Alex Philippidis Senior News Editor Genetic Engineering & Biotechnology News
Which drugs tanked during testing last year?
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)
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
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.
Sponsor: Eli Lilly
Indication: Rheumatoid arthritis (RA)
Type of drug: Anti-BAFF (B cell activating factor) monoclonal antibody
How it failed: The company said tabalumab showed a lack of efficacy in the Phase III FLEX-V study, which was investigating the compound for the treatment of patients with moderate-to-severe RA who had an inadequate response to one or more tumor necrosis factor (TNF) inhibitors.
Date of failure announcement: February 7
Cost of development write-off attributed to the drug: “Approximately” $60 million in costs related to the discontinuation of the rheumatoid arthritis program.4
#4. Fostamatinib (R788)
Sponsors: AstraZeneca and Rigel
Indication: Rheumatoid arthritis
Type of drug: Oral spleen tyrosine kinase inhibitor
How it failed: Fostamatinib with methotrexate (MTX) did not show statistically significant improvement compared to placebo in ACR20 response rates at 24 weeks in patients given 100 mg twice-daily for four weeks followed by 150 mg once daily, in Phase III OSKIRA-3 trial of patients inadequately responding to MTX and a single TNF-alpha antagonist. However, the drug did show statistically significant improvements in ACR20 response rates at 24 weeks in the 100 mg twice-daily group.
Date of failure announcement: June 4
Cost of development write-off attributed to the drug: AZ recorded a $136 million pre-tax impairment charge to R&D expense in second quarter of 2013 toward intangible assets relating to fostamatinib, which was excluded from core financial measures. AZ was solely responsible for all costs and expenses incurred by both parties up to December 4, 2013.5 Following release of topline results, AstraZeneca said it will not proceed with regulatory filings, and returned its rights to the compound to Rigel.6,7
Sponsor: Merck & Co.
Indication: Parkinson’s disease
Type of drug: Adenosine A2A receptor antagonist
How it failed: Company said initial review of data from three separate Phase III trials to assess safety and efficacy did not provide evidence of efficacy for preladenant compared with placebo. Two of the studies assessed preladenant when added to levodopa therapy in patients with moderate-to-severe PD; the third assessed preladenant as monotherapy in early PD. Citing its review, Merck discontinued the extension phases of the studies and said it no longer plans to pursue regulatory filings for the drug candidate.
Date of failure announcement: May 23
Cost of development write-off attributed to the drug: Approximately $181 million impairment charge in the second quarter of 2013, following discontinuation of the clinical development program.
Indication: Chronic coronary heart disease (CHD) in adults
Type of drug: Oral inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2)
How it failed: Did not meet primary endpoint of time to first occurrence of any major adverse cardiovascular event (MACE) from the composite of myocardial infarction (heart attack), stroke, and cardiovascular death (relative risk reduction of 6%; p=0.199) in Phase III STABILITY (STabilisation of Atherosclerotic plaque By Initiation of darapLadIb TherapY) trial.8
Date of failure announcement: November 12
Cost of development write-off attributed to the drug: No writedown announced, though one analyst has estimated GSK will take a £150 million (about $246.3 million) writedown9 pending formal announcement expected with release of Q4 and full-year 2013 results; next steps unknown pending completion of a second Phase III study of darapladib in acute coronary syndrome, called SOLID-TIMI 52.
#1. Iniparib (BSI-201; SAR240550)
Indications: Newly diagnosed, metastatic (stage IV) squamous non-small-cell lung cancer; platinum-resistant ovarian cancer
Type of drug: Benzamide (4-iodo-3-nitrobenzamide) structurally related to nicotinamide
How it failed: Did not meet its primary endpoint of achieving improvement in overall survival when added to gemcitabine/carboplatin chemotherapy compared to patients who received gemcitabine/carboplatin alone in Phase III ECLIPSE trial, which also found no clinically meaningful differences in the main safety parameters between the two arms. Company also said topline results of a Phase II study of iniparib in platinum-resistant ovarian cancer do not support further development of iniparib in this patient population.
Date of failure announcement: June 3
Cost of development write-off attributed to the drug: €384 million ($525 million) impairment loss on intangible assets charged in the first half of 2013, related to discontinuation of internal R&D programs for iniparib in non-small-cell lung cancer and ovarian cancer.
Writedowns used in ranking include both research and other costs and “impaired assets” charges connected with the drug, as disclosed by the companies (or projected, in one widely-reported case, by an analyst), as well as writedowns for layoffs and other restructuring actions that the companies directly attribute to the failure of a clinical trial or termination of a clinical development program.
The list does not include some widely reported failures where no information on writedowns related to a drug is available. For example, Merck KGaA noted in its Q1 2013 results that “The accounting impact has been taken into consideration,” without elaborating: It could be all or part of the €28.3 million (about $38.6 million) reported for “impairment losses.”
Two additional trial failures not listed here are expected to result in writedowns to be announced in coming days: Drisapersen, the Duchenne muscular dystrophy whose rights GlaxoSmithKline returned to Prosensa following a failed Phase III trial; and Rebamipide ophthalmic suspension, the dry eye syndrome drug Otsuka returned to Acucela following a failed Phase III trial that terminated the collaboration and resulted in the layoff of about 30 Acucela employees. Both Prosensa and Acucela still plan to develop their compounds, either alone or with new partners.
1 ODAC questioned why data from Aveo’s 517-patient TIVO Phase III clinical trial was heavy with results from Eastern European patients while failing to show a better rate of overall survival than any of five currently approved drugs for RCC. Aveo has cited other data from TIVO, showing that tivozanib slowed down progression of the disease—though the trial also showed that patients using Nexavar showed a better overall survival rate.
2 After the BATON study, Aveo said it was in talks with Astellas on next steps in CRC while data from a planned interim analysis, including biomarker data, were being analyzed.
3 However, Aveo lost out on most of a potential $1.3 billion in milestones, including $575 million in clinical and regulatory milestones—of which $90 million related to regulatory filings and market approval of tivozanib for RCC—plus more than $780 million in commercial milestones. Aveo received $125 million upfront under the collaboration, launched in 2011 to develop and commercialize the drug outside of Asia—as well as a $15 million milestone payment in December 2012 after FDA accepted the companies’ NDA for tivozanib. But Aveo failed to achieve other regulatory milestones, including FDA marketing approval ($30 million), European Medicines Agency (EMA) acceptance of a Marketing Authorization Application ($15 million), and marketing approval by EMA ($30 million).
4 Lilly said the end of development in RA and related writedown did not affect the Phase III ILLUMINATE development program for the compound in systemic lupus erythematosus, which the company said is ongoing and will continue as planned.
5 However, Rigel lost out on most of the $1.2 billion envisioned when the collaboration with AZ was inked in 2010. Rigel received $100 million upfront—plus $25 million for launching Phase III clinical trials, a fraction of up to $345 million in potential payments tied to development, regulatory, and first-sale milestones. The deal also included up to $800 million in sales-related milestones.
6 In September, Rigel said it would discontinue development of the drug for RA or lymphoma, the indication for a Phase II trial launched by AZ in 2012.
7 At the JP Morgan 32nd Annual healthcare Conference on January 16, 2014, Rigel said it expects to launch this year two clinical studies of the drug—a 150-patient Phase III trial to start in the first half of 2014, focused on immune thrombocytopenic purpura (ITP), with a primary endpoint of increased platelet numbers, and topline results in 2015; and a Phase II trial, set to start in the second quarter of 2014, assessing the drug candidate’s effect on Immunoglobulin A Nephropathy (IgA) nephropathy, with a primary endpoint of proteinuria reduction.
8 STABILITY trial also showed greater reductions in some predefined secondary endpoints that according to GSK require further analysis, with additional data forthcoming from a second Phase III study, SOLID-TIMI 52.
9 GSK is expected to furnish a figure when it releases fourth-quarter and full-year 2013 results on February 5. Estimate by Savvas Neophytou, an analyst with Panmure Gordon, as reported by several news outlets. See The Guardian, “GlaxoSmithKline falls on herat drug disappointment as FTSE awaits UK inflation data,” November 12, 2013; and Reuters, “GlaxoSmithKline drug misses goal in major study,” November 12, 2013.