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February 03, 2014

Top 10 Clinical Trial Failures of 2013

Which drugs tanked during testing last year?

Top 10 Clinical Trial Failures of 2013

Five of the trial failures on this list were for cancer indications. [© Ljupco Smokovski - Fotolia.com]

  • Below is a list of the top 10 biopharma clinical trial failures of 2013, ranked by the size of the writedowns associated with the trial outcome. The company with the greatest presence on this year’s failure list is Eli Lilly, with three compounds for which it wrote down a combined $105 million in 2013. To be fair, Lilly is continuing development of one of the compounds in other indications, and evaluating the long-term maintenance effect of another, so either or both of these could yet advance clinically this year despite the failed trials.

    Interestingly, five of the top 10 clinical trial failures listed below were for cancer indications, followed by two for rheumatoid arthritis candidates, and one each for investigational heart disease, depression, and asthma drugs.

    Four of the top 10 failures arose from collaborations in which smaller companies licensed their compounds to a biopharma giant, with the potential promise of hundreds of millions or even billions of dollars when milestone payments and royalties are accounted for. For those collaborations, this list includes, within footnotes, the money gained and lost out by the smaller partner stemming from the failure.

  • #10. Palifosfamide (ZIO-201 or isophosphoramide mustard)

    Sponsor: Ziopharm Oncology

    Indication: Metastatic soft tissue sarcoma

    Type of drug: DNA alkylating agent

    How it failed: Did not meet its primary endpoint of progression-free survival (PFS) in Phase III PICASSO 3 trial, designed to assess the drug as a first-line treatment for metastatic soft tissue sarcoma. Full data from PICASSO 3 will be submitted for publication in a scientific journal, the company said. Ziopharm said that while the trial’s independent data monitoring committee (IDMC) has recommended that patients be followed for overall survival (OS), the study's secondary endpoint, “the company does not expect to continue follow up for OS.”

    Date of failure announcement: March 26

    Cost of development write-off attributed to the drug: Total charges of “$1.6 million to $1.8 million,” primarily for onetime contractual severance benefits, in connection with the elimination of 40 filled positions under an April 3 restructuring that eliminated a total 65 positions. The restructuring resulted from the company’s decision to terminate development of the drug in first-line metastatic soft tissue sarcoma and place exclusive strategic focus on its synthetic biology programs being developed with Intrexon.

  • #9. Allovectin® (velimogene aliplasmid)

    Sponsor: Vical

    Indication: Metastatic melanoma

    Type of drug: Intratumoral cancer immunotherapy

    How it failed: Did not meet primary endpoint in Phase III trial of demonstrating a statistically significant improvement vs. first-line chemotherapy for either the primary endpoint of objective response rate at 24 weeks or more after randomization, nor did Allovectin meet the trial’s secondary endpoint of overall survival.

    Date of failure announcement: August 12

    Cost of development write-off attributed to the drug: $2.9 million, consisting of charges for employee termination benefits of $2.2 million, and for asset impairments of $0.7 million, both during the third quarter. On August 22, the company said it would terminate the program and eliminate 47 jobs (about 39% of total workforce), leaving it with 74 employees.

  • #8. Tivozanib (ASP4130)

    Sponsor: Astellas Pharma and Aveo Oncology

    Indication: Advanced renal cell carcinoma (RCC); Colorectal cancer (CRC)

    Type of drug: Oral tyrosine kinase inhibitor of VEGF receptors 1, 2, and 3

    How it failed: In June, FDA issued a Complete Response Letter (CRL) faulting as uninterpretable and inconclusive Aveo’s results from its TIVO-1 (TIvozanib Versus sOrafenib in 1st line advanced RCC) trial of lead product candidate tivozanib for advanced RCC, which compared the compound’s safety and efficacy to that of Nexavar® (sorafenib); and requesting a new RCC trial. FDA sided with its Oncologic Drugs Advisory Committee (ODAC), which in May voted 13–1 to recommend that FDA reject tivozanib for RCC.1

    In December, Aveo said data from a planned interim analysis of the Phase II BATON (Biomarker Assessment of Tivozanib in ONcology) study in patients with CRC indicated that the study was unlikely to meet its primary endpoint of showing superiority of tivozanib with modified FOLFOX6 compared to Avastin (bevacizumab) with modified FOLFOX6 as a first-line treatment in patients with advanced metastatic CRC.2

    Date of failure announcements: June 10; December 13

    Cost of development write-off attributed to the drug: Aveo cited $8 million (including $300,000 in impairment charges) restructuring expense for the nine months ending September 30, reflecting its layoff of 140 staffers—62% of its workforce—in June, following the advisory committee rejection. Three weeks later, Astellas Pharma told Aveo it would not pursue European approval for the drug candidate, and would stop funding RCC trials under their collaboration. No writedown announced by Astellas.3

  • #7. Edivoxetine

    Sponsor: Eli Lilly

    Indication: Add-on therapy for major depressive disorder

    Type of drug: Norepinephrine reuptake inhibitor

    How it failed: Did not meet the primary study objective of superior efficacy in depression after eight weeks of treatment. When added to a selective serotonin reuptake inhibitor (SSRI), edivoxetine did not separate from placebo on the Montgomery-Asberg Depression Rating Scale (MADRS) in three acute randomized placebo-controlled Phase III studies (LNBM, LNBQ, and LNBR). Detailed data to be disclosed in 2014 in “appropriate” scientific forums.

    Date of failure announcement: December 5

    Cost of development write-off attributed to the drug: About $15 million (pre-tax) fourth-quarter charge to R&D expense; company said it would not proceed with development of the drug for its stated indication, though an ongoing clinical study evaluating the long-term maintenance effect of edivoxetine will continue to completion.

  • #6. Enzastaurin (LY317615 HCl)

    Sponsor: Eli Lilly

    Indication: Prevention of relapse in patients with diffuse large B-cell lymphoma (DLBCL)

    Type of drug: Oral small molecule, serine/threonine kinase inhibitor of the PKC beta and AKT pathways

    How it failed: Did not meet primary endpoint of showing a statistically significant increase compared to placebo in disease-free survival in patients at high risk of DLBCL relapse following rituximab-based chemotherapy, in Phase III PRELUDE study.

    Date of failure announcement: May 10

    Cost of development write-off attributed to the drug: About $30 million second-quarter charge to R&D expense; company said it would halt development of enzastaurin.

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