels and pCR rates.

For the TNBC cohort, rates for serious adverse events were 28.1% vs. 15.6%, and rates for grade 3 or higher adverse events were 50.0% vs. 31.3% between the treatment and control arms, respectively. As reported previously, in the ER/PR+ HER2 negative cohort, similar frequencies were reported for adverse events of any grade between the treatment and control arms, with no unexpected toxicities experienced and no increase in serious adverse events. Grade 3 or worse adverse events in the ER/PR+ HER2 negative cohort were 55.2% on treatment arm versus 53.1% on control arm.

On June 19, 2014 Johnson & Johnson Innovation, LLC reported that Janssen Biotech, Inc. and Johnson & Johnson Innovation have formed a research collaboration with Weill Cornell Medical College aimed at developing compounds for targeting the function of a lymphoma causing protein (Press release Johnson & Johnson, JUN 19, 2014, View Source [SID:1234500594]). Through the collaboration, investigators at Weill Cornell and Janssen drug development researchers will collaborate to discover, validate and characterize inhibitors of the protein and further elucidate novel targeting methods.

On June 19, 2014 Takeda reported that it has voluntarily decided to end the development program for orteronel (TAK-700) for prostate cancer (Press release Takeda, JUN 19, 2014, View Source [SID:1234500592]). The decision follows the results of two Phase 3 clinical trials in metastatic, castration resistant prostate cancer (mCRPC). The studies found while orteronel plus prednisone could extend the time patients lived before their cancer progressed, it did not extend overall survival in these patients. After careful consideration of the data from these trials, the company has determined that the drug has not demonstrated a clinical profile sufficient to move forward in mCRPC, given the availability of other therapies.

On May 14, 2014, Takeda announced results from ELM-PC4, a pivotal, international, double blind, randomized Phase 3 trial in men with mCRPC who had not received chemotherapy, which showed that orteronel plus prednisone improved radiographic progression free survival (rPFS) compared to prednisone alone, one of the study’s two primary endpoints, but did not show a statistically significant improvement in the study’s second primary endpoint of overall survival (OS). A previously reported Phase 3 trial, ELM-PC5, in men with mCRPC that had progressed during or following chemotherapy, was unblinded in 2013 after a pre-specified interim analysis indicated that orteronel plus prednisone would likely not meet the primary endpoint of improved overall survival when compared to the control arm. The interim analysis did show an advantage for orteronel plus prednisone for the secondary endpoint, radiographic progression-free survival over the control arm. There were no significant safety concerns in either study.

Takeda is in communication with trial investigators and the relevant regulatory authorities, to provide them with updated and current information in compliance with local regulations. Takeda is working with trial investigators and local regulatory authorities to ensure that patients who participated in the orteronel (TAK-700) trials are transitioned to appropriate therapies so that trial participants receive appropriate care. Patients enrolled in the orteronel (TAK-700) clinical trials are urged to consult their study investigators to address any questions, and before making any changes to their medication.

Takeda remains committed to oncology and to the treatment of prostate cancer.