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P T. 2019;44(5): 235-242, 245-250

Drug and Device News May 2019

NEW DRUG APPROVALS

Mavenclad for Multiple Sclerosis

The FDA has approved cladribine tablets (Mavenclad, EMD Serono, Inc.) to treat relapsing forms of multiple sclerosis (MS) in adults, including relapsing-remitting disease and active secondary progressive disease. Because of its safety profile, cladribine is generally recommended for patients who have had an inadequate response to or cannot tolerate another MS drug.

For most people, MS starts with a relapsing-remitting course, in which episodes of worsening function are followed by recovery periods. In some patients, disability may progress independent of relapses, a process called secondary progressive MS (SPMS). In the early years of this process, many patients continue to experience relapses, a phase called active SPMS.

In clinical trials, 1,976 patients experienced a 58% relative reduction in the annualized relapse rate with cladribine compared with placebo. Eighty-one percent of patients were free of relapses after two years of short-course oral treatment with cladribine, compared with 63% of patients who received placebo. Patients treated with cladribine had a 33% reduction in the risk of three-month confirmed disability progression as measured by the Expanded Disability Status Scale compared with patients who received placebo.

The most common adverse reactions with cladribine included upper respiratory tract infections, headache, and decreased lymphocyte counts.

Cladribine has a boxed warning for increased risk of malignancy and fetal harm, and the drug must be dispensed with a patient medication guide. Cladribine is not to be used in patients with current malignancy, and health care professionals should evaluate cladribine’s benefits and risks in individuals with prior malignancy or increased risk of malignancy. The drug should not be used in pregnant women nor in women and men of reproductive potential who do not plan to use effective contraception during treatment and for six months afterward.

Other warnings include the risk of decreased lymphocyte counts, infections, hematologic toxicity, bone-marrow suppression, and liver injury. The drug has been associated with graft-versus-host disease following blood transfusions with nonirradiated blood. Cladribine is not recommended for patients with MS who have clinically isolated syndrome.

Sources: FDA and EMD Serono., March 29, 2019

Mayzent for Multiple Sclerosis

The FDA has approved siponimod tablets (Mayzent, Novartis) to treat adults with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome (CIS), relapsing-remitting MS, and active secondary progressive MS (SPMS).

MS typically begins with a relapsing-remitting course—episodes of worsening function followed by periods of recovery. CIS is a first episode of neurological symptoms that lasts at least 24 hours and is caused by inflammation or demyelination in the central nervous system. Most patients with relapsing-remitting MS will develop SPMS, which is marked by progressive, irreversible disability.

The approval is based on the phase 3, randomized, double-blind, placebo-controlled EXPAND study comparing the efficacy and safety of siponimod to placebo in patients with SPMS. Siponimod reduced the risk of three-month confirmed disability progression by 21% versus placebo (33% in patients with relapse activity in the two years prior to screening). Siponimod also reduced the annualized relapse rate by 55%.

The most common adverse reactions to siponimod included headache, high blood pressure, and transaminase increase.

Siponimod must be dispensed with a patient medication guide. The drug may increase the risk of infections or cause macular edema, transient decreases in heart rate, or a decline in lung function. Liver enzymes should be checked before initiating siponimod and closely monitored in patients with severe liver impairment. Health care professionals should monitor patients’ blood pressure during treatment. Women of childbearing potential should use effective contraception while taking siponimod and for 10 days after stopping the drug.

Health care professionals should also monitor patients for posterior reversible encephalopathy syndrome and patients who have had treatment with immunosuppressive or immune-modulating therapies.

Sources: Novartis, March 27, 2019; FDA., March 26, 2019

Jatenzo for Hypogonadism

Testosterone undecanoate (Jatenzo, Clarus Therapeutics) has received FDA approval for the treatment of men with certain forms of hypogonadism. These men have low testosterone levels because of specific medical conditions, such as genetic disorders like Klinefelter syndrome or tumors that have damaged the pituitary gland.

Testosterone undecanoate should not be used in men with age-related hypogonadism, even if their symptoms appear to be related to low testosterone. The drug’s benefits do not outweigh its risks for such use.

The new medication is administered via an oral capsule, whereas other available options are most commonly applied to the skin or injected.

Testosterone undecanoate’s efficacy was demonstrated in a four-month clinical trial involving 166 men with hypogonadism. Initially, patients received testosterone undecanoate 237 mg twice a day, and the dose was adjusted up or down to a maximum of 396 mg twice a day, based on testosterone levels. Eighty-seven percent of men receiving testosterone undecanoate achieved an average testosterone level within the normal range.

A boxed warning states that testosterone undecanoate can cause blood pressure to rise, increasing the risk of heart attack, stroke, and cardiovascular death. Health care providers should consider a patient’s individual heart-disease risks and ensure that blood pressure is adequately controlled before prescribing the drug; they also should periodically monitor blood pressure during treatment.

Common side effects in the trial included headache, an increase in hematocrit, a decrease in high-density lipoprotein cholesterol, high blood pressure, and nausea. An increase in prostate-specific antigen (PSA) was also observed. Patients should have their hematocrit, cholesterol, and PSA monitored regularly for changes. Those with benign prostate hyperplasia should be monitored for worsening of symptoms.

Source: FDA., March 27, 2019

Sunosi for Daytime Sleepiness

The FDA has approved solriamfetol (Sunosi, Jazz Pharmaceuticals) to improve wakefulness in adults with extreme daytime sleepiness associated with narcolepsy or obstructive sleep apnea (OSA). Solriamfetol is the first dual-acting dopamine and norepinephrine reuptake inhibitor approved for this indication.

OSA affects more than 18 million people in the U.S., and up to 200,000 people have narcolepsy. Once-daily solriamfetol is indicated with 75-mg and 150-mg doses for narcolepsy and 37.5-mg, 75-mg, and 150-mg doses for OSA.

Solriamfetol’s approval is based on results from the TONES phase 3 clinical program, which included four randomized, placebo-controlled studies demonstrating solriamfetol’s superiority to placebo. In 12-week clinical studies, approximately 68% to 74% of subjects taking solriamfetol 75 mg and 78% to 90% of subjects taking solriamfetol 150 mg reported improvement in their overall clinical condition as assessed by the Patient Global Impression of Change scale. The drug maintained its effect relative to placebo after six months of use.

The most common adverse reactions among patients with narcolepsy or OSA were headache, nausea, decreased appetite, and anxiety.

Solriamfetol is not indicated to treat OSA’s underlying airway obstruction, which should be treated for at least one month before beginning the drug for excessive daytime sleepiness in OSA. Modalities to treat the underlying airway obstruction should be continued during treatment with solriamfetol.

Source: Jazz Pharmaceuticals., March 20, 2019

Zulresso for Postpartum Depression

Brexanolone (Zulresso, Sage Therapeutics) has received FDA approval for the treatment of postpartum depression (PPD), making it the first treatment available for the most common medical complication of childbirth.

The approval of brexanolone is based on three multicenter, randomized, double-blind, parallel-group, placebo-controlled trials in women 18 to 45 years of age with moderate or severe PPD, who are six months or less postpartum at screening and have symptom onset no earlier than the third trimester and no later than the first four weeks after delivery. Brexanolone achieved the primary endpoint in all trials at all doses—a significant mean reduction from baseline in the Hamilton Rating Scale for Depression total score at 60 hours compared with placebo. Reduced symptoms were seen as early as 24 hours after taking the drug, which maintained its effect through the 30-day follow-up.

The most common adverse events in studies were sleepiness, dry mouth, loss of consciousness, and flushing. The drug is administered by continuous, 60-hour intravenous infusion. Brexanolone has a boxed warning about the risk of excessive sedation and sudden loss of consciousness during administration, and is available only under a risk evaluation and mitigation strategy (REMS).

Brexanolone is an allosteric modulator of both synaptic and extrasynaptic GABAA receptors.

Sources: Sage Therapeutics, March 19, 2019; Zulresso prescribing information., March 2019

Rocklatan for Intraocular Pressure

The FDA has approved netarsudil/latanoprost ophthalmic solution, 0.02%/0.005% (Rocklatan, Aerie Pharmaceuticals, Inc.) to reduce elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension.

The once-daily eye drop is a fixed-dose combination of latanoprost, a widely prescribed prostaglandin analog, and netarsudil, the active ingredient in Rhopressa (Aerie), a first-in-class Rho kinase inhibitor designed to target the trabecular meshwork. Diseased trabecular meshwork is considered to be the main cause of elevated IOP in open-angle glaucoma and ocular hypertension. Netarsudil works by restoring outflow through the trabecular meshwork, and latanoprost increases fluid outflow through a secondary mechanism, the uveoscleral pathway.

Netarsudil/latanoprost’s approval is based on data from two phase 3 registration trials, MERCURY 1 and MERCURY 2. An IOP reduction of 30% or higher was reported in more than 60% of patients taking netarsudil/latanoprost—almost twice the rate among patients taking latanoprost alone. Approximately twice as many patients taking netarsudil/latanoprost reached an IOP of 16 mmHg or lower and approximately three times as many patients reached 14 mmHg or lower, compared to those taking latanoprost alone.

The most common ocular adverse events in controlled clinical studies were conjunctival hyperemia, instillation-site pain, corneal verticillate, and conjunctival hemorrhage.

Source: Aerie Pharmaceuticals., March 12, 2019

Trazimera, a Herceptin Biosimilar

The FDA has approved trastuzumab-qyyp (Trazimera, Pfizer), a biosimilar to trastuzumab (Herceptin, Genentech), for the treatment of human epidermal growth factor receptor-2 (HER2)-overexpressing breast cancer and HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma.

The approval was based on the review of a comprehensive data package, which demonstrated a high degree of similarity between trastuzumab-qyyp and the originator product. This includes results from the REFLECTIONS B327-02 clinical comparative study, which showed clinical equivalence, finding a high degree of similarity and no clinically meaningful differences between trastuzumab-qyyp and the originator product in patients with first-line HER2-overexpressing metastatic breast cancer. Approximately 15% to 30% of breast cancers and 10% to 30% of gastric cancers are HER2-positive.

Trastuzumab-qyyp is the fourth biosimilar to Herceptin approved by the FDA.

Sources: FDA, March 14, 2019; Pfizer., March 11, 2019

Spravato for Depression

The FDA has approved esketamine nasal spray (Spravato, Janssen), in conjunction with an oral antidepressant, for treatment-resistant depression.

Esketamine has a boxed warning noting that patients are at risk for sedation and difficulty with attention, judgment, and thinking (dissociation), abuse and misuse, and suicidal thoughts and behaviors after administration of the drug. Esketamine is available only under a risk evaluation and mitigation strategy.

Patients self-administer esketamine under the instruction and supervision of a health care provider in a certified doctor’s office or clinic. Patients must be monitored by a health care provider for at least two hours after receiving their dose. During and after each use of the nasal spray, the provider will check the patient and determine when he or she is ready to leave. The spray device cannot be taken home. Both prescribers and patients must sign forms stating that patients understand they should arrange to get home safely and should not drive or use heavy machinery for the rest of the day. Esketamine must be dispensed with a patient medication guide.

Esketamine’s efficacy was evaluated in three four-week clinical trials and one longer-term maintenance-of-effect trial. In the three short-term studies, patients were randomized to receive esketamine or placebo nasal spray. All patients started a new oral antidepressant at the time of randomization and took it throughout the trials. The primary efficacy measure was the change from baseline on a scale used to assess the severity of depressive symptoms.

In one short-term study, esketamine demonstrated a statistically significant effect compared to placebo on the severity of depression, and some effect was seen within two days. The two other short-term trials did not meet the pre-specified statistical tests for effectiveness. In the longer-term maintenance-of-effect trial, patients in stable remission or with stable response who continued treatment with esketamine plus an oral antidepressant experienced a significantly longer time to relapse of symptoms than patients on placebo plus an oral antidepressant.

The most common side effects were dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, increased blood pressure, vomiting, and feeling drunk. Patients with unstable or poorly controlled hypertension or preexisting aneurysmal vascular disorders may be at increased risk for adverse cardiovascular or cerebrovascular effects.

The FDA granted esketamine fast track and breakthrough therapy designations.

Source: FDA., March 5, 2019

Generic Approvals

More Valsartan to Ease Shortage

The FDA has approved the marketing of a new generic version of valsartan by Alkem Laboratories Ltd.

Valsartan is an angiotensin II receptor blocker (ARB) that treats high blood pressure and heart failure. The FDA prioritized the review of Alkem’s application to help relieve a shortage of this critical medicine after multiple recalls of several manufacturers’ generic valsartan products were found to contain nitrosamine impurities.

As part of its investigation of nitrosamine impurities in generic ARBs, the agency is promoting new testing and manufacturing processes to help ensure ARBs are free from detectable levels of nitrosamine. In approving Alkem’s valsartan, the FDA evaluated the company’s manufacturing processes, ensuring it used appropriate testing methods to demonstrate that the drug does not contain N-Nitroso-dimethylamine or N-Nitrosodiethylamine.

Source: FDA., March 12, 2019

Pyridostigmine Bromide Syrup

Novitium Pharma secured FDA approval to market pyridostigmine bromide syrup, 60 mg/5 mL, the first generic version of Mestinon syrup (Bausch), 60 mg/5 mL. The drug is intended to improve muscle strength in patients with myasthenia gravis.

Source: FDA., March 8, 2019

Levofloxacin Ophthalmic Solution

Micro Labs Ltd. has received FDA permission to market levofloxacin ophthalmic solution, 1.5% for the treatment of corneal ulcer caused by susceptible bacterial strains. This is the first generic form of the discontinued brand product Iquix (Santen).

Source: FDA., February 27, 2019

Deferiprone Tablets

Taro Pharmaceutical Industries Ltd. has secured FDA approval to market 500-mg deferiprone tablets, the first generic version of 500-mg Ferriprox tablets (ApoPharma Inc). Deferiprone is used to treat patients with transfusional iron overload as a result of thalassemia syndromes when current chelation therapy is inadequate.

Source: FDA., February 8, 2019

Sevelamer Hydrochloride Tablets

The FDA has given Glenmark Pharmaceuticals permission to market 400-mg and 800-mg sevelamer hydrochloride tablets, the first generic version of Renagel (Genzyme) in these tablet strengths. Sevelamer is used to control serum phosphorus in patients with chronic kidney disease who are on dialysis.

Source: FDA., February 8, 2019

Levomilnacipran ER Capsules

Amneal Pharmaceuticals Company GmbH has received FDA permission to manufacture levomilnacipran extended-release (ER) capsules in 20-mg, 40-mg, 80-mg, and 120-mg strengths. This is the first generic version of Fetzima ER capsules (Allergan) in these strengths. Levomilnacipran is used for the treatment of major depressive disorder.

Source: FDA., February 4, 2019

Acyclovir Cream, 5%

Perrigo UK FINCO has won FDA approval to market acyclovir cream, 5%––the first generic version of Zovirax Cream, 5% (Bausch). Acyclovir cream is for recurrent herpes labialis (cold sores) in immunocompetent adults and adolescents aged 12 years and older.

Source: FDA., February 4, 2019

NEW INDICATIONS

Cimzia for Nonradiographic Axial Spondyloarthritis

Certolizumab pegol injection (Cimzia, UCB) has become the first FDA-approved treatment for adults with nonradiographic axial spondyloarthritis (nr-axSpA) with objective signs of inflammation.

Nr-axSpA is a type of inflammatory arthritis causing inflammation in the spine and other symptoms. It is called nonradiographic as no damage is visible on x-rays.

Certolizumab pegol’s safety was studied in a randomized clinical trial of 317 adults with nr-axSpA with objective signs of inflammation, indicated by elevated C-reactive protein levels and/or sacroiliitis on magnetic resonance imaging (MRI) scans. The trial measured the improvement response on the Ankylosing Spondylitis Disease Activity Score. Responses were greater for certolizumab pegol-treated patients than for placebo-treated patients. The overall safety profile in patients taking certolizumab pegol was consistent with the drug’s known safety profile.

The prescribing information for certolizumab pegol includes a boxed warning about the increased risk of serious infections leading to hospitalization or death, including tuberculosis, bacterial sepsis, invasive fungal infections, and other infections. The warning also advises that lymphoma and other malignancies, some fatal, have been reported in children and adolescents treated with tumor necrosis factor blockers such as certolizumab pegol. Certolizumab pegol must be dispensed with a patient medication guide.

Certolizumab pegol was originally approved in 2008 and is also indicated for adults with Crohn’s disease, moderate-to-severe rheumatoid arthritis, active ankylosing spondylitis, and moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

Source: FDA., March 28, 2019

Tecentriq for Extensive-Stage Small-Cell Lung Cancer

The FDA has approved atezolizumab (Tecentriq, Genentech) in combination with carboplatin and etoposide for the first-line treatment of adults with extensive-stage small-cell lung cancer (ES-SCLC).

The approval is based on results from the phase 3, multicenter, double-blind, randomized, placebo-controlled IMpower133 study. For patients receiving atezolizumab plus chemotherapy (carboplatin and etoposide) compared with those receiving chemotherapy alone, median overall survival was 12.3 months versus 10.3 months, and progression-free survival was 5.2 months versus 4.3 months. Safety for the atezolizumab/chemotherapy combination appeared to be consistent with the known safety profile of atezolizumab; the most common adverse reactions were fatigue/asthenia, nausea, alopecia, decreased appetite, constipation, and vomiting.

ES-SCLC is a highly aggressive, difficult-to-treat form of lung cancer with few treatment advances over the last two decades.

Atezolizumab is approved in combination with bevacizumab, paclitaxel, and carboplatin for the initial treatment of adults with metastatic nonsquamous non–small-cell lung cancer (NSCLC) with no EGFR or ALK genomic tumor aberrations, and for adults with metastatic NSCLC with disease progression during or after platinum-containing chemotherapy. Atezolizumab is also approved to treat urothelial carcinoma and triple-negative breast cancer.

Source: Genentech., March 18, 2019

Avycaz Use Extended To Pediatric Infections

The FDA has expanded the use of ceftazidime/avibactam (Avycaz, Allergan PLC) to include pediatric patients aged 3 months and older for the treatment of complicated intra-abdominal infections (cIAI) in combination with metronidazole, and complicated urinary tract infections (cUTI). This is the first FDA approval of a pediatric indication for cUTI and cIAI in more than a decade.

The expansion was approved based on results from two active-controlled clinical studies evaluating ceftazidime/avibactam in children or infants with cIAI or cUTI attributed to susceptible gram-negative microorganisms, as well as results from a single-dose pharmacokinetic study. In the cIAI study, the safety and efficacy of ceftazidime/avibactam (in combination with metronidazole) was compared with meropenem. In the cUTI study, ceftazidime/avibactam was compared with cefepime.

Across the trials, 128 pediatric patients were treated with ceftazidime/avibactam. Overall, the findings were similar to the previous determination of safety for ceftazidime/avibactam in adults with cIAI or cUTI, and no new safety concerns were identified in pediatric patients.

The studies’ primary objectives were to evaluate the safety and tolerability of ceftazidime/avibactam, and they were not powered for a statistical analysis of efficacy. The descriptive efficacy analyses in the pediatric studies were consistent with data from studies in adults with cIAI and cUTI.

Avibactam is a non–beta-lactam beta-lactamase inhibitor that protects ceftazidime against degradation by certain beta-lactamases. Ceftazadime is a third-generation cephalosporin.

Source: Allergan PLC., March 18, 2019

Dupixent for Atopic Dermatitis in Adolescents

Dupilumab (Dupixent, Regeneron/Sanofi) has secured FDA approval for the treatment of patients aged 12 to 17 years old with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.

In the pivotal phase 3 trial evaluating dupilumab monotherapy in adolescents with uncontrolled moderate-to-severe atopic dermatitis, safety and efficacy were generally consistent with that seen previously in adults, and was consistent through 52 weeks. At 16 weeks, the average improvement in the Eczema Area and Severity Index from baseline was approximately 66% for patients taking dupilumab compared with 24% for patients taking placebo. More than 10 times as many patients had clear or almost clear skin with dupilumab compared with placebo, as measured by an Investigator’s Global Assessment score of 0 or 1. Also, more than five times as many patients saw an overall disease improvement of at least 75% with dupilumab compared with placebo.

The most common adverse events were injection-site reactions; eye and eyelid inflammation including redness, swelling, and itching; oropharyngeal pain; and cold sores in the mouth or on the lips.

Dupilumab is a targeted biologic therapy that inhibits signaling of interleukin-4 and interleukin-13, key proteins that may play a central role in the type-2 inflammation that underlies atopic dermatitis and several other allergic diseases. Dupilumab is intended for subcutaneous injection every other week following an initial loading dose, and it can be used with or without topical corticosteroids.

The FDA gave this application priority review and breakthrough therapy designations.

Source: Regeneron/Sanofi., March 12, 2019

Tecentriq for Metastatic Triple-Negative Breast Cancer

The FDA has granted accelerated approval to atezolizumab (Tecentriq, Genentech) plus nab-paclitaxel chemotherapy for the treatment of unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) in adults whose tumors express programmed death ligand-1 (PD-L1) as determined by an FDA-approved test. This is the first immunotherapy regimen to be approved for breast cancer.

The accelerated approval is based on data from IMpassion130, a phase 3, multicenter, randomized, double-blind study, which showed that atezolizumab plus nab-paclitaxel improved progression-free survival by 40% (to 7.4 months) compared with nab-paclitaxel alone (4.8 months) in PD-L1–positive patients with unresectable locally advanced or metastatic TNBC who had not received prior chemotherapy for metastatic disease. Overall survival results were immature.

In the atezolizumab/nab-paclitaxel arm, safety appeared consistent with the known safety profiles of the individual medicines. The most common grade 3 and 4 side effects were low white-blood cell count, tingling or numbness in the hands and feet, decreased neutrophil count, feeling tired, low red-blood cell levels, low blood-potassium level, pneumonia, and increased aspartate aminotransferase. The most common side effects were hair loss, feeling tired, tingling or numbness in the hands and feet, nausea, diarrhea, low red-blood cell levels, constipation, cough, headache, low white-blood cell levels, decreased appetite, and vomiting.

TNBC represents 15% of all breast cancers and is more common in women younger than 50 years compared with other breast cancers. It is defined by the lack of expression and/or amplification of the targetable receptors for estrogen, progesterone, and HER2 amplification. Patients with metastatic TNBC generally experience rapid progression and shorter overall survival compared with other subtypes of breast cancer.

This indication received accelerated approval based on progression-free survival; continued approval may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Source: Genentech., March 8, 2019

Soliqua 100/33 for More Diabetes Cases

The FDA recently approved the expanded use of insulin glargine and lixisenatide injection, 100 units/mL and 33 mcg/mL (Soliqua 100/33, Sanofi). Previously approved as an add-on to diet and exercise in adults with type-2 diabetes mellitus (T2DM) who are uncontrolled on long-acting insulin or lixisenatide, insulin glargine and lixisenatide injection 100/33 can now be prescribed for patients uncontrolled on oral antidiabetic medicine.

The approval was based on data from the LixiLan-O clinical trial that showed, in adults with T2DM uncontrolled with metformin and/or a second oral antidiabetic therapy, that treatment with insulin glargine and lixisenatide injection 100/33 led to significantly greater reductions in blood sugar levels compared with insulin glargine and lixisenatide (−1.6%, −1.3%, and −0.9%, respectively). In addition, significantly more patients reached their target blood-sugar levels with insulin glargine and lixisenatide injection (74%) compared with insulin glargine (59%) or lixisenatide (33%).

Low blood-sugar events were similar between insulin glargine and lixisenatide injection (25.6%) and insulin glargine (23.6%) but lower with lixisenatide (6.4%). The most common adverse events, generally occurring at the beginning of treatment in the insulin glargine and lixisenatide injection 100/33 arm, were nausea and vomiting.

Lixisenatide is a glucagon-like peptide-1 receptor agonist.

Source: Sanofi., February 27, 2019

IV Push for Cinvanti

The FDA has approved a two-minute intravenous (IV) injection of aprepitant injectable emulsion (Cinvanti, Heron Therapeutics, Inc.) in addition to the previously approved administration method, a 30-minute IV infusion.

Aprepitant injectable emulsion, a polysorbate 80–free IV formulation of the substance P/neurokinin-1 receptor antagonist aprepitant, is indicated for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV). Aprepitant significantly reduces CINV in both the acute phase (up to 24 hours after chemotherapy) and the delayed phase (24 to 120 hours after chemotherapy).

The new method of administration was approved based on a study demonstrating bioequivalence and a comparable safety profile to IV fosaprepitant (Emend, Merck) when aprepitant is given as a 30-minute IV infusion and as a two-minute IV injection, also referred to as an IV push. In two other studies, patients receiving aprepitant reported fewer adverse events than those receiving fosaprepitant IV, including substantially fewer infusion-site reactions.

Source: Heron Therapeutics, Inc.., February 26, 2019

NEW FORMULATIONS

Herceptin Hylecta for Some HER2-Positive Breast Cancer

The FDA has approved trastuzumab/hyaluronidase-oysk for subcutaneous injection (Herceptin Hylecta, Genentech) to treat certain people with HER2-positive early breast cancer (node-positive, or node-negative and estrogen receptor/progesterone receptor–negative or with one high-risk feature) in combination with chemotherapy and HER2-positive metastatic breast cancer in combination with paclitaxel, or alone in people who have received one or more chemotherapy regimens for metastatic disease.

This new treatment includes the same monoclonal antibody as IV trastuzumab (Herceptin, Genentech) in combination with recombinant human hyaluronidase PH20, an enzyme that helps deliver trastuzumab under the skin. Trastuzumab/hyaluronidase-oysk is a ready-to-use formulation that can be administered in two to five minutes, compared with 30 to 90 minutes for IV trastuzumab.

The approval is based on three clinical studies in HER2-positive early breast cancer. The phase 3 HannaH study compared neoadjuvant and adjuvant trastuzumab/hyaluronidase-oysk to IV trastuzumab, both in combination with chemotherapy. The subcutaneous administration of trastuzumab/hyaluron-idase-oysk resulted in noninferior levels of trastuzumab in the blood and non-inferior clinical efficacy compared to IV trastuzumab. The phase 3 SafeHER study of adjuvant trastuzumab/hyaluronidase-oysk identified no new safety signals. And the Pref-HER patient preference study of adjuvant trastuzumab/hyaluronidase-oysk followed by IV trastuzumab, or the reverse sequence, found that 86% of people preferred trastuzumab/hyaluronidase-oysk over IV trastuzumab.

The most common side effects with trastuzumab/hyaluronidase-oysk for early breast cancer were joint pain, feeling tired, diarrhea, injection-site reaction, upper respiratory tract infection, rash, muscle pain, nausea, headache, swelling, flushing, fever, cough, and pain in extremity.

Trastuzumab is designed to block HER2 signaling that is believed to play a role in tumor growth and survival. Herceptin Hylecta adds Halozyme Therapeutics’ Enhanze drug-delivery technology, based on a proprietary recombinant human hyaluronidase PH20—an enzyme that temporarily degrades the glycosaminoglycan hyaluronan to aid in the dispersion and absorption of other injected therapeutic drugs.

Source: Genentech., February 28, 2019

Adhansia XR for ADHD

The FDA has approved methylphenidate hydrochloride extended-release capsules, CII (Adhansia XR, Adlon Therapeutics L.P.), for the treatment of attention-deficit/hyperactivity disorder (ADHD) in patients aged 6 years and older.

The approval was based on four clinical studies evaluating the drug’s efficacy and safety in patients with ADHD. One double-blind, randomized, placebo-controlled crossover study simulated an adult workplace environment (AWE). Efficacy assessments were conducted pre-dose and at 1, 2, 5, 8, 11, 14, and 16 hours post-dose. Adults receiving methylphenidate hydrochloride XR had a statistically significant improvement compared with those receiving placebo, achieving greater mean permanent measure of performance total (PERMP-T) scores averaged across all-time points on AWE days (post-dose scores, 281.3 vs. 254.5, respectively). Methylphenidate hydrochloride XR demonstrated statistically significant improvement over placebo in PERMP-T scores at 1, 2, 5, 8, 11, and 16 hours post-dose, but not at 14 hours post-dose.

Ten percent of methylphenidate hydrochloride XR patients discontinued treatment as a result of adverse reactions including nausea, bronchitis, viral gastroenteritis, viral infection, increased blood pressure, and hypomania.

Methylphenidate hydrochloride XR has a boxed warning about the potential for abuse and dependence. Prescription stimulants, including methylphenidate, are federally controlled Schedule II substances.

Adlon Therapeutics is a subsidiary of Purdue Pharma L.P.

Source: Adlon Therapeutics L.P.., March 1, 2019

Tremfya One-Press Injector

The FDA has approved a single-dose, patient-controlled guselkumab injector (Tremfya One-Press, Janssen) for adults with moderate-to-severe plaque psoriasis. The device fits in the hand and offers a controlled 100-mg subcutaneous injection that hides the needle throughout the process. Patients self-inject after physician approval and proper training.

Guselkumab’s efficacy and safety when administered with One-Press in patients with moderate-to-severe plaque psoriasis was evaluated in the double-blind, placebo-controlled ORION study. At week 16 among patients using guselkumab, 81% had an investigator’s global assessment (IGA) score of 0 or 1, 76% had a psoriasis area severity index (PASI) 90 response, 56% had an IGA score of 0, and 50% had a PASI 100 response, versus 0% for all these measures among patients using placebo.

In a questionnaire assessing patient experience with One-Press on a scale of 0 to 10, mean scores for satisfaction and ease of use were 9.18 and 9.24, respectively.

Source: Janssen., February 27, 2019

DRUG REINTRODUCTION

Zelnorm for IBS-C

The FDA has approved the reintroduction of tegaserod (Zelnorm, Sloan Pharma, SARL), a twice-daily oral treatment for irritable bowel syndrome with constipation (IBS-C) in women under the age of 65.

After its first approval in 2002, tegaserod became the prescription market leader for IBS-C in women. However, it was voluntarily withdrawn from the U.S. market in 2007 after a safety analysis found a higher chance of heart attack, stroke, and unstable angina in patients receiving tegaserod compared with placebo. Tegaserod remained available in the U.S. through an FDA-authorized expanded-access program.

The approval to reintroduce tegaserod comes after a complete safety review by the FDA and an FDA-assembled Gastrointestinal Drugs Advisory Committee. The review focused on the evaluation of data from 29 placebo-controlled trials and newly available sources of treatment-outcome data.

Tegaserod is a selective serotonin-4 (5-HT4) receptor agonist. In the first four weeks of trials, significantly more tegaserod patients than placebo patients reported improvement in abdominal pain, discomfort, and bloating. Frequency of bowel movements increased from a median of 3.8 per week at baseline to 6.3 per week at month one.

Tegaserod can cause serious side effects, including major cardiovascular events (some fatal), ischemic colitis and other intestinal problems, diarrhea (sometimes severe), and an increased risk of suicidal thoughts and behavior. The most common side effects are headache, abdominal pain, nausea, diarrhea, flatulence, dyspepsia, and dizziness.

Sources: U.S. WorldMeds, April 1, 2019; FDA, July 26, 2018

FDA REVIEW ACTIVITIES

Breakthrough Therapy Status

MT1621 for TK2 Deficiency

The FDA has granted a breakthrough therapy designation for MT1621 (Modis Therapeutics), a treatment for patients who have thymidine kinase 2 deficiency (TK2d).

TK2d is a genetic disorder that results in mitochondrial dysfunction, leading to inadequate energy production in cells. It presents at all ages and causes progressive and severe muscle weakness and respiratory insufficiency. TK2D is often fatal and there are no approved therapies.

MT1621 is an investigational deoxynucleoside combination therapy that targets the underlying pathophysiology of TK2d. In preclinical models, deoxynucleoside combination therapy has been shown to improve cell function and prolong life. Data from initial clinical studies suggest that this therapy may meaningfully alter the course of disease.

Source: Modis Therapeutics., February 19, 2019

CP101 for Recurrent Clostridium Difficile Infection

Finch Therapeutics Group has received an FDA breakthrough therapy designation for its drug CP101, intended to prevent recurrent Clostridium difficile infection.

Finch is actively enrolling patients with recurrent C. difficile in PRISM3, a randomized, placebo-controlled phase 2 clinical study. CP101 is an oral capsule administered in a single dose.

Source: Finch Therapeutics Group., February 8, 2019

Fast-Track Designations

MV-CHIK for Chikungunya

The FDA has granted a fast-track designation to Themis Bioscience for its vaccine candidate MV-CHIK for the prevention of chikungunya, a debilitating disease with global outbreak potential. The MV-CHIK program is the most advanced chikungunya vaccine candidate and it has already successfully completed phase 2 clinical development.

Source: Themis Bioscience., February 25, 2019

ARS-1 Epinephrine Spray for Allergic Reaction

ARS Pharmaceuticals, Inc. has received an FDA fast-track designation for ARS-1, intranasal epinephrine for severe allergic reactions to food, medications, and insect bites.

ARS-1 is an aqueous formulation of epinephrine nasal spray developed with Intravail, a nasal absorption-enhancing technology. ARS-1 has demonstrated comparable pharmacokinetics to an intramuscular injection of epinephrine in clinical studies using a low and safe intranasal dose.

ARS-1 is designed to be user-friendly, needle-free, and easily portable. The spray formulation may enable people to deliver epinephrine in emergencies more quickly and with less hesitation compared with available epinephrine auto-injectors.

Source: ARS Pharmaceuticals., February 19, 2019

Priority Review Status

Dupixent for Severe Chronic Rhinosinusitis With Nasal Polyps

The FDA has accepted for priority review the supplemental biologics license application for dupilumab (Dupixent, Regeneron/Sanofi) as an add-on maintenance treatment for adults with inadequately controlled severe chronic rhinosinusitis with nasal polyps (CRSwNP). The target action date for the FDA decision is June 26, 2019.

CRSwNP is a chronic upper-airway disease predominantly driven by type-2 inflammation and characterized by polyps that obstruct the sinuses and nasal passages. Patients often experience recurrence despite surgery and/or systemic corticosteroids. People with comorbid asthma and CRSwNP tend to have more severe disease and are often more difficult to treat. There are no FDA-approved biologic medicines to treat CRSwNP.

Dupilumab is a human monoclonal antibody designed to inhibit the signaling of interleukin-4 and interleukin-13, key proteins that play a central role in type-2 inflammation.

The application is supported by data from two phase 3 trials evaluating dupilumab combined with standard-of-care corticosteroid nasal spray in patients with recurring severe CRSwNP despite previous treatment with surgery and/or systemic corticosteroids.

Source: Regeneron and Sanofi., March 8, 2019

Emgality Injection for Episodic Cluster Headache

Eli Lilly and Company has been granted a priority review designation for galcanezumab-gnlm injection (Emgality), a preventive treatment for episodic cluster headache in adults. The decision is based on data from a phase 3 study involving 106 adults with episodic cluster headache.

Cluster headache, part of the group of primary headache disorders called trigeminal autonomic cephalalgias, is under-recognized and often misdiagnosed. People with episodic cluster headache represent 85% to 90% of cluster-headache sufferers. The pain associated with cluster headache can be deep, searing, burning, and stabbing. There are no approved preventive medications in the U.S.

The FDA approved Emgality in September 2018 for the preventive treatment of migraine in adults.

Source: Eli Lilly and Company., March 5, 2019

Fedratinib for Myelofibrosis

The FDA has accepted a new drug application for fedratinib (Celgene Corp.) and granted priority review, with a target action date of September 3, 2019.

Fedratinib is a highly selective Janus kinase 2 inhibitor for the treatment of myelofibrosis, a bone marrow disorder that disrupts the production of blood cells. Bone marrow is gradually replaced with fibrous scar tissue, which limits the marrow’s ability to make red blood cells. The disorder can lead to anemia, weakness, fatigue, and swelling of the spleen and liver, among other symptoms.

The application for fedratinib is based on results from a phase 3 trial (JAKARTA) in patients with primary or secondary myelofibrosis, as well as a single-arm, open-label phase 2 trial (JAKARTA2) in patients with primary or secondary myelofibrosis previously exposed to ruxolitinib (Jakafi, Incyte), the only FDA-approved treatment for the disease.

The FDA placed a clinical hold on the fedratinib program in November 2013 after potential cases of Wernicke’s encephalopathy were reported among subjects (approximately 1%) in clinical trials. The agency removed the clinical hold in August 2017.

Source: Celgene., March 5, 2019

Soliris for Neuromyelitis Optica Spectrum Disorder

The FDA has accepted with priority review a supplemental biologics license application for eculizumab (Soliris, Alexion Pharmaceuticals) as a treatment for patients with neuromyelitis optica spectrum disorder (NMOSD) who have anti-aquaporin-4 (AQP4) auto-antibodies. The application is supported by data from the PREVENT study.

NMOSD is a complement-mediated disorder of the central nervous system (CNS). Patients experience an unpredictable, relapsing, and deteriorating course of disease, with each relapse adding to disability and potentially leading to death. Optic neuritis can cause eye pain and blindness. Transverse myelitis can cause severe weakness, impaired mobility, sensory and motor disability, loss of bowel and bladder function, paralysis, and respiratory failure. Many patients sustain permanent, severe disability or die within six years of onset.

Three-quarters of NMOSD patients have anti-AQP4 auto-antibodies. AQP4 is a protein in certain brain and spinal cord cells that is critical for the survival of nerve cells. The binding of anti-AQP4 auto-antibodies activates the complement cascade, leading to the destruction of vital cells in the CNS, demyelination, and neuron death. Eculizumab inhibits the C5 protein in the terminal part of the complement cascade.

The Prescription Drug User Fee Act action date is June 28, 2019.

Source: Alexion Pharmaceuticals., February 22, 2019

Keytruda for Advanced Small-Cell Lung Cancer

The FDA has accepted and granted priority review for a new supplemental biologics license application for pembrolizumab (Keytruda, Merck) as monotherapy for patients with advanced small-cell lung cancer (SCLC) whose disease has progressed after two or more lines of prior therapy. The agency has set a target action date of June 17, 2019.

SCLC accounts for about 10% to 15% of lung cancers. The five-year survival rate in the U.S. for patients diagnosed with any stage of SCLC is estimated to be 6%.

Pembrolizumab, a humanized monoclonal antibody, increases the immune system’s ability to help detect and fight tumor cells by blocking the interaction between programmed death (PD)-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes.

The new application is based on data from the SCLC cohorts of the phase 2 KEYNOTE-158 trial and phase 1b KEYNOTE-028 trial. Pembrolizumab is being studied in combination with chemotherapy in the ongoing phase 3 KEYNOTE-604 study in patients with newly diagnosed extensive-stage SCLC.

Source: Merck., February 20, 2019

Polatuzumab Vedotin for Lymphoma

Genentech has been granted a priority review for polatuzumab vedotin in combination with bendamustine plus rituximab (Rituxan, Genentech) for the treatment of people with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). The FDA is expected to rule by August 19, 2019.

DLBCL is the most common form of non-Hodgkin’s lymphoma (NHL), accounting for approximately one in three cases. As many as 40% of patients relapse, at which point their prognosis is poor.

Polatuzumab vedotin is a first-in-class anti-CD79b antibody drug. The CD79b protein is highly specific and expressed in most types of B-cell NHL. Polatuzumab vedotin binds to CD79b and destroys these B cells through a targeted approach that is thought to minimize the effects on normal cells while maximizing tumor-cell death.

The FDA’s priority review decision is based on results of the GO29365 study. Polatuzumab vedotin, bendamustine, and rituximab, compared with bendamustine and rituximab alone: 1) improved median overall survival (12.4 vs. 4.7 months) in people with relapsed or refractory DLBCL not eligible for a hematopoietic stem-cell transplant; 2) led to a complete response in more patients (40% vs. 18%); and 3) increased median progression-free survival (7.6 vs. 2.0 months).

Source: Genentech., February 18, 2019

Entrectinib for Solid Tumors and NSCLC

The FDA has accepted for priority review Genentech’s applications for entrectinib in the treatment of patients with neurotrophic tropomyosin receptor kinase (NTRK) fusion-positive, locally advanced or metastatic solid tumors who have progressed following prior therapies or as initial therapy when there are no acceptable standard therapies, and for the treatment of patients with metastatic, ROS1-positive non–small-cell lung cancer (NSCLC).

Entrectinib (previously RXDX-101) is a selective tyrosine kinase inhibitor. In an integrated analysis of four phase 1 and phase 2 trials, entrectinib shrank tumors in more than half of people with NTRK fusion-positive solid tumors. Objective responses were seen across 10 solid tumor types, including people with and without CNS metastases at baseline. In these studies, entrectinib shrank tumors that had spread to the brain in 54% of patients, with more than a quarter of patients having a complete response.

Entrectinib shrank tumors in 77% of patients with locally advanced or metastatic ROS1-positive NSCLC and demonstrated a durable response of more than two years. The agent was shown to shrink intracranial tumors in 55% of patients with CNS metastases at baseline.

The FDA is expected to make a decision on approval by August 18, 2019.

Source: Genentech., February 19, 2019

Keytruda Plus Inlyta for Advanced Renal Cell Carcinoma

The FDA has granted priority review for pembrolizumab (Keytruda, Merck), an anti-programmed death-1 therapy, in combination with axitinib (Inlyta, Pfizer), a tyrosine kinase inhibitor, for the first-line treatment of patients with advanced renal cell carcinoma (RCC), which accounts for approximately nine out of 10 kidney cancers.

The phase 3 KEYNOTE-426 trial demonstrated that pembrolizumab in combination with axitinib, compared to sunitinib (Sutent, Pfizer), significantly improved overall survival and progression-free-survival in the first-line treatment of advanced RCC.

Source: Merck., February 15, 2019

Orphan Drug Designations

Etoposide Toniribate for Biliary Tract Cancer

Mundipharma EDO GmbH and Imbrium Therapeutics have received an orphan drug designation for etoposide toniribate for the treatment of relapsed/refractory biliary tract cancer.

Biliary tract cancer can develop in any part of the bile duct system. Radical surgery is the only curative treatment, but in most cases the cancer is inoperable. When first-line chemotherapy fails, patients have limited treatment options. The five-year survival rate is approximately 15%.

Etoposide toniribate metabolizes into its active form through enzymes in the gastrointestinal tract that are particularly active in cancer cells. Activated etoposide binds to and inhibits topoisomerase II, which is often elevated in tumors, resulting in damage to the tumor DNA and apoptosis.

Results of a phase 2 trial of 23 patients with refractory, metastatic, unresectable biliary tract cancer, who had relapsed following treatment with gemcitabine/cisplatin, showed a one-year overall survival rate of 44.4% with etoposide toniribate versus a rate of 11.3% with best supportive care (BSC). Overall, 55.6% of patients met the primary endpoint of disease control compared with 20% who received BSC.

Source: Mundipharma EDO GmbH and Imbrium Therapeutics., February 22, 2019

Verdiperstat for Multiple System Atrophy

Biohaven Pharmaceutical Holding Company Ltd. has received an orphan drug designation for verdiperstat (previously BHV-3241) for the treatment of multiple system atrophy (MSA).

MSA is a rare, rapidly progressive, and fatal neurodegenerative disease that leads to death after an average of six to 10 years from onset. MSA causes Parkinson’s disease-like movement problems, cerebellar ataxia, and problems with autonomic functions, including blood pressure control, bladder function, and digestion.

Verdiperstat is a potential first-in-class, oral, brain-penetrant, irreversible inhibitor of myeloperoxidase (MPO), an enzyme that acts as a key driver of pathological oxidative stress and inflammation in the brain.

In a phase 2a trial, after 12 weeks of treatment, placebo-treated patients worsened by 4.6 points on the Unified MSA Rating Scale, and verdiperstat-treated patients worsened by 3.7 points at the 300-mg twice-daily dose and by 2.6 points at the 600-mg twice-daily dose. Verdiperstat also significantly reduced MPO activity in human blood. Verdiperstat has been generally safe and well tolerated in approximately 250 patients.

Source: Biohaven Pharmaceuticals., February 19, 2019

OCU400 for Retinal Degenerative Disease

The FDA has granted an orphan drug designation for OCU400 (Ocugen) for the treatment of NR2E3 mutation-associated retinal degenerative disease. Inherited retinal diseases (IRDs) are caused by genetic mutations that lead to visual impairment and blindness.

OCU400 is a novel gene therapy with the potential to be broadly effective at restoring retinal integrity and function across a range of genetically diverse IRDs. Consisting of a functional copy of the nuclear hormone receptor gene NR2E3, OCU400 is delivered to target cells in the retina using an adeno-associated viral vector. Expression of the potent modifier gene NR2E3 within the retina may help reset retinal homeostasis, stabilizing cells and potentially rescuing photoreceptor degeneration. In a mouse model, NR2E3 delivery to retinal cells reversed disease progression.

Ocugen plans to initiate a phase 1/2a clinical study by 2020.

Source: Ocugen., February 14, 2019

Complete Response Letters

IV Meloxicam for Pain

Recro Pharma, Inc. has received a second complete response letter from the FDA about its application seeking approval for intravenous (IV) meloxicam for the management of moderate-to-severe pain. Recro officials expressed disappointment and vowed to work closely with the FDA to determine the best path forward to obtain approval.

The FDA’s new comments focused on the onset and duration of IV meloxicam, noting that the delayed onset fails to meet prescriber expectations for IV drugs. The letter also cited regulatory concerns about the role of IV meloxicam as a monotherapy in acute pain, as well as how it would meet patient and prescriber needs in that setting, given the FDA’s interpretation of the clinical trials data. The company strongly disagrees with the interpretation and the agency’s views on the clinical utility of IV meloxicam in the acute pain setting.

Source: Recro Pharma, Inc.., March 22, 2019

Zynquista for Type-1 Diabetes

The FDA has issued a complete response letter on the new drug application for investigational sotagliflozin (Zynquista, Lexicon Pharmaceuticals/Sanofi), a dual sodium-glucose cotransporter 1 and 2 inhibitor for the treatment of adults with type-1 diabetes in combination with insulin. Sanofi and Lexicon will work closely with the FDA to determine the appropriate next steps.

Source: Lexicon Pharmaceuticals, Inc.., March 22, 2019

DRUG SAFETY ISSUES

Guardian Told to Halt Compounding of Drugs

A federal court has ordered a Texas company to stop compounding drug products intended to be sterile until it complies with the federal Food, Drug, and Cosmetic Act (FD&C Act) and other requirements. The government says the company continued to violate the law despite previous FDA warnings, putting patients at risk.

U.S. Chief District Judge Barbara M.G. Lynn for the Northern District of Texas entered a consent decree of permanent injunction against JMA Partners, Inc., doing business as Guardian Pharmacy Services in Dallas, as well as company owner Jack R. Munn.

The government alleges that Guardian manufactured and distributed purportedly sterile drug products that were adulterated because they were made under unsanitary conditions and in violation of current good manufacturing practice requirements. The complaint also charges that Guardian manufactured and distributed misbranded drugs.

Compounding facilities that are not registered as outsourcing facilities can compound drugs only pursuant to valid patient-specific prescriptions. Despite repeated warnings that Guardian was in violation of the law, the government says, it continued to distribute more than half of its drugs for “office stock” throughout the country even though it did not produce those drugs in compliance with current good manufacturing practice regulations, nor did it receive new drug approvals or provide adequate directions for use.

In 2017, the FDA received adverse event reports concerning at least 43 patients who were administered eye injections during cataract surgery of a drug compounded by Guardian containing triamcinolone and moxifloxacin. An FDA investigation of the product revealed a high percentage of an excipient, poloxamer 407, and the presence of potential process-degradation products.

Source: FDA., March 12, 2019

DEVICE APPROVALS

New Alloy for Implants

The FDA has given 510(k) approval to the Europa Pedicle Screw System (MiRus)—the first agency-approved medical device using a new implant material called MoRe. This proprietary molybdenum rhenium alloy provides unprecedented strength, ductility, durability, and biological safety, MiRus says.

MoRe permits the design of smaller, stronger implants that will result in less soft-tissue disruption, quicker recovery, and better outcomes for patients undergoing a variety of surgical procedures for spinal, orthopedic, and other issues.

MoRe is the first alloy approved by the FDA for use in an implant that is not based on titanium, cobalt, or iron. The FDA requires a rigorous scientific investigation to establish the safety and effectiveness of a spine implant that utilizes a new medical alloy. MiRus developed a body of evidence that served as the basis for approval.

Source: MiRus., March 27, 2019

Optimizer Smart System For Chronic Heart Failure

The FDA has approved the Optimizer Smart system (Impulse Dynamics [USA]) for patients with chronic, moderate-to-severe heart failure who are not suited for treatment with other heart-failure devices such as cardiac resynchronization therapy to restore a normal timing pattern of the heartbeat.

About 5.7 million people in the United States have heart failure, and treatment options are limited for those with moderate-to-severe chronic disease.

The Optimizer Smart system has several components, including an implantable pulse generator, battery charger, programmer, and software. The pulse generator is implanted under the skin in the upper left or right chest and connected to three leads that are implanted in the heart. Then a physician tests and programs the device, which delivers electrical impulses to the heart during regular heartbeats to help improve its squeezing capability.

The FDA evaluated data from two randomized, multicenter clinical trials with 389 patients who had moderate-to-severe heart failure. All patients received optimal medical therapy, and 191 also received an Optimizer Smart system implant. Patients receiving the implant showed improvements in the distance they were able to walk in six-minute walking tests and improvements on standard assessments to measure heart-failure symptoms, such as how much the symptoms affect quality of life and how much the symptoms impede daily physical activities, compared with patients who received only medical therapy.

The Optimizer Smart system is indicated to improve six-minute walking distance ability, quality of life, and functional status of certain patients with heart failure. These patients have a marked limitation of physical activity and remain symptomatic despite optimal medical therapy. Patients should also have a regular heart rhythm, not be candidates for cardiac resynchronization therapy, and have a left-ventricular ejection fraction of 25% to 45%.

Potential complications associated with use of the device include infection, bleeding, or worsened heart failure, or problems with the device itself, such as a dislodgement or fracture of the leads implanted in the heart.

The FDA granted the Optimizer Smart system a breakthrough device designation.

Source: FDA., March 21, 2019

ClearMate for CO Poisoning

The FDA has allowed the marketing of ClearMate (Thornhill Research, Inc.), a device intended for use in emergency departments to help treat poisoning from carbon monoxide (CO). The device uses a novel method for quickly removing CO from the body by increasing a patient’s rate of breathing.

Each year in the U.S., approximately 500 people die from, and as many as 20,000 people visit emergency rooms for, unintended CO exposure. While the current standard treatment, administering 100% oxygen through a mask, can be done anywhere, only 60 medical centers nationwide have the hyperbaric units that are required to treat severe CO poisoning.

ClearMate—which consists of a gas mixer, valves, meters, breathing circuits, an oxygen reservoir, a mask, and hoses—speeds the elimination of CO from the body. It delivers both 100% oxygen and a mixture of oxygen and carbon dioxide, causing the patient to breathe faster. The increased breathing accelerates the rate at which the CO leaves the patient’s body.

The FDA reviewed data from multiple clinical studies that tested the effectiveness of the device on 100 patients. The studies demonstrated that the device was effective at eliminating CO. The combination of oxygen and carbon dioxide in ClearMate resulted in a faster elimination of CO than treatment with 100% oxygen alone, but was not faster than hyperbaric oxygen therapy. Patients did not experience any device-related complications in the clinical studies of efficacy or in a separate study of the device’s safety.

ClearMate was reviewed under the FDA’s de novo premarket review pathway.

Source: FDA., March 14, 2019

MitraClip Valve Use Expanded

The FDA has approved a new indication for a heart-valve repair device intended to reduce moderate-to-severe/severe mitral regurgitation.

When first approved in 2013, the Mitra-Clip Clip Delivery System (Abbott Vascular Inc.) was indicated to reduce mitral regurgitation in patients whose significant mitral regurgitation and heart failure symptoms result from abnormalities of the mitral valve (primary or degenerative mitral regurgitation) and whose risks for mitral valve surgery are prohibitive. The new indication covers patients with normal mitral valves who develop heart-failure symptoms and moderate-to-severe/severe mitral regurgitation because of diminished left-heart function (secondary or functional mitral regurgitation), despite being treated with optimal medical therapy.

The MitraClip is inserted in a minimally invasive procedure through the femoral vein and guided into the heart’s left ventricle, where it grasps the two leaflets of the mitral valve—clipping them together to reduce the backflow of blood.

The approval is based on a study of 614 patients with heart failure, with moderate-to-severe or severe secondary mitral regurgitation, who were randomly assigned either to continue their optimized medication treatment plus the MitraClip or to continue their optimized medication treatment only. In the Mitra-Clip group compared with the control group, risk of rehospitalization for heart-failure symptoms was reduced by approximately 47% and risk of death within two years decreased by approximately 37%.

Potential adverse events from device and implant procedure include death, stroke, major bleeding, and atrial fibrillation. The MitraClip is contra-indicated in patients who cannot tolerate blood thinners during or after the procedure or who have endocarditis of the mitral valve, rheumatic mitral valve disease, or evidence of blood clots in the heart or in veins leading to the heart.

Source: FDA., March 14, 2019

Accurian Nerve Ablation for Pain

Medtronic has received FDA clearance for its Accurian radio-frequency ablation system for nerve tissues, designed to treat chronic pain via a minimally invasive procedure.

A current produced by radio waves heats up small patches of nerves, preventing them from sending pain signals. Advanced software controls the amount of power delivered and the temperature of the procedure, ensuring more consistent and predictable lesion formations.

Accurian can perform standard, pulsed, and enhanced ablation procedures using internally cooled radio-frequency probes to create various lesion shapes, sizes, and volumes. It has independent channel control and chip-enhanced probes for easy on-screen identification, and smart features including downloadable procedure reports.

Source: FierceBiotech and Medtronic., February 27, 2019

Rosa One Spine System

The FDA has awarded 510(k) clearance to the Rosa One Spine System (Zimmer Biomet Holdings, Inc.) for robotically assisted thoracolumbar minimally invasive and complex spine surgeries.

Rosa One Spine combines robotics and navigation while delivering real-time patient “dynamic tracking” capability. The platform features 3D intraoperative planning software in addition to a navigation suite of technologies designed to improve implant as well as the accuracy and predictability of instrument placement.

Source: Zimmer Biomet., March 25, 2019

sTMS for Adolescent Migraine

The FDA has given a new 510(k) clearance to sTMS (eNeura, Inc.) expanding its indication—for acute and preventive treatment of migraine—to include children aged 12 years and older. eNeura received clearance for the indication in adults in 2017.

The noninvasive sTMS utilizes single-pulse transcranial magnetic stimulation (sTMS) to induce a mild electric current that modulates nerve cells in the brain; this is believed to interrupt the brain hyperactivity associated with migraine. Patients place the device at the back of their head and push a button to deliver a focused magnetic pulse. Clinical trials have shown that sTMS is as effective as migraine medications, without the risks or unwanted side effects.

Source: eNeura, Inc.., Febrary 27, 2019

DEVICE SAFETY ISSUES

Breast-Implant Warnings

The FDA has issued warning letters to two breast-implant manufacturers for failure to comply with their requirements, under their premarket approval orders, to conduct post-approval studies to assess the long-term safety and risks of their silicone-gel-filled implants. The warnings were sent to Mentor Worldwide LLC in Irvine, and Sientra, Inc. in Santa Barbara, both in California. The agency cited the low recruitment, poor data, and low follow-up rates in the manufacturers’ required post-approval studies.

Source: FDA., March 18, 2019

Surgical Staples and Staplers Tied to Deaths, Serious Injury

Surgical staples and staplers were implicated in 366 deaths, more than 9,000 serious injuries, and more than 32,000 malfunctions in seven-and-one-quarter years, the FDA says.

The agency has issued a “letter to health care providers” highlighting the increasing number of medical device reports (MDRs) associated with surgical staplers for internal use and implantable surgical staples—commonly used in many surgeries—and providing updated recommendations to help reduce the risks associated with their use. In coming months, the FDA plans to issue a draft guidance with labeling recommendations for manufacturers and to hold a public advisory committee meeting to discuss whether the current marketing pathway for these devices is appropriate.

From January 1, 2011 to March 31, 2018, the agency received more than 41,000 individual MDRs for surgical staplers and staples for internal use. The most common problems included opening of the staple line or malformation of staples, misfiring, difficulty in firing, failure of the stapler to fire the staple, and misapplied staples (such as staples being used on the wrong tissue or wrong-sized staples being used). Malfunctions or misuse may result in prolonged surgical procedures or unplanned, additional surgical interventions that may lead to other complications, such as bleeding, sepsis, tearing of internal tissues and organs, increased risk of cancer recurrence, and death.

The FDA reminded providers to review labeling instructions and indications for staplers and implantable staples, such as choosing appropriate-sized staples for the patient’s tissue type and thickness. The letter to providers also suggests considering alternative options if the tissues are swollen, prone to bleeding, or necrotic. The agency is also providing recommendations on how to recognize and manage device malfunction.

Source: FDA., March 8, 2019

FDA: Avoid Some Types Of Robot-Assisted Surgery

The FDA has warned against the use of robotically assisted devices for mastectomies and other cancer surgeries, as the products may pose safety risks and result in poor outcomes for patients. The agency issued 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 in women with cervical cancer, use of the devices in radical hysterectomies was associated with lower rates of disease-free survival and overall survival than in traditional surgery.

The FDA also urges patients to discuss the risks, benefits, and alternative procedure options with their doctors before making treatment decisions, and to ask their doctors about their training and experience and the outcomes of patients they have treated with robotically assisted surgery.

Source: FDA., February 28, 2019

HEADLINES ON DEADLINE

Gene Therapy Fast-Tracked for Huntington’s Disease

uniQure N.V. has received a fast-track designation for AMT-130, a gene therapy candidate for the treatment of Huntington’s disease. The agent comprises a recombinant AAV5 vector with a DNA cassette encoding a microRNA that non-selectively reduces human huntingtin protein in patients with Huntington’s disease. AMT-130 targets the highly toxic exon1 protein fragment, which is more toxic than the mutant huntingtin protein.

Huntington’s disease affects an estimated three to seven per 100,000 people of European ancestry. Adult-onset Huntington’s disease, the most common form, usually appears during the ages of 30 to 40 years. The rarer juvenile form begins in childhood or adolescence, and typically progresses at a faster rate than the adult-onset form. There are no approved therapies to delay the onset or slow the progression of the disease.

AMT-130 is the first, one-time administered adeno-associated viral gene therapy to enter clinical testing for Huntington’s disease. The company is on track to treat the first patient in the second half of 2019.

Source: uniQure N.V., April 8, 2019.

Once-Daily Dovato for HIV-1

The FDA has approved ViiV Healthcare’s Dovato, a complete, once-daily, single-tablet regimen of dolutegravir (DTG) and lamivudine (3TC) for the treatment of HIV-1 in adults without prior antiretroviral (ARV) treatment and no known resistance to DTG or 3TC.

Dolutegravir/lamivudine’s approval heralds a pivotal moment in HIV-1 treatment. Treatment-naïve people with the HIV-1 virus now have the option of taking fewer ARVs to achieve and maintain suppression.

The approval is based on results of the phase 3, randomized, double-blind, multicenter, parallel group, non-inferiority GEMINI 1 and GEMINI 2 studies involving more than 1,400 adults with HIV-1. At Week 48, DTG + 3TC demonstrated non-inferiority when compared to a three-drug regimen of DTG inhibitors in treatment-naïve, HIV-1 infected adults. Dolutegravir/lamivudine is a once-daily, single-tablet, two-drug regimen combining the integrase strand transfer inhibitor dolutegravir (Tivicay, 50 mg) with the nucleoside analogue reverse transcriptase inhibitor lamivudine (Epivir, 300 mg).

Dolutegravir/lamivudine is not recommended in patients with creatinine clearance < 50 mL/min, or in patients with severe hepatic impairment.

The most common adverse reactions observed in study participants receiving dolutegravir/lamivudine were headache, diarrhea, nausea, insomnia, and fatigue.

Source: Viiv Healthcare, April 8, 2019

Duaklir for COPD

Circassia Pharmaceuticals PLC has received FDA approval for Duaklir for the maintenance treatment of chronic obstructive pulmonary disease (COPD). Duaklir is a fixed-dose combination of the long-acting muscarinic antagonist (LAMA) aclidinium bromide (400 mcg) and long-acting beta-agonist (LABA) formoterol fumarate (12 mcg), administered twice-daily via the Pressair inhaler.

The approval is partly based on data from the phase 3 studies ACLIFORM, AUGMENT, and AMPLIFY. Duaklir’s label includes data from the phase 4 ASCENT study, showing the efficacy of aclidinium therapy in reducing COPD exacerbations, making Duaklir the only twice-daily LAMA/LABA in the U.S. to include such data in its prescribing information.

COPD is the third leading cause of death in the U.S. More than 12 million people have been diagnosed with COPD, but an additional 12 million are estimated to have COPD without realizing it.

Circassia expects to launch Duaklir in the U.S. after June 2019.

Source: Circassia, April 1, 2019