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April 17, 2017

25 Clinical Failures of Q1 2017

These Drug Candidates Missed their Primary Endpoints, With Varying Consequences

25 Clinical Failures of Q1 2017

High as the odds are for clinical success, a recent report found the overall likelihood of approval for all drug candidates that make it to Phase I is 9.6%—the cost of clinical failure is even higher.

  • The odds are high for drug candidates succeeding in clinical trials and winning regulatory approvals. Just how high was shown last year in a report on clinical drug development success rates by the Biotechnology Innovation Organization (BIO).

    BIO found the overall likelihood of approval (LOA) for all drug candidates that make it to Phase I was 9.6%—a figure that rises to 11.9% for all indications outside of oncology. Indeed, oncology had the lowest LOA (5.1%) among 14 major disease areas; the highest was hematology at 26.1%. BIO based its results on 9,985 clinical and regulatory phase transitions recorded and analyzed from 7,455 development programs, across 1,103 companies in the Biomedtracker database from 2006–2015.

    High as the odds are for success, the cost of clinical failure is even higher. Pfizer spent a reported $800 million-plus a decade ago to develop the cholesteryl ester transfer protein inhibitor torcetrapib before a failed Phase III trial prompted the Pharma giant to change course. More recently, published reports have used a cost estimate of $1.4 billion—a figure derived from the $1.395 billion in average out-of-pocket costs incurred by drug developers as estimated in 2014 by the Tufts Center for the Study of Drug Development, which also counted $1.163 billion in expected returns that investors forego while a drug is in development.

    Below is GEN’s list of 25 clinical failures reported during the first quarter of this year. As with GEN’s list of 2016’s top “Unlucky 13” trial failures, 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), and the date(s) of failure-related announcements. Not listed are failures for drugs that are already marketed and being developed for additional indications.

  • AC-1204

    Sponsor: Accera

    Indication: Alzheimer’s disease

    Type of drug: Ketosis-inducing compound

    How drug failed: Did not meet its primary endpoint in the Phase III NOURISH AD trial in mild-to-moderate Alzheimer’s disease. AC-1204 did not show a statistically significant difference at 26 weeks compared with patients treated with placebo, as measured by the Alzheimer's Disease Assessment Scale-Cognitive Subscale test (ADAS-Cog).

    Date of announcement: February 28

  • AEVI-001 (oral nonstimulant)

    Sponsor: Aevi Genomic Medicine (formerly Medgenics)

    Indication: Metabotropic glutamate receptor mutation-positive (mGluR+) attention-deficit/hyperactivity disorder (ADHD)

    Type of drug: Glutamate signaling modulator

    How drug failed: Did not meet its primary endpoint in the Phase II SAGA trial assessing the treatment in adolescents age 12–17 with mGluR+ ADHD. AEVI-001 did not show statistically significant reduction compared to placebo in ADHD symptoms as measured by the ADHD Rating Scale (ADHD-RS).

    Date of announcement: March 20

  • BTA585

    Sponsor: Aviragen Therapeutics

    Indication: Respiratory syncytial virus (RSV)

    Type of drug: Oral fusion inhibitor

    How drug failed: Did not meet its primary endpoint in a Phase IIa study in adults challenged intranasally with RSV. The study randomized three cohorts of 20 healthy adults who received either 400 mg BTA585, 600 mg BTA585, or placebo dosed twice a day for seven days. Primary endpoint was viral load from first dose of study drug through day 12 measured by area under the curve.

    Date of announcement: February 1

  • CD101

    Sponsor: Cidara Therapeutics

    Indication: Acute vulvovaginal candidiasis (VVC)

    Type of drug: Once-weekly therapy intended for the treatment and prevention of life-threatening invasive fungal infections

    How drug failed: Did not show sufficient efficacy to justify further development of the tested topical formulations in the Phase II RADIANT trial comparing CD101 to fluconazole. The trial enrolled 125 patients into three cohorts—one of 50 patients treated with CD101 Gel; a second cohort of 50 patients treated with CD101 Ointment; and a third cohort of 25 patients treated with oral fluconazole. The gel and ointment topical formulations were similar in efficacy, but lower in clinical and mycological cure rates compared to oral fluconazole.

    Date of announcement: February 21

  • Edasalonexent (CAT-1004)

    Sponsor: Catabasis Pharmaceuticals

    Indication: Duchenne muscular dystrophy (DMD)

    Type of drug: Inhibitor of NF-kB, a protein that is activated in DMD and drives inflammation and fibrosis, muscle degeneration, and suppresses muscle regeneration

    How drug failed: Did not meet primary efficacy endpoint in Part B of the MoveDMD® trial, which assessed the effects of edasalonexent using MRI T2 as a biomarker at 12 weeks. The primary efficacy endpoint was average change from baseline to week 12 in the MRI T2 composite measure of lower leg muscles for the pooled edasalonexent treatment groups of 67 mg/kg/day and 100 mg/kg/day, compared to placebo.

    Date of announcement: January 31

  • Emicizumab (ACE910)

    Sponsors: Roche/Genentech and Chugai Pharmaceutical

    Indication: Hemophilia A and inhibitors to factor VIII

    Type of drug: Bispecific monoclonal antibody designed to bring together factors IXa and X.

    How drug failed: Roche disclosed the death of a patient with hemophilia in the Phase III HAVEN 1 trial, assessing emicizumab in people 12+ years of age with hemophilia A and factor VIII inhibitors. In a statement posted on the website of the European Haemophilia Consortium, Roche said it received two reports of serious adverse events concerning a patient who experienced a serious rectal hemorrhage and received bypassing agents, including repeated doses of activated prothrombin complex, after which the patient developed signs of thrombotic microangiopathy.

    “Treatment of the haemorrhage was complicated because the patient declined blood transfusions,” Roche said. “The investigator’s assessment is that the cause of death was the rectal haemorrhage, and that this is not related to emicizumab.”

    Date of announcement: February 21

  • Idalopirdine (Lu AE58054)

    Sponsors: Lundbeck and Otsuka Pharmaceutical

    Indication: Alzheimer’s disease

    Type of drug: Selective antagonist of the 5-hydroxytryptamine type 6 (5-HT6) receptor

    How drug failed: Did not meet the primary endpoint in the Phase III STARBEAM and STARBRIGHT trials assessing idalopirdine in patients with mild-moderate Alzheimer's disease, measured by reduction in the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) total score. STARBEAM was designed to examine idalopirdine as adjunctive therapy to donepezil in patients with mild-to-moderate Alzheimer's disease. STARBRIGHT was designed to investigate idalopirdine as an adjunctive therapy to acetylcholinesterase inhibitors.

    The failures were disclosed four months after Lundbeck and Otsuka said both dosages of Idalopirdine in the earlier Phase III STARSHINE trial missed the study’s primary endpoint of reduced ADAS-cog total score when added to donepezil.

    Date of announcement: February 8

  • Ingrezza™ (valbenazine)

    Sponsor: Neurocrine Biosciences

    Indication: Tourette syndrome

    Type of drug: Once-daily highly-selective VMAT2 inhibitor that modulates dopamine release during nerve communication, showing little or no affinity for VMAT1, other receptors, transporters, and ion channels

    How drug failed: Did not meet the primary endpoint of change-from-baseline in the Yale Global Tic Severity Scale at Week 8 in the Phase II T-Forward trial. The study assessed valbenazine in adults, with two once-daily fixed doses of valbenazine evaluated vs. placebo in a 1:1:1 randomization. The study evaluated 124 patients over eight weeks of dosing followed by two weeks off-drug. Neurocrine said the study also showed significant improvement in overall symptoms of Tourette syndrome.

    Date of announcement: January 17

  • Lirilumab

    Sponsors: Innate Pharma and Bristol-Myers Squibb (BMS)

    Indication: Acute myeloid leukemia (AML)

    Type of drug: Fully human monoclonal antibody

    How drug failed: Did not meet its primary endpoint of leukemia-free survival (LFS) in the Phase II EffiKIR trial (IPH2102-201), designed to assess the candidate as a single-agent maintenance treatment in seniors whose AML was in first complete remission. The 150-patient EffiKIR trial found no statistically significant difference in LFS or other efficacy endpoints between the trial’s placebo arm and its two treatment arms—0.1 mg/kg q3months and 1 mg/kg q1month—the latter stopped in March 2015 by the trial’s data safety monitoring board. Lirilumab and related compounds blocking KIR receptors are licensed to BMS for all indications.

    Date of announcement: February 6

  • Metadoxine extended release (MDX)

    Sponsor: Alcobra

    Indication: Attention-deficit/hyperactivity disorder (ADHD)

    Type of drug: Extended-release oral formulation of metadoxine (pyridoxol L-2-pyrrolidone-5-carboxylate), an inhibitor of the gamma-aminobutyric acid (GABA) transaminase enzyme responsible for the degradation of GABA

    How drug failed: Did not meet the primary endpoint of a statistically significant difference from placebo in the Phase III MEASURE trial. MDX did not demonstrate a statistically significant change from baseline as measured using the Conners’ Adult ADHD Rating Scales.

    Date of announcement: January 17

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