Alex Philippidis Senior News Editor Genetic Engineering & Biotechnology News
In Missing Primary Endpoints, These Drugs Touched Off Stock Selloff, Layoffs, and Worse
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.
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.
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.
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.
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.
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.”
Sponsor: Eleven Biotherapeutics
Indication: Allergic conjunctivitis
Type of drug: IL-1 receptor inhibitor
How drug failed: Did not meet primary endpoint in Phase III trial assessing isunakinra in severe allergic conjunctivitis. Company said there were no statistically significant differences between the isunakinra treated group and the vehicle control group on the primary endpoint of ocular itching, or on any secondary endpoints.
Date of announcement: January 15 (trial failure)
Aftermath of failure: In announcing the failure, Eleven Bio declared, “we see no immediate path forward in allergic conjunctivitis” for Isunakinra, which had also failed a 2015 Phase III trial assessing the drug in dry eye disease. Investors sent the share price reeling, free-falling 78% to 52 cents the next trading day, January 19. That price skidded further, to 27 cents on February 11. On March 24, Eleven Bio’s President and CEO Abbie Celniker, Ph.D., said the company was evaluating strategic alternatives.
Three months later, the company licensed its IL-6 antagonist antibody technology to Roche for up to $270 million, in a deal that granted Roche a license to develop and commercialize Eleven Bio’s most advanced preclinical product candidate EBI-031, a treatment for diabetic macular edema (DME) and uveitis. The deal was completed August 16, causing shares—which had been climbing since the spring—to finish that day’s trading at their 2016 high of $5.41. A week later, Eleven Bio disclosed in a regulatory filing that it would lay off 14 people, 70% of its remaining staff.
Sponsor: Juno Therapeutics
Indications: Designed to treat acute lymphoblastic leukemia (ALL) as well as relapsed or refractory (r/r) chronic lymphocytic leukemia and non-Hodgkin lymphoma (NHL).
Type of drug: Chimeric antigen receptor T-cell (CAR-T) therapy
How drug failed: A young adult patient with r/r B cell ALL died three months after therapy of pulmonary aspergillosis during a Phase I dose-escalation trial of JCAR014. The patient received preconditioning with a combination of cyclophosphamide and fludarabine, as well as a higher JCAR014 cell dose than is now used on that trial, Juno said. The company has cited the use of fludarabine as a factor in this patient death, as well as the deaths of three other patients in a Phase II trial of another CAR-T therapy candidate, JCAR015.
Date of announcement: Disclosed July 13 through a regulatory filing that stated that the death was included in data presented by the company at the American Society of Hematology (ASH) meeting in December 2015. The regulatory filing was submitted to correct a July 7 statement by Mark Gilbert, Juno svp and CMO, who told analysts on a conference call that three patients had died in trials related to the company’s CAR-T candidates.
Aftermath of failure: Company said November 9 that it was continuing to enroll patients in an ongoing Phase I/II trial for JCAR014 in B-cell malignancies, adding in its Form 10-Q quarterly filing: “Although we do not plan to move JCAR014 into registration trials, we plan to use this trial to explore important questions that may improve our platform overall.” Juno said Phase I data on JCAR014 in high-risk, ibrutinib-refractory patients with CLL will be presented at ASH’s 58th Annual Meeting, set for December 3–6 in San Diego. The company also cited clinical data published in Science Translational Medicine by researchers at the Fred Hutchinson Cancer Research Center, showing that patients who received a dose of CD19-targeted, defined-composition engineered T cells after chemotherapy went into complete remission.
Sponsor: Juno Therapeutics
Indication: Acute lymphocytic leukemia (ALL)
Type of drug: CD19-directed chimeric antigen receptor technology (CAR-T) product candidate
How drug failed: Five patients died of cerebral edema during the Phase II ROCKET trial
Date of announcement: July 7 (following the deaths of a second and third patient within a week; the first death occurred earlier)
Aftermath of failure: Following Juno’s disclosure of the first three patient deaths, the FDA imposed a partial clinical hold, during which Juno changed the trial’s protocol by ending the use of fludarabine as a preconditioning drug along with cyclophosphamide and going back to the trial’s original protocol—changed during the second quarter—of cyclophosphamide preconditioning alone. Juno has blamed the use of fludarabine for the deaths of the three patients. Shares of Juno fell 33% between July 7 and 11, when they fell to $27.33, from which the price has fluctuated. On July 12, Juno said it was resuming the ROCKET trial following the FDA’s lifting of the partial clinical hold, which forced Juno to postpone earlier plans to pursue FDA approval in 2017 for JCAR015. In reporting third-quarter results November 9, Juno said it anticipated winning FDA approval for JCAR015 in the first half of 2018, and that ROCKET recommenced patient enrollment in August with the original protocol. However, following the November 23 disclosure of deaths, Juno placed another clinical hold on the ROCKET trial, and said it was evaluating its options regarding the JCAR015 program; shares plunged 35%
Sponsor: Dipexium Pharmaceuticals
Indication: Diabetic foot ulcer
Type of drug: Pexiganan cream 0.8%
How drug failed: Did not meet the primary clinical endpoint of superiority versus placebo or “vehicle”—namely the cream without its active ingredient of pexiganan—plus standardized wound care in two Phase III trials, OneStep-1 and OneStep-2. The trials assessed the candidate in patients with mild infections of diabetic foot ulcers (mild DFI). Locilex also did not show any meaningful difference in wound closure rate compared with vehicle, and neither trial met secondary endpoints of demonstrating a higher rate of eradication of bacteria for the Locilex arm, Dipexium added.
Date of announcement: October 25
Aftermath of failure: Dipexium said it would review pursuing other indications for Locilex. “The Company’s scientific team is continuing to evaluate the data from the OneStep clinical trials and in that process may identify other possible clinical indications for Locilex, but there can be no assurance that the Company will successfully identify a regulatory pathway forward for Locilex,” Dipexium stated November 9 in its Form 10-Q filing for the third quarter. The company has seen its share price melt down, plunging 88% from its October 24 close of $12.75, to $1.50 on November 3. Since then the price has fallen even further, closing at $1.35 on November 11.
Sponsor: Bristol-Myers Squibb
Indication: Non-small cell lung cancer (NSCLC)
Type of drug: Programmed death-1 (PD-1) immune checkpoint inhibitor
How drug failed: Did not meet its primary endpoint in the Phase III CheckMate -026 trial, namely progression-free survival in treatment-naïve NSCLC patients whose tumors expressed programmed death ligand 1 (PD-L1) at ≥5%. The trial was designed to assess Opdivo monotherapy as first-line therapy in patients with advanced NSCLC whose tumors expressed PD-L1 ≥1%
Date of announcement: August 5
Aftermath of failure: BMS stock fell 16% the day of the announcement, to $63.28, and eventually declined 35% to a 2016 low of $49.23 on October 24. In its third-quarter results announcement on October 27, the company disclosed that the final primary analysis of CheckMate -026 showed it did not meet the primary endpoint of superior progression-free survival (PFS) compared to chemotherapy. In patients with ≥5% PD-L1 expression, the median PFS was 4.2 months with Opdivo, compared with 5.9 months with platinum-based doublet chemotherapy. “While we are disappointed with the results of CheckMate -026, a setback in first-line lung in the short term, our overall strategic focus does not change,” BMS CEO Giovanni Caforio, M.D., said in a statement, repeating the company’s thinking expressed a month earlier by Fouad Namouni, M.D., BMS svp and head of oncology. The trial failure touched off intense speculation about Opdivo’s future development and immunotherapy in general, but had no apparent effect on Opdivo worldwide revenue, which zoomed during Q3 to $920 million, triple the year-ago figure.
Indication: Respiratory syncytial virus (RSV)
Type of drug: F-protein recombinant nanoparticle vaccine
How drug failed: Did not meet its primary and secondary efficacy endpoints in the Phase III Resolve trial, in which the vaccine was given to 11,856 adults age 60 and older. The trial’s primary endpoint was efficacy in preventing moderate to severe RSV-associated lower respiratory tract disease (RSV msLRTD), defined by the presence of multiple lower respiratory tract symptoms. The secondary objective called for demonstrating efficacy in reducing the incidence of all symptomatic respiratory disease due to RSV (RSV ARD [acute respiratory disease]).
Date of announcement: September 15 (trial failure); November 9 (job reduction)
Aftermath of failure: The company’s shares fell 86% from September 15 closing price of $8.34 per share in after-hours trading, to $1.15 as of 8:57 a.m. the following morning. On November 9, Novavax said it will eliminate approximately 30% of its workforce—164 jobs, the company told Reuters—in a restructuring projected to reduce 2017 spending by $70–100 million. At its investor and analyst meeting on November 9, the company said it will continue to conduct another Phase III trial involving the vaccine candidate (Prepare™), designed to determine the efficacy of maternal immunization with the company’s RSV F vaccine against symptomatic RSV lower respiratory tract infection with hypoxemia in infants through a minimum of the first 90 days of life. The Prepare trial is supported through an up-to-$89 million grant from the Bill & Melinda Gates Foundation.
Sponsor: Gilead Sciences
Indications: Chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and indolent non-Hodgkin lymphomas
Type of drug: First-in-class phosphoinositide 3-kinase (PI3k) inhibitor
How drug failed: FDA alerted healthcare professionals of “an increased rate of adverse events, including deaths,” in clinical trials of Zydelig in combination with other cancer medicines. Neither regulatory agencies nor the company disclosed the number of deaths.
Date of announcement: March 8 (European Medicines Agency review); March 14 (FDA alert)
Aftermath of failure: Gilead halted six trials of the drug in combination with other treatments in patients with CLL, SLL, and indolent non-Hodgkin lymphomas, the FDA disclosed, adding: “The FDA is reviewing the findings of the clinical trials and will communicate new information as necessary.” The FDA disclosure came three days after the European Medicines Agency said it would review data from the Zydelig trials “to assess whether the findings have any consequences for the authorized uses of Zydelig.” In a note to investors, Leerink Partners analyst Geoffrey Porges concluded: “These decisions by Gilead and the regulators effectively mean that Zydelig is dead in the water.” Sales of the drug are small at $129 million for January–September, though they grew from $92 million in Q1–Q3 2015.