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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]

  • Isunakinra (EBI-005)

    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.

  • JCAR014

    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.

  • JCAR015

    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%

  • Locilex

    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. 

  • Opdivo (nivolumab)

    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.

  • RSV F

    Sponsor: Novovax

    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.

  • Zydelig (idelalisib)

    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.

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