First 2-drug combo for advanced melanoma, plus 5 more FDA actions


First 2-drug therapy approved for advanced melanoma and four other recent approvals by FDA relating to new drugs and treatments.

FDA recently approved the use of Bristol-Myers Squibb’s (BMS) nivolumab (Opdivo) and ipilimumab (Yervoy), in combination as a treatment for patients with unresectable or metastatic melanoma without a BRAF mutation, known as BRAF wild-type melanoma.

FDA’s accelerated approval of the 2-drug regimen marks the first approval of combination immunotherapy treatments for advanced melanoma and comes less than one year after the first approval of nivolumab by the FDA. Each drug was previously FDA-approved as monotherapy for the treatment of advanced melanoma.

Related:Combo therapy yields intriguing results in melanoma progression

“Based on the findings reported in scientific meetings and prestigious medical publications, the combination of ipilimumab and nivolumab are clearly active against melanoma. We’re pleased that both BMS and the FDA acted quickly so that patients will have access to the latest advances in melanoma treatment,” said Louise M. Perkins, chief science officer with the Melanoma Research Alliance. “The pace of change in melanoma treatment is unprecedented and a testament to the amazing advances in both immunotherapy and targeted therapy research.”

Approximately half of patients’ melanomas harbor BRAF mutations and the other half are BRAF wild-type. Ipilimumab and nivolumab are two types of immunotherapy that help the body’s own immune system attack cancer cells. Ipilimumab is an anti-CTLA-4 inhibitor, while nivolumab is an anti-PD-1 drug.

The decision by FDA was based on the results of the CheckMate-069 trial, which looked at the combination of ipilimumab and nivolumab, compared to ipilimumab alone in previously untreated, BRAF wild-type patients. The Opdivo and Yervoy regimen demonstrated a 60% reduction in the risk of progression versus Yervoy alone.

Opdivo is associated with immune-mediated: pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, rash, other adverse reactions; infusion reactions; and embryofetal toxicity, according to BMS.


NEXT: FDA grants accelerated approval for Keytruda


FDA granted accelerated approval for Keytruda (pembrolizumab) to treat patients with advanced (metastatic) non-small cell lung cancer (NSCLC) whose disease has progressed after other treatments and with tumors that express a protein called PD-L1.

Related: Faster FDA approvals lead cancer drug boom

Keytruda, marketed by Merck & Co., in Whitehouse Station, N.J., is approved for use with a companion diagnostic, the PD-L1 IHC 22C3 pharmDx test, the first test designed to detect PD-L1 expression in non-small cell lung tumors. The PD-L1 IHC 22C3 pharmDx diagnostic test is marketed by Dako North America Inc. in Carpinteria, Calif.

Lung cancer is the leading cause of cancer death in the United States, with an estimated 221,200 new diagnoses and 158,040 deaths in 2015, while NSCLC is the most common type of lung cancer.

Related: Continued advances in cancer outcomes unveiled at ASCO

“Our growing understanding of underlying molecular pathways and how our immune system interacts with cancer is leading to important advances in medicine,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research. “Today’s approval of Keytruda gives physicians the ability to target specific patients who may be most likely to benefit from this drug.”

Keytruda works by targeting the cellular pathway known as PD-1/PD-L1 (proteins found on the body’s immune cells and some cancer cells). By blocking this pathway, Keytruda may help the body’s immune system fight the cancer cells.

In 2014, Keytruda was approved to treat patients with advanced melanoma following treatment with ipilimumab, a type of immunotherapy. Another drug, Opdivo (nivolumab), manufactured by Bristol-Myers Squibb, also targets the PD-1/PD-L1 pathway and was approved to treat squamous non-small cell lung cancer in 2015.


NEXT: Common side effects of Keytruda


The effectiveness of Keytruda for this use was demonstrated in a subgroup of 61 patients enrolled within a larger multicenter, open-label, multipart study. Tumors shrank in 41% of patients treated with Keytruda and the effect lasted between 2.1 and 9.1 months.

The most common side effects of Keytruda included fatigue, decreased appetite, shortness of breath or impaired breathing (dyspnea) and cough. Keytruda also has the potential to cause severe side effects that result from the immune system effect of Keytruda (known as “immune-mediated side effects”).

In a study of 550 patients with advanced NSCLC, severe immune-mediated side effects occurred involving the lungs, colon and hormone-producing glands. Other uncommon immune-mediated side effects were rash and inflammation of blood vessels (vasculitis). Women who are pregnant or breastfeeding should not take Keytruda because it may cause harm to a developing fetus or newborn baby. Across clinical studies, a disorder in which the body's immune system attacks part of the peripheral nervous system (Guillain-Barre Syndrome) also occurred.

FDA granted Keytruda breakthrough therapy designation for this indication because Merck demonstrated through preliminary clinical evidence that the drug may offer a substantial improvement over available therapies. The drug also received priority review status, which is granted to drugs that, at the time the application was submitted, have the potential to be a significant improvement in safety or effectiveness in the treatment of a serious condition.


NEXT: FDA approves Tresiba, Ryzodeg 70/30 for diabetes millitus treatment


FDA has approved insulin degludec injection (Tresiba, Novo Nordisk) and insulin degludec/insulin aspart injection (Ryzodeg 70/30, Novo Nordisk) for the treatment of diabetes mellitus.

Related: FDA warns of joint pain for DPP-4 diabetes drugs

More than 29 million Americans are affected by diabetes, with type 2 diabetes accounting for 90% to 95% of all diabetes cases. 

Tresiba is a once-daily, long-acting basal insulin indicated for use alone, or in combination with oral antidiabetic medications or bolus insulin to improve glycemic control in adults with type 1 and type 2 diabetes mellitus. Tresiba has a long duration of action, more than 42 hours, which allows patients to dose the medication at any time of the day. Tresiba is the first new basal insulin molecule to be approved by FDA in 10 years.

Ryzodeg 70/30 is a mixture of 70% insulin degludec, a long-acting insulin, and 30% insulin aspart, a rapid-acting human insulin analog indicated to improve glycemic control in adults with diabetes mellitus.

Related: FDA approves Synjardy for type 2 diabetes

"Long-acting insulins play an essential role in the treatment of patients with type 1 diabetes and in patients with type 2 diabetes with advanced disease," said Jean-Marc Guettier, MD, director of the Division of Metabolism and Endocrinology Products in FDA’s Center for Drug Evaluation and Research. “The FDA remains committed to support the development of innovative therapies for the treatment of diabetes.”

The safety and efficacy of Tresiba in combination with mealtime insulin in patient with type 1 diabetes were evaluated in two 26-week and one 52-week clinical trials involving 1,102 participants. In type 2 diabetes, Tresiba was evaluated in combination with mealtime insulin or as an adjunct to oral antidiabetic drugs in four 26-week and two 52-week clinical trials involving 2,702 participants.

The safety and efficacy of Ryzodeg 70/30 in combination with mealtime insulin in patient with type 1 diabetes were evaluated in one 26-week trial involving 362 participants and its safety and efficacy in patients with type 2 diabetes was assessed in four 26-week clinical trials involving 998 patients.

Results of the trials showed that Tresiba and Ryzodeg, given to patients who had inadequate blood sugar control at trial entry, reduced hemoglobin A1C (HbA1c) similarly to reductions achieved with previously approved long-acting insulins and long-acting or pre-mixed insulins, respectively.

Tresiba and Ryzodeg may cause hypoglycemia and should be closely monitored with changes to dosage, coadministration of other glucose-lowering medications, meal pattern, physical activity, and in patients with renal or hepatic impairment. These drugs should not be used in patients with diabetic ketoacidosis. Other common adverse reaction associated with both Tresiba and Ryzodeg include allergic reactions, injection-site reaction, itching, rash, edema, and weight gain.


NEXT: FDA approves cariprazine for schizophrenia and bipolar I disorder treatment


FDA has approved cariprazine (Vraylar, Allergan and Gedeon Richter Plc.) for the treatment of schizophrenia and bipolar I disorder in adults.

Related: GAO: Antipsychotic overuse "widepread" for dementia

Bipolar I disorder and schizophrenia are chronic and disabling mental health disorders. People with bipolar disorder experience unusually intense emotional states, called “mood episodes.” There are different types of bipolar disorder. Bipolar I disorder is defined by manic or mixed episodes that last at least seven days, or by manic symptoms that are so severe that the person needs immediate hospital care. Bipolar disorder affects approximately 3.6 million Americans.

Schizophrenia is a mental disorder that affects how a person thinks, feels and acts. A person with schizophrenia may have difficulty distinguishing between what is real and what is not. Schizophrenia is characterized by the presence of positive symptoms like delusions or hallucinations, as well as negative symptoms such as emotional unresponsiveness. Schizophrenia affects more than 2.6 million Americans.

Related: Long-acting schizophrenia drug may help with medication adherence

Vraylar is a once-daily, oral atypical antipsychotic approved for the acute treatment of adult patients with manic or mixed episodes associated with bipolar I disorder and for the treatment of schizophrenia in adults.

“While the mechanism of action of Vraylar is unknown, the interaction of cariprazine with dopaminergic and serotonergic receptors in the CNS may explain its activity. Cariprazine has high binding affinity and acts as a partial agonist at the dopamine D3 and D2 receptors. Notably, Vraylar’s is the only available atypical efficacy with higher affinity for the D3 receptor than the D2 receptor. Vraylar is also a partial agonist at serotonin 5-HT1A receptors and has antagonist activity at serotonin 5-HT2A receptors,” said Gary Sachs, MD, founding director of the Bipolar Clinic and Research Program at the Massachusetts General Hospital and associate professor of psychiatry at Harvard Medical School. “Vraylar may also offer advantages due to the comparatively long half-life of the drug [2 to 4 days] and its active metabolite [1 to 3 weeks]. Patients taking Vraylar might be less susceptible to adverse outcomes due to occasional partial adherence than those taking treatments with a short half-life.”

FDA's approval was based on 6 placebo-controlled clinical trials involving more than 2,700 adults in which Vraylar demonstrated robust efficacy without evidence of any worsening of the metabolic parameters that are of concern for several other compounds classified as atypical antipsychotics, according to Dr Sachs.

Some of the most common side effects associated with the use of Vraylar in bipolar disorder included extrapyramidal symptoms (EPS), dyspepsia, vomiting, and somnolence. As for Vraylar's use in treating schizophrenia, the most common side effects were EPS, including restlessness and tremors.

Vraylar is also being investigated for the treatment of bipolar depression and as adjunctive treatment for major depressive disorder in adults.


NEXT: FDA approves aspirin extended-release capsules for prevention of stroke and acute cardiac events


FDA has approved aspirin extended-release capsules (Durlaza, New Haven Pharmaceuticals, Inc.) for the prevention of stroke and acute cardiac events.

Related: Diabetes drug may reduce stroke, CV deaths

Platelets-specialized cells present in the blood that are involved in the formation of blood clots-play a key role in heart attacks, strokes, and peripheral vascular disease. Because of its ability to inhibit platelet aggregation, low-dose aspirin has been proven to reduce the risk of secondary cardiovascular events, including stroke and heart attack. While the body is constantly producing platelets 24 hours a day, current immediate-release aspirin has a duration of action of only 4 to 6 hours with a peak concentration after about 30 minutes.

Durlaza is the first, and only 24-hour, extended-release aspirin capsule. The extended-release microcapsule technology allows prolonged absorption and sustained platelet exposure to aspirin. It is indicated to reduce the risk of death and myocardial infarction (MI) in patient with chronic coronary artery disease, including patients with a history of MI or unstable as well as chronic angina. It is also approved to reduce the risk of death and recurrent stroke in patients who have had an ischemic stroke or transient ischemic attack.

Related:Investigational PCSK9 inhibitor lowers LDL-C, may reduce cardiovascular events

"Durlaza is an aspirin formulation for secondary prevention in high-risk CVD patients. The aspirin delivery technology in Durlaza extends the release of aspirin in a manner designed to provide a stable antiplatelet effect over the course of the day. The latter unique property of Durlaza is important as patients at risk generate new platelets throughout the day. Also, as one dosage form of any medication rarely works for all patients, Durlaza provides an alternative dosing option for patients who need aspirin for cardiovascular risk prevention," Paul Gurbel, MD, associate chief for research and director of the Sinai Center for Thrombosis Research, Sinai Hospital, Baltimore, professor of medicine, Johns Hopkins University, adjunct professor of medicine, Duke University, said in a press release.

Immediate-release aspirin, not Durlaza, should be used in situations where a rapid onset of action is required, such as acute treatment of MI or before percutaneous coronary intervention (PCI). Similarly to immediate-release aspirin, Durlaza increases the risk of bleeding and gastric ulceration, and may cause fetal harm when given to a pregnant woman.

Durlaza is expected to be available in the fourth quarter of 2015. 

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