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P T. 2018;43(2): 74-82, 104

Drug and Device News February 2018

NEW DRUG APPROVALS

Luxturna for Rare Vision Loss

The FDA has approved voretigene neparvovec-rzyl (Luxturna, Spark Therapeutics, Inc.) to treat biallelic RPE65 mutation-associated retinal dystrophy, which leads to vision loss and may cause complete blindness. It is the first directly administered gene therapy approved in the U.S. that targets a disease caused by mutations in a specific gene.

Hereditary retinal dystrophies are caused by mutations in any one of more than 220 genes. Biallelic RPE65 mutation-associated retinal dystrophy affects about 1,000 to 2,000 U.S. patients. The gene RPE65 provides instructions for making an enzyme that is essential for normal vision.

Voretigene neparvovec-rzyl delivers a normal copy of RPE65 directly to retinal cells, which then produce the protein that converts light to an electrical signal in the retina to restore vision. A natural adeno-associated virus was modified using recombinant DNA techniques to deliver the normal RPE65 gene.

Evidence of efficacy was based mainly on a phase 3 study of 31 participants by measuring the change from baseline to one year in patients’ ability to navigate an obstacle course at various light levels. Patients who received voretigene neparvovec-rzyl showed significant improvements in their ability to complete the obstacle course at low light levels compared with the control group.

The most common adverse reactions from treatment included conjunctival hyperemia, cataract, increased intraocular pressure, and retinal tear.

Source: FDA, December 19, 2017

Steglatro, Steglujan, and Segluromet for Diabetes

The FDA has approved three drugs for type-2 diabetes: Steglatro tablets (ertugliflozin), an oral sodium-glucose cotransporter 2 (SGLT2) inhibitor; Steglujan tablets (ertugliflozin/sitagliptin), the only fixed-dose combination of an SGLT2 inhibitor and the dipeptidyl peptidase-4 inhibitor sitagliptin; and Segluromet tablets (ertugliflozin/metformin hydrochloride), a fixed-dose combination. The products are a joint venture between Merck and Pfizer.

Steglatro (available in 5-mg and 15-mg tablets) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type-2 diabetes mellitus. Steglujan, which combines 5 mg or 15 mg ertugliflozin with 100 mg of sitagliptin, is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type-2 diabetes mellitus when treatment with both ertugliflozin and sitagliptin is appropriate. Segluromet, which combines 2.5 mg or 7.5 mg ertugliflozin with 500 mg or 1,000 mg of metformin hydrochloride, is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type-2 diabetes mellitus who are not adequately controlled on a regimen containing ertugliflozin or metformin, or in patients who are already treated with both ertugliflozin and metformin.

These FDA approvals were supported by seven phase 3 studies of approximately 4,800 patients.

Merck has established a list price (wholesale acquisition cost) of $8.94 per day for Steglatro, $17.45 per day for Steglujan, and $8.94 per day for Segluromet. Wholesale acquisition costs do not include discounts that may be paid on the products.

Source: Merck, December 22, 2017

Giapreza for Dangerously Low Blood Pressure

La Jolla Pharmaceutical has received FDA priority-review approval for angiotensin II injection (Giapreza) for intravenous infusion to increase blood pressure (BP) in adults with septic or other distributive shock.

In a clinical trial of 321 patients with shock and critically low BP, significantly more patients responded to treatment with angiotensin II injection compared with those treated with placebo. Angiotensin II injection effectively increased BP when added to conventional treatments used to raise BP.

Angiotensin II injection can cause dangerous blood clots with serious consequences (clots in arteries and veins, including deep venous thrombosis); prophylactic treatment for blood clots should be used.

Source: FDA, December 21, 2017

Rhopressa for Glaucoma

Netarsudil ophthalmic solution, 0.02% (Rhopressa, Aerie Pharmaceuticals) has received FDA approval to lower elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. The novel, once-daily eye drop is believed to reduce IOP by increasing the outflow of aqueous humor through the trabecular meshwork, the eye’s main fluid drain.

Source: Aerie Pharmaceuticals, December 18, 2017

Admelog for Diabetes

Admelog (insulin lispro injection, Sanofi-Aventis U.S.), a short-acting insulin indicated to improve control of blood sugar levels in adult and pediatric patients 3 years of age and older with type-1 diabetes mellitus and adults with type-2 diabetes mellitus, has received FDA approval.

Admelog is the first short-acting insulin approved through the 505(b)(2) abbreviated approval pathway. A new drug application submitted through this pathway may rely on the FDA’s finding that a previously approved drug is safe and effective or on published literature to support the safety and/or effectiveness of the proposed product.

Sanofi-Aventis U.S. submitted an application that relied, in part, on the FDA’s finding of safety and effectiveness for Humalog (insulin lispro injection, Eli Lilly and Co.) to support approval. The applicant demonstrated that reliance on the FDA’s finding of safety and effectiveness for Humalog was scientifically justified and provided Admelog-specific data to establish the drug’s safety and efficacy. The Admelog-specific data included two phase 3 clinical trials that enrolled approximately 500 patients each.

Source: FDA, December 11, 2017

Sinuva for Nasal Polyps

The mometasone furoate sinus implant (Sinuva, Intersect ENT, Inc.) has received FDA approval for treatment of recurrent nasal polyp disease in patients who have had previous ethmoid sinus surgery.

Placed during a physician office visit, the implant expands into the sinus cavity and delivers an anti-inflammatory steroid directly to the site of polyp disease for 90 days. Results from a randomized clinical trial demonstrated a 63% relative reduction in bilateral polyp grade (a measurement of the extent of ethmoid polyp disease) for patients treated with Sinuva, compared with control.

Nasal polyps are inflammatory growths along the lining of nasal passages or sinuses that can cause nasal congestion, infections, and loss of sense of smell. Approximately 635,000 Americans have had previous sinus surgery and continue to see their ENT physicians for treatment of recurring symptoms.

The FDA submission was supported by the results of clinical studies of 400 patients.

Source: Intersect ENT, Inc., December 11, 2017

Lonhala Magnair for COPD

The FDA has approved glycopyrrolate inhalation solution (Lonhala Magnair, Sunovion Pharmaceuticals, Inc.), also known as SUN-101/eFlow, for the long-term maintenance treatment of airflow obstruction in people with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.

The product is the first nebulized long-acting muscarinic antagonist approved for COPD treatment in the U.S. and the first use of Magnair, a portable, closed-system nebulizer designed to deliver the drug in two to three minutes as patients breathe normally. The drug is dosed at 25 mcg twice daily.

In clinical trials of the GOLDEN program, individuals treated with Lonhala Magnair demonstrated statistically significant and clinically important changes from baseline in trough forced expiratory volume in one second at week 12 versus placebo. Lonhala Magnair was generally well tolerated in clinical studies of up to 48 weeks, with the most common side effects being exacerbations and cough.

Source: Sunovion, December 5, 2017

Ozempic Injection for Diabetes

Novo Nordisk has received FDA approval for semaglutide injection 0.5 mg or 1 mg (Ozempic), a once-weekly glucagon-like peptide receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type-2 diabetes. The medication is administered on the same day each week and can be taken any time of the day with or without meals.

The approval is based on the results from a phase 3a clinical trial program. In people with type-2 diabetes, semaglutide injection showed clinically meaningful and statistically significant reductions in hemoglobin A1c compared with placebo, sitagliptin, and exenatide extended-release (Bydureon, AstraZeneca). Treatment with semaglutide injection also resulted in reductions in body weight. The most common adverse reactions reported in at least 5% of patients treated with semaglutide injection are nausea, vomiting, diarrhea, abdominal pain, and constipation.

Semaglutide injection will be launched in the Ozempic prefilled pen.

Source: Novo Nordisk, December 5, 2017

Xepi for Impetigo

The FDA has approved ozenoxacin cream, 1% (Xepi, Medimetriks Pharmaceuticals, Inc.), to treat impetigo, a highly contagious bacterial skin infection, in patients 2 months of age and older.

The approval is based on a clinical development program that includes the results of two phase 3, multicenter, randomized, double-blind, vehicle-controlled trials that enrolled 877 patients 2 months of age and older with impetigo.

Ozenoxacin cream or vehicle was applied topically twice daily for five days. Bacterial success, defined as bacterial eradication or presumed eradication, was achieved in 90.8% of patients using ozenoxacin cream versus 69.8% for placebo at the end of treatment. Ozenoxacin cream showed excellent antibacterial activity against Staphylococcus aureus and Streptococcus pyogenes, including methicillin-resistant S. aureus.

In the U.S., impetigo is estimated to account for approximately 10% of skin problems observed in pediatric clinics and is considered the most common bacterial skin infection. Ozenoxacin, a new chemical entity, belongs to a new generation of nonfluorinated quinolones.

Source: Medimetriks, December 14, 2017

Generic Approvals and Launches

Sildenafil Citrate Tablets

The little blue pill with big annual sales has gone generic. Teva Pharmaceutical Industries Ltd. has launched generic sildenafil citrate, while Pfizer, which markets branded Viagra, is offering its own generic at half the retail price. Viagra has annual sales of approximately $1.4 billion in the U.S.

Both Teva and Pfizer are offering various discount programs.

Sildenafil tablets are a phosphodiesterase-5 inhibitor indicated for the treatment of erectile dysfunction. More generics are expected go on sale in the summer of 2018.

Sources: Teva, December 11, 2017, and Associated Press, December 6, 2017

Atazanavir Capsules

Teva Pharmaceutical Industries Ltd. has launched the first generic version of Reyataz capsules (atazanavir, Bristol-Myers Squibb) in the U.S. Atazanavir sulfate capsules are a protease inhibitor indicated for use in combination with other antiretroviral agents for the treatment of human immunodeficiency virus-1 infection for patients 6 years of age and older weighing at least 15 kg.

Reyataz had annual sales of approximately $402 million in the U.S., according to IMS data as of October 2017.

Source: Teva, December 27, 2017

Baclofen Tablets

The FDA has approved Rubicon’s application to make baclofen tablets, 5 mg, the first generic version of Lioresal (Novartis). Baclofen is indicated for relief of spasticity resulting from multiple sclerosis, particularly flexor spasms and concomitant pain, clonus, and muscular rigidity.

Source: FDA, November 28, 2017

Capreomycin Injection

The FDA has granted Mylan Laboratories approval to market capreomycin for injection USP, 1 g/vial, the generic form of Akorn’s Capastat Sulfate (capreomycin) for injection, 1 g/vial.

Capreomycin is indicated for pulmonary infections caused by capreomycin-susceptible strains of Mycobacterium tuberculosis when the primary agents (isoniazid, rifampin, ethambutol, aminosalicylic acid, and streptomycin) have been ineffective or cannot be used because of toxicity or the presence of resistant tubercle bacilli. Capreomycin is used concomitantly with other appropriate antituberculosis agents.

Source: FDA, November 28, 2017

Praziquantel Tablets

Par Pharmaceutical has received approval to market praziquantel tablets USP, 600 mg, for the treatment of infections due to all species of Schistosoma and infections due to the liver flukes Clonorchis sinensis/Opisthorchis viverrini. The tablets are the generic form of Biltricide (Bayer Healthcare).

Source: FDA, November 27, 2017

NEW INDICATIONS

Repatha to Prevent Heart Attack and Stroke

Evolocumab (Repatha, Amgen) is now FDA-approved to prevent heart attacks, strokes, and coronary revascularizations in adults with established cardiovascular (CV) disease. The FDA also approved evolocumab as an adjunct to diet, alone or in combination with other lipid-lowering therapies (such as statins), to treat adults with primary hyperlipidemia to reduce low-density lipoprotein-cholesterol (LDL-C).

The Repatha CV outcomes study (FOURIER) demonstrated that adding evolocumab to optimized statin therapy resulted in a 20% reduction in major adverse CV events represented in the key secondary composite endpoint of time to first heart attack, stroke, or CV death. The study found a 15% reduction in the risk of the primary composite endpoint, which included hospitalization for unstable angina, coronary revascularization, heart attack, stroke, or CV death.

The magnitude of risk reduction in both the primary and key secondary composite endpoints grew over time, with the robust benefit starting as early as six months and accruing through the median 2.2 years of the study. Patients on evolocumab experienced a reduction in the risk of heart attack (27%), stroke (21%), and coronary revascularization (22%). Consistent with recent trials of more intensive LDL-C lowering, there was no observed effect on CV mortality or on hospitalization for unstable angina.

Source: Amgen, December 1, 2017

Adjuvant Perjeta For Breast Cancer

The FDA has approved pertuzumab (Perjeta, Genentech) in combination with trastuzumab (Herceptin, Genentech) and chemotherapy for adjuvant treatment of human epidermal growth factor receptor 2–positive(HER2+) early breast cancer at high risk of recurrence. Patients should receive this regimen for one year. The FDA also converted the previously granted accelerated approval of the pertuzumab-based regimen to full approval for neo adjuvant treatment of HER2+, locally advanced, inflammatory, or early-stage breast cancer.

The new indication is based on the phase 3 APHINITY study. At the time of the primary analysis (median 45.4 months follow-up), pertuzumab, trastuzumab, and chemotherapy reduced the risk of invasive breast cancer recurrence or death by 18% in the overall study population compared with trastuzumab and chemotherapy alone.

Pertuzumab is also approved for use in combination with trastuzumab and docetaxel in people who have HER2+ metastatic breast cancer and who have not received anti-HER2 therapy or chemotherapy for metastatic breast cancer.

Source: Genentech, December 20, 2017

Opdivo After Melanoma Surgery

Nivolumab (Opdivo, Bristol-Myers Squibb) has secured FDA approval for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection.

In the phase 3 CheckMate-238 trial, nivolumab demonstrated an 18-month recurrence-free survival (RFS) rate of 66.4% compared with 52.7% for ipilimumab (Yervoy, Bristol-Myers Squibb) in patients with stage IIIB/C or stage IV melanoma after surgery. The median RFS had not yet been reached in either group. Nivolumab reduced the risk of disease recurrence by 35% versus ipilimumab.

In CheckMate-238, adverse events (AEs) leading to discontinuation were reported in 9% of nivolumab-treated patients and 42% of ipilimumab-treated patients. Grade 3 or 4 AEs were experienced by 25% of patients in the nivolumab group and 55% of patients in the ipilimumab group.

Source: Bristol-Myers Squibb, December 20, 2017

Hydroxyurea for Pediatric SCD

The FDA has approved hydroxyurea (Siklos, Addmedica) to reduce the frequency of painful crises and the need for blood transfusions in pediatric patients 2 years of age and older with sickle cell disease (SCD) with recurrent moderate-to-severe painful crises.

Although hydroxyurea has been used to treat adults with SCD for many years, this is the first FDA approval of the medication for use in pediatric patients with the illness.

Approval was based on data from an open-label, single-arm trial of 405 pediatric patients (2–18 years of age) with SCD, 141 of whom had not been previously treated with hydroxyurea prior to enrollment. Among the 141 pediatric patients analyzable for efficacy, hydroxyurea use resulted in an increase in hemoglobin F. The percentage of patients with at least one vaso-occlusive episode, one episode of acute chest syndrome, one hospitalization due to SCD, or one blood transfusion decreased after 12 months of hydroxyurea treatment.

The most common adverse reactions to the drug include infections and neutropenia.

Source: FDA, December 21, 2017

Bosulif for Treatment-Naïve CML

Bosutinib (Bosulif, Pfizer, Inc.) has secured FDA approval to treat adults with newly diagnosed chronic-phase Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML).

The approval was based on results of the randomized, multicenter, multinational, open-label phase 3 BFORE study, in which 47.2% of patients taking bosutinib achieved a major molecular response at 12 months compared with 36.9% of patients taking imatinib. The complete cytogenic response rate by 12 months was 77.2% with bosutinib compared with 66.4% with imatinib. The most common adverse reactions with bosutinib were diarrhea, nausea, thrombocytopenia, rash, increased alanine aminotransferase, abdominal pain, and increased aspartate aminotransferase.

Bosutinib is an oral, once-daily tyrosine kinase inhibitor that inhibits the Bcr-Abl kinase that promotes CML; it is also an inhibitor of Src-family kinases. The FDA first approved it in September 2012 to treat adults with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy.

Source: Pfizer, Inc., December 19, 2017

Cabometyx for Treatment-Naïve RCC

The FDA has approved cabozantinib tablets (Cabometyx, Exelixis, Inc.) for the treatment of patients with advanced renal cell carcinoma (RCC).

The approval was based on the randomized, open-label, active-controlled phase 2 CABOSUN trial. Median progression-free survival among patients with previously untreated RCC receiving cabozantinib was 8.6 months versus 5.3 months for those receiving sunitinib (Sutent, Pfizer), a 62% improvement.

The most frequent grade 3–4 adverse reactions with cabozantinib were hypertension, diarrhea, hyponatremia, hypophosphatemia, palmar-plantar erythrodysesthesia, fatigue, increased alanine aminotransferase, decreased appetite, stomatitis, pain, hypotension, and syncope.

The FDA initially approved cabozantinib, a tyrosine kinase inhibitor, in April 2016 for the treatment of patients with advanced RCC who have previously received antiangiogenic therapy.

Source: Exelixis, Inc., December 20, 2017

Xeljanz for Psoriatic Arthritis

Pfizer has received FDA approval for tofacitinib (Xeljanz) and its extended-release formulation (Xeljanz XR) for the treatment of adults with active psoriatic arthritis (PsA) who have had an inadequate response or intolerance to methotrexate or other disease-modifying antirheumatic drugs (DMARDs).

Tofacitinib 5 mg is given twice daily, while tofacitinib extended-release 11 mg is given once daily. The recommended doses of tofacitinib, a Janus kinase inhibitor, are in combination with nonbiologic DMARDs; use with biologic DMARDs or potent immunosuppressants is not recommended.

Two pivotal studies in the phase 3 development program, OPAL Broaden and OPAL Beyond, demonstrated statistically significant improvements in American College of Rheumatology 20 (ACR20) response and change from baseline in the Health Assessment Questionnaire–Disability Index score at three months in patients receiving tofacitinib 5 mg twice daily with a nonbiologic DMARD, compared with those treated with placebo. The percentage of patients who achieved an ACR20 response at three months using tofacitinib versus placebo was 50% versus 33% in OPAL Broaden and 50% versus 24% in OPAL Beyond.

Source: Pfizer, December 14, 2017

Nucala for EGPA

The FDA has expanded the approved use of mepolizumab (Nucala, GlaxoSmithKline) to treat adults with eosinophilic granulomatosis with polyangiitis (EGPA), a rare autoimmune disease that causes vasculitis. This new indication marks the first FDA-approved therapy specifically to treat EGPA.

EGPA (formerly known as Churg–Strauss syndrome) is characterized by asthma, high levels of eosinophils, and inflammation of small- to medium-sized blood vessels that can affect various organ systems.

Mepolizumab was approved in 2015 to treat patients 12 years of age and older who have severe asthma with an eosinophilic phenotype despite receiving their current asthma medicines. Mepolizumab is an interleukin-5 antagonist mono clonal antibody (IgG1 kappa) produced by recombinant DNA technology in Chinese hamster ovary cells. It is administered once every four weeks by subcutaneous injection by a health care professional into the upper arm, thigh, or abdomen.

The safety and efficacy of mepolizumab were determined in a 52-week clinical trial that compared mepolizumab with placebo. Patients receiving mepolizumab achieved significantly more accrued time in disease remission (i.e., becoming symptom free) while on an oral corticosteroid dose less than or equal to 4 mg of prednisone, and a significantly higher proportion achieved remission at both week 36 and week 48.

Source: FDA, December 12, 2017

Taltz for Psoriatic Arthritis

The FDA has approved ixekizumab injection 80 mg/mL (Taltz, Eli Lilly and Company) for the treatment of adults with active psoriatic arthritis (PsA).

The efficacy and safety of ixekizumab were determined in two randomized, double-blind, placebo-controlled phase 3 studies—SPIRIT-P1 and SPIRIT-P2—which included more than 670 adults with active PsA. Patients in SPIRIT-P1 had never been treated with a biologic disease-modifying antirheumatic drug. Patients in SPIRIT-P2 had failed one or two tumor necrosis factor inhibitors.

The primary efficacy endpoint was the proportion of patients at 24 weeks achieving a 20% reduction in a composite measure of disease activity as defined by the American College of Rheumatology (an ACR20 response). Patients treated with ixekizumab achieved ACR20 at the following response rates versus patients receiving placebo: SPIRIT-P1, 58% versus 30%; and SPIRIT-P2, 53% versus 20%.

Ixekizumab may be administered alone or in combination with a conventional disease-modifying antirheumatic drug. The medication was first approved by the FDA in March 2016 for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

Source: Eli Lilly, December 1, 2017

Omidria for Pediatric Patients

The indication for phenylephrine/ ketorolac intraocular solution 1%/0.3% (Omidria, Omeros Corporation) has been expanded to include pediatric patients starting at birth. Omidria is used during cataract surgery or intraocular lens replacement to prevent intraoperative miosis and to reduce postoperative pain.

The supplemental new drug application was approved following review of efficacy and safety data from a pediatric clinical trial in 78 patients randomized to either Omidria or phenylephrine administered intraoperatively.

Source: Omeros, December 12, 2017

NEW FORMULATION

Prexxartan, the First Valsartan Oral Solution

The FDA has approved valsartan oral solution (Prexxartan, Medicure), the first approved oral liquid dosage form of the angiotensin II receptor blocker valsartan in the U.S.

Valsartan oral solution is indicated for the treatment of hypertension in adults and children 6 years of age and older to lower blood pressure to reduce the risk of fatal and nonfatal cardiovascular (CV) events, primarily strokes and myocardial infarctions (MI); for the treatment of heart failure patients (New York Heart Association class II–IV) to significantly reduce hospitalization in those who are unable to swallow valsartan tablets; and for the treatment of patients with stable left ventricular failure or left ventricular dysfunction following MI to reduce CV mortality in those who are unable to swallow valsartan tablets.

Sources: Medicure and FDA, December 19, 2017

LABELING UPDATE

Nilotinib Discontinuation Possible in Certain CML Patients

The FDA has updated the label of nilotinib (Tasigna, Novartis) to include information for providers about how to discontinue the drug in certain patients with chronic myeloid leukemia (CML), a first in CML treatment. Nilotinib, approved by the FDA in 2007, is indicated for the treatment of Philadelphia chromosome positive (Ph+) CML. With these updated dosing recommendations, patients with early (chronic) phase CML who have been taking nilotinib for three years or longer, and whose leukemia has responded to treatment according to specific criteria as detected by an FDA-authorized test, may be eligible to stop taking the drug.

Nilotinib is a kinase inhibitor that works in CML by blocking BCR-ABL, which promotes abnormal cell growth. This update adds information to the product label regarding the conditions under which patients may be eligible to discontinue treatment and notes that if treatment is stopped patients must be regularly monitored for disease recurrence.

The information about discontinuing nilotinib was based on two single-arm trials of patients with Ph+ chronic-phase CML. The trials measured how long patients were able to stop taking nilotinib without the leukemia returning (treatment-free remission [TFR]). In both trials, patients had to meet rigorous criteria showing how their cancer had responded to treatment before stopping nilotinib. In the first trial, among 190 newly diagnosed patients with CML who stopped nilotinib after taking it for three or more years and meeting other specified criteria, 51.6% were still in the TFR phase after 48 weeks and 48.9% were still in the TFR phase after 96 weeks. In the second trial, among the 126 patients who had stopped nilotinib after taking it for three or more years after switching from the cancer drug imatinib, 57.9% were still in the TFR phase after 48 weeks, and 53.2% were still in the TFR phase after 96 weeks.

The long-term outcomes of patients discontinuing versus continuing treatment are unknown at this time.

Source: FDA, December 22, 2017

FDA REVIEW ACTIVITIES

Breakthrough Therapy Status

Fingolimod for Pediatric MS

The FDA has granted a breakthrough therapy designation to fingolimod (Gilenya, Novartis) for the treatment of children and adolescents with relapsing multiple sclerosis (MS). Fingolimod is approved to treat relapsing forms of MS in adults but is not yet approved for children and adolescents.

In children, relapsing-remitting MS accounts for nearly all cases of MS. Although children have two to three times as many relapses as a typical adult-onset MS patient, there are no disease- modifying therapies approved for this population.

The designation is based on data from the phase 3 PARADIGMS study, which found treatment with fingolimod reduced the rate of relapses by 82%, compared with interferon beta-1a intramuscular injection.

Source: Novartis, December 18, 2017

Priority Review Designations

Rucaparib for Ovarian Cancer

The FDA has accepted a supplemental new drug application for rucaparib (Clovis Oncology) and granted priority review status to the application with a Prescription Drug User Fee Act date of April 6, 2018.

Rucaparib is an oral, small-molecule inhibitor of poly (ADP-ribose) polymerase 1 (PARP1), PARP2, and PARP3. It is a maintenance treatment for patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are platinum sensitive and are in a complete or partial response to platinum-based chemo therapy. Clovis is seeking approval for use of rucaparib for this indication regardless of a patient’s BRCA mutation status.

Source: Clovis, December 5, 2017

Fremanezumab for Migraine

The FDA has accepted for priority review the biologics license application (BLA) for fremanezumab (Teva), an anti-calcitonin gene-related peptide monoclonal antibody for the preventive treatment of migraine. Fremanezumab also received fast-track designation for the prevention of cluster headache.

The BLA includes data from the HALO trial program, which enrolled more than 2,000 patients with episodic migraine and chronic migraine, evaluating both quarterly and monthly dose regimens, in which fremanezumab achieved statistically significant results across all trial endpoints.

Fremanezumab is also being investigated for the prevention of chronic and episodic cluster headache as part of the phase 3 ENFORCE clinical research program. In addition, Teva recently initiated a fremanezumab phase 2 clinical program for the treatment of posttraumatic headache disorder.

Source: Teva, December 18, 2017

Fast-Track Designations

CA-008 for Postsurgical Pain

The FDA has granted a fast-track designation to CA-008 (Concentric Analgesics) for the treatment of postsurgical pain.

CA-008, a proprietary water-soluble prodrug that converts into capsaicin (the naturally occurring molecule that gives chili peppers their heat), is a potent TRPV-1 agonist with a long history of use as a topical analgesic. It selectively and reversibly desensitizes pain-conducting nerve fibers. TRPV-1 agonism evokes an initial neuronal excitation that is followed by a durable refractory state to provide long-lasting analgesia.

Results from a phase 1b clinical trial are expected in early 2018.

Source: Concentric Analgesics, December 7, 2017

RT-100 AC6 for Heart Failure

Renova Therapeutics has been granted a fast-track designation for RT-100 AC6 gene transfer for the treatment of heart failure with reduced ejection fraction.

RT-100 AC6 gene transfer involves infusing an inactivated adenovirus vector encoding human adenylyl cyclase type 6 into the arteries that feed the heart during cardiac catheterization. AC6 is a protein found in heart muscle cells that regulates heart function and appears to be down-regulated in heart failure patients.

Results of a phase 2 clinical trial indicate that a one-time administration of RT-100 safely increased heart function beyond optimal heart failure therapy. The treatment also lowered the heart failure hospitalization rate at 12 months, which will be the primary endpoint in the program’s upcoming phase 3 trial.

Source: Renova Therapeutics, December 14, 2017

Elamipretide for Optic Neuropathy

The FDA has given a fast-track designation to Stealth Biotherapeutics for elamipretide, developed to treat Leber’s hereditary optic neuropathy (LHON).

Approximately 35,000 people worldwide have LHON, an inherited mitochondrial disease that damages neurons in the retina. It primarily affects men between the ages of 18 and 30 years and often leads to severe and permanent legal blindness. ReSIGHT, a phase 2 study of topical delivery of elamipretide in people with LHON, began in 2016 and is expected to show top-line results by mid-2018.

Elamipretide has also been granted fast-track designation for two other rare mitochondrial diseases: primary mitochondrial myopathy and Barth syndrome.

Source: Stealth Biotherapeutics, December 18, 2017

NYX-783 for PTSD

The FDA has granted Aptinyx a fast-track designation for the development of NYX-783, a treatment for posttraumatic stress disorder (PTSD).

A hallmark of PTSD is an inability to appreciate that stimuli associated with traumatic events no longer constitute a threat. As learning processes are involved in fear extinction, NYX-783’s mechanism of enhancing synaptic plasticity and facilitating learning is highly relevant, Aptinyx says. Preclinical data suggest NYX-783 may target the underlying cause of PTSD, not simply palliate its symptoms. Aptinyx researchers highlighted the compound’s robust and long-lasting efficacy in preclinical models of depression, learning, and fear extinction.

Aptinyx has initiated a phase 1, double-blind, placebo-controlled clinical study to evaluate NYX-783 at multiple dose levels.

Source: Aptinyx Inc., December 7, 2017

Orphan Drug Designations

SER-287 for Pediatric Ulcerative Colitis

Seres Therapeutics, Inc., has received an orphan drug designation for its microbiome therapeutic candidate SER-287 for the treatment of ulcerative colitis (UC) in pediatric patients.

Seres has completed a placebo-controlled phase 1b study of SER-287 in patients with mild-to-moderate UC whose current therapies weren’t working. Treatment with SER-287 improved both clinical remission rates and endoscopic scores with a favorable safety profile. SER-287 phase 1b microbiome data are expected in early 2018.

SER-287 contains a consortium of live bacterial spores. It is thought to work through a novel mechanism of action by modulating the dysbiotic microbiome, reducing inflammation without immunosuppression. A healthy microbiome has been shown to maintain the integrity of the colonic barrier, reduce the signaling by proinflammatory molecules produced by certain bacteria, and induce regulatory T cells in the colon to modulate immune responses.

Source: Seres Therapeutics, December 4, 2017

Patisiran for Transthyretin-Mediated Amyloidosis

The FDA has expanded the orphan drug designation for patisiran (Alnylam Pharmaceuticals) to include treatment of transthyretin-mediated (ATTR) amyloidosis in addition to its prior designation for treatment of familial amyloidotic polyneuropathy.

Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressively debilitating disease in which mutations in the TTR gene cause abnormal amyloid proteins to accumulate and damage body organs and tissue, resulting in intractable peripheral sensory neuropathy, autonomic neuropathy, and/or cardio myopathy. Patients diagnosed with hATTR amyloidosis have a life expectancy of 2.5 to 15 years from symptom onset.

Patisiran is an investigational, intravenously administered RNAi therapeutic targeting transthyretin. It is designed to silence specific messenger RNA, potentially blocking the production of TTR protein. This may help clear TTR amyloid deposits in peripheral tissues and potentially restore function to these tissues.

Source: Alnylam, December 11, 2017

Ryplazim for Idiopathic Pulmonary Fibrosis

Prometic Life Sciences, Inc., has received orphan drug status for Ryplazim (plasminogen) for the treatment of idiopathic pulmonary fibrosis (IPF).

IPF is a chronic disease in which alveoli are impaired by scar tissue, leading to progressive decline in lung function. It usually affects adults 50 to 70 years of age, particularly those with a history of cigarette smoking.

Activated plasminogen, plasmin, is the main enzyme involved in the lysis of blood clots and clearance of extravasated fibrin. In an animal model proven to emulate pulmonary fibrosis in humans, Ryplazim performed favorably compared with recently approved IPF drugs, significantly reducing tissue scarring in the lungs.

Source: Prometic Life Sciences, December 18, 2017

Rare Pediatric Disease Designation

A001 for Leber’s Congenital Amaurosis

The FDA has granted a rare pediatric disease designation to AAV2/5-OPTIRPE65 (A001, MeiraGTx) for the treatment of patients with Leber’s congenital amaurosis due to mutations in the gene RPE65 (LCA2). In 2016, A001 received an orphan drug designation for the treatment of LCA2.

Leber’s congenital amaurosis is a group of autosomal-recessive, early-onset retinal dystrophies that cause severe sight impairment in childhood. The underlying deficit in up to 16% of all LCA cases lies in RPE65, a gene that plays a key role in the regeneration of visual pigment following exposure to light. A001 is an adeno-associated virus (AAV2/5) investigational gene therapy designed to deliver a codon-optimized RPE65 cDNA under the control of a synthetic RPE-specific promoter to the back of the eye.

MeiraGTx is conducting an open-label, multicenter phase 1/2 trial of A001 in patients 3 years of age and older who have been diagnosed with severe early-onset LCA2. MeiraGTx has completed the three dose-escalation cohorts of adults in this study.

Source: MeiraGTx, December 7, 2017

DRUG SAFETY ISSUE

Gadolinium Contrast Agents

The FDA is requiring a new class warning and other safety measures for all gadolinium- based contrast agents (GBCAs) for magnetic resonance imaging (MRI).

Gadolinium stays in patients’ bodies for months or years after its use. Its retention has not been directly linked to adverse health effects in patients with normal kidney function, and the FDA has concluded that the benefit of approved GBCAs outweighs potential risks. However, the agency is taking steps to alert health care professionals and patients about gadolinium retention after an MRI using a GBCA. These steps include requiring a new patient medication guide that every patient will be asked to read before receiving a GBCA and requiring manufacturers of GBCAs to conduct human and animal studies to further assess the safety of these contrast agents.

Patients who may be at higher risk for gadolinium retention include those requiring multiple lifetime doses, pregnant women, children, and patients with inflammatory conditions. Providers should minimize repeated GBCA imaging studies when possible, particularly closely spaced MRI studies. However, they should not avoid or defer necessary GBCA MRI scans.

Source: FDA, December 19, 2017

DEVICE APPROVALS

Vercise Deep Brain Stimulation To Treat Parkinson’s Symptoms

The FDA has approved the Vercise Deep Brain Stimulation (DBS) system (Boston Scientific Corporation) to treat the symptoms of Parkinson’s disease. DBS stimulates a targeted region of the brain through implanted leads powered by an implantable pulse generator.

The approval was based on the multicenter, prospective, double-blind, randomized, sham-controlled INTREPID study, which evaluated the safety and effectiveness of the system in 292 patients at 23 sites. It met its primary endpoint of mean change in waking hours with good symptom control (n = 160).

The filing was also supported by safety data from the European multicenter, prospective, single-arm VANTAGE study. In the VANTAGE study, 40 patients treated with the Vercise DBS system demonstrated a 63% improvement in motor function at 52 weeks from baseline as measured by the Unified Parkinson’s Disease Rating Scale III, as well as improvements in quality of life and medication usage.

The Vercise implantable pulse generator is the smallest rechargeable DBS device available in the U.S. and can have a battery life of more than 15 years.

The Vercise system independently controls the amount of current delivered by each electrode on the implanted leads. The leads have eight contacts with a total span of 15.5 mm, spacing between each contact of 0.5 mm, and multilumen construction. These features are designed to address common challenges in DBS therapy, such as fluctuations in symptoms and the progressive nature of the condition, by offering more adaptable delivery of stimulation.

Source: Boston Scientific, December 11, 2017

GammaPod Stereotactic Radiotherapy System

A noninvasive stereotactic radiotherapy system (GammaPod, Xcision Medical Systems, LLC) intended for use in treating cancer in breast tissue has received FDA approval.

Approximately 60% of all cancer patients will be treated with some form of radiation therapy. During radiation therapy, tumor cells are killed when their DNA is damaged by the radiation being absorbed into them. While radiation therapy has the potential to kill tumor cells, it can also damage healthy tissue around the tumor.

The GammaPod system is intended for use in the noninvasive stereotactic delivery of a radiation dose to a portion (partial volume) of the breast in conjunction with breast-conserving treatment. During the procedure, radiation is delivered to specific areas of the breast. The GammaPod has not been shown to be as effective as whole breast radiation therapy and is not intended to replace it.

GammaPod uses thousands of focused beams of radiation from 36 rotating radioactive Cobalt-60 sources in combination with a two-layer, vacuum-assisted cup that immobilizes the breast to achieve a more accurate delivery of radiation. The Gamma Pod design to immobilize the breast during treatment provides the benefit of minimizing the radiation dose to the surrounding healthy tissues in the breast, heart, and lungs.

For this clearance, the FDA reviewed scientific evidence, including a clinical study of 17 patients, which tested the feasibility of accurately delivering the prescribed dose to the breast tumor while minimizing radiation to the healthy tissue. The clinical evidence supports delivering the prescribed dose to the breast tumor with minimal radiation-induced side effects, such as skin redness or erythema.

The GammaPod system was reviewed through the pre-market notification 510(k) pathway.

Source: FDA, December 22, 2017

Injectable Bone Repair Treatment

The FDA has granted 510(k) clearance to Anika Therapeutics for a hyaluronic-acid (HA)–based injection indicated for filling bone voids or defects of the skeletal system (i.e., extremities and pelvis), which are not intrinsic to the stability of the bone, created during surgery or resulting from traumatic injury. The bone-void filler, which is composed of a synthetic, biocompatible bone-graft substitute material, is injected into a void, hardens at body temperature, and is then resorbed and replaced by the growth of new bone during the healing process.

While the use of autologous bone or autograft has been the gold standard of treatment for bone grafting, the increased risk of procedural complications has prompted a shift towards alternate treatments, such as synthetic, resorbable bone-graft substitute materials.

Anika’s bone-repair treatment is an injectable, settable osteo conductive calcium phosphate bone graft substitute material. It is provided in a kit with two components—an aqueous solution in a preloaded syringe and a dry powder—that must be mixed intraoperatively using the supplied mixing system prior to administration. It is provided sterile for single use in volumes ranging from 1.5 mL to 4 mL.

Source: Anika Therapeutics, December 27, 2017

Shock Wave Device for Diabetic Foot Ulcers

The FDA has permitted the marketing of the Dermapace system (Sanuwave, Inc.), the first shock wave device intended to treat diabetic foot ulcers.

About 25% of people with diabetes will experience a foot ulcer in their lifetimes. Amputation is sometimes necessary when circulation is so poor that a foot ulcer fails to heal or when treatment fails to stop the spread of an infection.

The Dermapace system is intended to be used in the treatment of chronic, full-thickness diabetic foot ulcers with wound areas no larger than 16 cm2 that extend through the epidermis, dermis, tendon, or capsule, but without bone exposure. The Dermapace system is an extracorporeal shock wave system that uses pulses of energy, similar to sound waves, to mechanically stimulate the wound. The device is intended for adult patients 22 years of age and older presenting with diabetic foot ulcers lasting more than 30 days. It should be used along with standard diabetic ulcer care.

The FDA reviewed clinical data from two multicenter, randomized, double-blind studies with 336 diabetic patients receiving either usual care, which includes wet-to-dry dressings or debridement as needed, plus the Dermapace system shock wave therapy or usual care plus sham shock wave therapy. Both groups included patients with poorly controlled and well-controlled blood glucose levels.

Patients who had between one and seven treatments with Dermapace showed an increase in wound healing at 24 weeks with a 44% wound closure rate. Patients treated with the sham shock wave therapy showed a 30% wound closure rate during the same time period.

The most common side effects observed were pain during application of the device, local bruising and numbness, migraines, nausea, fainting, wound infection, infection beyond the wound (cellulitis, osteomyelitis), and fever.

The Dermapace system was reviewed through the de novo pre-market review pathway. This action creates a new regulatory classification that would allow future devices to go through the FDA’s 510(k) process, under which devices can demonstrate substantial equivalence to this predicate device.

Source: FDA, December 28, 2017

CleanCision Retraction System

The FDA has cleared the CleanCision wound retraction and protection system (Prescient Surgical, Inc.) for commercialization. CleanCision has been shown to reverse and reduce the pervasive sources of surgical infection, clearing harmful bacteria throughout surgery when the threat of wound contamination is at its highest.

CleanCision provides access to the surgical site and uses a sterile irrigant solution, selected by the surgeon, to clear contamination invading the surgical incision. The wound edge is continuously and consistently irrigated while suction removes contaminants throughout the surgery. CleanCision is cleared for use in abdominal surgery and may aid in the prevention of wound edge contamination.

Source: Prescient Surgical, December 19, 2017

SPIRA-C Fusion Implant

The FDA has awarded 510(k) clearance to the SPIRA-C Open Matrix Cervical Interbody device (Camber Spine Technologies), an interbody fusion implant that uses a novel arched design and Surface by Design technology.

The 3D-printed titanium implants are designed to enhance fusion. The surface design includes a roughened titanium surface designed to promote bone cell proliferation and a pore size optimized for bone ingrowth. Long-term stability is achieved with endplate-to-endplate fusion.

The device is indicated for use at one or two contiguous levels in the cervical spine, from C3–C7, in skeletally mature patients who have had six weeks of non-operative treatment for degenerative disk disease with up to grade 1 spondylolisthesis. It is intended to be used with FDA-cleared supplemental fixation systems.

Source: Camber Spine Technologies, December 7, 2017

DEVICE SAFETY ISSUES

FDA Reaffirms Warnings About Power Morcellators

After a new review, the FDA has reaffirmed its warning against using laparoscopic power morcellators in gynecological surgeries to treat patients with suspected or confirmed cancer. The agency also reiterated that the devices should not be used in most women undergoing myomectomy or hysterectomy for uterine fibroids.

Recent medical studies suggest that one in 225 to one in 580 women undergoing surgery for uterine fibroids may have a hidden uterine sarcoma. The FDA also estimates that a leiomyosarcoma may be present in approximately one in 495 to one in 1,100 women undergoing surgery for uterine fibroids based on recent studies. These rates are generally consistent with estimates in a 2014 FDA review.

The FDA is continuing to monitor and evaluate the risks and benefits of laparoscopic power morcellation.

Source: FDA, December 14, 2017