Alex Philippidis Senior News Editor Genetic Engineering & Biotechnology News
In Missing Their Primary Endpoints, These Drugs Sparked Layoffs, Losses, and a CEO Resignation
When it comes to clinical trial failures, treatments across indications carry risks of missing primary or secondary endpoints in clinical studies. Yet over the past year or so, much attention has focused on studies in which cancer immunotherapies have come up short.
While many have shown dazzling results, such as complete remissions in numerous patients, others have failed, sometimes with deadly results. In August, for example, the FDA cited findings of a combined 78 reported deaths in two clinical studies when it alerted healthcare professionals to risks associated with the marketed programmed cell death protein 1 (PD-1) monoclonal antibody therapy Keytruda® in combination with dexamethasone and an immunomodulatory agent (lenalidomide or pomalidomide) for the treatment of patients with multiple myeloma.
The FDA in September also placed a partial clinical hold on three clinical trials investigating combination therapies based on the Bristol-Myers Squibb marketed cancer immunotherapy Opdivo® (nivolumab) in patients with relapsed or refractory multiple myeloma based on perceived risks—though the holds were lifted in December on two of the three studies.
However, the mere occurrence of a patient death did not stop the FDA in 2017 from approving the first two cancer immunotherapies to reach the market. According to the prescribing label, 11 deaths were reported for patients treated in clinical trials with Novartis’ Kymriah™ (tisagenlecleucel), while four of the 34 deaths occurring in clinical studies for the Gilead Sciences (Kite) treatment Yescarta™ (axicabtagene ciloleucel) were attributed to the product, according to the agency.
Last month, Pfizer and Merck KGaA reported the failure of their anti-programmed death ligand-1 (PD-L1) antibody Bavencio (avelumab) to meet its primary endpoint of superior overall survival (OS) compared with physician's choice of chemotherapy in Phase III JAVELIN Gastric 300. That failure, according to Bloomberg Gadfly’s Max Nisen, reflected the scramble among drug developers to gain competitive advantage in the increasingly crowded immuno-oncology category.
“The inevitable consequence of the massive profusion of trials for these medicines and the ever-higher bars they have to clear will be unexpected trial failures. Investors in the companies involved need to brace for impact,” Nisen predicted last month.
In Europe, researchers from King’s College London and the London School of Economics published a study in BMJ showing that of the 48 drugs approved for 68 indications following review by the European Medicines Agency between 2009–2013, most (39 or 57%) showed no improvement in survival or quality of life over active treatment, placebo, or as add-on treatment.
Despite the attention, the majority of the failed clinical trials that comprise GEN’s “Unlucky 13” list of the top clinical failures of 2017 consisted of drugs other than immune-oncology treatments—though six of the 13 candidates failed in cancer indications. Mere failure in a Phase III trial alone, even with fatalities, 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. Failed candidates making the list touched off a variety of consequences that included termination of development programs, losses in the millions, layoffs, and in one instance, the resignation of a CEO.
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.
Sponsor: OncoMed Pharmaceuticals
Indication: Colorectal cancer
Type of drug: Anticancer stem cell antibody designed to bind the Notch1 receptor
How drug failed: The company halted enrollment of patients in Phase Ib trial assessing brontictuzumab in combination with trifluridine/tipiracil (Lonsurf®) in third-line colorectal cancer patients, saying that the combination of brontictuzumab plus chemotherapy “was not tolerable in this patient population.” Brontictuzumab was one of two drug candidates whose failures within two weeks prompted OncoMed to eliminate half of its workforce.
Date of announcements: April 24, April 17
CA4P (combretastatin A4-phosphate, or fosbretabulin)
Sponsor: Mateon Therapeutics
Indication: Platinum-resistant ovarian cancer
Type of drug: Tubulin-binding vascular disrupting agent (VDA)
How drug failed: Company eliminated 60% of its workforce and ended development of its lead candidate after it missed its primary endpoint of progression-free survival (PFS) in the Phase II/III FOCUS trial. FOCUS assessed CA4P in combination with Roche-owned Genentech’s Avastin®(bevacizumab) and physician’s choice chemotherapy in patients with platinum-resistant ovarian cancer.
Date of announcement: September 26
Sponsors: Opthotech and Novartis
Indication: Wet age-related macular degeneration (AMD)
Type of drug: Anti PDGF-B pegylated aptamer
How drug failed: Fovista missed its primary endpoints in two Phase III trials, OPH1002 and OPH1003. Both evaluated the safety and efficacy of 1.5 mg of Fovista in combination with the Roche (Genentech)/Novartis-marketed drug vascular endothelial growth factor (VEGF) therapy Lucentis®, compared to Lucentis alone. Following the trial failures, Ophthotech slashed its workforce by approximately 80%. In July, Opthotech and Novartis revised their 2014 co-development agreement in anticipation of a third Phase III trial failure—a failure announced the following month.
Date of announcements: August 14, July 10, January 17
Sponsor: Juno Therapeutics
Indication: Adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL)
Type of drug: CD19-directed chimeric antigen receptor technology (CAR-T) cancer immunotherapy
How drug failed: Juno halted development of JCAR015, its lead CAR-T cancer immunotherapy, and terminated its Phase II ROCKET trial, nearly four months after the study was placed on its second clinical hold following two additional patient deaths. The deaths brought to five the number of patients who died from cerebral edema in the ROCKET study, on which the FDA imposed a partial clinical hold in July 2016, a hold that was lifted days later.
Date of announcement: March 1
Sponsor: Tenax Therapeutics
Indication: Low cardiac output syndrome (LCOS)
Type of drug: Calcium sensitizer
How drug failed: Levosimendan missed its co-primary endpoints in the Phase III LEVO-CTS trial of significant reductions in the dual endpoint of death or use of a mechanical assist device at 30 days, as well as in the quad endpoint of death, myocardial infarction, need for dialysis, or use of a mechanical assist device at 30 days. The failure caused a one-day 76% plunge in Tenax’s share price, from $1.95 to 46 cents. CEO John Kelley resigned in April, and Tenax began evaluating strategic alternatives that include a merger or sale. In July, both the FDA and Health Canada determined that another trial would be needed to support a future NDA filing for levosimendan. “We are currently evaluating clinical, regulatory, and financial options,” the company disclosed in its Form 10-Q for Q3 2017, filed in November.
Date of announcements: November 9, July 28, April 5, January 31
Prophage G-200 (heat shock protein peptide complex-96, or HSPPC-96)
Type of drug: Vaccine
How drug failed: Prophage G-200 failed a Phase II trial assessing the vaccine in combination with the Roche/Genentech marketed cancer drug Avastin® (bevacizumab) in patients with surgically resectable, recurrent glioblastoma, the company acknowledged in a February regulatory filing. A month later, Agenus announced a reorganization designed to refocus the company on clinical development of another vaccine program and two checkpoint inhibitor antibodies. The reorganization included the elimination of 50 jobs and the shutdown of a facility in Basel, Switzerland.
Date of announcements: March 30, February 21
SBC-103 (rhNAGLU enzyme)
Sponsor: Alexion Pharmaceuticals
Indication: Mucopolysaccharidosis (MPS) IIIB
Type of drug: Enzyme replacement therapy
How drug failed: In its Form 10-Q report for the third quarter filed in October, Alexion disclosed that it discontinued SBC-103 development in July based on results of a Phase I/II dose escalation study, and recorded a $31 million impairment charge. The disclosure came a month after the company announced it would eliminate approximately 20% of its workforce and move its headquarters from New Haven, CT, to Boston, MA, by mid-2018 in a restructuring that followed Ludwig Hantson, Ph.D., becoming CEO in March. Earlier that month, the company said it was eliminating 7% of its workforce. Alexion inherited SBC-103 in 2015 when it acquired Synageva for $8.4 billion. But in February, the company signaled a retreat from SBC-103 by reducing its investment in the candidate and recognizing an $85 million impairment charge against Q4 2016 earnings.
Date of announcements: October 26, September 12, March 13, February 16
Indication: Acute heart failure
Type of drug: Relaxin receptor agonist, a recombinant form of the human relaxin-2 hormone
How drug failed: Serelaxin missed its primary endpoints in the Phase III RELAX-AHF-2 trial of a reduction in cardiovascular death through day 180, or a reduction in worsening heart failure through day 5, Novartis acknowledged in March. The following month, Novartis took a $200 million charge against first-quarter earnings related to serelaxin, which the company cited as one of several factors in a 17% year-over-year decline in Q1 net income.
Date of announcements: April 25, March 22
Sponsors: OncoMed Pharmaceuticals and GlaxoSmithKline (GSK)
Indication: Small-cell lung cancer (SCLC).
Type of drug: Anticancer stem cell antibody designed to prevent signaling through both the Notch2 and Notch3 receptors.
How drug failed: Tarextumab plus chemotherapy failed to meet both its primary endpoint of progression-free survival (PFS) and secondary endpoints in the Phase II PINNACLE study. The placebo-controlled trial combined tarextumab with etoposide plus either cisplatin or carboplatin in patients with previously untreated extensive-stage SCLC. Tarextumab was one of two drug candidates whose failures within two weeks prompted OncoMed to eliminate half of its workforce.
Date of announcements: April 24, April 17
Indication: Amyotrophic lateral sclerosis (ALS)
Type of drug: Fast skeletal muscle troponin activator
How drug failed: Cytokinetics halted development of its lead candidate tirasemtiv in November after it missed its primary endpoint in the Phase III VITALITY-ALS trial. The company said that tirasemtiv failed to show change from baseline in slow vital capacity (SVC) following 24 weeks of double-blind, placebo-controlled treatment, then followed up in December with details. “We will seek advice from the academic leadership of VITALITY-ALS and its clinical investigators, regulatory authorities and other consultants before making decisions about continuing treatment with tirasemtiv in VIGOR-ALS,” an open-label extension study, Cytokinetics states on its website.
Date of announcements: December 8, November 21
Sponsor: Acorda Therapeutics
Indication: Parkinson’s disease
Type of drug: Oral adenosine A2a receptor antagonist developed as an adjunctive treatment to levodopa in Parkinson’s disease patients to reduce OFF time
How drug failed: Seven patients treated with tozadenant developed sepsis—five of whom died. As a result, Acorda on November 15 paused enrollment of new patients in its Phase III studies. Five days later, Acorda terminated development of tozadenant. Of the seven sepsis cases, four were associated with agranulocytosis, two had no white blood cell counts available at the time of the event, and one had a high white blood cell count.
Date of announcement: November 20
Sponsor: Inotek Pharmaceuticals
Type of drug: First-in-class, highly selective adenosine mimetic targeting the A1 subreceptor
How drug failed: Inotek acknowledged in January that its lead candidate trabodenoson missed its primary endpoint in the Phase III MATrX-1 trial of superiority to placebo in reduction of intraocular pressure (IOP) at all 12 of the study’s time points. The failure sparked a selloff that sent the share price plunging 64% that morning, to $2.20 in premarket trading. Six months later in July, Inotek halted development of trabodenoson after it failed a Phase II fixed-dose combination trial in combination with latanoprost, also in glaucoma, by showing no meaningful clinical advantage in IOP reduction at Day 56, after 4 additional weeks of treatment and night-time dosing. Inotek responded by exploring strategic alternatives, with relatively quick success. In September, the company announced a merger agreement with gene therapy developer Rocket Pharmaceuticals, a deal that is expected to close in the first quarter of 2018.
Date of announcements: September 12, July 7, January 3
Vadastuximab talirine (SGN-CD33A)
Sponsor: Seattle Genetics
Indications: Frontline older acute myeloid leukemia (AML); frontline high-risk myelodysplastic syndrome (MDS)
Type of drug: Antibody-drug conjugate (ADC) targeting CD33 protein
How drug failed: Company terminated its Phase III CASCADE trial in AML after reviewing unblinded data indicating a higher rate of deaths, including fatal infections, in the vadastuximab talirine arm compared with the control arm. Seattle Genetics also halted enrollment in all other clinical trials assessing the ADC. Two days later, the FDA placed the company’s IND on hold, barring clinical trials from resuming until the agency lifts the clinical hold.
Date of announcement: June 19