Pharm Exec's 2013 Pipeline Report - Pharmaceutical Executive


Pharm Exec's 2013 Pipeline Report

Pharmaceutical Executive

Cancer: Improving on Innovation

Leaders in the cancer space, old and new, are building on recent successes to bring even safer and more efficacious products to bear on the most notorious and deadly forms of the disease. In malignant melanoma, Bristol-Myers Squibb's Yervoy and Roche's Zelboraf —approved by FDA in March and August of 2011, respectively—will likely compete against next generation combination drugs conceived by the same parents.

Roche recently announced a Phase III trial—not yet enrolled—that would evaluate a combination of Zelboraf and GDC-0973, the latter a small molecule MEK inhibitor originating from Exelixis's kinase inhibitor research program. GSK is also getting into malignant melanoma with a BRAF inhibitor akin to Zelboraf called dabrafenib, which employs a companion diagnostic developed in concert with the French company bioMerieux SA. Dabrafenib is also being tested in combination with a MEK inhibitor, GSK/Japan Tobacco's trametinib. Both dabrafenib and trametinib are in preregistration as monotherapies in the United States and Europe, and GSK is conducting Phase III trials on the combination. Both of the GSK drugs reported positive data at ASCO this year, says Tatiana Spicakova, a consultant at Kantar Health. "For so long there was nothing for melanoma patients, and that has changed dramatically in the last couple of years. And now, with the BRAF/MEK inhibitor, combination products are supposed to be more efficacious and actually safer than the monotherapies."

The National Cancer Institute estimates that 76,250 new cases of melanoma will be diagnosed in the United States this year, and almost 10,000 patients will die from the disease. Yervoy, a monoclonal antibody and CTLA-4 inhibitor, only works in about one in four patients, but it works well in those patients. Zelboraf is faster acting and has excellent response rates due to its companion diagnostic, but only around half of the patient population carries the BRAF mutation.

BMS's nivolumab, a PD-1 inhibiting monoclonal antibody, is being tested for malignant melanoma (Phase II in Japan), renal cancer, and, surprisingly, non-small cell lung cancer, among other cancers and other diseases. Despite early phases of development, Stephanie Hawthorne, director at Kantar Health, and Spicakova say nivolumab could be huge, given its apparent range of activity. "Renal cell carcinoma and melanoma are smaller populations, but the lung cancer population is huge," says Hawthorne. Responses to nivolumab in non-small cell lung cancer, presented at ASCO this year, "were a big surprise to everyone because lung cancer is not usually thought of as a particularly immunogenic tumor," says Spicakova. "And it's supposed to have a better safety profile than Yervoy."

Thomson Reuters, Decision Resources, and Kantar Health are all predicting blockbuster sales for trastuzumab emtansine, also known as T-DM1—but better known as Roche's next generation Herceptin. It is in preregistration as a second-line therapy (behind Herceptin) for breast cancer. Backed by two Dako-developed companion diagnostics, next-gen Herceptin also targets the HER2 population, but adds ImmunoGen's anti-mitotic agent DM1 to create an antibody drug conjugate that links with a cytotoxic (e.g., chemotherapy) treatment. In Phase III studies, Roche is pitting T-DM1 head-to-head against it's own Xeloda plus GSK's Tykerb in second line treatment, and against Herceptin and Perjeta in the first-line, metastatic breast cancer setting. Given the success of Herceptin, which earned over $5 billion last year, "Roche is being very cautious about how to position these drugs relative to each other, because TDM-1 could very well cannibalize Herceptin' sales," says Hawthorne. Upon receiving approval in second-line treatment, Roche is expected to go after a first-line indication next, which "is the ultimate goal," says Thompson Reuters' Meekings. In the European Union, Herceptin's patent could expire in 2014, but is expected to hold out in the United States until 2018 or 2019.

In prostate cancer, a perennial area of interest for investors and analysts, the Norwegian biotech Algeta and partner Bayer are developing a Phase III radium-223 chloride product to be called Alpharadin in Europe, and Xofigo in the United States. Featuring a completely new mechanism of action, radium-223 employs a radioactive isotope that acts as a calcium mimic to target bone metastases without affecting normal bone marrow. Algeta is testing the drug in patients with metastatic hormone refractory prostate cancer (fast-tracked in the United States), and Bayer has initiated expanded access programs in the United States, Canada, Europe and Israel. Since roughly 70 percent to 95 percent of prostate cancer patients get bone metastasis, in addition to 75 percent of breast cancer patients and 40 percent of lung cancer patients, this product could cover a lot of ground. "Algeta leadership has said they believe they'll get 85 percent of the global prostate market, which is massive" all by itself, says Meekings. Radium 223 chloride has shown a significant improvement to overall survival—the gold standard of cancer drug endpoints—in hormone refractory prostate cancer patients.

Aragon Pharmaceuticals is in early stages of development with ARN 509 for prostate cancer as well, with one cohort of patients that didn't respond to Zytiga. It's early days, but Spicakova says ARN 509 could potentially best Medivation/Astellas' Xtandi (formerly MDV-3100), which was approved in August, three months prior to its PDUFA date. Selvaraju believes Xtandi will surpass Zytiga with forthcoming trial results. "When Medivation/Astellas unveils Xtandi's Phase III results in chemo-nave patients with hormone resistant prostate cancer, it's going to blow J&J's Zytiga away," says Selvaraju. "As you go earlier and earlier into the therapy paradigm, you're going to see better and better results with Xtandi."

In hematological cancers, Ariad Pharmaceuticals' ponatinib is awaiting approval in the United States and Europe for acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML), and could earn over $800 million by 2018, according to Latwis at Decision Resources. Celgene's pomalidomide, for multiple myeloma, is preregistered in the United States and Europe, and has a PDUFA date coming up in February 2013. Howard Liang, managing director, biotechnology at Leerink Swann, expects pomalidomide to gain approval and be "highly profitable" for Celgene, due to its sales synergy with Revlimid. Pharmacyclics and Janssen Biotech's orphan drug ibrutinib, a novel Bruton's tyrosine kinase (Btk) inhibitor for chronic lymphocytic leukemia (CLL), is in Phase III, and could reach blockbuster status by 2017, according to a Thompson Reuters estimate.


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