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Drug and Device News July/August 2019

NEW DRUG APPROVALS

Piqray for Breast Cancer

The FDA has approved alpelisib tablets (Piqray, Novartis) in combination with fulvestrant to treat postmenopausal women, and men with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced, or metastatic breast cancer, following progression on or after an endocrine-based regimen.

The agency also approved the thera-screen PIK3CA RGQ PCR Kit (QIAGEN Manchester, Ltd.), a companion test for detecting PIK3CA mutation in a tissue and/or liquid biopsy.

Alpelisib is the first PI3K inhibitor to demonstrate a clinically meaningful benefit in treating this type of breast cancer. The drug’s efficacy was studied in the randomized SOLAR-1 trial involving 572 postmenopausal women and men with HR-positive, HER2-negative, advanced, or metastatic breast cancer that had progressed during or after use of an aromatase inhibitor. Adding alpelisib to fulvestrant significantly prolonged median progression-free survival (11 months vs. 5.7 months) in patients whose tumors had a PIK3CA mutation.

Common side effects of alpelisib include high blood-sugar levels, creatinine increase, diarrhea, rash, decreased lymphocyte count, elevated liver enzymes, nausea, fatigue, low red blood-cell count, increased lipase, decreased appetite, stomatitis, and vomiting.

Under two FDA pilot programs intended to accelerate and improve the review process—the Real-Time Oncology Review program and the updated Assessment Aid review template—alpelisib’s approval came about three months ahead of its Prescription Drug User Fee Act deadline. The FDA also granted alpelisib a priority review designation.

Source: FDA, May 24, 2019

Zolgensma for Spinal Muscular Atrophy

Onasemnogene abeparvovec-xioi (Zolgensma, AveXis Inc.), the first gene therapy for children below age 2 with spinal muscular atrophy (SMA), has been approved by the FDA.

A mutation in the survival motor neuron 1 (SMN1) gene causes this rare disease, which is classified into several subtypes based on age of onset and severity. Infantile-onset SMA is the most severe and most common form. Children with SMA have difficulty holding their heads up, swallowing, and breathing. Most do not survive past early childhood.

Onasemnogene abeparvovec-xioi is an adeno-associated virus vector-based gene therapy that targets the cause of SMA. A single intravenous administration causes the expression of the SMN protein in motor neurons, improving muscle movement and function and survival.

The safety and efficacy of onasemnogene abeparvovec-xioi are based on trials involving 36 children with infantile-onset SMA who were aged between approximately 2 weeks and 8 months at study entry. Patients treated with the drug showed significant improvement in their ability to reach developmental motor milestones, such as head control and sitting without support, compared to the natural history of patients with the disease.

The most common side effects of onasemnogene abeparvovec-xioi are elevated liver enzymes and vomiting. The medication has a boxed warning about the risk of acute serious liver injury.

The FDA granted this application fast-track, breakthrough therapy, priority review, and orphan drug designations. The agency also awarded AveXis a rare pediatric disease priority review voucher for onasemnogene abeparvovec-xioi.

Source: FDA, May 24, 2019

Vyndaquel, Vyndamax For Cardiac Amyloidosis

The FDA has approved tafamidis meglumine and tafamidis (Vyndaquel and Vyndamax, Pfizer Inc.) for the treatment of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults, to reduce cardiovascular (CV) mortality and CV-related hospitalization. Both drugs are oral formulations of the first-in-class transthyretin stabilizer tafamidis.

Rare, life-threatening ATTR-CM is characterized by the buildup of abnormal deposits of amyloid protein in the heart, causing restrictive cardiomyopathy and progressive heart failure.

The approval was based on data from the pivotal phase 3 Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT), a global, double-blind, randomized, placebo-controlled clinical study. Tafamidis meglumine significantly reduced the hierarchical combination of all-cause mortality and frequency of CV-related hospitalizations compared with placebo over a 30-month period. Individual components of the primary analysis demonstrated a relative reduction in the risk of all-cause mortality and frequency of CV-related hospitalization of 30% and 32%, respectively.

The recommended dosage of tafamidis meglumine is 80 mg once daily, taken as four 20-mg capsules; tafamidis (developed for patient convenience) is dosed as a single daily 61-mg capsule. The drugs are not substitutable on a per-milligram basis.

Previously, the sole treatment options for ATTR-CM were symptom management and, rarely, heart (or heart and liver) transplant. Approximately 100,000 people in the U.S. are thought to have the disease, but only 1 to 2% have been diagnosed. Following diagnosis, a patient’s median life expectancy is approximately 2 to 3.5 years.

Source: Pfizer Inc, May 6, 2019

Ruzurgi for Lambert-Eaton Myasthenic Syndrome

The FDA has approved amifampridine tablets (Ruzurgi, Jacobus Pharmaceutical Company) for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in pediatric patients between ages 6 to below 17 years. Amifampridine is the first treatment specifically approved for children with LEMS.

A rare autoimmune disorder, LEMS affects the connection between nerves and muscles, causing weakness, fatigue, and other symptoms. Although it can be associated with other autoimmune diseases, it usually occurs in patients with cancer.

The use of amifampridine in pediatric patients is supported by evidence from adequate, well-controlled studies of the drug in adults with LEMS; pharmacokinetic data from adult patients; pharmacokinetic modeling and simulation to identify the dosing regimen in pediatric patients; and safety data from children between the ages of 6 and below 17 years.

Amifampridine’s effectiveness was shown in a randomized, double-blind, placebo-controlled withdrawal study of 32 adults taking the drug for at least three months prior to study entry. The study compared patients continuing on amifampridine with patients who had switched to placebo. In a test assessing the time it took to rise from a chair, walk 3 meters, and return to the chair, patients taking amifampridine were less impaired than patients taking placebo. Also, scores from a self-assessment scale for LEMS-related weakness suggested that the latter perceived greater weakness than did the former.

Amifampridine’s most common side effects in pediatric and adult patients were paresthesia, abdominal pain, indigestion, dizziness, and nausea. Side effects reported in children were similar to those in adults.

The FDA granted amifampridine priority review, fast track, and orphan drug designations.

Source: FDA, May 6, 2019

Qternmet XR for Diabetes

The FDA has approved dapagliflozin, saxagliptin, and metformin hydrochloride extended release tablets (Qternmet XR, AstraZeneca) as a once-daily oral adjunct treatment to diet and exercise to improve glycemic control in adults with type-2 diabetes (T2D).

The approval is based on data from two phase 3 trials that evaluated combinations of dapagliflozin (a selective sodium-glucose cotransporter-2 inhibitor) and saxagliptin (a dipeptidyl peptidase-4 inhibitor) on a background of metformin over 24 weeks in patients with inadequately controlled T2D.

In the first trial, patients receiving dapagliflozin 5 mg/saxagliptin 5 mg plus metformin showed statistically significant decreases in hemoglobin A1c (HbA1c) levels, and an increased number achieved the recommended treatment goal of HbA1c < 7%. In the second trial, patients receiving dapagliflozin 10 mg/saxagliptin 5 mg plus metformin extended release showed statistically significant decreases in HbA1c levels, and a greater number achieved HbA1c < 7%. The safety results of the individual medicines were consistent with their known profiles.

Source: AstraZeneca, May 3, 2019

Dengvaxia, a Dengue Vaccine

The FDA has approved Dengvaxia (Sanofi Pasteur), the first vaccine for the prevention of dengue disease caused by all dengue virus serotypes (1–4), in patients aged 9 through 16 years living in endemic areas who have previous laboratory-confirmed dengue infection.

Dengue, the world’s most common mosquito-borne viral disease, is endemic in the U.S. territories of American Samoa, Guam, Puerto Rico, and the U.S. Virgin Islands but it is rare in the continental U.S. A first infection typically causes no symptoms or mild symptoms in individuals, but a subsequent infection can lead to severe or even fatal illness. Care is limited to symptom management. Infection by one type of dengue virus usually provides immunity against that specific serotype, but a later infection with any other serotype increases the risk of severe dengue disease.

The vaccine’s safety and effectiveness were determined in three randomized, placebo-controlled studies involving approximately 35,000 individuals. Dengvaxia was found to be approximately 76% effective in preventing symptomatic, laboratory-confirmed dengue disease in individuals aged 9 through 16 years who previously had laboratory-confirmed dengue disease. The most common side effects (which were similar for Dengvaxia and placebo) were headache, muscle pain, joint pain, fatigue, injection-site pain, and low-grade fever.

Dengvaxia is a live, attenuated vaccine, administered as three separate injections followed by two additional shots six and 12 months later. It is not approved for use in individuals without previous infection from any dengue virus serotype or in those for whom this information is unknown. This is because in people who have not been infected with dengue virus, Dengvaxia appears to act like a first dengue infection—and a subsequent infection can result in severe dengue disease.

Dengvaxia received a priority review and a tropical disease priority review voucher.

Source: FDA, May 1, 2019

Duobrii for Plaque Psoriasis

The FDA has approved halobetasol propionate/tazarotene lotion, 0.01%/0.045% (Duobrii, Bausch Health Companies Inc.) for the topical treatment of plaque psoriasis in adults. Bausch believes the lotion has the potential to delay some patients from switching to more expensive biologic treatments.

The safety and efficacy of once-daily halobetasol propionate/tazarotene lotion were assessed in two phase 3, prospective, multicenter, randomized, double-blind clinical trials in 418 patients aged 18 years and older with moderate-to-severe plaque psoriasis. Treatment success, the primary endpoint, was defined as improvement of at least two grades from baseline in an Investigator Global Assessment score and “clear”/“almost clear” skin. At eight weeks, more patients had achieved treatment success with halobetasol propionate/tazarotene lotion compared with vehicle in both studies (study 1, 36% vs. 7%; study 2, 45% vs. 13%). The most common adverse events included redness, itching, swelling, burning, stinging, application-site pain, folliculitis, thinning of the skin, peeling, and rash.

A phase 3, multicenter, open-label study assessed the long-term safety of halobetasol propionate/tazarotene lotion over one year in subjects with plaque psoriasis. Patients used the lotion for up to 24 weeks of continuous use and up to 52 weeks of as-needed use.

Topical retinoids such as tazarotene have had limited use as monotherapy due to tolerability concerns, but halobetasol propionate/tazarotene provides improved local tolerability.

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

Skyrizi for Plaque Psoriasis

Risankizumab-rzaa (Skyrizi, AbbVie) has received approval for the treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy.

The drug is administered by two subcutaneous injections every 12 weeks following two initiation doses at Weeks 0 and 4. It can be administered in-office or by self-injection after training.

The safety and efficacy was assessed in adults with moderate-to-severe plaque psoriasis across four randomized, placebo, and/or active-controlled pivotal studies: ultIMMa-1, ultIMMa-2, IMMhance, and IMMvent. Coprimary endpoints were a Psoriasis Area and Severity Index (PASI) 90 score (PASI 90 = 90% improvement) and static Physician Global Assessment score of clear/almost clear (sPGA 0/1) at 16 weeks compared with placebo.

At 16 weeks in ultIMMa-1 and ultIMMa-2, 75% of risankizumab-rzaa patients achieved PASI 90 compared with 5% and 2% of placebo patients, respectively. PASI 100 (100% improvement) was achieved in 36% of risankizumab-rzaa patients compared with 0% of placebo patients, and in 51% of risankizumab-rzaa patients compared with 2% of placebo patients, respectively. At 52 weeks, 82% and 81% of risankizumab-rzaa patients had achieved PASI 90, and 56% and 60% of patients had achieved PASI 100, respectively. Most risankizumab-rzaa subjects who achieved PASI 90 or 100 at Week 16 maintained the response at one year.

The most common adverse events included upper respiratory tract infections, headache, fatigue, injection-site reactions, and tinea infections. Before starting treatment with risankizumab-rzaa, patients must undergo an initial evaluation for tuberculosis.

Risankizumab-rzaa, a selective inter-leukin-23 inhibitor, is part of a collaboration between Boehringer Ingelheim and AbbVie.

Source: AbbVie, April 23, 2019

Eticovo, an Enbrel Biosimilar

The FDA has approved etanercept-ykro (Eticovo, Samsung Bioepis Co., Ltd.), a biosimilar to etanercept (Enbrel, Amgen), across all eligible indications for the treatment of rheumatoid arthritis, ankylosing spondylitis, plaque psoriasis, psoriatic arthritis, and polyarticular juvenile idiopathic arthritis.

In a 52-week phase 3 clinical study that randomized 596 patients with rheumatoid arthritis across 70 sites in 10 countries, etanercept-ykro demonstrated comparable safety and efficacy to etanercept. The American College of Rheumatology 20% improvement rate was 80.8% in the etanercept-ykro arm and 81.5% in the etanercept arm.

Etanercept-ykro is a tumor necrosis factor blocker. Like etanercept, it carries a boxed warning about possible serious infections and malignancies.

Etanercept-ykro is the second biosimilar to etanercept; the FDA approved etanercept-szzs (Erelzi, Sandoz, Inc.) in August 2016.

Sources: Samsung Bioepis Co., Ltd., April 29, 2019; FDA, May 29, 2019

Generic Approvals

Pentamidine Isethionate for Inhalation Solution

Seton Pharmaceuticals, LLC, has received FDA permission to market pentamidine isethionate for inhalation solution, 300 mg/vial, the first generic form of NebuPent (Fresenius Kabi USA). Pentamidine isethionate is used to prevent Pneumocystis jiroveci pneumonia (PJP) in high-risk patients with human immunodeficiency virus who have a history of one or more episodes of PJP and/or a peripheral CD4+ lymphocyte count of less than 200/mm.

Source: FDA, April 24, 2019

Rufinamide Oral Suspension

Bionpharma Inc. and Hikma Pharmaceuticals International Ltd. have received FDA permission to market rufinamide oral suspension, 40 mg/mL, for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome. These are the first generic versions of this formulation of Banzel (Eisai).

Source: FDA, April 23, 2019

Everolimus Tablets for Oral Suspension

The FDA has granted permission to Mylan Pharmaceuticals, Inc. to market everolimus 2-mg, 3-mg, and 5-mg tablets for oral suspension. Branded as Afinitor Disperz (Novartis), everolimus is for adults and pediatric patients aged 1 year and older with tuberous sclerosis complex–associated partial-onset seizures who have subependymal giant cell astrocytoma that requires therapeutic intervention but that can’t be curatively resected.

Source: FDA, April 19, 2019

Valrubicin Intravesical Solution

Custopharm, Inc. will be marketing valrubicin intravesical solution USP, 200 mg/5 mL (40 mg/mL) in single-dose vials––the first generic form of Valstar (Endo Pharmaceuticals). The drug is used for the treatment of bacillus Calmette-Guérin–refractory carcinoma in situ of the urinary bladder in patients for whom immediate cystectomy would be associated with unacceptable morbidity or mortality.

Source: FDA, April 19, 2019

NEW INDICATIONS

Revlimid Plus Rituximab for Previously Treated Lymphoma

The FDA has approved lenalidomide (Revlimid, Celgene Corporation) with rituximab for adults previously treated for follicular lymphoma (FL) or marginal zone lymphoma (MZL). This is the first FDA-approved combination treatment regimen for patients with these indolent forms of non-Hodgkin’s lymphoma (NHL) that does not include chemotherapy.

The approval is based primarily on results from the randomized, double-blind, phase 3 AUGMENT study. Treatment with lenalidomide and rituximab, compared with rituximab and placebo, improved progression-free survival to 39.4 months versus 14.1 months, respectively. Adverse reactions included neutropenia, diarrhea, constipation, cough, fatigue, rash, pyrexia, leukopenia, pruritus, upper respiratory tract infections, abdominal pain, anemia, headache, and thrombocytopenia.

Lenalidomide has a boxed warning for embryo-fetal toxicity, hematologic toxicity, and venous and arterial thromboembolism. It is available only through a restricted distribution program.

The FDA gave the application for this indication a priority review designation.

Source: Celgene, May 28, 2019

Vraylar Use Expanded For Bipolar Depression

Cariprazine (Vraylar, Allergan PLC) has secured FDA approval for expanded use to treat depressive episodes associated with bipolar I disorder (bipolar depression) in adults. Cariprazine was previously approved in the U.S. to treat manic or mixed episodes associated with bipolar I disorder in adults.

The new approval is based on data from three pivotal trials––RGH-MD-53, RGH-MD-54, and RGH-MD-56––in which cariprazine demonstrated greater improvement than placebo in change from baseline to Week 6 on the Montgomery Asberg Depression Rating scale total score. In all three studies, the cariprazine 1.5-mg dose demonstrated statistical significance compared with placebo. Also, in RGH-MD-54, the cariprazine 3-mg dose showed statistical significance compared with placebo. Common adverse events included nausea, akathisia, restlessness, and extrapyramidal symptoms.

Cariprazine, an oral, once-daily, second-generation antipsychotic, is also approved to treat schizophrenia in adults. The drug carries boxed warnings about increased mortality in elderly patients with dementia-related psychosis, and suicidal thoughts and behaviors in pediatric and young adult patients.

Cariprazine was discovered and co-developed by Gedeon Richter PLC and is licensed by Allergan in the U.S. and Canada.

Source: Allergan and Gedeon Richter, May 28, 2019

Jakafi Approved for Graft-Versus-Host Disease

Ruxolitinib (Jakafi, Incyte Corporation) has been approved to treat steroid-refractory, acute graft-versus-host disease (GVHD) in adults and pediatric patients aged 12 years and older.

Graft-versus-host disease can occur after an allogeneic stem-cell transplant; it can be acute or chronic and affect multiple organ systems. Some patients with steroid-refractory acute GVHD develop severe disease, and one-year mortality rates are approximately 70%.

FDA approval was based on data from REACH1, an open-label, single-arm, multicenter study of ruxolitinib in combination with corticosteroids in 71 patients with steroid-refractory, grade II–IV acute GVHD. In the 49 patients who were refractory to steroids alone, the Day-28 overall response rate was 57%, with a complete response rate of 31%. The most frequently reported adverse reactions were infections and edema; the most common laboratory abnormalities were anemia, thrombocytopenia, and neutropenia.

Source: Incyte, May 24, 2019

Fragmin for Pediatric VTE

The FDA has approved dalteparin sodium injection (Fragmin, Pfizer) for subcutaneous use to reduce the recurrence of symptomatic venous thromboembolism (VTE) in pediatric patients aged 1 month and older. This condition can include deep vein thrombosis (DVT) and pulmonary embolism, which can lead to death.

Most children who have VTE are fighting a serious underlying primary illness, such as cancer or congenital heart disease. Previously, there were no FDA-approved therapies for VTE in pediatric patients, and Dalteparin is the first anticoagulant indicated for pediatric patients.

The FDA first approved dalteparin, a type of heparin, in 1994 for adults. Its efficacy in children was based on a single trial involving 38 pediatric patients with symptomatic DVT and/or pulmonary embolism who were treated with dalteparin for up to three months. At study completion, 21 patients had achieved resolution of the qualifying VTE, seven patients showed regression, two patients showed no change, no patients experienced VTE progression, and one patient experienced a recurrence of VTE.

Common side effects with dalteparin are bleeding, including hemorrhage; thrombocytopenia; hematoma or pain at the injection site; and transient elevation of transaminases.

Dalteparin has a boxed warning for the potential occurrence of epidural or spinal hematomas in patients who are anticoagulated as a result of taking certain medications called low molecular weight heparins or heparinoids and who are receiving neuraxial anesthesia or undergoing spinal puncture.

The FDA gave this application a priority review designation.

Source: FDA, May 16, 2019

Gattex for Children Aged 1 With Short Bowel Syndrome

The FDA has extended the indication of teduglutide for injection (Gattex, Takeda Pharmaceuticals USA) to include children aged 1 year and older with short bowel syndrome (SBS) who require parenteral support (PS).

In children, SBS is a life-threatening, chronic, and rare malabsorption disorder resulting from the surgical removal of a large portion of the intestine, typically due to congenital or acquired conditions or to trauma. Patients are unable to absorb enough nutrients and fluids from what they eat and drink alone. Teduglutide, a recombinant analog of human glucagon-like peptide-2, helps the remaining intestine to absorb more nutrients.

In a 24-week pediatric study, 69% of patients (18/26) who took teduglutide 0.05 mg/kg each day (the recommended dose) reduced PS volume by 20% or more, with a 42% mean reduction in PS volume from baseline. Thirty-eight percent of patients (10/26) reduced PS infusion by at least one day per week, and 12% (3/26 patients) completely ended PS.

The most common adverse reactions in adults in clinical trials were abdominal pain, nausea, upper respiratory tract infection, abdominal distension, injection-site reaction, vomiting, fluid overload, and hypersensitivity.

Source: Takeda, May 17, 2019

Venclexta Plus Gazyva for Chronic Lymphocytic Leukemia

The FDA has approved venetoclax (Venclexta, AbbVie) in combination with obinutuzumab (Gazyva, Genentech) as a chemotherapy-free regimen for previously untreated patients with chronic lymphocytic leukemia or small lymphocytic lymphoma.

With a median follow-up of 28 months in the prospective, multicenter, open-label, randomized, phase 3 CLL14 trial, venetoclax plus obinutuzumab reduced the risk of disease progression or death by 67% compared with chlorambucil plus obinutuzumab. Median progression-free survival was not reached in either treatment arm. Higher rates of minimal residual-disease negativity were observed with venetoclax plus obinutuzumab than with obinutuzumab plus chlorambucil in bone marrow (57% vs. 17%) and peripheral blood (76% vs. 35%) three months after treatment completion.

Serious adverse reactions were reported in 49% of patients in the venetoclax plus obinutuzumab arm, usually because of febrile neutropenia and pneumonia. The most common adverse reactions of any grade were neutropenia, diarrhea, fatigue, nausea, anemia, and upper respiratory tract infection.

Venclexta, an oral B-cell lymphoma-2 inhibitor, is jointly commercialized by AbbVie and Genentech in the U.S. The FDA gave a breakthrough therapy designation for this combination therapy, which was approved under the Real-Time Oncology Review pilot program in just over two months.

Source: AbbVie, May 15, 2019

Bavencio Plus Inlyta for Advanced Kidney Cancer

The FDA has approved avelumab (Bavencio, EMD Serono) in combination with axitinib (Inlyta, Pfizer Inc.) for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

The approval was based on positive results from the randomized, multicenter, open-label, phase 3 JAVELIN Renal 101 trial. In the intent-to-treat (ITT) population, avelumab plus axitinib, compared with sunitinib, significantly improved median progression-free survival (13.8 months vs. 8.4 months) and objective response rate (51.4% vs. 25.7%). The ITT population included patients regardless of programmed death ligand-1 (PD-L1) expression and across prognostic risk groups.

The most common adverse reactions were diarrhea, fatigue, hypertension, musculoskeletal pain, nausea, mucositis, palmar-plantar erythrodysesthesia, dysphonia, decreased appetite, hypothyroidism, rash, hepatotoxicity, cough, dyspnea, abdominal pain, and headache. Serious adverse reactions occurred in 35% of patients receiving avelumab plus axitinib, and the incidence of major adverse cardiovascular events was higher in those patients than in patients receiving sunitinib.

Avelumab is a PD-L1 immunotherapy and axitinib is a kinase inhibitor.

Sources: EMD Serono and Pfizer Inc., May 14, 2019

Eylea for Diabetic Retinopathy

Aflibercept injection (Eylea, Regeneron Pharmaceuticals, Inc.) has been approved to treat all stages of diabetic retinopathy (DR).

Approximately eight million people live with DR, which is the main cause of blindness in working-age U.S. adults. The disease generally starts as non-proliferative diabetic retinopathy (NPDR), which often progresses to proliferative diabetic retinopathy (PDR). Aflibercept, a vascular endothelial growth factor (VEGF) inhibitor, is approved with two dosing options: every eight weeks (after five initial monthly injections) or every four weeks.

Aflibercept injection is designed to block new blood-vessel growth and decrease vascular permeability in the eye by blocking VEGF-A and placental growth factor, which are involved in angiogenesis.

The approval was based on results from the randomized, multicenter, controlled, phase 3 PANORAMA trial of 402 patients with NPDR without diabetic macular edema. Patients received aflibercept once every 8 weeks (after five initial monthly doses) or once every 16 weeks (after three initial monthly doses and one eight-week interval). At one year, a two-step or greater improvement from baseline in the diabetic retinopathy severity scale was reported in 65% of patients in the once-every-16-weeks arm, 80% of patients in the once-every-eight-weeks arm, and 15% of patients in the sham-injection arm.

The most common adverse reactions were conjunctival hemorrhage, eye pain, cataract, vitreous detachment, vitreous floaters, and increased intraocular pressure.

Source: Regeneron, May 13, 2019

Cyramza Monotherapy for Some Liver Cancer Cases

The FDA has approved ramucirumab (Cyramza, Eli Lilly) as monotherapy for the second-line treatment of patients with hepatocellular carcinoma (HCC), with a minimum alpha-fetoprotein (AFP) level of 400 ng/mL, who were previously treated with sorafenib.

The approval was based on results from the global, randomized, double-blind, placebo-controlled phase 3 REACH-2 trial in patients selected using the AFP prognostic biomarker, which can be assessed through a blood test.

Hepatocellular carcinoma is the most common form of liver cancer. About 40% of patients with advanced HCC have high AFP levels, and are among those with the poorest prognosis. Prior to ramucirumab’s approval, there were no treatment options specifically aimed at patients with increased AFP levels.

In REACH-2, ramucirumab versus placebo significantly increased median overall survival (8.5 months vs. 7.3 months) and median progression-free survival (2.8 months vs. 1.6 months). The most common adverse reactions were fatigue, peripheral edema, hypertension, abdominal pain, decreased appetite, proteinuria, nausea, and ascites.

The FDA has removed ramucirumab’s boxed warning for potential hemorrhage, gastrointestinal perforation, and impaired wound healing, but updated labeling has warnings and precautions about these and other adverse events.

Source: Eli Lilly, May 13, 2019

Kadcyla for Adjuvant Breast Cancer Treatment

The FDA has approved ado-trastuzumab emtansine (Kadcyla, Genentech) for the adjuvant treatment of people with HER2-positive early breast cancer who have residual invasive disease after neo-adjuvant treatment based on taxane and trastuzumab (Herceptin, Genentech).

This approval is based on results from KATHERINE, an international, multicenter, two-arm, randomized, open-label, phase 3 study. Compared with trastuzumab, ado-trastuzumab emtansine as adjuvant treatment significantly reduced the risk of invasive breast cancer recurrence or death from any cause by 50% in people with HER2-positive early breast cancer with residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment. At three years, 88.3% of ado-trastuzumab emtansine patients had no return of breast cancer, compared with 77.0% of trastuzumab patients.

The most common grade 3 or higher side effects were decreased platelet count and high blood pressure. The most common side effects were fatigue, nausea, increased blood levels of liver enzymes, musculoskeletal pain, bleeding, decreased platelet count, headache, numbness, tingling or pain in the hands or feet, and joint pain. Ado-trastuzumab emtansine has a boxed warning about the risk of hepatotoxicity, cardiac toxicity, and embryo-fetal toxicity.

Ado-trastuzumab emtansine was approved in about 12 weeks under the Real-Time Oncology Review and Assessment Aid pilot programs. Trastuzumab also received a breakthrough therapy designation.

Source: Genentech, May 3, 2019

Tibsovo Monotherapy for Some Leukemia Patients

Ivosidenib (Tibsovo, Agios Pharmaceuticals, Inc.) is now indicated for adults with newly diagnosed acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation, who are 75 years of age or older or have comorbidities that preclude intensive induction chemotherapy.

In 6% to 10% of patients with AML, the mutated IDH1 enzyme blocks normal blood stem-cell differentiation, contributing to the genesis of acute leukemia. These mutations have been associated with poor prognoses.

Ivosidenib’s efficacy was evaluated in an open-label, single-arm, multicenter trial of 28 adults, aged ≥ 75 years or with comorbidities that precluded intensive induction chemotherapy, with newly diagnosed AML with an IDH1 mutation. The rate of complete remissions (CR) was 28.6% and the rate of CR with partial hematologic improvement (CRh) was 14.3%. The combined CR and CRh rate (the primary endpoint) was 42.9%. One year after treatment, 58.3% of patients who achieved CR or CRh were in remission.

Differentiation syndrome occurred in 25% of patients; ivosidenib has a boxed warning about this risk. The most common adverse reactions were diarrhea, fatigue, decreased appetite, edema, nausea, leukocytosis, arthralgia, abdominal pain, dyspnea, myalgia, constipation, differentiation syndrome, dizziness, prolonged electrocardiogram QT, mucositis, and vomiting.

The application was granted priority review and accepted under the Real-Time Oncology Review pilot program. Ivosidenib, an IDH1 inhibitor, was initially approved in July 2018 for adults with relapsed or refractory AML and an IDH1 mutation.

Source: Agios Pharmaceuticals, Inc., May 2, 2019

Mavyret for Pediatric HCV

The FDA has approved glecaprevir/pibrentasvir (Mavyret, AbbVie Inc.) to treat all six genotypes of hepatitis C virus (HCV) in children aged 12 to 17 years old. Glecaprevir/pibrentasvir was approved to treat HCV in adults in 2017.

An estimated 23,000 to 46,000 children in the U.S. have HCV infection.

Dosing information is provided for adults and pediatric patients aged 12 years or more or weighing at least 99 lbs who are infected with any of six identified HCV genotypes without cirrhosis or with compensated cirrhosis.

The safety and efficacy of glecaprevir/pibrentasvir in children was evaluated during clinical trials of 47 patients with genotype 1, 2, 3, or 4 HCV infection without cirrhosis or with mild cirrhosis. One hundred percent of patients who received glecaprevir/pibrentasvir for eight or 16 weeks had no virus detected in the blood 12 weeks after finishing treatment. In pediatric patients with cirrhosis, a history of kidney and/or liver transplant, or genotype 5 or 6 HCV infection, glecaprevir/pibrentasvir’s safety and efficacy are supported by previous studies in adults. Adverse reactions (headache and fatigue) were consistent with those in adult trials.

Treatment duration depends on treatment history, viral genotype, and cirrhosis status. Glecaprevir/pibrentasvir is not recommended in patients with moderate cirrhosis; it is contraindicated in patients with severe cirrhosis and in patients taking atazanavir and rifampin. Hepatitis B virus (HBV) reactivation has been reported in adults coinfected with HCV/HBV, during or after treatment with HCV direct-acting antivirals, who were not receiving HBV antiviral therapy.

Source: FDA, April 30, 2019

Kalydeco For Children With CF From 6 Months Old

Ivacaftor (Kalydeco, Vertex Pharmaceuticals Inc.) has been approved for use in children aged 6 months to less than 12 months with cystic fibrosis (CF) who have at least one mutation in their CF transmembrane conductance regulator (CFTR) gene that is responsive to ivacaftor based on clinical and/or in vitro assay data. Ivacaftor is already approved for patients aged 12 months and older.

The current approval is based on data from ARRIVAL, a 24-week, phase 3, open-label safety cohort of 11 children (6 to ≤ 12 months old) who have CF with one of 10 CFTR gene mutations (G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, G1349D, or R117H). The study demonstrated a safety profile similar to that seen in previous studies of older children and adults. Most adverse events (most often cough, nasal congestion, and rhinorrhea) were mild or moderate. Three serious adverse events, all considered unrelated to the study treatment, were seen in three patients.

Mean baseline sweat chloride for the children in this cohort was 101.5 mmol/L (n = 11). Following 24 weeks of treatment with ivacaftor, the mean sweat chloride level was 43.1 mmol/L (n = 6). In the six subjects with paired sweat chloride samples at baseline and Week 24, there was a mean absolute change of −58.6 mmol/L.

Source: Vertex Pharmaceuticals, April 30, 2019

Benlysta for Pediatric Lupus

The FDA has approved the use of intravenous (IV) formulation of belimumab (Benlysta, GlaxoSmithKline) in children as young as 5 years of age who have lupus.

This extends the current indication in the U.S. for IV belimumab in adults to include patients aged 5 years and older with active, autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving standard therapy. Belimumab, a B-lymphocyte stimulator-specific inhibitor, is the first medicine specifically approved in the U.S. for both adults and children with SLE.

A multicenter, randomized, double-blind, post-approval commitment study (PLUTO) included 93 children between 5 and 17 years old with SLE. The proportion of children achieving a clinically meaningful improvement in disease activity, as assessed by the SLE responder index response rate, was numerically higher in patients receiving IV belimumab plus standard therapy (52.8%) compared with those receiving placebo plus standard therapy (43.6%) at Week 52.

The proportion of patients experiencing more than one adverse event (AE) and one serious AE was 79.2% and 17.0% in the belimumab group, compared with 82.5% and 35.0% in the placebo group, respectively. Adverse events leading to discontinuation included lupus nephritis, hepatitis A, hypertransaminasemia, acute pancreatitis, post-herpetic neuralgia, retinal vasculitis, and pancreatitis.

This application received a priority review.

Source: GlaxoSmithKline, April 26, 2019

Praluent to Prevent Heart Attack, Stroke, Unstable Angina

The FDA has approved alirocumab (Praluent, Regeneron Pharmaceuticals, Inc./Sanofi) to reduce the risk of heart attack, stroke, and unstable angina requiring hospitalization in adults with established cardiovascular (CV) disease.

The ODYSSEY OUTCOMES trial assessed the effect on CV outcomes of adding alirocumab to maximally tolerated statins in 18,924 patients who had an acute coronary syndrome within one year of enrolling in the trial. Alirocumab recipients experienced a statistically significant reduced risk of 15% for major CV events—a primary endpoint that included time to first heart attack, stroke, death from coronary heart disease, or unstable angina requiring hospitalization.

Compared with placebo, alirocumab reduced risks in patients by 27% for stroke, 14% for nonfatal heart attack, 39% for unstable angina requiring hospitalization, and 15% for all-cause mortality. However, these results are not considered statistically significant as statistical testing was performed outside of the hierarchy.

Except for injection-site reactions, adverse events (noncardiac chest pain, nasopharyngitis, and myalgia) were similar between the groups.

The FDA also approved alirocumab as an adjunct to diet, alone or in combination with other lipid-lowering therapies (e.g., statins and ezetimibe), for the treatment of adults with primary hyperlipidemia (including heterozygous familial hyper-cholesterolemia) to reduce low-density lipoprotein cholesterol.

Alirocumab is a proprotein convertase subtilisin/kexin type 9 inhibitor.

Source: Regeneron Pharmaceuticals, Inc., April 26, 2019

Xeomin for Blepharospasm

The FDA has broadened the indication for incobotulinumtoxinA (Xeomin, Merz Americas), making it a first-line treatment for blepharospasm in adults.

Blepharospasm causes muscles around the eyes to contract involuntarily. Patients can experience excessive blinking, light sensitivity, dry eyes, eye irritation, and watering eyes; symptoms can become worse over time.

In a phase 3, randomized, double-blind, placebo-controlled, multicenter trial with 61 patients, incobotulinumtoxinA demonstrated statistically significant improvement compared with placebo, with a difference of −1.2 from baseline in Jankovic Rating Scale Severity subscore at Week 6 after injection. Safety findings were similar to those from previous studies.

Like all botulinum toxin, incobotulinumtoxinA has a boxed warning indicating that its effects may spread from the area of injection to produce symptoms consistent with botulinum toxin effects.

IncobotulinumtoxinA was approved by the FDA in 2010 for the treatment of blepharospasm previously treated with onabotulinumtoxinA.

Sources: Merz Americas, May 13, 2019; Xeomin prescribing information, July 2018

Sorilux for Plaque Psoriasis in Adolescents

The FDA has approved the use of calcipotriene foam, 0.005% (Sorilux, Mayne Pharma Group Ltd.) in adolescents, enabling treatment of plaque psoriasis of the scalp and body in all patients aged 12 years and older.

In 2010, the agency approved calcipotriene based on evidence from two eight-week, placebo-controlled clinical trials in patients with mild-to-moderate plaque psoriasis of the body and one eight-week, placebo-controlled trial in patients with moderate plaque psoriasis of the scalp. Further data were obtained from a follow-on open-label study in patients 12 to 17 years old with psoriasis.

Calcipotriene is a synthetic vitamin D analog that has a receptor-binding affinity similar to that of natural vitamin D.

Source: Mayne Pharma, May 22, 2019

NEW FORMULATION

Nayzilam Nasal Spray

Midazolam for Seizures

Midazolam nasal spray CIV (Nayzilam, UCB) has secured approval for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity in patients aged 12 years and older. It is the first FDA-approved nasal treatment for seizure clusters.

The single-use spray can be carried by patients and used by non–health-care professionals when a seizure cluster occurs.

Midazolam’s effectiveness for the acute treatment of seizure clusters or acute repetitive seizures that are distinct from a patient’s typical seizure pattern, in patients with epilepsy aged 12 years and older, was established in the randomized, double-blind, placebo-controlled Study 1, which enrolled 201 patients on a stable regimen of antiepileptic drugs. A statistically significant higher percentage of midazolam-treated patients met the primary efficacy endpoint of treatment success: termination of seizures within 10 minutes after the initial blinded dose, and absence of recurrent seizures within six hours of that dose. Numerical differences favored midazolam in seizure termination within 10 minutes (80.6% vs. 70.1%) and in absence of seizure recurrence between 10 minutes and six hours (58.2% vs. 37.3%).

The most common adverse reactions were somnolence, headache, nasal discomfort, throat irritation, and rhinorrhea.

Serious cardiorespiratory adverse reactions have been observed after the administration of midazolam. Patients and caregivers should be informed of the risk of respiratory depression and cardiac and respiratory arrest.

Nayzilam is a schedule IV controlled substance.

Source: UCB, May 20, 2019

FDA REVIEW ACTIVITIES

Breakthrough Therapy Status

Pomalyst for Kaposi Sarcoma

The FDA has granted pomalidomide (Pomalyst, Celgene Corporation) a breakthrough therapy designation for the treatment of patients with human immunodeficiency virus (HIV)-positive Kaposi sarcoma with prior systemic chemotherapy and patients with HIV-negative Kaposi sarcoma.

Kaposi sarcoma is a multicentric tumor caused by Kaposi sarcoma-associated herpes virus. There are no approved therapies for HIV-positive patients who are refractory to or intolerant of systemic chemotherapy.

Pomalidomide is an immunomodulatory imide drug––a proprietary, small-molecule, orally available compound used to treat certain blood cancers. Immunomodulatory imide agents are thought to have multiple mechanisms of action.

Source: Celgene, May 13, 2019

Fast-Track Designations

Molgradex for Autoimmune Pulmonary Alveolar Proteinosis

Savara Inc. has received a fast-track designation for Molgradex, an inhaled formulation of recombinant human granulocyte–macrophage colony-stimulating factor.

Molgradex is being investigated in a phase 3 study of patients with autoimmune pulmonary alveolar proteinosis. The drug is also in phase 2a development for nontuberculous mycobacteria (NTM) lung infection in patients with non-cystic fibrosis and patients who have cystic fibrosis with chronic NTM lung infection.

Source: Savara Inc., May 6, 2019

Full-Spectrum Microbiota For Autism Spectrum Disorder

Finch Therapeutics Group, Inc. has received a fast-track designation for its full-spectrum microbiota (FSM) therapy for children with autism spectrum disorder (ASD).

Approximately one in 59 children is diagnosed with ASD, and there are no FDA-approved medications for the core symptoms. Studies show that individuals with ASD commonly suffer from gastrointestinal (GI) symptoms, such as constipation, diarrhea, and abdominal pain, which may be caused by an abnormal gut microbiome.

In an open-label study, Arizona State University researchers treated 18 children with ASD with FSM, an oral capsule containing a diverse community of microbiota, capable of restoring an unbalanced microbiome. The treatment was well tolerated and reduced GI symptoms by 77% and core ASD symptoms by 24% at eight weeks post-treatment. A two-year follow-up study found sustained improvements in GI symptoms and core behavioral ASD symptoms.

A phase 2 FSM study is enrolling adults with ASD, and there are plans to conduct a phase 2 study in children with ASD.

Source: Finch Therapeutics Group, April 29, 2019

PTR-01 for Recessive DEB

Phoenix Tissue Repair, Inc. has secured a fast-track designation for PTR-01, for recessive dystrophic epidermolysis bullosa (DEB), a genetic disorder.

This disorder is caused by mutations in the gene for collagen type VII (C7), a protein essential for the formation of anchoring fibrils, which connect the epidermis and dermis. Patients with the recessive form of DEB (RDEB) tend to have particularly severe symptoms as a result of severe insufficiency of functional C7. Symptoms, which begin in infancy, are caused by extreme skin and mucosal fragility. There are no approved disease-modifying therapies.

PTR-01 is a protein replacement therapy that uses a recombinant C7, designed to be systemically available through intravenous delivery. Preclinical studies have demonstrated improved survival in RDEB models.

Phoenix Tissue Repair has opened enrollment of the second cohort in its ongoing phase 1/2 trial in adults with RDEB. In addition to PTR-01’s safety and tolerability, the trial will assess biologic activity.

Source: Phoenix Tissue Repair, April 30, 2019

Priority Review Designations

Darolutamide for Prostate Cancer

The FDA has accepted the new drug application and granted priority review to darolutamide (Bayer) for the treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC). The decisions were based on data from a phase 3 trial.

In CRPC, the cancer keeps progressing even when testosterone is reduced to very low levels. Treatment options for castration-resistant patients are evolving rapidly, but until recently, there were no effective ones for CRPC patients with rising prostate-specific antigen levels while on androgen deprivation therapy and no detectable metastases.

Darolutamide is a nonsteroidal androgen receptor antagonist with a chemical structure that binds to the receptor and exhibits antagonistic activity, inhibiting receptor function and the growth of prostate cancer cells. A phase 3 study in metastatic hormone-sensitive prostate cancer is ongoing.

Darolutamide is being developed jointly by Bayer and Orion Corporation.

Source: Bayer, April 29, 2019

Orphan Drug Designations

Dexpramipexole for Hypereosinophilic Syndrome

The FDA has granted Knopp Biosciences an orphan drug designation for dexpramipexole, an oral drug to treat eosinophilic inflammatory disorders.

Eosinophils play a central role in severe diseases such as asthma and hypereosinophilic syndrome, which is an often-incapacitating disorder that has limited treatment options. Dexpramipexole has been shown to selectively, profoundly, and persistently reduce blood and tissue eosinophil levels in multiple clinical trials.

Dexpramipexole is entering phase 2 clinical trials in eosinophilic asthma, as well as phase 3 development in hypereosinophilic syndrome.

Source: Knopp Biosciences, April 24, 2019

AL101 for Adenoid Cystic Carcinoma

Ayala Pharmaceuticals has received an orphan drug designation for AL101 for the treatment of adenoid cystic carcinoma (ACC), which affects approximately 15,000 Americans. Current treatment options include surgery, chemotherapy, and radiation therapy, but there is no approved drug.

AL101 is a gamma secretase inhibitor developed as a Notch inhibitor for oncology indications. The Notch signaling pathway plays an important role in tumori-genesis in several solid and hematological malignancies. Upon ligand binding of the Notch receptor, an important step in the receptor activation is cleavage by gamma secretase, which frees the Notch intracellular signaling domain. In a mouse model, AL101 had a significant inhibitory effect on tumor growth.

AL101 is currently in phase 2 development for ACC patients with tumor-bearing Notch-activating mutations.

Source: Ayala Pharmaceuticals, May 13, 2019

Complete Response Letters

HTX-011 for Postoperative Pain

Heron Therapeutics, Inc. has received a complete response letter from the FDA regarding its new drug application for HTX-011 for the management of postoperative pain.

In the letter, the FDA said that they were unable to approve the application in its present form based on the need for additional chemistry, manufacturing, and controls and nonclinical information. The agency did not identify any clinical safety or efficacy issues, and there is no requirement for further clinical studies or data analyses. Heron will request a meeting with the agency to discuss its plan for resolving the issues.

HTX-011 is an extended-release formulation of the local anesthetic bupivacaine in a fixed-dose combination with the anti-inflammatory meloxicam for the management of postoperative pain. Five diverse surgical models showed that HTX-011 is significantly better at reducing pain than placebo or bupivacaine solution. The drug has received fast track, breakthrough therapy, and priority review designations.

Source: Heron Therapeutics, May 1, 2019

Barhemsys for Postoperative Nausea

Acacia Pharma Group PLC has received a second complete response letter from the FDA regarding its new drug application for amisulpride injection (Barhemsys) for postoperative nausea and vomiting. The letter identified continuing deficiencies at the contract manufacturer of amisulpride, and Acacia is now seeking an alternative supplier. The FDA raised no concerns regarding any of the data in the application.

Source: Acacia Pharma Group PLC, May 3, 2019

DRUG SAFETY ISSUES

Insomnia Medications Get Stronger Warnings

The FDA is requiring a new boxed warning on some prescription insomnia drugs after identifying 20 deaths and 46 serious injuries that resulted from complex sleep behaviors following the use of these medications. These behaviors include sleepwalking, sleep driving, and engaging in other activities while not being fully awake, such as unsafe use of a stove.

The new warnings will be required for eszopiclone (Lunesta, Sunovion Pharmaceuticals), zaleplon (Sonata, Pfizer), and zolpidem (Ambien and Ambien CR [Sanofi Aventis]; Edluar [Mylan]; Intermezzo [Purdue Pharma]; and Zolpimist [Aytu BioScience]).

Incidents can occur after the first dose of medicine, after a longer period of treatment, in patients without any history of these behaviors, and even at the lowest recommended doses.

In addition to the boxed warning, the agency is requiring the addition of a contraindication in patients who have experienced an episode of complex sleep behaviors after taking the medications.

The FDA reviewed 66 cases submitted to their Adverse Event Reporting System or found in medical literature of patients engaged in activities while not fully awake that resulted in serious injury or death after taking eszopiclone, zaleplon, or zolpidem. The 46 reports of nonfatal serious injuries included accidental overdoses, falls, burns, near-drowning, exposure to extreme cold which led to loss of limb or near death, self-injuries (e.g., gunshot wounds), and apparent suicide attempts. The 20 deaths were from carbon monoxide poisoning, drowning, fatal falls, hypothermia, fatal vehicle collisions with the patient driving, and apparent suicide.

Source: FDA, April 30, 2019

DEVICE APPROVALS

Synovasure Test to Detect Prosthetic Joint Infections

The FDA has permitted marketing of the Synovasure Lateral Flow Test Kit (CD Diagnostics Inc.) to aid the detection of periprosthetic joint infection in the synovial fluid of patients being evaluated for revision surgery, which is performed to replace or compensate for a failed implant.

Previously, there were no FDA-authorized diagnostic tests specifically designed to help determine whether the inflammation around a prosthetic joint was from infection or some other cause.

Typically, physicians evaluate for potential infections related to joint-replacement surgery using X-ray images or laboratory analysis of joint fluid, which can take days. The Synovasure Lateral Flow Test Kit detects human alpha defensins in the synovial fluid of patients who have a total joint replacement in approximately 10 minutes. Alpha defensins are anti-microbial proteins released by activated neutrophils in response to infection.

The test is intended to help determine whether there is an infection present in synovial fluid. The results are meant to be used in conjunction with other clinical and diagnostic findings to assist in a diagnosis of prosthetic joint infection.

A clinical study analyzed 305 prospective synovial fluid samples collected from individuals with a total knee or hip joint replacement who were being evaluated for revision surgery. Data showed that 89.5% of subjects with an infection diagnosis based on standard-of-care criteria were also identified as positive for alpha defensin by the Synovasure Lateral Flow Test Kit.

The FDA reviewed the test through the de novo premarket pathway. The agency also established criteria that determine the requirements for tests that detect non-microbial analytes to aid in the detection of infections.

Source: FDA, May 23, 2019

Zika Virus Antibody Test

The FDA has authorized the marketing of a diagnostic test to detect Zika virus immunoglobulin (IgM) antibodies in human blood.

ZIKV Detect 2.0 IgM Capture ELISA (InBios International, Inc.) is the first diagnostic test for the virus that the FDA has allowed to be marketed in the U.S. Previously, tests to detect Zika virus IgM antibodies, including this one, had been authorized only for emergency use. The Zika virus is spread primarily through the bite of an infected Aedes mosquito. The virus has been linked to neurological complications and to micro-cephaly in newborns.

The FDA reviewed a clinical study of 807 test samples and a variety of analytical studies demonstrating that ZIKV Detect 2.0 IgM Capture ELISA was safe and effective at identifying IgM antibodies against Zika in the blood. IgM antibodies indicate an early immune response.

The test is for use only in patients with clinical signs and symptoms consistent with Zika virus infection, and/or patients who meet the Centers for Disease Control and Prevention’s (CDC’s) Zika virus epidemiological criteria. Results from ZIKV Detect are intended to be used in conjunction with other evidence. Negative results do not preclude the possibility of Zika virus infection.

The FDA reviewed the test through the de novo premarket review pathway and has now established criteria that determine the requirements for Zika virus antibody tests.

Source: FDA, May 23, 2019

New Tests for Chlamydia and Gonorrhea

The FDA has granted 501(k) clearance for two tests that can detect Chlamydia trachomatis and Neisseria gonorrhoeae, which cause chlamydia and gonorrhea. The Aptima Combo 2 Assay (Hologic Inc.) and the Xpert CT/NG (Cepheid) are the first devices to be cleared for extragenital diagnostic testing of these infections via specimens from the throat and rectum.

The number of sexually transmitted infections in the U.S. is increasing, according to the CDC. Although chlamydia and gonorrhea are easily treated, they can cause serious complications, including infertility, if left untreated.

The FDA reviewed clinical data from a cross-sectional study coordinated by the Antibacterial Resistance Leadership Group. The multisite clinical study of more than 2,500 patients evaluated the diagnostic accuracy of multiple nucleic-acid amplification tests for detecting N. gonorrhoeae and C. trachomatis from throat and rectal sites. Results demonstrated the safety and effectiveness of the Aptima Combo 2 Assay and Xpert CT/NG for extragenital testing for chlamydia and gonorrhea.

Source: FDA, May 23, 2019

Xvivo to Preserve Lungs for Transplant

The FDA has approved the Xvivo Perfusion System with Steen Solution Perfusate (Xvivo Perfusion Inc.), which can temporarily ventilate, oxygenate, and perfuse preservation solution through lungs that were initially deemed unacceptable for transplant. The device gives the transplant team time to assess lung function more carefully when lungs are perfused with a solution outside the body, enabling the team to determine whether the lungs can be made viable for transplant.

The Xvivo Perfusion System was first granted marketing authorization in 2014 under a humanitarian device exemption but has now been reviewed under the more stringent premarket approval pathway.

Lung transplantation remains the only known life-saving treatment for end-stage lung disease, but many patients die while awaiting suitable lungs. On average, only 15% of lungs from deceased donors are suitable for transplantation.

Xvivo enables marginal-quality lungs that initially failed to meet standard transplant criteria to be ventilated, oxygenated, and perfused at a standard normal body temperature for up to five hours. This allows surgeons to reassess the lungs’ transplant suitability, and enables the transplantation of a certain percentage that were initially deemed unsuitable. The device consists of a perfusion cart with mechanical and electrical components that ventilate, oxygenate, and perfuse the lungs.

The FDA evaluated a study of 332 sets of donor lungs in three groups. One group, the control, included lungs initially deemed suitable for transplant that were provided to 116 recipients after standard preservation; one group comprised lungs initially deemed unsuitable for transplant that, after being perfused with the Xvivo system, were implanted into 110 recipients; and the third group of lungs were perfused with the Xvivo system, were still deemed unsuitable after perfusion, and were not implanted into patients. The one-year survival rate was 94% for the control group compared with 86.4% for the lung-perfusion patients. The difference in rates was not deemed to be clinically significant.

The most common adverse events associated with this device include acute rejection, bronchial complications, respiratory failure, and infections.

Source: FDA, April 26, 2019

Plenity for Weight Loss

The FDA has cleared a cellulose and citric acid capsule called Plenity (Gelesis) as an aid to weight management, when used in conjunction with diet and exercise, in adults with a body mass index (BMI) of 25–40 kg/m2.

Plenity is the first prescription weight-management product cleared for use in overweight adults with a BMI as low as 25 kg/m2, with or without comorbidities such as hypertension, type-2 diabetes, or dyslipidemia.

Plenity capsules, taken with water before lunch and dinner, are made by cross-linking cellulose and citric acid to create a three-dimensional hydrogel matrix. The capsules release thousands of nonaggregating particles that rapidly absorb water in the stomach, creating small, individual gel pieces that have the elasticity of plant-based foods without caloric value. The gel pieces increase the volume and elasticity of stomach and small-intestine contents, contributing to a feeling of fullness and inducing weight loss.

A multicenter, double-blind, placebo-controlled pivotal study assessed Plenity’s effect on body weight in 436 overweight or obese adults after six months of treatment. Fifty-nine percent of adults in the treatment group achieved a weight loss of 5% or greater. Weight loss was greater with Plenity than with placebo (−6.4% vs. −4.4%), and 26% of adults who completed treatment with Plenity achieved a weight loss of at least 10%. The most common treatment-related adverse events were gastrointestinal disorders.

Plenity is considered a medical device because it achieves its primary intended purpose through mechanical modes of action that are consistent with mechano-biology constructs.

Source: Gelesis, April 14, 2019

DEVICE SAFETY ISSUES

Blood Test Analyzers From Beckman Coulter Recalled

Some Beckman Coulter hematology analyzers are reporting erroneous high platelet levels that could lead to improper and life-threatening treatment decisions—a problem that may affect more than 2,000 laboratories nationwide, the FDA says.

The agency has alerted hospitals, laboratories, and providers of a Class 1 recall of Beckman Coulter DxH 800, DxH 600, and DxH 900 hematology analyzers, which count the number of different types of red and white blood cells, platelets, hemoglobin, and hematocrit levels in a blood sample. The recall is related to the devices’ platelet-analyzing function. Inaccurate platelet counts could lead providers to conclude that patients are suitable for surgery when they may not be, to withhold platelet transfusion in patients who may need it, or to delay or miss the diagnosis of serious blood disorders.

Beckman Coulter notified customers in August 2018 that it had identified a trend of erroneously elevated platelet results. The company says that a software update might help alert laboratory personnel to inaccurate results. However, the FDA has not evaluated the software and is working with Beckman Coulter to determine if the update alone can adequately address the recall.

The FDA recommends that laboratory personnel use backup analyzers to confirm platelet results or perform manual platelet estimates/screening, and that they follow the instructions in the Urgent Medical Device Correction letter dated May 20, 2019, before reporting platelet counts out of the laboratory.

Laboratories from large medical centers to small community hospitals may be affected. The FDA is unable to determine how many patient samples may have been affected; it has not received reports of serious adverse events linked directly to the hematology analyzers.

Source: FDA, May 23, 2019

Illicit Diabetes Devices

The FDA is warning of risks associated with the use of unapproved or unauthorized devices for diabetes management, including continuous glucose monitoring systems, insulin pumps, and automated insulin dosing systems.

According to the agency, some manufacturers are illegally marketing unauthorized devices for diabetes management that have not been reviewed by the agency. Companies are also illegally marketing components, such as unauthorized continuous glucose monitors that some patients may integrate into unauthorized automated insulin dosing systems. In addition, some patients are combining devices or components that are not intended for use with other devices.

The use of unapproved or unauthorized devices could result in inaccurate blood-glucose measurements or unsafe insulin dosing, which can lead to injury or death.

Source: FDA, May 17, 2019

Terumo Recall

Terumo Medical Corporation has recalled its Solopath Balloon Expandable TransFemoral System and Re-Collapsible Balloon Access System due to potential dislodging of the tip from the sheath’s outer rim, resulting in the loss of smooth transition from the tip surface to the expandable sheath’s outer surface.

These sterile, single-use devices are designed to help insert and guide the placement of catheters or other medical devices from a blood vessel to the femoral or iliac arteries.

Use of the affected devices could cause vessel dissection, false lumen, pseudo-aneurysm, hemorrhage, inability to transition through the skin to the iliac artery in the hip area, vessel perforation, and vessel disruption. The firm has received 14 reports of malfunctions, with two injuries and no deaths. The FDA identified the recall as Class I.

Terumo is discontinuing the products, which were distributed from July 22, 2016 to March 13, 2019.

Source: FDA, May 30, 2019

Integra Cranial Products

lntegra LifeSciences has recalled 24,587 LimiTorr Volume Limiting Cerebrospinal Fluid (CSF) Drainage Systems and MoniTorr Intracranial Pressure (ICP) External CSF Drainage and Monitoring Systems because of possible breakage of the LimiTorr transducer and MoniTorr panel mount stopcock.

The products are used to monitor ICP and to drain CSF from the brain to reduce ICP, or to provide temporary CSF drainage in patients with infected shunts. They can also be used for controlled CSF drainage from the lumbar subarachnoid space.

The FDA has identified this as a Class I recall. Device failure could result in infection, fever, headache, over-drainage, backflow of air that becomes trapped within the intracranial cavity, or death. Serious injuries (but no deaths) associated with infection and CSF over-drainage have been reported.

The devices were distributed from March 1, 2017 to March 31, 2019.

Source: FDA, May 24, 2019

Ethicon Circular Staplers

Ethicon recalled 92,496 Endo-Surgery Curved Intraluminal Staplers with Adjustable Height Staples and Endo-Surgery Endoscopic Curved Intraluminal Staplers with Adjustable Height Staples because of insufficient firing and failure to completely form the staples.

This Class I recall affects products CDH21A, CDH25A, CDH29A, CDH33A, ECS21A, ECS25A, ECS29A, and ECS33A that were distributed from March 15, 2018 to March 8, 2019.

Surgeons use the staplers in the gastrointestinal tract. Through a review of complaints and returned products, Ethicon confirmed uncut washers in the stapler and malformed staples as a result of insufficient firing. An investigation detected a shift in a manufacturing process that had occurred in March 2018 and continued through March 8, 2019, when the line was shut down.

The use of affected products may cause serious patient harm or death. Ethicon has confirmed serious injuries in two patients.

Source: FDA, May 16, 2019