Alex Philippidis Senior News Editor Genetic Engineering & Biotechnology News
These Drugs Failed to Meet Primary Endpoints, with Consequences beyond the R&D Budget
Biopharmas spend millions, or billions, to develop new drugs, yet the consequences of failure in mid- to late-stage clinical trials can go beyond the R&D budget.
Numerous aftermaths of trial failure can be seen in this year’s Top 10 Clinical Trial Failures of 2014. Six of the 10 saw immediate pushback from investors, in the form of sharp one-day declines in their stock per-share prices. Three of the 10 saw a halt to development in the indication that touched off a trial failure. One saw its entire clinical development program halted, resulting in its developer taking a charge against earnings. And for two candidates on this year’s list, trial failures sparked company restructurings that included elimination of jobs.
Mere failure in a Phase III trial alone was not the sole criterion for inclusion on this list, since numerous drugs fail pivotal trials—sometimes, numerous times—before eventually generating enough positive data to garner a marketing approval. Unlike past years, fewer drug developers were willing to simply write off failed drugs through charges against earnings—the basis of a ranking used in past years.
Following is a list of top 10 clinical failures of 2014. Drug candidates are listed in alphabetical order with their sponsor(s), the indication in which the failure occurred, the type of drug, how the drug failed its trial(s), the date of failure-related announcements, and the aftermath.
Bitopertin (RG 1678)
Type of drug: Glycine reuptake inhibitor
How drug failed: Did not meet primary endpoints in two Phase III studies evaluating the drug candidate for persistent, predominant “negative symptoms” of schizophrenia. Negative symptoms defined to include social withdrawal and lack of motivation. In the studies, adding bitopertin to antipsychotic therapy did not significantly reduce negative symptoms at 24 weeks compared to placebo. The candidate also failed to meet primary endpoint in a third Phase III trial focused on its effect on sub-optimally controlled symptoms.
Dates of announcements: January 21, 2014; April 15, 2014
Aftermath of failure: Following the third trial failure in April, Roche discontinued two additional trials that assessed the drug candidate for its effects on “sub-optimally controlled symptoms” of schizophrenia, such as hallucinations and delusions, and other symptoms that do not resolve despite treatment with an antipsychotic. The company, however, opted to continue a sixth Phase III trial (NightLyte), also focused on sub-optimally controlled symptoms.
Indication: Metastatic castration-resistant prostate cancer (mCRPC)
Type of drug: Tyrosine kinase inhibitor
How it failed: Did not meet its primary endpoint of demonstrating a statistically significant increase in overall survival (OS) for patients compared to prednisone, according to topline data in the Phase III COMET-1 trial. Exelixis said it plans to present additional data, including secondary and exploratory endpoints “at a future medical conference,” according to its third-quarter 2014 Form 10-Q, submitted November 4 to the SEC.
COMET-1 was intended to support a new indication for Cabozantinib, which is marketed under the name COMETRIQ® both in the U.S. and Europe for progressive, metastatic medullary thyroid cancer (MTC), and in Europe additionally for unresectable locally advanced MTC. Based on the topline results, Exelixis said it “deprioritized” the clinical development of cabozantinib in mCRPC and halted enrollment in other company-sponsored studies in mCRPC.
Date of announcement: September 1, 2014
Aftermath of failure: Company eliminated about 65% of its workforce—approximately 150 jobs—and said in its third-quarter Form 10-Q that it will take a one-time charge in 2014 amounting to 95% of between $6 million and $7 million for termination benefits toward the layoffs, which shrunk the company’s workforce to 80 employees. A $3.3 million restructuring charge was recorded for the third quarter—$2.6 million for severance, $0.7 million for property, and equipment write-downs. The remaining 5% will be reflected in first-quarter 2015 results.
Company also reversed $2.1 million of previously recorded stock-based compensation expenses, and cancelled 692,896 stock options with performance objectives that could no longer be achieved.
Sponsors: OncoGenex Pharmaceuticals and Teva Pharmaceutical Industries
Indication: Metastatic castrate-resistant prostate cancer (CRPC)
Type of drug: Antisense clusterin inhibitor
How it failed: Did not meet endpoint of significantly extending overall survival (OS) in men with CRPC versus docetaxel and prednisone alone, in Phase III SYNERGY trial. Median OS in the Custirsen arm was 23.4 months, versus 22.2 months for the control group.
OncoGenex has said it remains committed to Custirsen, with two other Phase III trials ongoing—AFFINITY, designed to compare survival among men with metastatic CRPC following treatment with Custirsen plus second-line cabazitaxel and prednisone, versus second-line chemotherapy alone; and ENSPIRIT, which is assessing custirsen with docetaxel, versus only docetaxel, in patients with advanced or metastatic NSCLC whose disease progressed after initial chemotherapy.
Dates of announcements: April 28, 2014; December 30, 2014
Aftermath of failure: OncoGenex saw its share price fall 60%, to $3.85 on the day it announced the failure of the SYNERGY trial. In December, OncoGenex terminated a five-year-old collaboration with Teva and regained rights to Custirsen. In their termination agreement, Teva agreed to pay OncoGenex $27 million, “subject to certain adjustments,” as called for under the companies’ 2009 collaboration agreement. That agreement gave Teva rights to Custirsen in return for agreeing to pay OncoGenex up to $430 million—$60 million in upfront, equity investment, and development-cost payments; the rest in payments tied to regulatory and sales milestones. Those numbers did not include additional tiered royalties.
Sponsor: GlaxoSmithKline (GSK)
Indication: Coronary heart disease
Type of drug: Selective and orally active inhibitor of Lp-PLA2 (lipoprotein-associated phospholipase A2), an enzyme that is found in blood and in atherosclerotic plaques. Elevated Lp-PLA2 activity has been implicated in the development and progression of atherosclerosis.
How it failed: In the Phase III (STabilisation of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) study, Darapladip did not meet primary endpoint of extending the time to first occurrence of any major adverse cardiovascular event (MACE) comprising cardiovascular death, myocardial infarction (MI), and stroke compared with placebo. GSK presented data to that effect in March 2014 at the American College of Cardiology Scientific Session in Washington, DC, four months after disclosing the failed outcome—an announcement that placed Darapladip on GEN’s List of Top 10 Clinical Trial Failures of 2013. No difference was seen in the treatment groups in the time to first occurrence of MACE. During 3.7 years median follow-up, the primary endpoint of MACE occurred in 9.7% of patients in the Darapladip group and 10.4% of patients in the placebo group
Darapladip also did not meet its primary endpoint of achieving a reduction of time to first occurrence of any event from the composite of coronary heart disease death, heart attack, and urgent coronary revascularisation for myocardial ischemia, compared with placebo in the Phase III Stabilisation Of pLaques usIng Darapladib— Thrombolysis In Myocardial Infarction 52 (SOLID-TIMI 52).
Date of announcements: March 30, 2014; May 13, 2014; October 22, 2014
Aftermath of failure: Company acknowledged in May that the SOLID-TIMI 52 outcome “does not support a regulatory submission in atherosclerosis.” GSK went further in its third quarter release in October, removing Darapladip from its “Phase III/Registration Pharmaceuticals and Vaccines pipeline,” saying the drug candidate’s atherosclerosis program was one of two clinical programs “which were stopped in Q2.”
Sponsor: GlaxoSmithKline (GSK)
Type of drug: Cancer immunotherapeutic
Indication: Non-small cell lung cancer (NSCLC)
How it failed: Did not meet its first or second co-primary endpoints in Phase III MAGRIT trial; did not significantly extend disease-free survival (DFS) when compared to placebo in either the overall MAGE-A3 positive population (first co-primary endpoint) or in those MAGE-A3-positive patients who did not receive chemotherapy (second co-primary endpoint).
MAGRIT was designed to assess the effect of MAGE-A3 on Stage IB, II and IIIA completely resected NSCLC patients whose tumors expressed the MAGE-A3 gene. GSK said MAGRIT trial was continued in order to investigate the third co-primary endpoint of DFS in a gene signature positive sub-population, which was designed to identify a subset of MAGE-A3 positive patients that may benefit from the treatment. An independent third-party analysis of a proportion of the data (to identify a gene signature classifier) concluded that assessment of the third co-primary endpoint was not feasible due to insufficient treatment effect, the company added.
Date of announcements: March 20, 2014; April 2, 2014
Aftermath of failure: Investors sent the share price down by $1 or almost 2%, to $53.07 the day following announcement of the MAGRIT failures. GSK halted development of MAGE-A3 for NSCLC, but has continued development for melanoma—the indication of the separate Phase III DERMA trial that had not met its first co-primary endpoint in September 2013, namely DFS in the overall MAGE-A3 positive population. A readout of data on the second co-primary endpoint, DFS in the gene signature population, is expected later this year.
Sponsor: Nymox Pharmaceutical
Indication: Benign prostatic hyperplasia (BPH)
Type of drug: Apoptosis stimulant.
How it failed: Did not meet primary efficacy endpoints in two Phase III studies, NX02-0017 and NX02-0018. Those endpoints were, respectively, improvement in International Prostate Symptom Score (IPSS) after 365 days, and improvement in American Urological Association Symptom Index (AUASI) after 365 days. While drug efficacy reached levels similar to earlier studies, it was not statistically significant in comparison to placebo, the company added.
Date of announcement: November 2, 2014
Aftermath of failure: Share price fell nearly 82% on November 3. The share-price loss propelled the company to the top of GEN’s List of Top 10 Wall Street Losers of 2014. Company put on hold development of NX-1207 for BPH, a program stretching back to 2002, while continuing development for low-grade, localized prostate cancer, an area that has shown promise for the drug candidate, according to the company.
Revolixys™ Kit (pegnivacogin and anivamersen)
Sponsor: Regado Biosciences
Indication: Coronary artery disease (excluding those with ST-elevated myocardial infarction) undergoing percutaneous coronary intervention
Type of drug: Anticoagulation system consisting of pegnivacogin, an injectable anticoagulant aptamer specifically targeting coagulation Factor IXa; and its complementary injectable oligonucleotide active control agent, anivamersen.
How it failed: Company terminated its Phase III REGULATE-PCI trial after the study’s Data and Safety Monitoring Board indicated that the level of serious allergic adverse events associated with Revolixys “was of a frequency and severity such that they recommended that we do not enroll any further patients,” according to a company statement issued at the time. The board analyzed data from the first approximately 3,250 patients enrolled in what was intended to be a 13,200-patient trial comparing the safety and efficacy of Revolixys Kit with bivalirudin.
Date of announcements: August 25, 2014; September 24, 2014
Aftermath of failure: Company’s share price fell 60%, to $1.13, the day of the failure announcement. In September, company eliminated 60% of its workforce—20 jobs—“across all operational sites,” and took a $2 million fourth-quarter charge in connection with one-time termination costs and facility shutdown expenses. The company also engaged MTS Health Partners and Cowen & Co. as strategic advisors to help “identify strategic alternatives to maximize shareholder value;” and wrote down clinical assets totaling $8.9 million in third quarter 2014 results.
On October 10, 2014, the company named its president Michael A. Metzger, to the additional post of CEO and director, succeeding David J. Mazzo, Ph.D., who resigned. And on January 14 of this year, Regado announced plans to merge with Tobira Therapeutics, creating a combined company focused on developing new treatments for liver and inflammatory diseases.
Sponsor: Eli Lilly
Indication: Systemic lupus erythematosus
Type of drug: Anti-BAFF (B cell activating factor) monoclonal antibody
How it failed: Did not meet primary endpoint in two Phase III trials reporting results in 2014, in addition to a Phase III failure in 2013 (1)
In the ILLUMINATE 1 study, tabalumab did not achieve the primary endpoint, at either dose studied, of statistically significant improvement on SRI-5 (SLE Responder Index-5, a measurement of lupus disease activity and response), compared to standard of care therapy.
In ILLUMINATE 2, the higher dose of tabalumab met this endpoint, the first time a lupus study has achieved this efficacy measure as a primary endpoint in a Phase III trial. However, the collective data from the studies did not meet expectations for efficacy in the context of existing treatments, according to Lilly. The company said it intends to submit these data for disclosure “in appropriate upcoming scientific venues.”
Date of announcement: October 2, 2014
Aftermath of failure: Development halted on October 2, 2014. Company took a $63 million charge associated with the termination of tabalumab development in the third quarter.
- (1) In 2013, Tabalumab showed a lack of efficacy in the Phase III FLEX-V study, which investigated the compound for the treatment of patients with moderate-to-severe rheumatoid arthritis who had an inadequate response to one or more tumor necrosis factor (TNF) inhibitors.
Tecemotide (formerly Stimuvax or L-BLP25)
Sponsors: Merck KGaA and Oncothyreon
Indication: Stage III non-small cell lung cancer (NSCLC).
Type of drug: MUC1 antigen-specific cancer immunotherapy
How it failed: Did not meet either the primary endpoint of showing significant improvement in overall survival (OS) or any of the secondary endpoints (progression-free survival [PFS], time to progression [TTP] and time to treatment failure) compared to placebo in Phase I/II study EMR 63325-009, Oncothyreon disclosed on August 18, 2014. The study assessed Tecemotide on 178 Japanese patients with Stage III unresectable, locally advanced NSCLC who had received concurrent or sequential chemoradiotherapy (CRT), with a minimum of two cycles of platinum-based chemotherapy and radiation dose ≥50 Gy.
Date of announcement: September 12, 2014
Aftermath of failure: Merck KGaA halted clinical program in NSCLC, which includes the Phase III START2 and INSPIRE studies. The company said it will continue to supply tecemotide for ongoing investigator-sponsored trials in other indications
Sponsors: Merck & Co., and Endocyte
Indication: Platinum-resistant ovarian cancer (PROC)
Type of drug: Conjugate of folic acid (vitamin B9) linked to an anticancer agent, the potent vinca alkaloid desacetylvinblastine hydrazide (DAVLBH).
How it failed: Did not demonstrate efficacy on prespecified outcome of progression-free survival (PFS) in patients with PROC in Phase III PROCEED trial, designed to assess vintafolide in combination with pegylated liposomal doxorubicin (PLD) compared to PLD plus placebo for the treatment of folate receptor-positive PROC. Trial halted at recommendation of its Data Safety Monitoring Board.
The companies have highlighted more positive results from ongoing Phase IIb TARGET trial, evaluating vintafolide/docetaxel combination in NSCLC, showing the combination met the primary endpoint of improved progression free survival (PFS) and demonstrated initial positive trends in secondary endpoints of overall survival and response rate.
Date of announcement: May 2, 2014; May 19, 2014
Aftermath of failure: Endocyte’s share price plunged 62%, to $6.62, on May 2, 2014, the day the PROCEED trial failure was announced. On May 19, 2014, the companies announced withdrawal of conditional marketing authorization applications (CMA) from the European Medicines Agency (EMA) for vintafolide and companion imaging components, imaging agent etarfolatide and intravenous (IV) folic acid, for adult patients with folate receptor-positive, platinum-resistant ovarian cancer, in combination with PLD. The companies cited further review of interim data from the PROCEED trial.