FDA Approves Erivedge (vismodegib) Capsule for the Treatment of Advanced Basal Cell Carcinoma
 In January 2012 the FDA approved Erivedge (vismodegib) capsule for the treatment of adults with basal cell carcinoma that has spread to other parts of the body, that has come back after surgery, or that cannot be treated with surgery or radiotherapy.
Erivedge is the first and only FDA-approved medicine for the treatment of advanced forms of basal cell cancer. Erivedge is being developed and will be commercialized by Roche and Genentech under a collaboration agreement between Curis and Genentech. Curis earned a $10 million milestone payment from Genentech as a result of the FDA's approval of Erivedge in this indication and is also entitled to receive royalties on future sales of the product. Erivedge is expected to be available in the USA within one-to-two weeks of approval and to be distributed through specialty pharmacies. Roche has also submitted an MAA for Erivedge in the European Union (EU), which is currently under review by the European Medicines Agency (EMA). The FDA approval is based on results from the pivotal multicenter, international, single arm, 2-cohort, open label, ERIVANCE BCC phase II clinical trial (protocol ID: SHH4476g; NCT00833417) that enrolled 104 patients with advanced BCC, including locally advanced BCC (n=71) and metastatic BCC (n=33). According to the protocol, patients were treated with PO Erivedge (150 mg), once daily until disease progression or unacceptable toxicity. In this trial, the overall response rate (ORR), the primary endpoint of the trial, was 43% (27/63) in patients with locally advanced BCC and 30% (10/33) in patients with metastatic BCC, as assessed by independent review. The median duration of response was 7.6 months.
The FDA Approves Inlyta for the Second Line Treatment of Patients With Advanced Renal Cell Carcinoma (RCC)
In January 2012, the FDA approved Pfizer's anticancer drug Inlyta (axitinib) for the treatment of patients with advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. The approval is based on data from the AXIS phase III clinical trial (protocol ID: A4061032; NCT00678392), in which Inlyta extended median PFS to 6.7 months compared with 4.7 months with sorafenib (Nexavar; Bayer/Onyx) representing a 43% improvement in median PFS compared to sorafenib for an HR of 0.67 (p<0.0001).
Amgen to Acquire Micromet
In January 2012, Amgen and Micromet entered into a definitive merger agreement under which Amgen will acquire Micromet for $11 per share in cash. The transaction values Micromet at approximately $1.16 billion.
The acquisition includes blinatumomab, a Bispecific T cell Engager (BiTE) antibody in phase II clinical development in acute lymphoblastic leukemia (ALL). Blinatumomab is also in clinical development for the treatment of non-Hodgkin's lymphoma (NHL), and could have applications in other hematologic malignancies. As part of the deal, in addition to blinatumomab, Amgen is acquiring unencumbered rights to solitomab (MT110), proprietary BiTE antibody technology, potential milestone and royalty payments from existing licensees of BiTE and other technologies, and Micromet's Munich site, which will operate as an Amgen R&D center of excellence.
User Fee Programs for Generic Drugs and Biosimilars
In January 2012, the FDA completed its recommendations for 3 user fee programs including the fifth authorization of the Prescription Drug User Fee Act (PDUFA V), and new user fee programs for human generic drugs and biosimilar biological products.
The current program, known as PDUFA IV, will expire on September 30, 2012 unless reauthorized by Congress. Under the recommendations, fees paid by industry would support continued timely review of critical prescription drugs, as well as advance the development of drugs for rare diseases, provide for enhanced communication with small or emerging companies, increase the use of standardized electronic data to improve quality and efficiency, and foster the use of new clinical endpoints that improve drug development times and help address unmet medical needs. The proposed new Generic Drug User Fee program would provide the FDA with needed funding at a time when generic drug applications are on the rise. Currently, generic drugs account for 2/3 of all prescriptions dispensed in the USA. The FDA receives 800 to 900 new generic-drug-related applications annually that are increasingly complex and frequently involve products manufactured outside the USA. In exchange for fees on facilities and product applications, the proposal includes performance metrics such as review timeframes and a commitment to achieve parity between surveillance inspections of foreign and domestic establishments by the 2017 fiscal year. As a result, FDA expects that the proposal would effectively eliminate the review backlog and significantly reduce review times. The proposed Biosimilar and Interchangeable Products User Fee program is intended for products approved under a new abbreviated approval pathway for biological products shown to be biosimilar to or interchangeable with an FDA-licensed biological product. The Affordable Care Act of 2010 contains a subtitle called the Biologics Price Competition and Innovation Act (BPCI) of 2009, which established this pathway. The recommended user fee program for biosimilars includes fees for products in development to generate revenue in the near-term and to provide FDA with the resources needed to support development-phase meetings with sponsors of biosimilar biological product candidates.
Avastin in Ovarian Cancer
In December 2011, the European Commission approved Avastin (bevacizumab) in combination with standard chemotherapy (carboplatin and paclitaxel) as a first line treatment following surgery for women with advanced (Stage IIIb/c and Stage IV) epithelial ovarian, primary peritoneal or fallopian tube cancer.
Approval is based on results from 2 phase III clinical trials (protocol ID: GOG-0218 and MREC-ICON7, EUDRACT-2005-003929-22, ISRCTN91273375, ROCHE-MREC-ICON7, EU-20730, MREC-06/MRE02/52) in which the progression-free survival (PFS) of women with newly diagnosed advanced ovarian cancer treated with Avastin plus chemotherapy and Avastin maintenance, was longer compared to those on chemotherapy alone. However, the gains in PFS were marginal; median PFS was 14.1 months with bevacizumab plus chemotherapy versus 10.3 months with chemotherapy alone, for a gain of 3.8 months in the former trial (Burger RA, et al., NEJM, 29 Dec 2011;365(26):2473-83) and only a couple of months in the ICON7 trial (Perren TJ, et al., NEJM, 29 Dec 2011;365:2484-96). Overall survival (OS) was in essence similar in the Avastin and chemotherapy alone groups in both trials. Based on these results it is unlikely that Genentech will seek FDA approval for Avastin for the ovarian cancer indication. However, data from these trials is being further analyzed as it appears that adding Avastin to chemotherapy may have benefited more significantly certain trial population subgroups.
Reprogramming Cancer Cells to Proliferate Indefinitely In Vitro
Investigators at the Lombardi Comprehensive Cancer Center, Georgetown University Medical School (Washington, DC) and the National Institutes of Health (NIH), report that Rho kinase inhibitor Y-27632, in combination with fibroblast feeder cells, induces normal cells and tumor epithelial cells from many tissues of patients with cancer to survive and proliferate indefinitely in vitro, without transduction of exogenous viral or cellular genes (Liu X, etal, Am J Pathol, 16 Dec 2011; epub ahead of print).
Usually normal cells die after a few divisions and cells from most common malignancies do not survive in vitro. Being able to maintain cancer cells from individual patients indefinitely would revolutionize the practice of pathology and the personalized treatment of cancer. Rapid proliferation of tumor cells in vitro from small biopsy specimens and frozen tissue could enhance the performance of cell-based diagnostics and therapeutics and greatly expand the value of biobanking. Also, In the future, pathologists who now work with frozen or set in wax tissues will be able to establish live cultures of normal and cancer cells from patients to diagnose tumors and screen treatments. Having a patient’s cells available throughout a patient’s treatment would enable oncologists to test treatments that kill these cancer cells without affecting normal cells and also test for resistance and chemosensitivity to single or combination therapies. In addition, this process allows for the genetic manipulation of epithelial cells ex vivo and their subsequent evaluation in vivo in the same host.
In the conditionally reprogrammed cells process, primary prostate and breast cancer cells, for example, are reprogrammed toward a basaloid, stem-like phenotype that, unlike islating rare stem-like cells, can generate 2×106 cells in 5 to 6 days from needle biopsy specimens and cultures from both cryopreserved tissue and fewer than 4 viable cells. Continued cell proliferation is dependent on both feeder cells and Y-27632; conditionally reprogrammed cells retain a normal karyotype and remain nontumorigenic. This technique also efficiently establishes cell cultures from human and rodent tumors. For example, conditionally reprogrammed cells established from human prostate adenocarcinoma formed tumors in SCID mice. Interestingly, the stem-like behavior in these cells is reversible; conditionally reprogrammed cells differentiate into adult cells upon withdrawal of ROCK.
Y-27632 is a selective, ATP-competitive inhibitor of Rho-associated protein kinase (ROCK) including p160Rock and Rock-II. It was originally used to block apoptosis of dissociated cultured human embryonic stem cells (hESC), increasing their survival and cloning efficiency without affecting their pluripotency. Fibroblast feeder cells to keep cells alive were also used to extend survival of hESC but it was their combination with ROCK inhibition that produced the desired results in normal and malignant epithelial cells.
Combination of HEr2 Inhibitors in Breast Cancer
In the multicenter international, double blind, randomized phase III clinical trial (TOC4129g; WO20698; NCT00567190), known as CLEOPATRA (CLinical Evaluation Of Pertuzumab And TRAstuzumab), that randomly assigned 808 patients with metastatic HEr2-positive breast cancer to trastuzumab and docetaxel as first line chemotherapy in combination with pertuzumab or placebo, median PFS was extended an additional 6 months (18.5 months versus 12.4 months), a 38% reduction in risk for progression without any significant increase in AE (Baselga J, etal, SABCS11, Abs. S5-5 and Baselga J, etal, NEJM, 7 Dec 2011; epub ahead of print).
Pertuzumab binds to different HEr2 epitopes than trastuzumab and therefore complements the action of trastuzumab. Pertuzumab prevents HEr2 from dimerizing with other ligand-activated HEr, most notably HEr3 and also stimulates antibody-dependent, cell-mediated cytotoxicity.(ADCC). The positive results of the trial illustrate the effectiveness of combining targeted agents with complimentary modes of action. The combination of pertuzumab and trastuzumab provide a more comprehensive blockade of HEr2 signaling, resulting in greater antitumor activity than either agent alone in HEr2-positive tumor models. In phase II clinical trials, the pertuzumab plus trastuzumab regimen was active in patients with HEr2-positive metastatic breast cancer as well as in patients with early breast cancer.
In October 2011, Dana-Farber Cancer Institute and Brigham and Women's Hospital launched Profile, a large scale research program in a major effort to scan tumor tissue from adult cancer patients for hundreds of gene mutations linked to cancer (external link). The program will be extended to pediatric patients with cancer at Dana-Farber and Children's Hospital Boston in 2012. The program, nearly two years in development, is one of the most extensive research projects in cancer genomics to be undertaken nationally. (more . . .)
In October 2011, Roche reported that in the HannaH multicenter (n=101), international, open label, phase III clinical trial (protocol ID: BO22227; 2008-007326-19; NCT00950300), conducted outside the USA, in women with HEr2-positive early breast cancer, treatment with a new, investigational subcutaneous (SC) injection of Herceptin (trastuzumab) produced comparable results to Herceptin administered as an IV infusion. SC Herceptin takes around 5 minutes to administer whereas the IV formulation takes around 30 minutes to infuse. Also, SC administration may allow patients to spend less time in hospital and significantly reduce pharmacy time, as no medicine preparation time is required. No new safety signals were observed and AE were overall consistent with Herceptin IV. Data from the trial will be submitted for presentation at an upcoming medical meeting and will support a marketing application to regulatory authorities in the European Union in 2012. Herceptin SC uses Enhanze technology, developed by Halozyme Therapeutics, that enables SC injection of large volumes of a medication and enhances PK. The process works by reversibly breaking down hyaluronan that forms a barrier in the tissues between cells under the skin.
According to results reported in September 2011 at the European Multidisciplinary Cancer Congress (Baselga J, etal, EMCC11, Abs. 9LBA) from the pivotal BOLERO-2 (Breast cancer trials of OraL EveROlimus-2) phase III clinical trial (protocol ID: CRAD001Y2301, EUDRACT Number: 2008-008698-69; NCT00863655), treatment with Afinitor (everolimus) tablets plus exemestane (Aromasin) more than doubled PFS to 6.9 months compared to 2.8 months (hazard ratio= 0.43; p<0.0001) and reduced the risk of cancer progression by 57% versus exemestane alone, in patients with Er+HEr2- advanced breast cancer that recurred or progressed while on or following previous treatment with hormonal therapies, letrozole or anastrozole. The data from BOLERO-2 supports worldwide regulatory submissions, which are planned by the end of 2011. Additional data from BOLERO-2 will be presented at upcoming medical congresses in 2011. Worldwide, approximately 220,000 new cases of Er+HEr2- advanced breast cancer are diagnosed each year. Everolimus is also being investigated in BOLERO-1, a phase III clinical trial (protocol ID: CRAD001J2301; EUDRACT Number: 2008-006556-21; NCT00876395) for the treatment of patients with HEr2+ advanced breast cancer.
Astex Pharmaceuticals was formed in September 2011 by the merger of SuperGen and Astex Therapeutics. The company's approved drug Dacogen is marketed in North America by Eisai and in the rest of the world by Johnson & Johnson (Cilag). Astex Pharmaceuticals' royalty income from the worldwide sales of Dacogen was $28.5 million in the first six months of 2011, compared to $24.1 million in the first six months of 2010. The company's pipeline includes 7 novel anticancer agents in clinical development, 3 of which are currently partnered or optioned to large pharmaceutical companies.
In September 2011, GE Healthcare announced plans to dedicate $1 billion of its total R&D budget over the next 5 years to expand its advanced cancer diagnostic and molecular imaging capabilities, as well as its technologies for the manufacture of biopharmaceuticals and for cancer research. The company also established a $100 million open innovation challenge in New York City. The investment will focus on developing new oncology solutions and build on advanced technologies and research already in progress. GE Healthcare already offers a wide oncology-focused portfolio and a strategy that combines cellular research, medical imaging, laboratory diagnostics, biopharmaceutical manufacturing technologies and information technology.
In August 2011, the European Commission approved Roche's Tarceva (erlotinib) in Europe as first line monotherapy in patients with locally advanced or metastatic nsclc with epidermal growth factor receptor (EGFr) activating mutations. Treatment with Tarceva more than triples the number of responders and nearly doubles progression free survival (PFS) compared to chemotherapy. Approval is based on two trials, one in Western populations, dubbed EURTAC (protocol ID: EURTAC-SLCG // GECP06/01; EudraCT:2006-003568-73; NCT00446225), conducted in Europe and one in Asian populations, dubbed OPTIMAL (protocol ID: ML20981; NCT00874419), conducted in China (Zhou C, etal, Lancet Oncol, Aug 2011;12(8):735-42). EGFr activating mutation-positive nsclc occurs in approximately 10% of Western patients with nsclc and in approximately 30% of Asian patients. Roche Molecular Systems is developing the cobas EGFR Mutation Test, a companion diagnostic for Tarceva, to identify patients with EGFr mutations. The CE Mark for this test is expected for the second half of 2011. WW sales of Tarceva were CHF614 million (~$678.8 million) in 1H11, up 4% from 1H10 levels.
In August 2011, the FDA approved Xalkori (crizotinib) capsules for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive locally advanced or metastatic non-small cell lung cancer (nsclc), as detected by an FDA-approved test. In August 2011, the FDA approved Abbott Molecular's Vysis ALK Break Apart FISH Probe Kit, to identify the presence of the ALK fusion gene for patient selection. The effectiveness of Xalkori is based on objective response rates (ORR). Xalkori received accelerated approval from the FDA, so Pfizer is required to conduct post-marketing clinical trials to further evaluate its clinical benefit. Xalkori is available immediately in the USA through a number of specialty pharmacies. The FDA approval of Xalkori is based on data from two multicenter, single arm trials that enrolled 255 patients with locally advanced or metastatic ALK-positive nsclc, including PROFILE 1005, a phase II clinical trial (protocol ID: A8081005; NCT00932451), and a part 2 expansion cohort of a phase I clinical trial (protocol ID: A8081001; NCT00585195). The trials' primary efficacy endpoint was ORR according to RECIST, as evaluated by the investigator. Duration of response was also evaluated. In these trials the ORR was 50% (1 CR and 67 PR) and 61% (2 CR and 69 PR) and the median duration of response was 41.9 weeks and 48.1 weeks, respectively. The most common adverse events (>/=25%) across both trials were vision disorder, nausea, diarrhea, vomiting, edema and constipation. Grade 3 or 4 adverse events in at least 4% of patients in both trials included ALT increased and neutropenia. About 11,000 patients with nsclc in the USA, and about 40,000 globally may be candidates for treatment with Xalkori. It is anticipated that the drug will be priced at $9,600 per month.
In August 2011, the National Cancer Institute (NCI) added the Clinical Proteomic Tumor Analysis Consortium (CPTAC; http://proteomics.cancer.gov/programs/cptacnetwork) to its initiatives in molecular cancer and genomics such as the Cancer Genome Atlas (TCGA; http://cancergenome.nih.gov). Comprising of teams from 5 USA centers, the CPTAC is a comprehensive and coordinated effort to accelerate the understanding of the molecular basis of cancer through the application of robust, quantitative, proteomic technologies and workflows.
In August 2011, the FDA granted accelerated approval to Seattle Genetics' anticancer drug Adcetris (brentuximab vedotin), an antibody-drug conjugate (ADC) comprising an anti-CD30 monoclonal antibody (MAb) attached by a protease-cleavable linker to the microtubule disrupting agent monomethyl auristatin E (MMAE), for two indications, for the treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates, and for the treatment of patients with systemic anaplastic large cell lymphoma (ALCL) after failure of at least one prior multi-agent chemotherapy regimen. The indications for Adcetris are based on response rate; no data are available demonstrating improvement in patient-reported outcomes or survival with Adcetris. Adcetris is the first drug approved by the FDA for Hodgkin lymphoma in more than 30 years, and provides a new therapeutic alternative for Hodgkin lymphoma and systemic ALCL in these settings. The Adcetris approvals were based on data from two open label, single arm clinical trials, a pivotal trial in relapsed Hodgkin lymphoma after ASCT (protocol ID: SG035-0003; NCT00848926) and a pivotal trial in relapsed systemic ALCL (protocol ID: SG035-0004; NCT00866047). The primary endpoint of both trials was overall response rate (ORR) as assessed by an independent review facility. The objective response was 73% and the median duration of response was 6.7 months (range=1.3 to 21.9+ months) among patients with Hodgkin lymphoma and 86% and 12.6 months (range=0.1 to 15.9+ months), respectively, in patients with ALCL.
In August 2011, the FDA approved Zelboraf (vemurafenib) for the treatment of BRAF V600E mutation-positive, inoperable or metastatic melanoma, as determined by an FDA-approved test. The FDA also approved the cobas 4800 BRAF V600 Mutation Test, a diagnostic test developed by Roche Molecular Diagnostics to identify patients eligible for treatment. Zelboraf is the first and only FDA-approved personalized medicine that improves survival in patients with BRAF V600E mutation-positive metastatic melanoma that affects half of all cases of melanoma. The FDA approval of Zelboraf is based on results from two clinical trials, BRIM3 (protocol ID: NO25026; 2009-012293-12; NCT01006980) and BRIM2 (protocol ID: NP22657; NCT00949702), in patients with BRAF V600E mutation-positive, inoperable or metastatic melanoma as determined by the cobas BRAF Mutation Test. In the BRIM3 trial that compared Zelboraf to dacarbazine, at the time of the analysis, median OS of patients treated with Zelboraf had not been reached and was 7.9 months for those on chemotherapy. Median PFS was 5.3 months for those treated with Zelboraf compared to 1.6 months for those on chemotherapy. The confirmed investigator-assessed response rate of the Zelboraf-treated group was 48.4% (CR=1% + PR=47.4%) compared to a PR rate of 5.5% in the chemotherapy treated group (p<0.0001). In the BRIM2 trial, Zelboraf shrank tumors in 52% percent of trial participants. Possible serious side effects with Zelboraf include severe allergic reactions; severe skin reactions; QT prolongation, which can potentially be life-threatening; abnormal liver function tests; eye problems; or new melanoma lesions. Common side effects of Zelboraf include joint pain, rash, hair loss, tiredness, sunburn or sun sensitivity, nausea, itching, or warts. Zelboraf may cause cutaneous squamous cell carcinoma. While taking Zelboraf, patients are to avoid sun exposure. Roche has also submitted new drug applications for Zelboraf in the EU, Switzerland, Australia, New Zealand, Brazil, India, Mexico and Canada. In the meantime, a global Expanded Access Program (EAP) is currently available for patients with previously treated or untreated BRAF V600 mutation-positive metastatic melanoma.
In July 2011, the U.S. Court of Appeals for the Federal Circuit that specializes in patent cases ruled in a 2 to 1 decision that when a gene is isolated from the human body, it is significantly different with a distinctive chemical identity and nature compared to how it exists in nature. This decision overturned parts of an earlier decision by a U.S. District Court in New York City that ruled that patents on the BRCA 1 and 2 gene sequences, and in effect all other human genes, are invalid. In the current decision, the court argued that patents cover isolated DNA that has been cleaved to make it just a fraction of a naturally occurring DNA molecule. Myriad Genetics, the holder of the patent, sells tests that assess a woman's risk of developing breast or ovarian cancer based on detection of mutations in the BRCA1 and BRCA2 genes. Companies, researchers, or doctors testing for these mutations would be violating Myriad's patent unless they perform whole genome sequencing. The U.S. Supreme Court may eventually hear the case.
In July 2011, the FDA issued a new draft guidance intended to provide drug developers with guidance on the agency's policy for reviewing a companion diagnostic and the corresponding therapy. The agency's goal is to help stimulate early collaborations between drug and diagnostics developers to ensure proper patient selection if the drug is approved for routine use. The draft guidance clarifies the FDA's definition of a companion diagnostic; recommends early engagement between the FDA and manufacturers so that the agency's expectations are included in development plans; highlights the FDA's intention to conduct simultaneous reviews of a drug or biologic therapy and its corresponding companion diagnostic; and identifies instances where the FDA may approve a targeted medicine in the absence of a cleared or approved companion diagnostic. In cases where the therapy is intended to treat a serious or life-threatening disease or condition for which there is no available or satisfactory treatment and when the potential benefits outweigh the risks of not having a cleared or approved companion diagnostic, the therapy may be approved first while the companion diagnostic may be approved or cleared later through the appropriate submission process.
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