Hopes raised, hopes dashed — the last half of 2012 has seen plenty of both. Enthusiasm over a bumper crop of U.S. Food and Drug Administration approvals has been tempered by a long list of phase 3 trial disappointments.
Oncology agents led the way, starting with two drugs being studied for the treatment of non-small cell lung cancer. The addition of Eli Lilly’s pemetrexed (Alimta) to a regimen of bevacizumab (Avastin) and chemotherapy produced improvements in progression-free survival (PFS) but not overall survival (OS). ArQule and Daiichi Sankyo stopped a phase 3 study of tivantinib after concluding that improvements in OS would not be reached. For ArQule, the silver lining was the FDA’s grant of a special protocol assessment, allowing the start up of a phase 3 trial of tivantinib in patients with liver cancer.
Amgen ended a large phase 3 trial of ganitumab after a data monitoring committee determined that the addition of ganitumab to gemcitabine (Gemzar) would not result in significant OS improvements in patients with pancreatic cancer versus gemcitabine alone. A phase 2 trial of ganitumab in locally advanced pancreatic cancer was also stopped.
Two separate studies of agents to treat kidney cancer also caused consternation. Temsirolimus (Torisel), currently on the market for advanced renal cell carcinoma, was no better at extending PFS when combined with bevacizumab than a combination of bevacizumab and interferon alfa-2a. And Aveo is reevaluating data from a head-to-head trial of its tivozanib versus sorafenib (Nexavar) after the FDA expressed concern about OS data that Aveo planned to include in a new drug application later this year.
Not all news from oncology was disappointing. Immunogen released a deeper dive into OS data for trastuzumab emtansine, or T-DM1 (Kadcyla), showing a 5.8-month OS benefit in previously treated HER2-positive metastatic breast cancer patients versus lapatinib (Tykerb) plus capecitabine (Xeloda). And Celgene’s multiple myeloma oral drug, pomalidomide — a derivative of thalidomide — improved PFS in patients who were refractory to lenalidomide (Revlimid) and bortezomib (Velcade).
Alzheimer’s data quandary
Is half a loaf better than nothing? That seems to be the message from researchers who conducted two large studies of solanezumab, Eli Lilly’s experimental Alzheimer’s agent.
Solanezumab missed its primary endpoint in two pivotal trials, but in a subsequent analysis, researchers found a biomarker they say opens a new avenue for Alzheimer’s research. Reduced levels of beta-amyloid in the blood, they contend, can be a surrogate for lower levels of the protein in the brain. Moreover, they believe this finding explains how a subpopulation in one of the studies met a secondary endpoint, reduction in cognitive decline.
As Lilly mulls whether to pursue FDA approval on secondary data, observers raise questions: Will the FDA require another phase 3 trial to validate the bio-marker theory? Or will the agency be willing to accept substandard data to help Alzheimer’s patients cope as best as they can with a disease for which no effective therapies exist? The questions loom larger in the wake of Janssen and Pfizer’s announcement on Aug. 6 that they had pulled the plug on development of an IV formulation of another hyped Alzheimer’s treatment in late-stage development, bapineuzumab.
MS drugs take spotlight
Biogen Idec steamed toward approval of its oral MS agent, BG-12, with publication of two pivotal studies in the New England Journal of Medicine. In both the DEFINE and CONFIRM studies, the primary endpoint (reductions in relapse rates) was reached with ease. Safety profiles were favorable in both studies as well, bolstering the perception among patient advocates that BG-12 may have come as close as anything to bridging the efficacy/safety tradeoff that defines MS therapies. In DEFINE, BG-12 was compared to placebo; in CONFIRM, glatiramer acetate (Copaxone) was a comparator drug.
On BG-12’s heels, Sanofi and Genzyme published positive data from two pivotal trials of alemtuzumab (Lemtrada) in the Lancet. In both, alemtuzumab was significantly more effective at reducing annualized relapse rates than the active comparator, interferon beta-1a (Rebif).
| FDA BIOLOGIC AND SPECIALTY DRUG APPROVALS, AUG. 1–OCT. 31, 2012 | ||||
| Date (type) | Manufacturer | Drug (trade name); administration | Indication | Notes |
| New marketing approvals | ||||
| Aug. 3 (BLA) | Sanofi/Regeneron | ziv-aflibercept (Zaltrap); IV infusion | In combination with FOLFIRI, for mCRC resistant to oxaliplatin chemo regimen | Angiogenesis inhibitor is a reformulation of aflibercept (Eylea), approved for wet AMD |
| Aug. 9 (NDA) | Talon Therapeutics | vincristine sulfate LIPOSOME injection (Marqibo); IV infusion | Relapsing Ph-negative acute lymphoblastic leukemia in adults | Patient population in U.S. is less than 500 |
| Aug. 27 (NDA) | Gilead | elvitegravir, cobicistat, emtricitabine, tenofovir (Stribild); oral | HIV in treatment-naive adults | Single-pill, daily regimen; known as “Quad” during clinical trials |
| Aug. 31 (NDA) | Medivation/Astellas | enzalutamide (Xtandi); oral | mCRPC in men previously treated with docetaxel | OS gain 4.8 mo. vs placebo; yearly $90,000 cost similar to Provenge |
| Sept. 4 (NDA) | Pfizer | bosutinib (Bosulif); oral | Ph-positive CML resistant or intolerant to prior therapy | For use in patients with chronic, accelerated, or blast phase |
| Sept. 12 (NDA) | Sanofi/Genzyme | teriflunomide (Aubagio); oral | Relapsing multiple sclerosis | 36% drop in relapse vs placebo, but failed head-to-head vs Rebif |
| Sept. 27 (NDA) | Onyx/Bayer | regorafenib (Stivarga); oral | mCRC after treatment with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy | Approved under accelerated review; Bayer also filed supplemental NDA Aug. 30 for gastrointestinal cancer indication |
| Oct. 26 (NDA) | Teva | omacetaxine mepesuccinate (Synribo); SC injection | CML with resistance and/or intolerance to two or more tyrosine kinase inhibitors | For use in patients with chronic or accelerated phase |
| New indication | ||||
| Sept. 28 (sBLA) | Abbott | adalimumab (Humira); SC injection | Ulcerative colitis (UC) | UC becomes seventh indication for the TNF-α blocker |
| SELECTED FDA-RELATED ACTIVITIES, AUG. 1–OCT. 31, 2012 | ||||
| Manufacturer | Drug (trade name) | Type of drug | Proposed use | Notes |
| Halozyme/Baxter | HyQ | Immune globulin 10% and recombinant human hyaluronidase (rHuPH20) | Primary immunodeficiency disease | Aug. 1 CRL asked for additional preclinical data; FDA concerned about effect of non-neutralizing antibodies on reproduction |
| Janssen | abiraterone (Zytiga) | androgen deprivation therapy | mCRPC in men who have not yet undergone chemo | Now approved in post-chemo setting; FDA Aug. 28 gave priority review to extended indication |
AMD=age-related macular degeneration, BLA=biologics license application, CML=chronic myelogenous leukemia, CRL=complete response letter, EGFR=epidermal growth factor receptor, IV=intravenous, mCRC=metastatic colorectal cancer, mCRPC=metastatic castration-resistant prostate cancer, NDA=new drug application, OS=overall survival, SC=subcutaneous, VEGF=vascular endothelial growth factor.
Sources: FDA, FierceBiotech; manufacturers’ news releases, product labeling, and SEC filings; weblogs; and wire reports
Both drugs, along with the approval of teriflunomide (see table) and others in development (see article on page 24) usher in a new phase of MS treatment.
Did you hear?
Sloan Kettering officials wrote in the New York Times that the cancer center won’t give patients ziv-aflibercept (Zaltrap) because of its $11,000 a month price. ... Teva and Samsung have given up trying to reproduce rituximab, ending those biosimilar programs.
Footnotes
All clinical trials described in Drug Track are phase 3, randomized, controlled studies unless otherwise specified.