Alex Philippidis Senior News Editor Genetic Engineering & Biotechnology News

Which candidates are on their way from the lab to the medicine chests of thousands?

According to the CDC, in 2008, over 200,000 women in the U.S. were diagnosed with breast cancer, and over 40,000 women in the U.S. died from it. What new weapons are drug companies adding to the arsenal against this disease? GEN has already given you the top 10 best-selling drugs of the 21st century; now, we present a list of drug candidates for which breast cancer is at least one proposed or approved indication, and for which one indication has reached Phase III or Registration phases.

Each entry includes the name of the drug candidate, the sponsor (and where applicable, collaboration partners), method of action, indication, and phase of trial. Some products are still in clinical trial phases for new indications or formulations after winning marketing approval for initial indications; these approvals, where applicable, are listed on the bottom of each entry.

Afinitor® (everolimus)

Sponsor: Novartis

Method of Action: Mammalian target of rapamycin (mTOR) inhibitor

Indications/Phase of Trial: Hepatocellular carcinoma; human epidermal growth factor receptor 2-positive (HER2+) breast cancer first-line and second-line; lymphoma; nonfunctional carcinoid tumor (Phase III; all new indications)

Approved in July in U.S., EU for advanced hormone-receptor-positive (HR+) and human epidermal growth factor Receptor 2-negative (HER2-) metastatic breast cancer with exemestane in postmenopausal women who have already received certain other medicines for their cancer

Approved earlier for adults with pancreatic neuroendocrine tumors (PNET) that cannot be treated with surgery; adults with advanced renal cell carcinoma (RCC) when certain other medicines have not worked; adults with angiomyolipoma, seen with tuberous sclerosis complex (TSC), when surgery is not required immediately; and adults and children with TSC who have a brain tumor called subependymal giant cell astrocytoma (SEGA) that cannot be removed completely by surgery

Avastin (Bevacizumab; RG435)

Sponsor: Roche/Genentech

Method of Action: Monoclonal antibody; Vascular endothelial growth factor (VEGF) inhibitor

Indications/Phase of Trial: U.S.: Relapsed ovarian cancer, platinum-sensitive (Registration); first-line metastatic breast cancer and first-line metastatic ovarian cancer (both Phase III).

EU: Relapsed platinum-resistance ovarian cancer (Phase III)

Metastatic colorectal cancer, treatment beyond progression (Registration); adjuvant breast cancer, HER2- and HER2+; adjuvant NSCLC; first-line glioblastoma (GBM) multiforme; high-risk carcinoid (all Phase III)

Approved for metastatic colorectal cancer (mCRC) when started with the first or second intravenous 5-FU–based chemotherapy for metastatic cancer; advanced nonsquamous non-small-cell lung cancer (NSCLC) with carboplatin and paclitaxel in people who have not received chemotherapy for their advanced disease; metastatic RCC (mRCC) with interferon alfa; and GBM in adult patients whose cancer has progressed after prior treatment. Effectiveness based on tumor response, as no data have shown whether Avastin improves disease-related symptoms or survival in people previously treated for GBM

Approval conditionally granted in 2008 and withdrawn November 2011 for HER2- metastatic breast cancer (mBC) with Paclitaxel

Buparlisib (BKM120)

Sponsor: Novartis

Method of Action: Pan-PI3K inhibitor

Indications/Phase of Trial: mBC (Phase III and confirmatory Phase I/II); with Fulvestrant, in postmenopausal women with hormone receptor-positive HER2- locally advanced or mBC which progressed on or after aromatase inhibitor (AI) treatment (Phase III; BELLE-2 study recruiting as of November 2012); with Fulvestrant, in postmenopausal women with hormone receptor-positive HER2- AI-treated, locally-advanced or mBC who progressed on or after mTOR inhibitor-based treatment (Phase III; BELLE-3 study, recruiting as of October 2012); with Paclitaxel in patients with HER2- inoperable locally advanced or mBC, with or without PI3K pathway activation (Phase III; BELLE-4 study, recruiting as of November); metastatic castration-resistant prostate cancer (CRPC; Phase II; recruiting as of October); recurrent glioblastoma (Phase II; recruiting as of November); recurrent/metastatic head and neck squamous cell carcinoma (Phase II; recruiting as of October); endometrial cancer (Phase I/II); NSCLC (Phase I/II); prostate cancer (Phase I/II); GBM multiforme (Phase I/II); with Fulvestrant in postmenopausal women with estrogen receptor-positive metastatic breast cancer (Phase I); previously treated advanced colorectal cancer (Phase I)

Faslodex (Fulvestrant Injection)

Sponsor: AstraZeneca

Method of Action: Estrogen receptor antagonist

Indications/Phase of Trial: First line HR+ mBC (Phase III; FALCON study commenced Oct. 29)

Approved for HR+ mBC in women who have experienced menopause and whose breast cancer has worsened after they were treated with antiestrogen medications

Herceptin (Trastuzumab; RG597)

Sponsor: Roche, in partnership with Halozyme

Method of Action: Humanized monoclonal antibody designed to target and block the function of HER2+

Indications/Phase of Trial: EU: Early HER2+ breast cancer, subcutaneous formulation (Registration)

Approved for early-stage HER2+ breast cancer that has spread into the lymph nodes, and HER2+ breast cancer that has not spread into the lymph nodes and is estrogen receptor/progesterone receptor-negative (ER-/PR-) or have one high-risk feature. High-risk is defined as estrogen receptor/progesterone receptor-positive (ER+/PR+) with one of the following features: tumor size >2 cm, age <35 years, or tumor grade 2 or 3. Can be used with Adriamycin® (doxorubicin), Cytoxan® (cyclophosphamide), and either Taxol® (paclitaxel) or Taxotere® (docetaxel); or with Taxotere and Paraplatin® (carboplatin); or alone after treatment with multiple other therapies, including an anthracycline (Adriamycin)-based chemotherapy

Also approved alone for the treatment of HER2+ breast cancer in patients who have received one or more chemotherapy courses for metastatic disease; and with paclitaxel for first-line treatment of HER2+ mBC

Iniparib (Tivolza; BSI-201; SAR240550)

Sponsor: Sanofi, through acquisition of original developer BiPar Sciences

Method of Action: Poly (ADP-ribose) polymerase 1 (PARP1) inhibitor

Indications/Phase of Trial: Stage IV squamous NSCLC (Phase III; NME); solid tumors such as sarcoma and breast, uterine, lung, and ovarian cancers (Phase I/II)

Phase III trial in breast cancer failed January 2011 by failing to improve survival and progression-free survival (PFS) in breast cancer patients

Nexavar® (Sorafenib)

Sponsor: Onyx Pharmaceuticals

Method of Action: Dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases

Indications/Phase of Trial: Liver cancer adjuvant (Phase III; STORM study); kidney cancer adjuvant (Phase III; SORCE/ASSURE study); thyroid cancer monotherapy (Phase III; DECISION study); breast cancer with capecitabine (Phase III; RESILIENCE study)

Approved for hepatocellular carcinoma (HCC) and RCC

Perjeta (Pertuzumab; RG1273)

Sponsor: Roche/Genentech

Method of Action: HER2/neu receptor antagonist

Indications/Phase of Trial: EU: With Herceptin and docetaxel chemotherapy for previously-untreated HER2+ mBC or locally recurrent, inoperable breast cancer in patients who have not received previous treatment or whose disease has returned after treatment in the early-stage setting (Registration)

U.S.: Approved June 2012 for HER2+ mBC with Herceptin (trastuzumab) and docetaxel, in patients who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease

Switzerland: Approved August 2012 for HER2+ breast cancer with Herceptin (trastuzumab) and docetaxel in patients with advanced or locally recurring breast cancer that has not previously been treated with chemotherapy

Ridaforolimus (MK-8669; AP23573; formerly Deforolimus)

Sponsor: Merck, under exclusive worldwide license agreement with Ariad Pharmaceuticals

Method of Action: Oral inhibitor of mammalian target of rapamycin inhibitor (mTOR)

Indications/Phase of Trial: Maintenance therapy for metastatic soft-tissue sarcoma and bone sarcomas after at least four chemotherapy cycles (under review after receiving Complete Response letter from FDA in June; NME); breast cancer with exemestane, compared to breast cancer with dalotuzumab and exemestane (Phase II; recruiting as of November); advanced head and neck cancer, NSCLC and colon cancer, with cetuximab (Phase II); pediatric patients with advanced solid tumors (Phase I; recruiting as of September); with dalotuzumab in pediatric patients with advanced solid tumors (Phase I; recruiting as of August); advanced RCC, with vorinostat (Phase I; recruiting as of October 2012); breast cancer, with dalotuzumab (Phase I: recruiting as of September); endometrial and ovarian cancers, with paclitaxel and carboplatin (Phase I; recruiting as of September 2012); advanced cancer, with MK-2206 and MK-0752 (Phase I: recruiting as of September 2012); advanced cancer, with dalotuzumab, MK-2206 and MK-0752 (Phase I: recruiting as of August 2012)

Tivozanib (ASP4130; AV-951)

Sponsor: Aveo Oncology and Astellas

Method of Action: Tyrosine kinase inhibitor; inhibits VEGF receptor 1, 2, and 3

Indications/Phase of Trial: U.S.: Advanced RCC (Registration; NDA filed September 2012); tivozanib biomarkers in solid tumors (Phase II; BATON study); stage IV metastatic colorectal cancer (mCRC), with mFOLFOX6, and compared with bevacizumab and mFOLFOX6 (Phase II; recruiting as of November); additional data as first-line therapy for advanced RCC, followed by sunitinib (Phase II; TAURUS study, enrollment initiated in October 2012); advanced solid tumors, with capecitabine (Xeloda®; Phase I; recruiting as of October)

EU: Advanced RCC (Phase III)

Trastuzumab-DM1 (T-DM1; Trastuzumab emtansine; RG3502)

Sponsor: Roche, with linker technology developed by ImmunoGen

Method of Action: Antibody-drug conjugate, consisting of the antibody trastuzumab and the chemotherapy DM1 attached via a stable linker

Indications/Phase of Trial: U.S.: HER2+, unresectable locally-advanced or mBC who have received prior treatment with Herceptin (trastuzumab) and a taxane chemotherapy (Registration; Priority review approved Nov. 7; action date Feb. 26, 2013)

EU: Marketing Authorization Application for HER2+ mBC accepted for review by European Medicines Agency

Tyverb/Tykerb (lapatinib)

Sponsor: GlaxoSmithKline

Method of Action: Human epidermal growth factor receptor-2 (Her2) and epidermal growth factor receptor (EGFR) dual kinase inhibitor

Indications/Phase of Trial: mBC with trastuzumab (Registration); breast cancer, adjuvant therapy (Phase III); Gastric cancer (Phase III); head & neck squamous cell carcinoma, resectable disease (Phase III)

Xgeva (denosumab)

Sponsor: Amgen, with commercialization by GlaxoSmithKline in countries where Amgen has no presence

Method of Action: Fully human monoclonal antibody that specifically targets a ligand known as RANKL that binds to a receptor known as RANK

Indications/Phase of Trial: Delay or prevention of bone metastases in breast cancer (Phase III); delay or prevention of bone metastases in prostate cancer (Phase III)

Approved for prevention of fractures in men with advanced prostate cancer

Rejected in April for supplemental Biologics License Application to treat men with CRPC at high risk of developing bone metastases

Yondelis® (trabectedin)

Sponsor: Johnson & Johnson; developed in collaboration with PharmaMar

Method of Action: Binds to minor groove of DNA, interfering with the cell division and gene transcription processes, as well as DNA’s repair machinery

Indications/Phase of Trial: U.S.: Locally advanced or metastatic soft tissue sarcoma excluding leiomyosarcoma and liposarcoma who have relapsed or are refractory to standard-of-care treatment (Phase III; recruiting as of November); soft tissue sarcoma, excluding liposarcoma and leiomyosarcoma (L-type sarcoma), in previously-treated patients who cannot be expected to benefit from currently available therapeutic options (Phase III; recruiting as of November); locally advanced or metastatic L-sarcoma (liposarcoma or leiomyosarcoma) who were previously treated with at least an anthracycline and ifosfamide-containing regimen, or an anthracycline-containing regimen and one additional cytotoxic chemotherapy regimen, compared with dacarbazine group (Phase III; recruiting as of November); breast cancer and pediatric tumors (Phase II); Advanced malignancies and liver dysfunction (Phase I; recruiting as of November)

EU: Approved for advanced or metastatic soft tissue sarcoma, and for relapsed platinum-sensitive ovarian cancer, with DOXIL®/Caelyx®

Xtandi® Capsules (Enzalutamide; formerly MDV3100)

Sponsor: Medivation in collaboration with Astellas

Method of Action: Androgen receptor inhibitor

Indications/Phase of Trial: Prechemotherapy CRPC in patients who have failed luteinizing hormone-releasing hormone (LHRH) analog treatment only, as well as patients who have failed both LHRH analog and anti-androgen treatment. (Phase III; PREVAIL study); prostate cancer neoadjuvant therapy (Phase II); prechemo metastatic prostate cancer in Europe (Phase II; TERRAIN); prechemo metastatic and nonmetastatic prostate cancer patients in U.S. (Phase II; STRIVE); prostate cancer Hormone-naïve (Phase II; ASPIRE); prostate cancer with docetaxel (Phase I); breast cancer (Phase I)

EU: Marketing Authorization Application submitted June 2012 to European Medicines Agency, for patients with metastatic CRPC who have received docetaxel-based chemotherapy

Japan: Metastatic CRPC who have received docetaxel-based chemotherapy (Phase II)

Approved Aug. 31 for patients with metastatic CRPC who have previously received docetaxel. As a post-marketing requirement, Medivation and Astellas agreed to conduct an open-label safety study of Xtandi (160 mg/day) in patients at high risk for seizure, with data to be submitted to FDA in 2019

This drug candidate list is as disclosed by 40 biopharma companies holding the highest market capitalization levels as recorded by GEN in August (and in some cases, by their smaller collaboration partners). Status information is from the pipeline review pages of biopharma companies as well as subsequent press releases or other public disclosures, such as quarterly results.

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