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December 05, 2016

Unlucky 13: Top Clinical Trial Failures of 2016

In Missing Primary Endpoints, These Drugs Touched Off Stock Selloff, Layoffs, and Worse

Unlucky 13: Top Clinical Trial Failures of 2016

This year’s list of failed clinical candidates includes four whose trials included patient deaths, six drugs that touched off stock-price declines of more than 60%, and six that eliminated jobs due to trial failures. [© Ljupco Smokovski/Fotolia.com]

  • It costs billions, or maybe just millions, to develop a new drug. In March, the Tufts Center for the Study of Drug Development updated its cost estimates to $2.558 billion through approval—climbing to $2.87 billion when post-approval studies are figured in.

    In recent years, estimates have climbed as high as $4 billion (Bernard Munos of the InnoThink Center for Research In Biomedical Innovation in 2012), much higher (up to $12 billion for the priciest drugs, as calculated that same year by Forbes), and much lower ($43.4 million in 2003 dollars [$57 million today], according to a 2011 study published in BioSocieties by Donald W. Light, Ph.D., of Rowan University School of Osteopathic Medicine, and economist Rebecca Warburton of the University of Victoria).

    Whatever the cost number, biopharmas can blow millions on R&D spending with a single failed trial. This year’s list of failed clinical candidates includes: four whose trials included patient deaths, whether the drug was a factor or not; six drugs that touched off stock-price declines of more than 60%, another four with smaller stock declines; and six that eliminated jobs due to trial failures. 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.

    The following is GEN’s “Unlucky 13” list of the top clinical failures of 2016. Drug candidates are listed in alphabetical order, along with their sponsor(s), the indication in which the failure occurred, the type of drug, how the drug failed its trial(s), the date(s) of failure-related announcements, and the aftermath. 

  • Ad-RTS-hIL-12

    Sponsor: Ziopharm Oncology

    Indication: Glioblastoma (GBM) 

    Type of drug: Viral gene therapy candidate for the controlled expression of interleukin 12 (IL-12)

    How drug failed: Three patients died in a Phase I study of Ad-RTS-hIL-12 plus oral veledimex for a form of brain cancer. Two patient deaths occurred 6.7 months following a 20 mg dose, and the third, 3.9 months after treatment with a 40 mg dose, Ziopharm said. The third patient died of an intracranial hemorrhage that occurred sometime following discharge from a treating center, 15 days after starting on a 30-mg dose of the gene therapy. The company added a few days later that the third death was deemed unrelated to the gene therapy candidate , citing an analysis of additional information by the company and the study's Safety Review Committee. The study was designed to assess the combination of Ad-RTS-hIL-12 with orally administered veledimex in patients with recurrent or progressive GBM or grade III malignant glioma.

    Date of announcement: The deaths were first disclosed July 14 during a presentation by Ziopharm CEO Laurence Cooper, M.D., Ph.D., at an American Society of Hematology workshop, a presentation whose slides were submitted as a regulatory filing to the U.S. Securities and Exchange Commission. The following day, Ziopharm announced the deaths in a press release. On July 19, Ziopharm cited the Safety Review Committee finding.

    Aftermath of failure: The company saw its stock price slide 26% between July 8 and July 22, when it reached $4.49. However, the study remained open for enrollment, and Ziopharm completed enrollment in the 30 mg dose cohort. In its Form 10-Q filing for the third quarter, dated November 9, Ziopharm said it expected to provide further updates on the progress of the study, including longer-term survival follow up, at the upcoming Society for Neuro-Oncology 21st Annual Scientific Meeting.

  • Algenpantucel-L

    Sponsor: NewLink Genetics

    Indication: Resected pancreatic cancer

    Type of drug: Whole-cell immunotherapy consisting of irradiated allogeneic pancreatic cancer cells genetically engineered to express the murine enzyme α-GT.

    How drug failed: Did not meet its primary endpoint in the Phase III IMPRESS trial: statistically significant overall survival. Overall survival from time of randomization was 29.3 months for both groups combined. Median survival was only 27.3 months for the study group, compared with 30.4 months for the control group. There was also no statistical difference for long-term survival. Three-year survival was 41.4% and 42.1%, and four-year survival was 32.6% and 32.7% for the control and study groups, respectively. IMPRESS assessed algenpantucel-L (300 million cells every two weeks for six months, followed by every month for another six months) in combination with standard of care, versus standard of care alone. A total of 722 patients with surgically removed cancers were enrolled at more than 70 sites in the U.S. from May 2010 to September 2013.

    Date of announcement: May 9 (trial failure); July 29 (workforce reduction)

    Aftermath of failure: Investors responded with a three-day selloff that sent NewLink’s shares tumbling 41%, bottoming out on May 12 at $9.71. More than two months later, the company said it was eliminating 100 jobs, 43% of its workforce, in a restructuring that included winding down commercial manufacturing capacity for algenpantucel-L as well as its HyperAcute Cellular Immunotherapy clinical trials that did not include a checkpoint inhibitor combination. The company also disclosed plans to consolidate its facilities space from 133,000 square feet to approximately 66,000 square feet, and refocus its capital spending to primarily support drug discovery and development. 

  • Birinapant

    Sponsor: TetraLogic Pharmaceuticals

    Indication: Myelodysplastic syndromes (MDS)

    Type of drug: Bivalent second mitochondrial activator of caspases (SMAC) mimetic

    How drug failed: Did not meet primary endpoint of response rate after four months of therapy in a Phase II study in which it was co-administered with azacitidine in first-line, higher risk patients suffering from MDS. Birinapant failed to show any clinical benefit over placebo and met the bounds for futility, TetraLogic said. Company terminated the trial following an interim analysis of the first 62 patients randomized in the study.

    Dates of announcements: January 6 (trial failure); January 28 (job reductions); November 2 (selloff of Birinapant)

    Aftermath of failure: News of the trial failure sparked a 76% plunge in TetraLogic’s share price the following day, to $0.407. Later in January, the company eliminated two-thirds of its workforce, 19 jobs, leaving it with nine employees as of April. Among the people whose jobs were eliminated were the company’s CSO, G. Glenn Begley, Ph.D., and COO/CMO Lesley Russell. TetraLogic hired Houlihan Lokey Capital to assist in an evaluation of strategic alternatives, and recorded a one-time restructuring charge of $2 million in the first quarter of fiscal 2016. In November, TetraLogic announced plans to sell Birinapant and another clinical-stage cancer candidate, the skin-directed histone deacetylase (HDAC) inhibitor remetinostat, plus all associated intellectual property, to Medivir for up to $238 million—of which up to $130 million-plus was for Birinapant.

  • Fel d 1

    Sponsor: Circassia Pharmaceuticals

    Indication: Cat allergy

    Type of drug: Synthetic Peptide Immuno-Regulatory Epitope (SPIRE), one in a class of immunotherapies

    How drug failed: Did not meet primary endpoint in a Phase III study by showing itself nearly equal to placebo in reducing subjects’ combined allergy symptom and rescue medication use score from baseline a year after the start of dosing.

    The study compared a four-dose course of Fel d 1 allergen peptides, two sequential courses (eight doses), and placebo. The primary endpoint was the difference in the mean combined Total Rhinoconjunctivitis Symptom Score (TRSS) and rescue medication scores (the Combined Score) between the treatment and placebo groups.  Additional prespecified endpoints included a range of symptom, rescue medication, and quality-of-life improvement measures.

    Date of announcement: June 20

    Aftermath of failure: Shares of Circassia fell 64%, accounting for most of the stock’s 72% decline this year (as of November 10). In announcing the trial failure, Circassia began a review of the study’s full data, concluding in September that no confounding factors affected the outcome, as well as the implications for its allergy portfolio—while stopping investment in the cat allergy candidate. The company added that it will await results from its Phase IIB house dust mite allergy study, expected in the spring of 2017, then review its allergy portfolio and decide on development plans for its candidates.

  • Fispemifene

    Sponsor: Apricus Biosciences

    Indications: Secondary hypogonadism and sexual dysfunction

    Type of drug: Selective estrogen receptor modulator (SERM) 

    How drug failed: Did not meet the primary endpoint of statistically significant improvement in erectile function, or the secondary endpoint of statistically significant improvement in low libido, in a Phase IIB study among men with secondary hypogonadism and sexual dysfunction.

    Dates of announcements: March 28 (trial failure); April 6 (job and expense reductions)

    Aftermath of failure: Apricus immediately ended all ongoing fispemifene clinical activities on secondary hypogonadism, and shifted its resources to other pipeline candidates. Investors sold off shares, causing the price to plummet 47%, to 71 cents on the day of the failure announcement, then sink another 20%, to 57 cents on April 1. Five days later, the company said it would eliminate about 30% of its staff, including executives, by the end of the third quarter. Apricus also eliminated some of its directors and reduced the cash compensation of the directors it retained. Apricus also committed to cutting operating expenses (excluding non-cash, stock-based compensation expense and depreciation expense) by about 30% this year, and by 60% in 2017. On October 21, with shares trading at 27 cents, down 80% from before the trial failure, the company carried out a 1-for-10 reverse stock split, sending shares to $2.39 on the next trading day of October 24. Apricus licensed U.S. rights to fispemifene from Forendo Pharma in 2014, in a deal that could have generated up to $305 million-plus for Forendo.

  • Galeterone

    Sponsor: Tokai Pharmaceuticals

    Indication: Metastatic castration-resistant prostate cancer (mCRPC)

    Type of drug: Androgen receptor antagonist

    How drug failed: Did not meet its primary endpoint in the Phase III ARMOR3-SV trial, which compared the candidate to Xtandi® (enzalutamide) in treatment-naïve mCRPC patients whose prostate tumors expressed AR-V7.

    Date of announcements: July 26 (trial termination); July 29 (job reduction)

    Aftermath of failure: Tokai terminated the ARMOR3-SV trial, sending shares cratering 79% on a single day, to $1.10. Three days later, the company announced plans to eliminate 60% of its workforce, shrinking to approximately 10 employees, by the end of the third quarter. In its third-quarter Form 10-Q filing, dated November 3, Tokai said it was analyzing unblinded data from ARMOR3-SV to evaluate potential paths forward for galeterone and its drug discovery program, known as ARDA (Androgen Receptor Degradation Agents): “Based on preliminary data reviewed to date, however, there is a substantial likelihood that we will not pursue the development of galeterone in AR-V7 positive mCRPC in the future.”

    In the filing, Tokai also disclosed that it decided in August to stop enrollment in its ongoing Phase II ARMOR2 expansion clinical trial of galeterone in mCRPC patients with acquired resistance to Xtandi®, and to not proceed with a planned study of galeterone in mCRPC patients who rapidly progress on either enzalutamide or Zytiga® (abiraterone acetate). A month later, the company’s board launched a review of strategic alternatives: “Potential strategic alternatives that we may explore and evaluate during this process include a sale of the company, a reverse merger, a business combination, or a sale, license, or other disposition of company assets.”

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