- New Specialty Drug Approval
- New Drug Approvals
- New Indications
- FDA Safety Update
- Pipeline Update
- Biosimilar Update
- Drug Shortages/Discontinuations
New Specialty Drug Approval
FDA Approves First Gene Therapy: Kymriah®
On August 30th 2017, the U.S. Food and Drug Administration (FDA) approved the first gene therapy for use in the United States. Kymriah® (tisagenlecleucel) is a cell-based gene therapy approved for the treatment of patients up to 25 years of age with refractory or relapsed (second or later relapse) B-cell precursor acute lymphoblastic leukemia (ALL). ALL is the most common childhood cancer in the United States with approximately 3,100 patients 20 years of age and younger diagnosed each year. It is a cancer of the bone marrow and blood which results in abnormal production of lymphocytes (a type of white blood cell). Fifteen to 20% of patients with ALL experience relapsed or refractory disease.
Kymriah is a customized therapy utilizing the patient’s own T-cells. The patient’s T-cells are extracted and genetically modified to include a new gene containing a protein known as chimeric antigen receptor (CAR). CAR directs the T-cells to target and kill leukemia cells that contain the specific antigen, CD19, on the surface. The multicenter clinical trial responsible for Kymriah’s approval was conducted in 63 pediatric and young adult patients with relapsed or refractory B-cell precursor ALL. In this trial, the overall survival rate at 12 months was 80%, which is substantially higher than has been previously reported for other treatment options (such as blinatumomab and clofarabine).
This first-of-its-kind treatment does not come without risks; Kymriah has the potential to cause serious side effects. It carries a black box warning for neurological toxicities and cytokine release syndrome (CRS), which results in high fever and flu-like symptoms. Both of these adverse effects can be life-threatening. Other potential side effects include: serious infections, low blood pressure, acute kidney injury, fever, and decreased oxygen levels. There is also an increased risk of infection after treatment due to the destruction of healthy B cells as a subsequent effect of therapy.
Due to the potential for severe adverse effects, Kymriah was approved with a Risk Evaluation and Mitigation Strategy (REMS) program. Hospitals and clinics involved in dispensing Kymriah must be specially certified. Healthcare providers administering Kymriah are required to be trained on managing neurological events and CRS. NPS is planning to review Kymriah for placement on the national formularies. For additional information on Kymriah, please view the FDA’s press release. For more information on gene therapy, please visit the FDA website.
New Drug Approvals
First Drug Approved to Treat Parkinson’s Dyskinesia
Gocovri® (amantadine extended-release [ER] capsules) has received FDA approval for the treatment of dyskinesia in patients with Parkinson’s disease (PD) receiving levodopa-based therapy, with or without concurrent dopamine therapy. It is the first drug therapy to receive approval for this specific use. Approximately 90% of people affected with PD receiving levodopa therapy will eventually experience unpredictable involuntary movements known as dyskinesia. As PD progresses, patients’ symptoms return more often resulting in the need for higher doses of levodopa. When the effects of levodopa therapy wear off, patients experience slowness of movement, rigidity, impaired walking, tremor, and postural instability known as “off time.” Gocovri has been found to reduce both dyskinesia and off time in Parkinson’s disease patients receiving levodopa.
Gocovri is taken every night at bedtime allowing for high concentrations in the morning and sustained concentrations throughout the day. In two Phase 3 controlled trials, Gocovri demonstrated a 37% to 46% reduction in Unified Dyskinesia Rating Scale total score, whereas patients who received placebo demonstrated a 12% to 16% reduction. In Study 1 and Study 2, patients reported a 3.6- and 4-hour increase in functional daily “on time.” In the placebo arm, patients reported a 0.8- and 2.1-hour increase in “on time.” The most commonly reported adverse reactions (>10%) associated with amantadine ER included: hallucinations, dizziness, dry mouth, fluid retention (usually in the lower limbs), constipation, falls, and low blood pressure upon standing. NPS is planning to review Gocovri for placement on the national formularies. For additional information on the new Parkinson’s disease dyskinesia medication, please view the manufacturer’s press release.
Victoza® Receives Expanded Indication
The U.S. FDA has approved a new indication for the injectable drug Victoza® (liraglutide). The type 2 diabetes medication is now indicated to reduce the risk of major adverse cardiovascular events (myocardial infarction [MI], stroke and cardiovascular [CV] death) in adults with type 2 diabetes mellitus (T2DM) who have established cardiovascular disease. The glucagon-like peptide-1 (GLP-1) receptor agonist was first approved in 2010 as an adjunct to diet and exercise to improve blood glucose control in adults with type 2 diabetes. Jardiance® (empagliflozin), another diabetes medication first approved as an adjunct to diet and exercise to improve blood glucose control in type 2 diabetes patients, also has received an expanded indication for reducing the risk of CV death in adults with T2DM and established CV disease.
The approval of Victoza’s new indication was based on the results of the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) clinical trial. In this study, liraglutide significantly reduced the risk for the composite endpoint evaluating major adverse CV events by 13% compared to placebo. Major adverse CV events were defined as: CV death, non-fatal MI, or non-fatal stroke. Liraglutide also reduced CV deaths by 22%, all-cause mortality by 15%, and advanced kidney disease by 22%. Victoza is administered as a subcutaneous injection once daily with a maximum dose of 1.8 mg per day. The average wholesale price (AWP) for a 3 mL pen containing 18 mg (10-day supply) of Victoza is $322.67.
Austedo® Now Indicated for Tardive Dyskinesia
On August 30, 2017, the FDA granted approval to Austedo® (deutetrabenazine) for the treatment of tardive dyskinesia in adults. Prior to this approval, deutetrabenazine was previously only indicated for the treatment of chorea associated with Huntington’s disease. Austedo is the second medication to receive FDA approval for tardive dyskinesia. Approximately 500,000 people in the U.S. are affected by tardive dyskinesia which is generally caused by long-term use of medications such as anti-psychotics. The potentially irreversible condition is characterized by repetitive movements of the tongue, lips, face, trunk, and extremities.
The approval of deutetrabenazine for tardive dyskinesia was based on the results from two Phase 3, 12-week, randomized, double-blind, placebo-controlled trials evaluating patients with TD caused by anti-psychotics or the gastrointestinal agent metoclopramide. Patients who received deutetrabenazine exhibited significant improvement in the primary endpoint assessing abnormal involuntary movements compared to patients who received placebo. The most common side effects in patients who received Austedo for the treatment of tardive dyskinesia were insomnia and nasopharyngitis. Austedo is expected to compete directly with Ingrezza® (valbenazine), another vesicular monoamine transporter 2 (VMAT2) inhibitor indicated for tardive dyskinesia.
Austedo is available in three tablet strengths (6 mg, 9 mg, and 12 mg) with an AWP of $65.76, $73.98, and $98.64 per each tablet, respectively. The starting dose of Austedo for the treatment of tardive dyskinesia is 12 mg daily with dose titration by 6 mg at weekly intervals to a maximum dose of 48 mg/day. Austedo is currently a specialty medication on the NPS national formulary. For additional information on Austedo’s new indication, please view the manufacturer’s press release.
FDA Safety Update
Drug Safety Communication Issued for Kayexelate®
The FDA has issued a drug safety communication for the potassium-lowering medication Kayexalate® (sodium polystyrene sulfonate [SPS]). The FDA is recommending administration of Kayexelate be separated from other orally administered medications by at least 3 hours. A study demonstrated the drug can bind to many oral medications causing decreases in absorption and reduced therapeutic effects. This recommendation applies to both orally administered prescription and over-the-counter (OTC) products. SPS is available as the brand-name product Kayexelate and as the generic brands Kalexate®, Kionex®, and other non-branded generics. Drug labels of SPS containing products will be updated to include this new recommendation.
Kayexalate is used for the treatment of high levels of potassium in the blood. Although it is important to have adequate potassium levels, elevated levels can cause heart problems that can sometimes be fatal. A study evaluating six oral medications (blood pressure medications: amlodipine, metoprolol; the antibiotic amoxicillin; the diuretic furosemide; the seizure medication phenytoin; and the blood-thinner warfarin) showed significant binding of SPS to these oral drugs. Based on these findings, it is expected other orally administered medications would also be subject to the binding properties of SPS. As a result, it is advised that SPS be taken 3 hours before or after any OTC or prescription medications to avoid binding. This time interval was determined based on the amount of time SPS or the other oral medications require to pass through the stomach. For patients with gastroparesis or other stomach conditions that may cause a delay in food moving from the stomach to the small intestine, the time interval between administration of SPS and other oral medications should be increased to 6 hours.
For additional details, please view the FDA’s Drug Safety Communication.
New Diabetes Follow-on Biologic Sits on Sidelines
Long-acting insulin products, such as Lantus® (insulin glargine injection), are indicated to improve blood glucose control in adult and pediatric patients with type 1 diabetes and adults with type 2 diabetes. In July 2017, Lusduna Nexvue® (insulin glargine injection), a “follow-on” product to Lantus, received tentative approval by the U.S. FDA. The manufacturer of Lusduna, has announced their product has met all required regulatory standards for follow-on biologics demonstrating clinical and nonclinical safety, efficacy, and quality. However, due to a patent infringement lawsuit with Sanofi, the developer of Lantus, Lusduna cannot be marketed in the U.S. for a period of 30 months (starting in September 2016) or until the patent dispute has been resolved.
In December 2015, the FDA approved the first “follow-on” biologic product: Basaglar® (insulin glargine injection). However, Basaglar’s commercial launch was delayed for 12 months, until December 2016, due to patent litigation. Both Lusduna Nexvue and Basaglar are considered to be follow-on biologic products as they are similar, but not identical, to the already FDA-approved reference product, Lantus. Due to the complex structure of these large molecules they are approved under a different regulatory pathway from traditional generic drugs. As a result, the products are referred to as follow-on biologic products. NPS will provide ongoing communication regarding the patent disputes and commercial launch of Lusduna Nexvue.
First Cancer Biosimilar Receives U.S. FDA Approval
In September 2017, the U.S. FDA approved the first biosimilar for the treatment of cancer: Mvasi® (bevacizumab-awwb). Mvasi is approved as a biosimilar to reference product Avastin® (bevacizumab) and received approval for the treatment of adult patients with specific types of cancer, including metastatic colorectal cancer, non-squamous non-small cell lung cancer, glioblastoma, metastatic renal cell carcinoma, and cervical cancer. Mvasi is usually given in combination with other cancer therapies.
Biosimilar products are biologic products that have been determined to be highly similar to an existing biologic product (i.e, the reference product). The biosimilar product has no clinically relevant differences in terms of safety and efficacy from the reference product. Mvasi was granted FDA approval on the basis of animal data, pharmacokinetic / pharmacodynamic data, immunogenicity data, and safety / effectiveness data. Similar to Avastin, Mvasi carries a black box warning regarding the potential for a number of serious complications, including: gastrointestinal perforations, impaired wound healing, and severe bleeding. As with the reference product, Mvasi also carries a number of warnings/precautions including the potential for blood clots leading to heart attack or stroke, high blood pressure, and infusion-related reactions.
Although Mvasi has been approved for use in the U.S. by the FDA, it is unclear when the biosimilar will become commercially available as Avastin’s patents may delay the launch of Mvasi until 2019. NPS plans to provide ongoing communication regarding the U.S. launch of Mvasi. For additional details on the biosimilar, please view the manufacturer’s press release or FDA press release.
Discontinuation of Certain Generic Products
In September 2017, the FDA reported the discontinuation of ciprofloxacin 500 mg tablets by Mylan Pharmaceuticals Inc. The product discontinuation is due to a business decision and is not related to the quality, safety, or efficacy of the product. Other generic ciprofloxacin products are expected to remain commercially available. Ciprofloxacin is a broad spectrum antimicrobial agent indicated for the treatment of certain infections caused by susceptible strains of bacteria.
It was also reported that Sandoz has decided to permanently discontinue ranitidine 150 mg and 300 mg tablets supplied in 30 count, 60 count, 250 count, and 1000 count containers. Ranitidine is indicated for the treatment of a number of stomach conditions, including: duodenal ulcers, erosive esophagitis, gastric ulcer, and gastroesophageal reflux disease (GERD). Sandoz has also announced the 25 mg and 50 mg tablet strengths of methazolamide will be permanently discontinued; both strengths are supplied in a 100 count container. Methazolamide is indicated for the treatment of ocular conditions where a decrease in intraocular pressure is needed. Both the ranitidine and methazolamide product discontinuations are due to business decisions and are not related to safety, efficacy, or quality of the products. Other generic versions of these drug products are expected to remain commercially available.
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