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Drug and Device News December 2016

NEW DRUG APPROVALS

Lartruvo for Soft-Tissue Sarcoma

The FDA has granted accelerated approval to olaratumab (Lartruvo, Eli Lilly) in combination with doxorubicin to treat adults with certain types of soft-tissue sarcoma (STS), which are cancers that develop in muscles, fat, tendons, or other soft tissues. Olaratumab is approved for use with the FDA-approved chemotherapy drug doxorubicin for the treatment of patients with STS who cannot be cured with radiation or surgery and who have a type of STS for which an anthracycline (chemotherapy) is an appropriate treatment.

Olaratumab is a platelet-derived growth factor (PDGF) receptor-alpha–blocking antibody. When stimulated, PDGF receptors cause tumor growth. Olaratumab is the first new therapy approved for the initial treatment of STS since doxorubicin’s approval more than 40 years ago.

Source: FDA, October 19, 2016

Zinplava for C. Difficile Infections

The FDA has approved bezlotoxumab (Zinplava, Merck), a monoclonal antibody indicated to reduce the recurrence of Clostridium difficile infection (CDI) in patients 18 years of age or older who are receiving antibacterial drug treatment for CDI and are at high risk for CDI recurrence. Bezlotoxumab is not indicated for the treatment of CDI. It is not an antibacterial drug. Bezlotoxumab should be used only in conjunction with antibacterial drug treatment of CDI.

As with all therapeutic proteins, there is a potential for immunogenicity after the administration of bezlotoxumab. After treatment in two phase 3 studies, however, none of the 710 evaluable patients tested positive for treatment-emergent anti-bezlotoxumab antibodies.

Source: Merck, October 21, 2016

Flublok Quadrivalent Flu Vaccine

A quadrivalent formulation of Flublok influenza vaccine (Protein Sciences Corporation) has received FDA approval. Flublok Quadrivalent protects against four strains of influenza—three of the same strains found in trivalent Flublok plus an additional B strain. The product is approved for adults 18 years of age and older and will be available in prefilled syringes beginning in 2017.

Source: Protein Sciences, October 11, 2016

Generic Approvals and Launches

Olmesartan Medoxomil/Hydrochlorothiazide and Olmesartan Medoxomil Tablets

The FDA has approved the first generic versions of Daiichi Sankyo’s Benicar HCT and Benicar, which together had U.S. sales of approximately $1.8 billion for the 12 months ending with August, according to IMS Health.

Olmesartan medoxomil and hydrochlorothiazide tablets, 20 mg/12.5 mg, 40 mg/12.5 mg, and 40 mg/25 mg (Benicar HCT), and olmesartan medoxomil tablets, 5 mg, 20 mg, and 40 mg (Benicar), can be marketed by Mylan Pharmaceuticals. Both products are indicated for the treatment of hypertension.

Meanwhile, Sun Pharmaceutical Industries Ltd. has announced the U.S. launch of authorized generic versions of both products.

Sources: FDA and Mylan, October 26, 2016; and Sun Pharmaceutical Industries, October 27, 2016

Olmesartan Medoxomil, Amlodipine, And Hydrochlorothiazide Tablets

Two companies have secured FDA approval to market the first generic olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets, sold under the brand name Tribenzor (Daiichi Sankyo). Par Pharmaceutical, Inc., and Torrent Pharmaceuticals Ltd. can sell tablets in 20mg/5 mg/12.5 mg, 40 mg/5 mg/12.5 mg, 40 mg/5 mg/25 mg, 40 mg/10 mg/12.5 mg, and 40 mg/10 mg/25 mg. A third company, Sun Pharmaceutical Industries Ltd., says it has launched authorized generic versions. The medication is indicated for treatment of hypertension.

Sources: FDA, October 26, 2016; and Sun Pharmaceutical Industries, October 27, 2016

Amlodipine and Olmesartan Medoxomil Tablets

The FDA has authorized Macleods Pharmaceuticals Ltd. and Teva Pharmaceuticals USA, Inc., to produce amlodipine and olmesartan medoxomil tablets, 5 mg/20 mg, 5 mg/40 mg, 10 mg/20 mg, and 10 mg/40 mg. These are the first generic versions of Azor (Daiichi Sankyo), used for treatment of hypertension. In addition, Sun Pharmaceutical Industries Ltd. says it has launched authorized generic versions.

Sources: FDA, October 26, 2016; and Sun Pharmaceutical Industries, October 27, 2016

Ribavirin for Inhalation Solution

The FDA has approved ribavirin for inhalation solution USP, 6 g per vial, to be marketed by Navinta LLC. This is the first generic version of Virazole for inhalation solution (Valeant Pharmaceuticals), used for the treatment of hospitalized infants and young children with severe lower respiratory tract infections due to respiratory syncytial virus.

Source: FDA, October 6, 2016

Generic Antihistamine/Decongestant

Acella Pharmaceuticals has secured approval for a sugar-free bioequivalent to the antihistamine/decongestant Bromfed-DM cough syrup (brompheniramine maleate, pseudoephedrine hydrochloride, and dextromethorphan hydrobromide syrup, 2 mg/30 mg/10 mg per 5 mL). This combination is used to temporarily relieve symptoms caused by the common cold, flu, allergies, and other breathing illnesses.

Source: Acella Pharmaceuticals, October 28, 2016

Nystatin/Triamcinolone Cream

Glenmark Pharmaceuticals has secured final FDA approval for nystatin and triamcinolone acetonide cream USP, 100,000 units/g and 1 mg/g. This is a generic version of the antifungal agent Mycolog-II cream, 100,000 units/g, 0.1% (Delcor Asset Corporation), which is no longer marketed in the United States.

Source: Glenmark Pharmaceuticals, October 25, 2016

Benztropine Mesylate Tablets

ANI Pharmaceuticals, Inc., has announced the launch of benztropine mesylate tablets USP 0.5 mg, 1 mg, and 2 mg. The product is indicated for use as an adjunct to the therapy for all forms of parkinsonism and may also be useful in the control of extrapyramidal disorders (except tardive dyskinesia) due to neuroleptic drugs.

Source: ANI Pharmaceuticals, October 25, 2016

Aripiprazole Tablets

Dr. Reddy’s Laboratories has launched aripiprazole USP in 2-mg, 5-mg, 10-mg, 15-mg, 20-mg, and 30-mg tablets— a generic version of the second-generation antipsychotic agent Abilify (Otsuka Pharmaceutical Company). Oral Abilify has the following indications: schizophrenia; acute treatment of manic and mixed episodes associated with bipolar I; adjunctive treatment of major depressive disorder; irritability associated with autistic disorder; and treatment of Tourette’s disorder.

Source: Dr. Reddy’s Laboratories, October 13, 2016

NEW INDICATION

Keytruda for Metastatic Lung Cancer

The FDA has cleared pembrolizumab (Keytruda, Merck), an anti-programmed death receptor-1 (PD-1) therapy, for the first-line treatment of patients with metastatic non–small-cell lung cancer (NSCLC) whose tumors have high programmed death ligand-1 (PD-L1) expression (i.e., a tumor proportion score [TPS] of 50% or more), as determined by an FDA-approved test, with no epidermal growth factor receptor or anaplastic lymphoma kinase genomic tumor aberrations. With this new indication, pembrolizumab is the only anti–PD-1 therapy to be approved in the first-line treatment setting for these patients.

In addition, the FDA approved a labeling update to include data from the KEYNOTE-010 trial in the second-line or greater treatment setting for patients with metastatic NSCLC whose tumors express PD-L1 (TPS of 1% or more), as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy.

Source: Merck, October 24, 2016

FDA REVIEW ACTIVITIES

Priority Review Status

Ribociclib for Breast Cancer

The FDA has accepted the new drug application (NDA) for ribociclib (LEE011, Novartis) and has granted the drug a priority review for the first-line treatment of postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced or metastatic breast cancer in combination with letrozole. The NDA was partly based on results from a phase 3 trial that showed that ribociclib plus letrozole reduced the risk of disease progression or death by 44% compared with letrozole alone (hazard ratio, 0.556; P = 0.00000329), significantly extending progression-free survival.

Ribociclib is a selective cyclin-dependent kinase (CDK) inhibitor, a class of drugs that helps slow the progression of cancer by inhibiting two proteins, CDK4 and CDK6. These proteins, when overactivated in a cell, can allow cancer cells to grow and divide too quickly.

Source: Novartis, November 1, 2016

Brigatinib for NSCLC

The FDA has accepted for review the new drug application for brigatinib (Ariad Pharmaceuticals), an investigational oral anaplastic lymphoma kinase (ALK) inhibitor, for patients with metastatic ALK-positive non–small-cell lung cancer (NSCLC) who have progressed on crizotinib. The FDA granted a priority review and set an action date of April 29, 2017.

An ongoing phase 3 trial is assessing the efficacy and safety of brigatinib in comparison with crizotinib in patients with locally advanced or metastatic ALK-positive NSCLC who have not received prior treatment with an ALK inhibitor.

Source: Ariad Pharmaceuticals, October 31, 2016

Spinraza for Spinal Muscular Atrophy

The FDA has accepted for priority review a new drug application for nusinersen (Spinraza, Biogen), an investigational treatment for spinal muscular atrophy (SMA). If approved, nusinersen would be the first therapy for SMA, a leading genetic cause of infant mortality.

Nusinersen is an antisense oligonucleotide that is designed to alter splicing of the SMN2 gene in order to increase the production of fully functional SMN proteins.

Source: Biogen, October 28, 2016

Opdivo for Bladder Cancer

The FDA has accepted a supplemental biologics license application that seeks to expand the use of nivolumab (Opdivo, Bristol-Myers Squibb) to patients with locally advanced unresectable or metastatic urothelial carcinoma that has progressed on or after platinum-containing therapy. The FDA granted the application a priority review, with an action date of March 2, 2017.

The submission was based on data from a phase 2, single-arm study, which evaluated the safety and efficacy of nivolumab in 270 patients with metastatic or unresectable urothelial carcinoma that had progressed or recurred after treatment with a platinum-based agent in the metastatic setting or within one year after neoadjuvant/adjuvant platinum therapy. In this trial, nivolumab achieved an objective response rate (the primary endpoint) of 19.6%.

Source: Bristol-Myers Squibb, October 21, 2016

Ingrezza for Tardive Dyskinesia

The FDA has accepted for priority review a new drug application for valbenazine (Ingrezza, Neurocrine Biosciences) for the treatment of patients with tardive dyskinesia. The target action date is April 11, 2017.

Vesicular monoamine transporter 2 (VMAT2), a protein in the human brain, is primarily responsible for repackaging and transporting monoamines (dopamine, norepinephrine, serotonin, and histamine) in presynaptic neurons. Valbenazine is an investigational, highly selective VMAT2 inhibitor that modulates dopamine release during nerve communication, showing little or no affinity for VMAT1 or other receptors, transporters, and ion channels.

Source: Neurocrine Biosciences, October 11, 2016

Fast-Track Designations

OTL 38 Molecule “Lights Up” Cancer

The FDA has granted fast-track status to a Purdue University scientist’s optical imaging technology that may significantly improve outcomes for patients with pancreatic cancer.

Dr. Philip Low developed the OTL 38 molecule, which will move quickly to phase 3 trials in human cancer patients. The molecule, given to patients intravenously, attaches to receptors on cancer cells and glows, identifying the cells that should be surgically removed.

Positive results from a phase 2 study of OTL 38 were important to gaining fast-track status. In that study, 96% of the tissue that was illuminated in patients was confirmed by pathology to be cancerous, and 98% of the malignant lesions identified by the surgeons fluoresced brightly because of their uptake of the fluorescent dye.

Source: Purdue University, October 26, 2016

Resolaris for Muscular Dystrophy

Resolaris (aTyr Pharma) has been granted fast-track status by the FDA for the treatment of patients with facioscapulohumeral muscular dystrophy (FSHD), making it the first therapeutic candidate for FSHD to receive this designation. Resolaris, a designated orphan drug in FSHD, is being studied in a phase 1b/2 clinical program. The treatment is derived from a naturally occurring protein released in vitro by human skeletal-muscle cells. FSHD, a rare genetic myopathy affecting an estimated 19,000 people in the United States, has no approved treatments.

Source: aTyr Pharma, October 24, 2016

CC8464/ASP1807 for Neuropathic Pain

The FDA has granted a fast-track designation to the drug candidate CC8464/ASP1807 (Chromocell Corporation/Astellas Pharma) for the management of neuropathic pain associated with idiopathic small-fiber neuropathy. In 2015, Chromocell and Astellas entered into a collaboration agreement for the development and commercialization of CC8464/ASP1807 for the management of neuropathic pain and other pain indications. Chromocell recently dosed the first subject in a phase 1 trial designed to evaluate the safety, tolerability, and pharmacokinetics of an oral formulation of CC8464/ASP1807.

Chromocell’s CC8464 is an oral, highly selective, peripherally restricted NaV1.7 inhibitor that has been shown to be effective in animal models of human neuropathic and inflammatory pain. NaV1.7 is an ion channel involved in pain transmission.

Source: Chromocell Corporation, October 12, 2016

Breakthrough Therapy Status

NiCord Graft Modality

The FDA has granted breakthrough therapy status to NiCord (Gamida Cell, Ltd.), an investigational graft modality for bone marrow transplantation in patients with high-risk blood cancers, such as leukemia and lymphoma. An international, phase 3 registration study is expected to begin before the end of the year.

Data from phase 1/2 studies of NiCord have demonstrated clinically meaningful improvements in the time to neutrophil engraftment compared with cord blood transplantation. In addition, NiCord study data have shown fewer infections, reduced lengths of hospitalization, quicker platelet engraftment, and improved nonrelapse mortality compared with unmanipulated cord blood transplantation.

Source: Gamida Cell, October 11, 2016

Orphan Drug Designations

YS-ON-001 for Liver Cancer

The FDA has granted an orphan drug designation for the biologic product candidate YS-ON-001 (Yisheng Biopharma Co.) for the treatment of patients with hepatocellular carcinoma. YS-ON-001 is a multicomponent complex with immunomodulatory properties, such as promoting Th1-biased immunity; inducing the activation and proliferation of dendritic cells, B cells, and natural killer cells; promoting macrophage M1 polarization; and down-regulating regulatory T cells.

Source: Yisheng Biopharma, October 24, 2016

TNT009 for Anemia

The FDA has granted orphan drug status to TNT009 (True North Therapeutics) for the treatment of patients with autoimmune hemolytic anemia (AHA), including cold agglutinin disease (CAD), a form of AHA for which there are limited treatment options. TNT009 is currently in a phase 1b trial in patients with CAD, and positive interim results from this study were reported in June 2016.

TNT009 is a first-in-class monoclonal antibody that selectively targets C1s, a serine protease within the C1-complex in the immune system’s complement pathway. TNT009 prevents downstream disease processes involving phagocytosis, inflammation, and cell lysis.

Source: True North Therapeutics, October 13, 2016

New or Revised Applications

Subcutaneous Rituximab For Blood Cancers

The FDA has accepted the biologics license application for a subcutaneous formulation of rituximab (Genentech) for multiple blood cancer indications. The product is a coformulation with a proprietary recombinant human hyaluronidase enzyme (the Enhanze platform, Halozyme Therapeutics). It is marketed under the brand name MabThera SC in countries outside the United States.

Source: Halozyme, November 3, 2016

Xaracoll for Postsurgical Pain

A new drug application for Xaracoll (bupivacaine hydrochloride collagen-matrix implants, Innocoll AG) has been submitted to the FDA for the treatment of postsurgical pain. The submission was based on successful results from the MATRIX trials, which showed statistically significant differences in the primary endpoint (the sum of pain intensity in both studies), as well as statistically significant reductions in opioid use and other secondary endpoints.

Source: Innocoll, November 3, 2016

Niraparib for Ovarian Cancer

Tesaro, Inc., has completed a rolling new drug application submission to the FDA for the use of niraparib in the maintenance treatment of patients with platinum-sensitive, recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response to platinum-based chemotherapy. Niraparib is an oral, once-daily poly (ADP-ribose) polymerase inhibitor. The FDA granted the drug a fast-track designation in September 2016.

Source: Tesaro, November 1, 2016

Baxdela for Skin Infections

New drug applications have been submitted to the FDA for the approval of intravenous and oral formulations of delafloxacin (Baxdela, Ligand Pharmaceuticals/Melinta Therapeutics) for the treatment of patients with acute bacterial skin and skin-structure infections. Delafloxacin is an investigational anionic fluoroquinolone with a broad spectrum of antimicrobial activity, including activity against methicillin-resistant Staphylococcus aureus.

The submissions were based on results from two phase 3 studies. In both trials, delafloxacin met the primary endpoint of noninferiority to a combination regimen of vancomycin plus aztreonam in reducing lesion size at the primary infection site 48 to 72 hours after treatment.

Source: Ligand Pharmaceuticals, October 24, 2016

Shingrix Shingles Vaccine

A biologics license application has been submitted to the FDA for a candidate shingles (herpes zoster) vaccine, Shingrix (GlaxoSmithKline), seeking approval for prevention of the disease in people 50 years of age or older. In phase 3 data, the nonlive recombinant vaccine not only reduced the incidence of shingles, but also reduced the overall incidence of postherpetic neuralgia, a form of chronic pain associated with shingles. Regulatory approval is being sought for the vaccine to be given intramuscularly in two doses, with a two- to six-month interval between doses.

Shingrix combines glycoprotein E, a protein found on the varicella zoster virus that causes shingles, with an adjuvant system, AS01B, which is intended to enhance the immunological response to the antigen.

Source: GlaxoSmithKline, October 24, 2016

ZS-9 for Hyperkalemia

The FDA has accepted for review the resubmission of a new drug application for sodium zirconium cyclosilicate (ZS-9, ZS Pharma/AstraZeneca), a potential new medication for the treatment of patients with hyperkalemia. Sodium zirconium cyclosilicate is an insoluble, nonabsorbed compound with a structure designed to preferentially capture potassium ions. The compound has been studied in three double-blind, placebo-controlled trials and in one ongoing 12-month, open-label study in patients with hyperkalemia, representing a treatment population of more than 1,600 patients.

Source: AstraZeneca, October 18, 2016

Avycaz for Urinary Tract Infections

The FDA has accepted for filing a supplemental new drug application for Avycaz (ceftazidime/avibactam). The manufacturer, Allergan, is seeking the addition of new phase 3 clinical trial data to the current product label. The new data involve the use of Avycaz in patients with complicated urinary tract infections, including pyelonephritis, due to designated susceptible pathogens. The FDA is expected to take action on the filing during the first quarter of 2017.

Source: Allergan, October 11, 2016

Labeling Changes

Xtandi for Prostate Cancer

The FDA has approved a supplemental new drug application to update the product labeling for enzalutamide capsules (Xtandi, Astellas Pharma) to include new clinical data versus bicalutamide from the TERRAIN study. The updated label includes data showing that enzalutamide reduced the risk of radiographic progression or death by 40% compared with bicalutamide in men with metastatic castration-resistant prostate cancer, with median radiographic progression-free survival of 19.5 months for the enzalutamide group compared with 13.4 months for the bicalutamide group (hazard ratio, 0.60).

Source: Astellas Pharma, October 21, 2016

Tarceva for Lung Cancer

The FDA has modified the indication for erlotinib (Tarceva, Astellas Pharma Global Development, Inc.) for the treatment of non–small-cell lung cancer (NSCLC) to limit the medication’s use to patients whose tumors have specific epidermal growth factor receptor (EGFR) mutations.

The labeling change applies to patients with NSCLC receiving maintenance or second- or greater-line treatment. These indications will be limited to patients whose tumors have EGFR exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test. The first-line indication previously was limited to patients with EGFR exon 19 deletions or exon 21 substitution mutations.

Source: FDA, October 18, 2016

Other Regulatory Issues

Methylphenidate ER

Lannett Company, Inc., has received notice from the FDA that it will seek to withdraw approval of the company’s abbreviated new drug application for methylphenidate hydrochloride extended-release (ER) tablets. Lannett stated that it will review the scientific rationale for the FDA’s position and compile the scientific evidence needed to convince the agency’s Office of Generic Products that the methylphenidate ER tablets should continue to be marketed. The company has until December 19, 2016, to submit new data.

Source: Lannett Company, October 19, 2016

FDA Confirms Xarelto Efficacy

In July 2016, the hand-held, point-of-care INRatio device (Alere, Inc.) was recalled because of the potential to generate inaccurate results. This device was used to monitor warfarin therapy in the control group of the pivotal ROCKET-AF trial, which provided the primary data to support the 2011 approval of the blood-thinner rivaroxaban (Xarelto, Janssen). Because of the concern about the INRatio device, the FDA’s Center for Drug Evaluation and Research conducted a series of analyses to assess the effect that this faulty monitoring device may have had on the ROCKET-AF study results.

The agency determined that effects of the device on strokes or bleeding, including intracranial bleeding, were minimal. The FDA concluded that rivaroxaban is a safe and effective alternative to warfarin in patients with nonvalvular atrial fibrillation.

Source: FDA, October 11, 2016

DRUG SAFETY ISSUES

Checkpoint Inhibitors And Myocarditis Deaths

Checkpoint inhibitors are popular treatments for cancer, but an article in the New England Journal of Medicine has warned that combining the checkpoint inhibitors nivolumab (Opdivo) and ipilimumab (Yervoy)—both marketed by Bristol-Myers Squibb—could lead to death in a small number of patients. According to the article, two melanoma patients receiving combination treatment with nivolumab and ipilimumab died from fulminant myocarditis. Autopsies showed that the immune systems of both patients had attacked their hearts.

According to the article, myocarditis has occurred in 0.27% of patients treated with nivolumab and ipilimumab in pharmacovigilance studies, suggesting that the patients in the new report had experienced a rare, potentially fatal, T-cell–driven drug reaction.

In addition to nivolumab and ipilimumab, two other checkpoint inhibitors are on the market: pembrolizumab (Keytruda, Merck) and atezolizumab (Tecentriq, Genentech).

Source: BioSpace, November 3, 2016

Testosterone Warnings

The FDA has approved class-wide labeling changes for all prescription testosterone products, adding a new warning and updating the “abuse and dependence” section to include new safety information from published literature and case reports regarding the risks associated with abuse of and dependence on testosterone and other anabolic steroids.

The abuse of testosterone, usually at doses higher than those typically prescribed and usually in conjunction with other anabolic steroids, is associated with serious safety risks affecting the heart, brain, liver, mental health, and endocrine system. Reported serious adverse outcomes include heart attack, heart failure, stroke, depression, hostility, aggression, liver toxicity, and male infertility. Individuals abusing high doses of testosterone have also reported withdrawal symptoms, such as depression, fatigue, irritability, loss of appetite, decreased libido, and insomnia.

Source: FDA, October 25, 2016

Ceftriaxone/Lansoprazole Tied to Heart Condition

Researchers at Columbia University studied the combination of ceftriaxone (Rocephin, Roche), an antibiotic, and lansoprazole (Prevacid, Takeda), a heartburn medication. Alone, these medications carry no known heart-related risks—but when used together, they may increase the chance that patients develop a heart condition known as long QT syndrome, which can cause abnormal heart rhythms and, in rare cases, sudden death, according to the investigators. The study found that patients taking ceftriaxone and lansoprazole together were 1.4 times more likely to have a prolonged QT interval than were patients who were taking either drug alone.

Source: Columbia University Medical Center, October 10, 2016

CLINICAL TRIAL NEWS

Bremelanotide for Hypoactive Sexual Desire Disorder

Positive, statistically significant results have been reported from the phase 3 clinical trial program for bremelanotide (Palatin Technologies), an investigational on-demand treatment for premenopausal women diagnosed with hypoactive sexual desire disorder. Two studies in the clinical program have met their prespecified coprimary efficacy endpoints.

Bremelanotide, a melanocortin 4 receptor agonist drug candidate, is a synthetic peptide analogue of the naturally occurring hormone alpha-MSH (melanocyte-stimulating hormone). In clinical trials, bremelanotide was self-administered on an as-needed (not chronic) basis in anticipation of sexual activity.

Source: Palatin Technologies, November 1, 2016

Emicizumab for Hemophilia

Four patients have experienced serious thrombotic events in a clinical trial of the experimental hemophilia medication emicizumab (ACE910, Genentech/Roche), dimming hopes for the potential blockbuster drug, according to a Reuters report. The patients were being treated for breakthrough bleeding. A Roche spokesman told Reuters that the cases involved patients who were treated with one of two bypassing agents. He added that both agents—Shire’s FEIBA and Novo’s Novo-Seven—carried thrombosis warnings.

Emicizumab is an investigational humanized bispecific monoclonal antibody engineered to simultaneously bind factors IXa and X. The drug is being closely watched because it could change the way hemophilia is treated.

Source: Reuters, November 2, 2016

Verubecestat for Alzheimer’s Disease

Research leading to the discovery and development of verubecestat (Merck) for the potential treatment of patients with Alzheimer’s disease (AD) has been published in Science Translational Medicine.

Verubecestat, an investigational small-molecule inhibitor of the enzyme beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1), emerged from several years of detailed analysis of the structure and function of the BACE1 protein. Subsequent phase 1 data from both healthy volunteers and AD patients demonstrated that once-daily doses of verubecestat for one week provided significant reductions of up to 80% in the levels of amyloid-beta peptide production, a key marker of BACE1 activity.

The efficacy and safety of verubecestat are being evaluated in two pivotal phase 3 trials, EPOCH and APECS, for the treatment of patients with mild-to-moderate AD and prodromal AD, respectively.

Source: Merck, November 2, 2016

Lynparza for Ovarian Cancer

Results of a phase 3 study designed to determine the efficacy of olaparib (Lynparza, GlaxoSmithKline) as monotherapy for the maintenance treatment of women with platinum-sensitive, relapsed, BRCA-mutated ovarian cancer demonstrated a statistically significant improvement in progression-free survival among patients treated with olaparib compared with those given placebo.

Olaparib is a first-in-class oral poly (ADP-ribose) polymerase inhibitor that is believed to exploit deficiencies in the tumor DNA damage response pathway to preferentially kill cancer cells. It is approved by the FDA for the treatment of women with BRCA-mutated ovarian cancer.

Source: AstraZeneca, October 26, 2016

Adalimumab Biosimilar Candidate

In a pivotal phase 3 trial, BI 695501 (Boehringer Ingelheim), a biosimilar candidate to Humira (adalimumab, AbbVie), met the study’s primary efficacy endpoint by establishing equivalence with Humira in patients with active rheumatoid arthritis. Secondary endpoints comparing the efficacy, safety, and immunogenicity of BI 695501 with that of Humira were also met.

Source: Boehringer Ingelheim, October 26, 2016

Tramiprosate for Alzheimer’s Disease

Efficacy analyses have been conducted of phase 3 data for the investigational amyloid-targeted drug tramiprosate (Alzheon) in patients with mild or moderate Alzheimer’s disease (AD). These evaluations involved patient subgroups based on the number of epsilon-4 alleles of apolipoprotein E (APOE4), a major genetic risk factor in up to 65% of AD patients. The results showed a gene–dose effect at the high dosage of tramiprosate (150 mg twice daily). Patients with two APOE4 alleles (APOE4/4 homozygotes) showed the largest clinical benefit and those with one APOE4 allele (APOE4 heterozygotes) showed an intermediate benefit, while APOE4 noncarriers showed no benefit from tramiprosate. The results provided the first evidence from a large clinical trial to associate the efficacy of an amyloid-targeted agent with APOE4 status in AD patients.

Source: Alzheon, October 25, 2016

Xgeva for Bone Complications Caused by Multiple Myeloma

A phase 3 study evaluating denosumab (Xgeva, Amgen) versus zoledronic acid met the primary endpoint of noninferiority (hazard ratio, 0.98) in delaying the time to the first on-study skeletal-related event (SRE) in patients with multiple myeloma. The secondary endpoints of superiority in delaying the time to the first SRE and superiority in delaying the time to first-and-subsequent SREs were not met. The hazard ratio of Xgeva versus zoledronic acid for overall survival was 0.90.

Xgeva targets the RANK ligand pathway to prevent the formation, function, and survival of osteoclasts, which break down bone. Xgeva is indicated for the prevention of SREs in patients with bone metastases from solid tumors and for the treatment of adults and skeletally mature adolescents with giant-cell tumors of bone that are unresectable or where surgical resection is likely to result in severe morbidity. Xgeva is also indicated in the U.S. for the treatment of hypercalcemia of malignancy that is refractory to bisphosphonate therapy. Xgeva is not indicated for the prevention of SREs in patients with multiple myeloma.

Source: Amgen, October 20, 2016

Locilex for Diabetic Foot Infections

Two phase 3 trials of pexiganan cream 0.8% (Locilex, Dipexium Pharmaceuticals) in patients with mild infections of diabetic foot ulcers did not meet the primary clinical endpoint of superiority compared with placebo cream plus standardized wound care. The results also did not show any meaningful differences in wound closure rates between the pexiganan arm and the vehicle arm in each study. Further, neither trial met the secondary endpoint of demonstrating a higher rate of eradication of bacteria for the pexiganan arm.

Pexiganan cream 0.8% is a chemically synthesized, 22-amino acid peptide isolated from the skin of the African clawed frog.

Source: Dipexium Pharmaceuticals, October 25, 2016

Elagolix for Pelvic Pain Associated With Endometriosis

Positive results have been reported from two replicate pivotal phase 3 trials evaluating the efficacy and safety of elagolix (AbbVie/Neurocrine Biosciences), a gonadotropin-releasing hormone receptor antagonist, in premenopausal women with endometriosis.

In the two studies, both dosages of elagolix demonstrated a statistically significant (P < 0.001) improvement compared with placebo in the percentage of dysmenorrhea (DYS) and nonmenstrual pelvic pain (NMPP) responders. In the first study, at three months, 46% of patients treated with 150 mg once daily and 76% treated with 200 mg twice daily of elagolix were classified as DYS responders compared with 20% of patients in the placebo group. In addition, 50% of patients treated with 150 mg once daily and 55% of those treated with 200 mg twice daily of elagolix were classified as NMPP responders compared with 36% of patients in the placebo group. The second pivotal study demonstrated similar results.

Source: AbbVie, October 19, 2016

Tenofovir Prodrug For HBV Infection

Positive interim data have been reported for CMX157 (ContraVir Pharmaceuticals), a prodrug of tenofovir, from an ongoing phase 2a multiple-ascending-dose clinical trial. The study is comparing CMX157 with tenofovir disoproxil fumarate (TDF) (Viread, Gilead Pharmaceuticals) in patients chronically infected with hepatitis B virus (HBV).

The interim data were obtained from 10 HBV-infected patients who completed 14 days of once-daily oral dosing of 25 mg of CMX157, and from two HBV patients treated for 14 days of oral dosing with 300 mg TDF. The CMX157-treated patients showed an average 99% reduction in the HBV viral load compared with baseline. Significantly, the observed antiviral activity for CMX157 was comparable with that observed in TDF-treated patients, but at 1/12th the dose (25 mg of CMX157 versus the standard 300 mg of TDF).

Source: ContraVir Pharmaceuticals, October 13, 2016

AZD9412 for Asthma

AstraZeneca has decided to stop a phase 2a trial for the inhaled interferon (IFN)-beta product AZD9412 based on an interim analysis in which an overall very low number of reported severe exacerbations could make primary endpoint conclusions difficult.

Synairgen, based in the United Kingdom, licensed AZD9412 to AstraZeneca in June 2014. AZD9412 acts as an antiviral protein.

In the INEXAS study, asthma patients were treated with AZD9412 or placebo at the onset of common cold symptoms. Previous research has shown that common colds can cause severe asthma exacerbations and that boosting the lung’s antiviral defenses with AZD9412 during this time could prevent exacerbations.

Source: Synairgen October 12, 2016

AB103 for Necrotizing Soft-Tissue Infections

After reviewing the first 50 patients for safety, an independent data monitoring committee has recommended that the phase 3 ACCUTE trial of AB103 (Atox Bio), a candidate for the treatment of patients with necrotizing soft-tissue infections (NSTI; “flesh-eating bacteria”), continue without modification.

AB103 is a peptide that binds to the CD28 costimulatory receptor, thereby modulating the host’s immune response. By modulating, but not inhibiting, the immune response, AB103 dampens the “out-of-control” acute inflammatory response that leads to tissue and organ damage.

The ACCUTE trial is a randomized, placebo-controlled study that plans to enroll 290 patients with NSTI at approximately 60 centers in the United States. The participants are receiving AB103 or placebo, administered as a single dose during or shortly after surgical debridement, in addition to standard-of-care treatment.

Source: Atox Bio, November 3, 2016

Nuplavid for Schizophrenia

Acadia Pharmaceuticals has announced the initiation of a six-week phase 3 study to evaluate pimavanserin (Nuplavid) for the adjunctive treatment of schizophrenia in patients with an inadequate response to antipsychotic therapy. Antipsychotics currently indicated for schizophrenia primarily target the dopaminergic pathway. As a selective serotonin inverse agonist (SSIA), pimavanserin belongs to a new class of antipsychotic medications with a mechanism of action targeting serotonergic 5-HT2A receptors while avoiding activity at dopamine and other receptors commonly targeted by other antipsychotics.

The FDA approved pimavanserin for the treatment of patients with hallucinations and delusions associated with Parkinson’s disease psychosis in April 2016. The drug is not approved for the adjunctive treatment of patients with schizophrenia.

Source: Acadia Pharmaceuticals, November 3, 2016

PRX-102 for Fabry Disease

The first patient has been dosed in a global phase 3 study of PRX-102 (Protalix BioTherapeutics), a modified version of the recombinant human alpha-GAL-A protein, for the treatment of patients with Fabry disease. The BALANCE trial is a 24-month, randomized, double-blind, active-control study of PRX-102 for the treatment of Fabry disease in patients with impaired renal function. The trial is designed to enroll 78 patients previously treated with Fabrazyme (agalsidase beta, Sanofi/Genzyme) with a stable dose for at least six months. Enrolled patients will be randomly assigned to continue treatment with 1 mg/kg of either Fabrazyme or PRX-102, administered via intravenous infusion every two weeks.

Source: Protalix BioTherapeutics, October 25, 2016

DEVICE APPROVALS

BreathID Lab System For H. Pylori Detection

The BreathID Lab System and breath-test kits (Exalenz Bioscience), developed for Helicobacter pylori bacterium detection, have received marketing clearance from the FDA. The system was designed to facilitate the diagnosis of H. pylori infection in large numbers of breath samples at a central location. Patients at clinics and medical centers breathe into two designated collection bags, and the breath samples are sent for analysis to central laboratories, where the new system will be installed.

Source: Exalenz Bioscience, November 1, 2016

Amplatzer PFO Occluder Device to Limit Stroke Risk

The FDA has approved the Amplatzer PFO Occluder device (St. Jude Medical, Inc.) to reduce the risk of a stroke in patients who previously experienced a stroke believed to be caused by a blood clot that passed through a small hole in the heart—called a patent foramen ovale (PFO)—and then traveled to the brain.

The Amplatzer PFO Occluder is inserted through a catheter that is placed in a leg vein and advanced to the heart. It is then implanted close to the hole in the heart between the right atrium and the left atrium.

The device was on the market more than a decade ago under a humanitarian device exemption (HDE), but it was voluntarily withdrawn by the manufacturer in 2006 after the FDA concluded that the target population for the device was greater than 4,000 patients and that the device no longer qualified for HDE approval.

Source: FDA, October 28, 2016

Evarrest Fibrin Sealant Patch

The FDA has approved an expanded indication for Evarrest fibrin sealant patch (Ethicon), which leverages biologics to stop problematic bleeding during surgery. The expanded indication supports the use of Evarrest as an adjunctive hemostat for a broad range of patient types and surgical situations. The new indication for Evarrest was supported by a head-to-head study that demonstrated the product’s superior hemostatic efficacy compared with that of Tachosil fibrin sealant patch (Baxter).

Source: Ethicon, October 25, 3016

DEVICE SAFETY ISSUES

Infection Risk With Heater–Cooler Devices

The Centers for Disease Control and Prevention (CDC) has warned health care providers about the potential risk of infection from certain devices used during open heart (open chest) surgery. New information indicates that some LivaNova PLC (formerly Sorin Group Deutschland GmbH) Stöckert 3T heater–cooler devices, used during many of these surgeries, might have been contaminated during manufacturing, which could put patients at risk for life-threatening infections.

Laboratory tests showed that Mycobacterium chimaera organisms from the heater–cooler devices matched bacteria found in patients in several states. These results build on previous evidence from Europe that suggests the bacteria contaminated these devices during manufacturing in Germany.

Source: CDC, October 13, 2016

Battery Failure in St. Jude Defibrillators

The FDA and St. Jude Medical have alerted physicians, patients, and caregivers to respond immediately to elective replacement indicator (ERI) alerts on implantable cardioverter defibrillators and cardiac resynchronization therapy defibrillators from St. Jude. Because of problems with the batteries, patients do not have the normal three-month lead time for device replacement. Some batteries have run out within 24 hours of the patient receiving an ERI alert. The warning applies only to St. Jude devices manufactured before May 2015.

Source: FDA, October 11, 2016

FDA Warning: Radiation Therapy Devices

The FDA has expressed concern about the risks to patients from the use of devices manufactured and sold by Multidata Systems International Corporation. The agency knows of at least two Multidata medical devices manufactured and distributed in the United States for which the FDA never received nor reviewed 510(k) pre-market notifications. These devices include accessories to radiation therapy devices and the Dual Channel Electrometer. In addition, Multidata has not registered or listed its devices with the FDA, as required by federal law.

Source: FDA, October 20, 2016

Tracheostomy Tube Set Recalled

According to the FDA, Teleflex has recalled the Willy Rusch tracheostomy tube set because of the possibility that the connector may disconnect from the tracheostomy tube during use on a ventilated patient. If the connector detaches from the tracheostomy tube shaft during use, it can deprive the patient of adequate ventilation and would require immediate medical intervention, including changing the tracheostomy tube and placing a new tube. The use of affected products may cause serious adverse health consequences, including oxygen deprivation, brain damage, and death.

Source: FDA, October 20, 2016

OTHER DEVICE NEWS

Wrist-Worn Heart Rate Monitors

In a study published online in JAMA Cardiology, researchers at the Cleveland Clinic assessed the accuracy of four popular wrist-worn heart rate (HR) monitors under conditions of varying physical exertion. Fifty healthy adults (average age, 37 years) wore standard electrocardiographic limb leads and a Polar H7 chest-strap monitor. In addition, each subject was randomly assigned to wear two different wrist-worn HR monitors. Four monitors were assessed: Fitbit Charge HR (Fitbit), Apple Watch (Apple), Mio Alpha (Mio Global), and Basis Peak (Basis).

The investigators found that the HR monitors had variable accuracy when compared with an electrocardiogram. While the Basis Peak overestimated HR during moderate exercise, the Fitbit Charge HR underestimated HR during more vigorous exercise. The Apple Watch and Mio Fuse had 95% of values within −27 beats per minute (bpm) and +29 bpm of the electrocardiogram, whereas Fitbit Charge HR had 95% of values within −34 bpm and +39 bpm, and the corresponding values for the Basis Peak were within −39 bpm and +33 bpm.

“Because cardiac patients increasingly rely on these monitors to stay within physician-recommended, safe HR thresholds during rehabilitation and exercise, appropriate validation of these devices in this group is imperative,” the authors wrote.

Source: Medical Xpress, October 12, 2016