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P T. 2019;44(4): 170-177, 202

Drug and Device News April 2019

NEW DRUG APPROVALS

Esperoct for Hemophilia A

The FDA has approved turoctocog alfa pegol (Esperoct, Novo Nordisk) for the treatment of hemophilia A (congenital factor VIII deficiency). Turoctocog alfa pegol is indicated for adults and children for routine prophylaxis to reduce the frequency of bleeding episodes, for on-demand treatment and control of bleeding episodes, and for perioperative management of bleeding.

The approval is based on results from a preregistration clinical program that included 270 previously treated people with severe hemophilia A and more than five years of clinical exposure. Turoctocog alfa pegol was shown to provide effective routine prophylaxis in people with severe hemophilia A through a simple, fixed-dosing regimen of one injection every four days in adults and adolescents or every three or four days (twice weekly) in children.

Turoctocog alfa pegol maintained a median annualized bleed rate of 1.18 when dosed at 50 IU/kg every four days in adults and adolescents. It was also found to be efficacious in treatment and control of bleeding episodes and perioperative management. Turoctocog alfa pegol was well tolerated and no safety concerns were identified. Its overall safety profile is similar to that reported for other long-acting factor VIII products.

Turoctocog alfa pegol is an extended half-life factor VIII molecule that provides a 1.6-fold half-life prolongation in adults and adolescents and a 1.9-fold half-life prolongation in children compared to standard half-life factor VIII products.

Because of third-party intellectual property agreements, Novo Nordisk will not be able to launch Esperoct before 2020 in the U.S.

Source: Novo Nordisk, February 19, 2019

Egaten for Fascioliasis

Triclabendazole (Egaten, Novartis) has become the first FDA-approved drug for the treatment of fascioliasis in patients who are 6 years of age and older.

Fascioliasis, or liver fluke infestation, is a neglected tropical disease that infects about 2.4 million people worldwide, with 180 million more at risk of infection. It is caused by two parasitic flatworms (Fasciola hepatica and F. gigantica) that can infect humans who ingest the larvae in contaminated water or food. Fascioliasis causes significant pain and discomfort if it is untreated.

Triclabendazole is the sole treatment for fascioliasis recommended by the World Health Organization (WHO) and is included on its Model List of Essential Medicines. WHO supplies the drug during epidemic outbreaks and for use in endemic countries, and the new FDA approval should facilitate drug licensing and import to these countries. Novartis has been donating triclabendazole to the WHO since 2005.

Source: Novartis, February 14, 2019

Cablivi for Rare Blood-Clotting Disorder

The FDA has approved caplacizumab-yhdp injection (Cablivi, Ablynx) for the treatment of adults with acquired thrombotic thrombocytopenic purpura (aTTP), a rare, life-threatening disorder that causes extensive blood clots throughout the body.

Clots can cut off oxygen and blood supply to major organs and cause stroke and heart attacks. Patients can develop aTTP through cancer, human immunodeficiency virus, pregnancy, lupus, or infections, or after having surgery, bone-marrow transplantation, or chemotherapy.

The new drug is the first therapy specifically indicated for the disorder, in combination with plasma exchange and immunosuppressive therapy. Patients with aTTP undergo hours of treatment with daily plasma exchange, and many have a recurrence of aTTP even after weeks of treatment. Caplacizumab-yhdp may reduce those recurrences.

In a randomized, placebo-controlled trial of 145 patients, platelet counts improved faster in the caplacizumab-yhdp group compared with the placebo group. After treatment with caplacizumab-yhdp, fewer patients had an aTTP-related death, an aTTP recurrence during the treatment period, or at least one treatment-emergent major thrombotic event.

Common side effects with caplacizumab-yhdp were bleeding of the nose or gums and headache. The drug’s prescribing information carries a warning about the risk of severe bleeding.

The FDA granted caplacizumab-yhdp priority review and orphan drug designations.

Source: FDA, February 6, 2019

Jeuveau for Aesthetic Procedures

The FDA has approved prabotulinumtoxinA-xvfs (Jeuveau, Evolus, Inc.) for temporary improvement in the appearance of moderate-to-severe glabellar lines associated with corrugator and/or procerus muscle activity in adults.

In two phase 3, randomized, multicenter, double-blind, placebo-controlled trials, prabotulinumtoxinA-xvfs met the primary endpoint of reducing the severity of glabellar lines, defined as a 2-point composite improvement agreed upon by physician and patient at day 30. PrabotulinumtoxinA-xvfs, compared with placebo, reached this goal in 67.5% versus 1.2% of subjects in study one (EV-001) and in 70.4% versus 1.3% of subjects in study two (EV-002). No serious drug-related adverse events were reported.

Jeuveau, a proprietary 900 kDa purified botulinum toxin type A formulation, carries a boxed warning about the distant spread of toxin effect. The effects of all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life-threatening, and deaths have been reported with other products.

Jeuveau is not approved for the treatment of spasticity or any conditions other than glabellar lines.

Sources: Evolus, Inc., February 1, 2019; Jeuveau prescribing information, February 2019

Generic Approvals

Fluticasone Propionate and Salmeterol Inhalation Powder

Mylan Pharmaceuticals has received FDA approval to market fluticasone propionate and salmeterol inhalation powder as Wixela Inhub in three strengths: 100 mcg/50 mcg, 250 mcg/50 mcg, and 500 mcg/50 mcg. This is the first generic form of Advair Diskus (GlaxoSmithKline), one of the most commonly prescribed inhalers for asthma and chronic obstructive pulmonary disease (COPD).

Advair Diskus had U.S. sales of $4.2 billion for the 12 months ending November 30, 2018, according to IQVIA.

All three strengths of the drug are used for the twice-daily treatment of asthma in patients 4 years of age and older, and the 250 mcg/50 mcg formulation is used for maintenance treatment of airflow obstruction and exacerbation reduction in COPD patients.

Sources: FDA, January 30, 2019; Mylan, January 31, 2019

Lurasidone Hydrochloride Tablets

The FDA has approved the first generic versions of lurasidone hydrochloride (Latuda, Sunovion Pharmaceuticals), which has annual sales of more than $3 billion. However, patent litigation and negotiated settlements between Sunovion and generics manufacturers may delay their marketing.

Accord Healthcare Inc., Lupin Ltd., InvaGen Pharmaceuticals, Inc., Amneal Pharmaceuticals Company GmbH, and Torrent Pharmaceuticals Ltd. have received FDA permission to market lurasidone hydrochloride. Tablets will be available in 20-mg, 40-mg, 60-mg, 80-mg, and 120-mg strengths from every company except Torrent, which will not make 60-mg tablets.

According to Sunovion’s parent company, Sumitomo Dainippon Pharma Co., Ltd., several unnamed generics companies that have settled patent litigation will be permitted to distribute generic lurasidone starting on February 21, 2023, but other patent infringement lawsuits are still pending.

Lurasidone is indicated for the treatment of schizophrenia and depressive episodes associated with bipolar I disorder (bipolar depression) in adults.

Sources: FDA, January 3, 2019; Lupin Ltd., January 7, 2019; Sumitomo Dainippon Pharma Co., Ltd., November 27, 2018

Sirolimus Oral Solution

Novitium Pharma LLC has secured FDA approval to market sirolimus oral solution, 1 mg/mL, for prophylaxis of organ rejection in patients 13 years of age or older who are receiving renal transplants. The drug is the first generic formulation of Rapamune (PF Prism CV).

Source: FDA, January 28, 2019

Ingenol Mebutate Gel

Perrigo UK has received permission to market Ingenol Mebutate Gel, 0.05% and 0.015%, the first generic versions of Leo Laboratories’ Picato Gel in these strengths. The gel is a topical treatment for actinic keratosis.

Source: FDA, January 7 and 9, 2019

NEW INDICATIONS

Lonsurf for Gastric Cancer

The FDA has approved trifluridine/tipiracil (Lonsurf, Taiho Oncology, Inc.) to treat adults with metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma who previously received at least two prior lines of chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan, and, if appropriate, HER2/neu-targeted therapy.

The approval after an FDA priority review is based on data from the global, randomized, phase 3 TAGS trial evaluating trifluridine/tipiracil plus best supportive care (BSC) versus placebo plus BSC in 507 patients with previously treated advanced gastric cancer or GEJ adenocarcinoma following progression or intolerance to previous standard therapy. Median overall survival was 5.7 months in the trifluridine/tipiracil group and 3.6 months in the placebo group.

In the trifluridine/tipiracil group, grade 3 or worse adverse events of any cause occurred in 267 patients (80%); the most frequent were neutropenia and anemia. One treatment-related death was attributed to cardiopulmonary arrest.

Trifluridine is a thymidine-based nucleoside analog, and tipiracil increases trifluridine exposure by inhibiting trifluridine’s metabolism by thymidine phosphorylase. The FDA previously approved trifluridine/tipiracil for the treatment of patients with metastatic colorectal cancer who have been previously treated with standard chemotherapy.

Sources: Taiho Oncology, Inc., February 25, 2019; The Lancet Oncology, October 21, 2018

Alimtra Plus Keytruda For Metastatic NSCLC

Pemetrexed for injection (Alimtra, Eli Lilly and Company) has received FDA approval in combination with pembrolizumab (Keytruda, Merck) and platinum based chemotherapy for the first-line treatment of patients with metastatic nonsquamous non–small-cell lung cancer (NSCLC) with no EGFR or ALK genomic tumor aberrations.

The approval was based on data from the phase 3 KEYNOTE-189 trial, which enrolled patients regardless of programmed death ligand-1 expression. The trial demonstrated that pemetrexed, in combination with pembrolizumab plus platinum-based chemotherapy, significantly lengthened overall survival and progression-free survival compared with pemetrexed plus platinum chemotherapy with placebo.

Severe adverse reactions occurring in at least 20% of patients included fatigue, diarrhea, dyspnea, vomiting, nausea, rash, decreased appetite, constipation, and pyrexia.

Source: Eli Lilly and Company., January 31, 2019

Imbruvica and Gazyva For Untreated CLL/SLL

Ibrutinib (Imbruvica, AbbVie/Janssen) plus obinutuzumab (Gazyva, Roche) has received FDA approval for use in adults with previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

The combination comprises the first chemotherapy-free, anti-CD20 treatment for CLL and SLL in the U.S. Ibrutinib is a first-in-class, oral, once-daily therapy that works primarily by inhibiting the Bruton’s tyrosine kinase enzyme.

In the phase 3 iLLUMINATE study, patients treated with ibrutinib and obinutuzumab had a 77% reduction in the risk of disease progression or death compared with patients who received chlorambucil plus obinutuzumab. The combination regimen also showed an 85% reduction in risk of progression or death compared with chlorambucil plus obinutuzumab in patients with high-risk disease.

The most common adverse reactions in iLLUMINATE participants treated with ibrutinib plus obinutuzumab were neutropenia, thrombocytopenia, rash, diarrhea, musculoskeletal pain, bruising, cough, infusion-related reaction, hemorrhage, and arthralgia.

This approval was the 10th for ibrutinib in six different disease areas since 2013.

Sources: AbbVie and BioSpace, January 28, 2019

Osphena for Vaginal Dryness

The FDA has added moderate-to-severe vaginal dryness—a symptom of vulvar and vaginal atrophy (VVA) caused by menopause—to the indication of ospemifene (Osphena, Duchesnay Inc.).

The approval was based on new safety and efficacy data acquired through a confirmatory, phase 3, randomized, double-blind, placebo-controlled, multicenter study evaluating the efficacy and safety of ospemifene in patients with moderate-to-severe vaginal dryness. Ospemifene is nonhormonal and helps improve specific vaginal tissues by increasing superficial cells, decreasing parabasal cells, and reducing vaginal pH.

Prior to this approval, ospemifene was indicated only for the treatment of moderate-to-severe dyspareunia (painful intercourse), also a symptom of VVA, due to menopause.

Before menopause, estrogen helps maintain the thickness, elasticity, and lubrication of vaginal tissues. However, as women age, estrogen levels drop, causing changes in these tissues, which can lead to dryness, itching, burning, and painful intercourse. Ospemifene provides an oral option for women who prefer a nonhormonal treatment alternative.

Osphena carries a boxed warning about the risks of endometrial cancer and cardiovascular disorders.

Source: Duchesnay Inc., January 29, 2019

NEW FORMULATIONS

Lotemax SM for Eye Surgery

The FDA has approved loteprednol etabonate ophthalmic gel, 0.38% (Lotemax SM, Bausch + Lomb), a new gel formulation for the treatment of postoperative inflammation and pain following ocular surgery. Compared to loteprednol etabonate ophthalmic gel, 0.5% (Lotemax Gel), the new formulation delivers a submicron particle size for faster drug dissolution in tears and provides a two-fold greater penetration to the aqueous humor.

The FDA approval was based on data from two randomized, multicenter, double-masked, parallel-group, vehicle-controlled studies in 742 patients with postoperative inflammation following cataract surgery. At day 8, for Lotemax SM versus vehicle, 30% versus 15% of patients achieved complete inflammation resolution and 74% versus 49% were pain-free.

Source: Bausch Health Companies Inc., February 25, 2019

Premixed Vancomycin Injection

The FDA has approved Xellia Pharmaceuticals’ premixed vancomycin injection in a ready-to-use bag. Overcoming a long-standing industry challenge, it is the first vancomycin product that is stable in solution at room temperature for 16 months.

The premixed solution will be available in single-dose, flexible bags of 500 mg/100 mL, 1 g/200 mL, 1.5 g/300 mL, and 2 g/400 mL.

FDA approval was obtained on the basis of more than 60 nonclinical experiments, including studies to confirm that the new formulation does not adversely impact the efficacy profile of the active ingredient, vancomycin. Vancomycin injection is a glycopeptide antibacterial agent indicated for the treatment of septicemia, infective endocarditis, skin and skin structure infections, bone infections, and lower respiratory tract infections.

The FDA designated this application as a qualified infectious disease product in February 2018.

Source: Xellia Pharmaceuticals, February 19, 2019

Tosymra, a Sumatriptan Nasal Spray for Migraine

The FDA has approved a new sumatriptan nasal spray (Tosymra, Dr. Reddy’s Laboratories Ltd.) for the acute treatment of migraine with or without aura in adults.

Tosymra, a mist-like nasal spray, is formulated using a proprietary novel excipient known as Intravail to achieve blood levels similar to a 4-mg sumatriptan subcutaneous injection, resulting in rapid onset of action. Independent research shows that 26% to 40% of migraine patients are not optimally controlled with their current treatment.

Source: Dr. Reddy’s Laboratories Ltd., January 28, 2019

FDA REVIEW ACTIVITIES

Breakthrough Therapy Status

CP101 for Recurrent C. Difficile Infection

Finch Therapeutics Group, Inc., has received a breakthrough therapy designation for CP101, a drug to prevent recurrent Clostridium difficile.

C. difficile is a bacterial infection that annually affects more than 500,000 patients and leads to an estimated 29,000 deaths. CP101, administered orally in a single dose, is designed to break the cycles of infection by restoring the balance of the gut microbiome.

Finch is enrolling patients with recurrent C. difficile in PRISM3, a randomized, placebo-controlled phase 2 study to assess the safety and efficacy of CP101.

Source: Finch Therapeutics Group, Inc., February 8, 2019

V114 for Invasive Pneumococcal Disease

Merck has received a breakthrough therapy designation for V114, a preventive treatment against invasive pneumococcal disease (IPD) caused by the vaccine serotypes in children 6 weeks to 18 years of age. V114 is also under development for the prevention of IPD in adults. Both indications are being studied in phase 3 clinical trials.

The designation is based in part on immunogenicity data from two studies: a phase 1/2 study of four different lots of a new formulation of V114 in healthy adults and infants, and a phase 2 pediatric trial. In both studies, V114 induced an immune response in infants for two disease-causing serotypes (22F and 33F) not contained in the currently available 13-valent pneumococcal conjugate vaccine while demonstrating noninferiority for the serotypes contained in both vaccines.

Source: Merck, January 30, 2019

Fast-Track Designations

Renexus for Macular Telangiectasia Type 2

The FDA has granted a fast-track designation for Neurotech Pharmaceuticals’ NT-501 (Renexus) for the treatment of macular telangiectasia (MacTel).

MacTel is a rare neurodegenerative disease that alters the retinal vasculature and causes localized retinal degeneration. Type 2, the most common classification, typically affects both eyes, and results in the deterioration of central vision over 10 to 20 years.

Renexus is a drug-delivery system that uses human-derived cells encapsulated in a semipermeable hollow-fiber membrane that allows for the selective passage of therapeutic proteins. The device is inserted during a single outpatient procedure through a small scleral incision and can be removed through the same incision. The implanted device can deliver medication for at least two years.

In a phase 2 study, Renexus slowed the progression of retinal degeneration compared with a sham treatment.

Source: Neurotech Pharmaceuticals, Inc., February 12, 2019

ONM-100 for Tumors and Metastatic Lymph Nodes

The FDA has accepted the investigational new drug application and granted a fast-track designation for ONM-100 (OncoNano), an intravenously administered imaging agent to detect tumors and metastatic lymph nodes in solid cancers during surgery.

ONM-100 is delivered to the tumor and subsequently fluoresces in the acidic tumor microenvironment, which allows surgeons to visualize the tumor during surgery using existing infrared-based surgical cameras.

OncoNano is concluding the phase 1 clinical trial for ONM-100.

Source: OncoNano Medicine, Inc., January 4, 2019

Priority Review Status

Bavencio Plus Inlyta for Kidney Cancer

The FDA has accepted for priority review the supplemental biologics license application for avelumab (Bavencio, EMD Serono) in combination with axitinib (Inlyta, Pfizer) for patients with advanced renal cell carcinoma (RCC). The application has been given a target action date of June 2019.

RCC is the most common form of kidney cancer. Approximately 20% to 30% of patients are first diagnosed at the metastatic stage, when the five-year survival rate is approximately 12%.

Avelumab, a human anti-programmed death ligand-1 antibody, has been shown in preclinical models to engage both the adaptive and innate immune functions and release the suppression of the T cell-mediated antitumor immune response. Axitinib is designed to inhibit tyrosine kinases, including vascular endothelial growth factor receptors 1, 2, and 3; these receptors can influence tumor growth, vascular angiogenesis, and progression of cancer.

Source: EMD Serono, February 11, 2019

Keytruda for Head and Neck Squamous Cell Carcinoma

The FDA has awarded priority review to the newly accepted supplemental biologics license application for pembrolizumab (Keytruda, Merck) as monotherapy or in combination with platinum and 5-fluorouracil chemotherapy for the firstline treatment of patients with recurrent or metastatic head and neck squamouscell carcinoma.

Head and neck cancer includes tumors that develop in or around the throat, larynx, nose, sinuses, and mouth; most are squamous-cell carcinomas. U.S. researchers estimate that more than 65,000 new cases of head and neck cancer will be diagnosed in 2019.

Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between programmed death (PD)-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes that may affect both tumor cells and healthy cells.

This application is based in part on data from a phase 3 trial in which pembrolizumab significantly improved overall survival compared with the standard of care as monotherapy in patients whose tumors expressed PD-L1 with a combined positive score (CPS) of at least 20 and a CPS of at least 1, and in combination with chemotherapy in the total patient population.

The FDA has granted priority review to this application and set a target action date of June 10, 2019.

Source: Merck, February 11, 2019

Imipenem/Cilastatin With Relebactam And Zerbaxa for Bacterial Infections

The FDA has granted priority review to the newly accepted regulatory filings for two antibacterial agents from Merck.

The first is a new drug application for the combination of relebactam with imipenem/cilastatin (MK-7655A) for the treatment of complicated urinary tract infections and complicated intra-abdominal infections caused by certain susceptible gram-negative bacteria in adults with limited or no available alternative therapies. Relebactam is an investigational, intravenous, class A and C beta-lactamase inhibitor. The target action date for this application is July 16, 2019.

The second is a supplementary new drug application for intravenous ceftolozane/tazobactam (Zerbaxa) to treat adults with nosocomial pneumonia, including ventilator-associated pneumonia caused by certain susceptible gram-negative microorganisms. Ceftolozane is a cephalosporin antibacterial and tazobactam is a beta-lactamase inhibitor. The target action date for this application is June 3, 2019.

Source: Merck, February 5, 2019

Pexidartinib for Tenosynovial Giant Cell Tumor

The FDA has accepted a new drug application and granted priority review for pexidartinib (Daiichi Sankyo) for the treatment of adults with symptomatic tenosynovial giant cell tumor (TGCT).

TGCT, also called pigmented villonodular synovitis or giant-cell tumor of the tendon sheath, is a nonmalignant tumor that can be locally aggressive and debilitating. It affects the synoviumlined joints, bursae, and tendon sheaths, resulting in swelling, pain, stiffness, and reduced mobility in the affected joint or limb. TGCT can be localized or diffuse; some cases are not amenable to the primary treatment, surgery. There are no approved systemic therapies.

Pexidartinib is an investigational, novel, oral small molecule that potently inhibits colony stimulating factor-1 receptor, a primary growth driver of abnormal cells in the synovium that cause TGCT. Pexidartinib also inhibits c-kit and FLT3-ITD.

The application is based on results from the ENLIVEN study, which evaluated pexidartinib in patients with symptomatic advanced TGCT for whom surgical removal of the tumor would be associated with potentially worsening functional limitation or severe morbidity. Hepatic toxicities (some serious) were more frequent with pexidartinib than placebo.

The FDA target action date for this application is August 3, 2019.

Source: Daiichi Sankyo, February 5, 2019

Orphan Drug Designations

MP101 for Huntington’s Disease

Mitochon Pharmaceuticals’ MP101 has received an orphan drug designation from the FDA for the treatment of Huntington’s disease. The company said that MP101–a mitochondrial targeted compound–has been shown to protect both spiny neurons and general neurons and minimize brain-volume loss in patients with Huntington’s disease. Combined, these effects could significantly alter the disease’s progression in patients.

MP101 and MP201 are mitochondrial targeted, once-a-day, oral therapies that safeguard cells from the damage caused by numerous degenerative processes. In preclinical studies, both compounds showed significant protective and functional benefits in disease models. These include brain-volume sparing in Huntington’s disease; protection from demyelination in multiple sclerosis; and preserving dopamine neurons in Parkinson’s disease.

Mitochon will be initiating phase 1 studies in normal healthy volunteers this year and phase 2 studies are expected to take place in 2020.

Source: Biospace, March 5, 2019

ACE-083 for Charcot-Marie-Tooth Disease

The FDA has granted an orphan drug designation to Acceleron Pharma Inc.’s ACE-083, a locally acting “Myostatin+” muscle agent, for the treatment of Charcot-Marie-Tooth (CMT) disease.

Clinical trials to date have demonstrated that treatment with ACE-083 results in substantial increases in muscle volume in target muscles. If ongoing studies show that such increases lead to improved functional outcomes, ACE-083 could become an important new therapy for patients with CMT.

ACE-083 is being evaluated in two phase 2 trials: one in CMT and one in facioscapulohumeral muscular dystrophy (FSHD). Preliminary results from part 2 of the trials are expected by the end of 2019 for CMT and during the second half of 2019 for FSHD.

In 2018, the FDA granted fast-track designation for ACE-083 in CMT and fast-track and orphan drug designations for the treatment of patients with FSHD.

ACE-083 is a therapeutic candidate based on follistatin, which occurs naturally. The drug uses the Myostatin+ approach to obstruct multiple TGF-beta superfamily ligands, and is designed to have a concentrated effect to specifically maximize growth and strength in the muscles into which ACE-083 is administered.

CMT is one of the most common inherited neurologic diseases, estimated to affect more than 125,000 people in the United States. Symptoms include muscle weakness in the hands and lower legs, which can result in foot drop leading to frequent trips and falls. There are currently no approved therapies for CMT.

Source: Acceleron, March 5, 2019

APX001 for Cryptococcosis

Amplyx Pharmaceuticals has received an orphan drug designation for APX001, a first-in-class antifungal agent for the treatment of cryptococcosis, an infection of the lungs or central nervous system caused by the fungus Cryptococcus. People with a weakened immune system are at risk for cryptococcosis.

The standard therapy of intravenous amphotericin B plus flucytosine requires inpatient hospitalization and has been known to cause significant side effects, including anemia and kidney toxicity. APX001, in combination with fluconazole, is a once-daily, all-oral treatment for cryptococcal meningitis. APX001A, the active moiety of APX001, inhibits the highly conserved fungal enzyme Gwt1, compromising growth of major fungal pathogens. In nonclinical studies, APX001 has shown broad-spectrum activity against common species of Candida and Aspergillus, including multidrug-resistant strains such as Candida auris and rare, hard-to-treat molds including several species of Fusarium, Scedosporium, and fungi from the Mucorales order.

A phase 2 clinical trial is evaluating the efficacy and safety of both intravenous and oral APX001 for the first-line treatment of patients with fungal infections.

Source: Amplyx Pharmaceuticals, February 11, 2019

BL-8040 for Pancreatic Cancer

The FDA has granted an orphan drug designation to BioLineRx Ltd. for BL-8040, a treatment for pancreatic cancer.

Pancreatic cancer has a low rate of early diagnosis as a result of often nonspecific symptoms. The five-year survival rate is 7 to 8%.

BL-8040 is a short synthetic peptide used to treat hematologic malignancies, solid tumors, and stem-cell mobilization. It functions as a high-affinity, best-in-class antagonist for CXCR4, a chemokine receptor directly involved in tumor progression, angiogenesis, metastasis, and cell survival. CXCR4 is overexpressed in many human cancers; its expression often correlates with disease severity. In clinical and preclinical studies, BL-8040 has shown robust mobilization of cancer cells and immune cells, sensitization of cancer cells to anticancer therapies, and direct anticancer effect by inducing apoptosis.

Source: BioLineRx Ltd., February 4, 2019

PBT434 for Multiple System Atrophy

Prana Biotechnology Ltd. has received an orphan drug designation for PBT434, the first such designation for a drug to treat multiple system atrophy (MSA).

PBT434 prevented alpha-synuclein accumulation, preserved neurons, and improved motor function in a widely accepted animal model of MSA. Alpha-synuclein is of great interest because aggregated forms of the protein are a pathological hallmark of Parkinsonian conditions.

Prana expects to complete a phase 1 clinical trial of PBT434 this year.

Source: Prana Biotechnology Ltd., January 31, 2019

BI-1206 for Mantle Cell Lymphoma

BioInvent International AB has received an orphan drug designation for the antibody BI-1206 for the treatment of mantle cell lymphoma (MCL).

A phase 1/2a study of BI-1206 with approximately 30 patients is ongoing in the U.S. and Europe. The trial is evaluating BI-1206 in combination with rituximab in patients with indolent relapsed or refractory B-cell non-Hodgkin’s lymphoma. MCL is one of the targeted sub-indications, along with follicular lymphoma and marginal zone lymphoma.

Source: BioInvent International AB, January 30, 2019

BBT-877 for Idiopathic Pulmonary Fibrosis

Bridge Biotherapeutics Inc. has received an orphan drug designation for BBT-877, an autotaxin inhibitor under development for idiopathic pulmonary fibrosis treatment. Autotaxin is an enzyme engaged in inflammation and fibrosis.

A phase 1 study will assess the drug in two phases: a single-ascending dose phase with five cohorts and a multiple-ascending dose phase with three cohorts.

Source: Bridge Biotherapeutics, January 16, 2019

Label Update

New Darzalex Dosing Option

The FDA has approved a dosing regimen for daratumumab (Darzalex, Janssen) that gives patients with multiple myeloma the option of splitting the first infusion over two consecutive days. The approval is based on data from the global, multi-arm phase 1b EQUULEUS clinical study. The drug’s safety profile was comparable when administered initially as a split or single dose.

Daratumumab, a CD38-directed antibody, received its first FDA approval for multiple myeloma in 2015.

Source: Janssen, February 12, 2019

Complete Response Letters

Iclaprim for Skin Infections

The FDA has sent a complete response letter to Motif Bio PLC about its application for iclaprim for the treatment of acute bacterial skin and skin-structure infections. The letter indicates that additional data are needed to evaluate the risk for liver toxicity before the application may be approved.

Motif Bio plans to request a meeting with the FDA as soon as possible to discuss options to address the deficiencies.

Source: Motif Bio PLC, February 14, 2019

ALKS 5461 for Depression

Alkermes PLC has received a complete response letter from the FDA regarding its application for ALKS 5461 for the adjunctive treatment of major depressive disorder. The FDA is requesting additional clinical data to provide substantial evidence of the effectiveness of ALKS 5461. Alkermes plans to meet with the FDA in the near future to discuss the letter and potential next steps.

The application was based on data from more than 30 clinical trials and more than 1,500 patients in which ALKS 5461 demonstrated a consistent profile of antidepressant activity, safety, and tolerability in the adjunctive treatment of depression, Alkermes says.

Source: Alkermes PLC, February 1, 2019

Apomorphine Sublingual Film

The FDA has issued a complete response letter to Sunovion Pharmaceuticals Inc. regarding its application for apomorphine sublingual film (APL-130277) to treat Parkinson’s disease patients’ “off” episodes (the re-emergence or worsening of symptoms otherwise controlled by medications). The agency requested additional information and analyses, but no new clinical studies.

APL-130277, a novel formulation of apomorphine and a dopamine agonist, is being developed for on-demand management of off episodes.

Source: Sunovion Pharmaceuticals Inc., January 30, 2019

DEVICE APPROVALS

Orsiro Stent for CAD

The FDA has approved the Orsiro drug-eluting stent (DES) system (Biotronik), the first ultrathin DES to outperform the clinical standard, Xience (Abbott).

In the BIOFLOW-V pivotal trial at two years, Orsiro demonstrated a target lesion failure rate of 7.5% versus 11.9% for Xience, as well as a 47% lower ischemia-driven target lesion revascularization rate and a 70% lower rate of spontaneous target-vessel myocardial infarction.

For use in percutaneous coronary intervention procedures, the cobalt chromium metal stent elutes sirolimus via BIOlute, a bioabsorbable polymer coating. Beneath the bioabsorbable layer is proBIO, a passive coating on the bare metal surface, designed to reduce nickel ion release.

Orsiro is indicated for improving coronary luminal diameter in patients, including those with diabetes mellitus with symptomatic heart disease, stable angina, unstable angina, non–ST-elevation myocardial infarction, or documented silent ischemia due to atherosclerotic lesions in the native coronary arteries with a reference vessel diameter of 2.25 to 4.0 mm and lesion length of 36 mm or less.

Source: Biotronik, February 22, 2019

Robotic Aid for TMS

The FDA has cleared the TMS-Cobot (Axilum Robotics/MagVenture), a robotic platform for transcranial magnetic stimulation (TMS) that will facilitate treatment for depression.

TMS therapy is an effective, non-invasive option for patients who do not respond to antidepressants. During treatment, a magnetic coil applies magnetic pulses to a particular part of the patient’s brain to reach the neural network controlling mood and emotion. The patient is fully awake and may resume normal activities right after treatment. Patients typically receive 20 to 30 treatment sessions, one per weekday.

The robotic system provides continuous motion tracking that follows patients’ head movements during treatment. It also reduces manual coil-handling time for the TMS operator, an aid to high-volume TMS providers.

The TMS-Cobot, developed by Axilum Robotics, is indicated for the spatial positioning and orientation of the treatment coil of the MagVenture TMS Therapy system. MagVenture TMS Therapy is indicated for the treatment of major depressive disorder in adults who have failed to receive satisfactory improvement from prior antidepressant medication in the current episode.

Source: MagVenture, February 20, 2019

Interoperable t:Slim X2 Insulin Pump for Diabetes

The FDA has permitted marketing of the t:Slim X2 insulin pump with interoperable technology (Tandem Diabetes Care Inc.) to deliver insulin under the skin for children and adults with diabetes. This new type of insulin pump, called an alternate controller enabled (ACE) infusion pump, is the first interoperable pump, meaning it can be used with different components that make up diabetes therapy systems. This will allow patients to tailor their diabetes management to individual device preferences.

Diabetes therapy systems may comprise an ACE insulin pump and other compatible medical devices, including automated insulin dosing systems, continuous glucose monitors, blood glucose meters, or other electronic devices.

The interoperable t:Slim X2 pump delivers insulin at set or variable rates. It can be digitally connected to automatically communicate with and receive drug dosing commands from other diabetes management devices; when not connected to other devices, it can be used to infuse insulin on its own.

The FDA reviewed interoperable t:Slim X2 pump-performance data demonstrating that the device can dose insulin accurately and reliably and at the user-programmed rates and volumes. The agency also assessed the ability of the pump to communicate with external devices with appropriate reliability, cybersecurity, and fail-safe modes.

Risks associated with use of the interoperable t:Slim X2 pump are similar to other infusion pumps and may include infection, bleeding, pain, skin irritations, and tube blockages that can affect drug delivery.

Source: FDA, February 14, 2019

M6-C Artificial Cervical Disc

The FDA has approved the M6-C artificial cervical disc (Orthofix Medical Inc.) for patients suffering from cervical disc degeneration.

The M6-C artificial cervical disc was developed to replace an intervertebral disc damaged by cervical disc degeneration. Designed to restore physiological motion to the spine, the M6-C disc is indicated as an alternative to cervical fusion. The M6-C artificial cervical disc preserves motion by restoring biomechanical function at the treated level after native disc removal and may reduce subsequent degeneration of adjacent vertebral segments. The M6-C device mimics the anatomic structure of a natural disc by incorporating an artificial visco-elastic nucleus and fiber annulus.

Pre-market approval was based on clinical data that evaluated the safety and effectiveness of the M6-C artificial cervical disc compared to anterior cervical discectomy and fusion (ACDF) for the treatment of symptomatic cervical radiculopathy with or without cord compression. Patients presented with degenerative cervical radiculopathy requiring surgical intervention.

At 24 months, 90.5% of patients who received the M6-C disc demonstrated a meaningful clinical improvement in the Neck Disability Index, and 91.2% saw a meaningful clinical improvement in arm-pain score compared with 77.9% in ACDF patients. Prior to surgery, 80.6% of M6-C disc patients and 85.7% of ACDF patients were taking pain medication for their cervical spine condition; the use of pain medication at 24 months fell to 14.0% of M6-C disc patients and 38.2% of ACDF patients.

The M6-C artificial cervical disc was developed by Spinal Kinetics, which Orthofix acquired in April 2018.

Source: Orthofix Medical Inc., February 7, 2019

MANTA for Closure of Femoral Arterial Access

Teleflex Inc. has received premarket approval from the FDA for the MANTA Vascular Closure Device. The device is indicated for closure of femoral arterial access sites while reducing time to hemostasis, after the use of 10–20F devices or sheaths (12–25F outer diameter) in endovascular catheterization procedures.

The prospective, multicenter, single-arm SAFE MANTA IDE clinical trial demonstrated that the MANTA device achieves fast and reliable biomechanical closure with rapid hemostasis. The major complication rate of 5.3% and VARC-2 Major Vascular Complications rate of 4.2% compare favorably to suture-mediated devices.

Source: Teleflex, February 4, 2019

Aortic Dissection Device

The FDA has approved the Zenith Dissection Endovascular System (Cook Medical), which provides physicians with a less invasive alternative to open surgery for repair of type B dissections of the descending thoracic aorta. The system consists of a proximal stent-graft component and a distal bare-stent component.

Thoracic endovascular aortic repair is acknowledged as the treatment of choice for complicated type B aortic dissection. These procedures are meant to prevent malperfusion of aortic branches and aortic rupture.

Source: Cook Medical, February 4, 2019

DEVICE SAFETY ISSUES

Medtronic Dual Chamber Implantable Pulse Generators

Medtronic, Inc., has recalled 13,440 dual chamber implantable pulse generators (IPGs) due to the possibility of a software error that can result in a lack of pacing. The class I recall applies to Adapta, Versa, Sensia, Relia, Attesta, Sphera, and Vitatron A, E, G, and Q series models distributed between March 6, 2017 and January 7, 2019. IPGs are implanted cardiac pacemakers used to provide stimulation to increase heart rate in patients with bradycardia or no heart rhythm.

Patients and physicians cannot predict whether and when the software error might occur. A lack of pacing could result in patients experiencing slow heartbeat or low blood pressure, and symptoms such as light-headedness or fainting, and death. Medtronic said it knows of four reported occurrences in two patients where a pause in pacing therapy was clinically apparent due to this circuit error. In letters to physicians, Medtronic recommends programming to a nonsusceptible pacing mode as the primary mitigation for patients implanted with an affected device until the software update has been installed.

Customers who have questions or need information regarding this recall may contact Medtronic’s Technical Services at 1-800-505-4636.

Sources: FDA, February 15, 2019; Medtronic, January 7, 2019

FDA Urges Caution With Robotically Assisted Surgical Devices

The FDA has warned against the use of robotically assisted devices for mastectomies and other cancer surgeries, and says the products may pose safety risks and poor outcomes for patients.

The agency said it decided to issue its warning after reviewing studies suggesting that robotically assisted devices were being used to perform cancer procedures for which there is limited data on their safety and effectiveness.

One recent study in the New England Journal of Medicine reported that use of the devices in radical hysterectomies in women with cervical cancer was associated with lower rates of disease-free survival and overall survival than traditional surgery.

Source: FDA, February 28, 2019

Breast Implants Add Risk For Lymphoma, FDA Says

Patients with breast implants, regardless of filling or texture, have an increased risk of developing breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) within the scar capsule adjacent to the implant, the FDA says. Providers should be aware of BIA-ALCL—particularly in patients with new swelling, lumps, or pain around breast implants—to expedite diagnosis.

Estimated incidence rates of BIA-ALCL range from a high of one per 3,817 patients to a low of one in 30,000. While most patients who develop BIA-ALCL have had textured implants, there have been reports of BIA-ALCL in patients with smooth-surface implants, and many reports do not include the surface texture of the implant at the time of diagnosis.

An estimated 1.5 million patients receive breast implants worldwide every year. A new FDA analysis identified 457 unique medical-device reports to the agency for BIA-ALCL, including the death of nine patients that may be attributable to BIA-ALCL.

Providers should consider the possibility of BIA-ALCL when treating a patient with late-onset, peri-implant seroma. They should collect fresh seroma fluid and representative portions of the capsule and send for pathology tests to rule out BIA-ALCL. They should develop an individualized treatment plan with the patient’s multidisciplinary care team. And they should report all confirmed cases of BIA-ALCL in individuals with breast implants to MedWatch, the FDA Safety Information and Adverse Event Reporting program.

Source: FDA, February 6, 2019

Lifepak 15 Defibrillator May “Lock Up” After Giving Shock

Stryker is notifying 13,003 users of its Lifepak 15 monitor/defibrillators that the devices may “lock up” after delivering a shock. The monitor display will be blank, with LED lights indicating the power is on, but the keypad and device functions will not respond. A device in this state has the potential to delay delivery of therapy, resulting in serious injury or death.

Since commercialization of the Lifepak 15 in 2009, Stryker has learned of 58 complaints reported globally for this issue, including six in which the patient died following a delay in therapy. In these six cases, at least one shock was delivered prior to the device locking up.

The company is contacting customers to schedule service on devices, which will include an update to the firmware for a component on the System Printed Circuit Board Assembly. Stryker anticipates that all devices subject to this field action will be serviced by December 31, 2019. Customers who experience this issue should contact Stryker as soon as possible at 1-800-442-1142, option 7.

The company is advising customers to continue to use the Lifepak 15 according to the operating instructions until the correction can be completed. If a device locks up during patient use, the steps from the General Troubleshooting Section (pages 10–18) of the LIFEPAK 15 Monitor/Defibrillator Operating Instructions should be followed immediately.

Source: Stryker, February 1, 2019