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Feb 5, 2013

Top 10 Clinical Trial Failures of 2012

Which drugs couldn't pass muster last year? Find out here.

Top 10 Clinical Trial Failures of 2012

Many of these firms lost millions—or billions—when drugs they’d invested in heavily failed. [© ioannis kounadeas - Fotolia.com]

  • Clinical trial failures can kill biopharma companies. While some larger firms can eventually recuperate from the loss of millions invested in a drug that fails its trials, for many companies it can mean layoffs, buyouts, and even shutdowns—just look at TeGenero, a company that filed for insolvency in 2006 after its disasterous Phase I clinical trial of TGN1412 nearly killed its first human subjects.

    You've seen a list of the best-selling drugs of the 21st century; now, get ready for the top 10 biopharma clinical trial failures of 2012. The top five are ranked by the size of the writedowns taken by the drug developer(s) following the trial outcome. The bottom five, for which no writedowns have been announced, were listed alphabetically.

  • #10. Zaltrap (aflibercept)

    Sponsor: Sanofi and Regeneron Pharmaceuticals

    Indication: Prostate cancer

    Type of drug: Angiogenesis inhibitor

    How it failed: Did not meet primary endpoint of improvement in overall survival following intravenous infusion as a first-line treatment for metastatic androgen-independent prostate cancer in combination with docetaxel and prednisone, in VENICE Phase III study.

    Date of failure announcement: April 5

    Cost of development write-off attributed to the drug: No writedown announced. Companies said they would undertake detailed analysis of the VENICE data, followed by presentation of full results.

  • #9. Torisel (temsirolimus or CCI-779)

    Sponsor: Pfizer

    Indication: First-line renal cell carcinoma in combination with Roche/Genentech’s Avastin (bevacizumab); Second-line renal cell carcinoma following therapy with Pfizer's Sutent (sunitinib)

    Type of drug: Mammalian target of rapamycin (mTOR) inhibitor

    How it failed: Did not meet primary endpoint of superiority in extending PFS over Bayer’s Nexavar (sorafenib) in INTORSECT Phase III trial (B1771003); while PFS was numerically higher in patients treated with temsirolimus, the difference was not statistically significant. Did not meet primary endpoint of superiority in extending PFS over bevacizumab plus interferon-alfa-2a, or IFN-alpha-2a in INTORACT Phase III trial (B1771006).

    Dates of failure announcement: May 16; August 10

    Cost of development write-off attributed to the drug: No writedown announced; Pfizer said it would conduct additional analysis of additional efficacy endpoints and safety data for the combination treatments in both arms.

  • #8. Solanezumab

    Sponsor: Eli Lilly

    Indication: Mild-to-moderate Alzheimer’s disease

    Type of drug: Amyloid beta (Aß) antibody

    How it failed: Did not meet both cognitive and functional primary endpoints in either of the two EXPEDITION Phase III trials. After pre-specified secondary subgroup analyses in patients with mild Alzheimer's disease showed a statistically significant reduction in cognitive decline, Lilly modified the statistical analysis plan for EXPEDITION2 to specify a single primary endpoint of cognition, but the revised primary endpoint did not achieve statistical significance. No statistically significant slowing of cognitive decline in patients with moderate Alzheimer's disease.

    Date of failure announcement: August 24

    Cost of development write-off attributed to the drug: No writedown announced; Eli Lilly disclosed plans December 12 for a third Phase III trial.

  • #7. Avastin (bevacizumab)

    Sponsor: Roche (Genentech)

    Indication: Triple-negative adjuvant breast cancer: a year of treatment in addition to chemotherapy following surgery

    Type of drug: Angiogenesis inhibitor

    How it failed: Did not show statistically significant improvement in invasive disease-free survival compared with patients treated with chemotherapy alone, in BEATRICE Phase III trial. Final overall survival data are expected in 2013.

    Date of failure announcement: December 7

    Cost of development write-off attributed to the drug: No writedown announced.

  • #6. Amigal (migalastat hydrochloride)

    Sponsor: Amicus Therapeutics and GlaxoSmithKline

    Indication: Fabry disease

    Type of drug: Pharmacological chaperone

    How it failed: Did not meet primary endpoint of analysis of 50% or greater reduction in kidney interstitial capillary GL-3 after six months of treatment with Amigal compared to placebo in Study 011 Phase III trial. While 13/32 (41%) Amigal-treated patients showed 50% or greater reduction versus 9/32 (28%) in the placebo group, the difference did not achieve statistical significance.

    Date of failure announcement: December 19

    Cost of development write-off attributed to the drug: No writedown announced, pending additional study and analysis. Six-month secondary endpoints for Study 011 set to be presented at the Lysosomal Disease Network WORLD Symposium (LDN WORLD), Feb. 12–15, 2013, in Orlando, FL. Secondary endpoints include urine GL-3 and renal function (iohexol GFR, eGFR and 24-hour urine protein). Second Phase III global registration study (Study 012) is also underway to compare open-label Amigal to enzyme replacement therapy.

  • #5. Pomaglumetad methionil (mGlu2/3)

    Sponsor: Eli Lilly

    Indication: Acute exacerbation of Schizophrenia

    Type of drug: Metabotropic glutamate 2/3 (mGlu 2/3) receptor agonist

    How it failed: Independent futility analysis concluded H8Y-MC-HBBN, the second of Lilly's two pivotal Phase III studies, was unlikely to be positive in its primary efficacy endpoint if enrolled to completion. The first Phase III trial, H8Y-MC-HBBM, did not show superiority to placebo in either the overall or predefined genetic subpopulation (based on the Positive and Negative Syndrome Scale, PANSS) at the two doses investigated (40 mg and 80 mg BID). Also unsuccessful was the HBCO Phase II study, which investigated Pomaglumetad methionil as an adjunctive treatment with atypical antipsychotics, did not meet its primary endpoint.

    Date of failure announcement: August 29

    Cost of development write-off attributed to the drug: “$25 million to $50 million” charge against third-quarter R&D.

  • #4. TC-5214 (Mecamylamine)

    Sponsor: AstraZeneca and Targacept

    Indication: Adjunct therapy to an antidepressant in patients with major depressive disorder who did not respond adequately to initial antidepressant treatment

    Type of drug: Neuronal nicotine receptor antagonist

    How it failed: Did not meet the primary endpoint of change on the Montgomery-Asberg Depression Rating Scale (MADRS) total score after eight weeks of adjunct treatment with TC-5214 as compared to placebo in the RENAISSANCE 4 and RENAISSANCE 5 Phase III studies.

    Date of failure announcement: March 20

    Cost of development write-off attributed to the drug: $50 million asset-impairment charge by AZ, which terminated an agreement to license the drug and returned it to Targacept after paying $200 million up-front and spending $250 million on research and clinical trials; $2.386 million in severance and other charges recorded by Targacept in Q1 2012, related to a restructuring that followed the trial failures. Targacept’s workforce was reduced by 65 employees, or about 46%, for annual savings of about $12.9 million.

  • #3. Dalcetrapib (JTT-705)

    Sponsor: Roche

    Indication: Stable coronary heart disease (CHD) following an acute coronary syndrome

    Type of drug: Cholesteryl ester transfer protein (CETP) inhibitor

    How it failed: Failed to meet primary endpoint of lowering cardiovascular risk beyond level achieved with intensive statin treatment, in dal-OUTCOMES Phase III trial, halted following results of second interim analysis.

    Date of failure announcement: May 7

    Cost of development write-off attributed to the drug: CHF 242 million ($259.3 million) in charges consisting of CHF 130 million ($139.3 million) for restructuring costs, consisting of provisions for remaining trial costs and write-offs of inventories and property, plant and equipment; and CHF 112 million ($120 million) for the write-off of previously acquired intangible assets.*

  • #2. Bapineuzumab

    Sponsor: Johnson & Johnson with Pfizer

    Indication: Mild-to-moderate Alzheimer’s disease

    Type of drug: Anti-beta-amyloid monoclonal antibody

    How it failed: Failed to meet co-primary clinical endpoints of change in the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), and the Disability Assessment for Dementia (DAD), in Phase III studies of patients who are not ApoE4 noncarriers (Study 301) and patients who are (Study 302), led by J&J’s Janssen Alzheimer Immunotherapy.

    Date of failure announcement: August 6

    Cost of development write-off attributed to the drug: $700 million in-process research and development charge in Q3 2012.

  • #1. BMS-986094 (formerly INX-189)

    Sponsor: Bristol-Myers Squibb

    Indication: Hepatitis C

    Type of drug: Nucleotide polymerase (NS5B) inhibitor

    How it failed: Drug administration in Phase IIb study suspended following the occurrence of heart failure in one patient who received the highest daily dose, 200 mg, in combination with BMS’ daclatasvir, another hepatitis C drug candidate.

    Date of failure announcement: August 1

    Cost of development write-off attributed to the drug: $1.8 billion noncash impairment charge in Q3 2012.


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