PCSK-9 inhibitors achieve next milestone, plus 4 more FDA actions


A summary of five FDA actions taken within the last few weeks.

FDA’ s Endocrinologic and Metabolic Drugs Advisory Committee recommended this week to approve cholesterol-lowering drug evolocumab (Repatha) from Amgen in a 15-0 vote. It also voted 13-3 in favor of FDA approving Sanofi and Regeneron's Praluent (alirocumab), but most panel members called for a restricted label in high-risk patients with genetic conditions causing elevated cholesterol, rather than wider use in the general elevated cholesterol population. 

The panel said that evolocumab should be approved in a rare disease called homozygous familial hypercholesterolemia (HoFH), a genetic disorder that causes very high cholesterol levels and can lead to heart attacks in childhood, according to an article in Forbes. The panel also said the drug could be used in other indications such as the more common heterozygous familial hypercholesterolemia (heFH), but stopped short of recommending it for the general elevated cholesterol population.

The drug manufacturers are hoping for approval for more general use in patients with elevated cholesterol who cannot tolerate statins or who cannot achieve their LDL-C targets on statin therapy alone, according to PMLive. Evolocumab has already been recommended for approval in Europe for hoFH as well as the larger target population.

In briefing documents released late last week, FDA staff generally approved of alirocumab’s safety and efficacy.

Related: Move over Sovaldi: Could the PCSK9 inhibitors be a bigger cost challenge?

“The benefit-risk profile of alirocumab is favorable,” according to the briefing documents prepared by FDA staff. “Alirocumab provides clinically meaningful mean reductions of LDL-C in patients not achieving adequate reductions with their existing statin, or in patients unable or unwilling to take status to achieve their LDL goals.” In clinical studies, alirocumab provided up to 63% mean reductions on top of statin therapy in patients with high cardiovascular risk who were not well-controlled, despite their current therapies.

Related: Statins: Discontinue in terminal illnesses

In a randomized, double-blind study of patients with a history of statin intolerance, alirocumab demonstrated greater efficacy than ezetimibe and a lower rate of muscle-related adverse events than with either statin or ezetimibe treatment. “These data indicate that alirocumab is a valuable treatment for patients who are unable or unwilling to take a statin and support the proposed indication in this patient population,” the document said.

Based upon currently available clinical data, Anna Goldbeck, a principal in the National Pharmacy Practice at Buck Consultants at Xerox expects utilization management controls for PCSK-9 Inhibitors to include prior authorization with step therapy as a component. 

According to Goldbeck, the criteria utilized will likely include:

  • A small segment of the population diagnosed with familial hypercholesterolemia 

  • Patients with high cholesterol not controlled by other cholesterol-lowering therapies, titrated to appropriate dosing levels

  • Patients with high cholesterol that cannot tolerate or have contraindications to other cholesterol-lowering therapies (eg, statins)

"Also, we would expect continued use of the PCSK9s to be limited to those  meeting specific reauthorization criteria, which would focus on demonstrated effectiveness [cholesterol levels]," Goldbeck said.


NEXT: FDA grants priority review to expand use of Brilinta


FDA has granted priority review for ticagrelor (Brilinta, AstraZeneca) for patients with a history of heart attack.

Brilinta is an oral antiplatelet used for acute coronary syndromes (ACS). It acts as a P2Y12 receptor antagonist to inhibit platelet activation and reduce the rate of thrombotic cardiovascular events, such as heart attack or cardiovascular (CV) death.

Related:FDA approves new administration option for Brilinta

"AstraZeneca believes there is clear need for treatment options beyond the current standard of care of aspirin for the long-term prevention of atherothrombotic cardiovascular events in patients with a history of myocardial infarction; recent research has shown that 1 in 5 patients will have a further heart attack, stroke or CV death in the subsequent 3 years following a heart attack, even if patients were event free after 12 months," according to a company statement.

The acceptance of the supplemental New Drug Application is based on the results of the PEGASUS-TIMI 54 study, which included more than 21,000 patients. The study investigated ticagrelor tablets plus low-dose aspirin compared to placebo plus low-dose aspirin, for the chronic secondary prevention of atherothrombotic events in patients who had experienced a heart attack 1 to 3 years prior to study enrollment.

Related: Grassroots FDA partnership aims to reduce heart disease deaths

Study results showed that twice-daily doses of either ticagrelor 60 mg or 90 mg significantly reduced risk of CV death, myocardial infarction, or stroke compared with placebo. However, treatment with ticagrelor increased risk of major bleeding.

The most common adverse reactions associated with the use of Brilinta include an increased risk of bleeding and dyspnea. Brilinta is contraindicated in patients with a history of intracranial hemorrhage and active pathological bleeding. It is also contraindicated in patients with severe hepatic impairment. Maintenance doses of aspirin greater than 100 mg have been shown to decrease effectiveness of Brilinta and should be avoided. 


NEXT: Actemra gets breakthrough therapy designation for scleroderma


FDA has granted breakthrough therapy designation to tocilizumab (Actemra, Genentech) for the treatment of systemic sclerosis, or scleroderma, a rare and potentially life-threatening disease with no FDA-approved therapy.

The breakthrough therapy designation was granted based on 48-week data from the phase 2 faSScinate study, presented as an oral presentation in Rome at EULAR 2015.

Related:Breakthrough therapy designation: FDA’s newest mechanism for accelerating approval for promising pipeline therapies

The aspects of systemic sclerosis where tocilizumab showed encouraging results in the phase 2 faSScinate trial were excessive skin thickening, deterioration of lung function and patient-reported outcome measures, according to Elena Hitraya, MD, PhD, group medical director, Genentech Immunology.

“Skin thickening and deterioration of lung function are important causes of increased morbidity and mortality in systemic sclerosis,” Dr Hitraya said. “By impacting these important aspects of disease [tocilizumab] may reduce disability, reduce the associated costs to the healthcare system as well as improve health-related quality of life. An effective disease-modifying drug could also reduce the 30% 10-year mortality associated with systemic sclerosis.”

Breakthrough designation represents a recognition by the FDA that the systemic sclerosis population we are studying with [tocilizumab] is an important area of unmet medical need, according to Jeff Siegel, MD, senior group medical director, Genentech Immunology. “The designation provides recognition that FDA believes the data are strong and that [tocilizumab] may provide benefit for a serious aspect of systemic sclerosis,” Dr Siegel said.

Related:FDA grants Lucentis breakthrough therapy for diabetic retinopathy

Systemic sclerosis is a debilitating rare, chronic autoimmune disease characterized by blood vessel abnormalities and scarring in the skin, joints and multiple internal organs. It affects 75,000 to 100,000 people in the United States and has the highest mortality of any autoimmune rheumatic disease, according to Dr Hitraya. It affects predominantly women and most commonly affects patients aged 30 to 50 years.

“Skin involvement can be debilitating by affecting patients’ ability to work or even to perform ordinary tasks of daily living like dressing and bathing,” she said. “Lung involvement is one of the most common forms of internal organ system involvement and represents one of the main causes of increased mortality.”


NEXT: Antiepileptic drug can now be used in pediatric patients


FDA has expanded the indication for topiramate (Qudexy XR, Upsher-Smith Laboratories) extended-release capsules within the pediatric population.

Qudexy XR, a once-daily, broad-spectrum antiepileptic drug, was previously approved for use as initial monotherapy in patients aged 10 years and older with partial-onset seizures (POS) or primary generalized tonic-clonic seizures. With this approval, it now offers prescribers an additional first-line treatment option in patients aged 2 years and older who are experiencing these seizures.

Related:Pediatric migraine drug gets FDA green light

The ability to sprinkle the drug onto soft food makes it a useful option for young children who may have difficulty swallowing whole capsules or tablets. 

Related:FDA approves drug to treat rare bile acid synthesis disorders in kids, adults

It is also approved as an adjunctive therapy in patients aged 2 years or older with POS, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome.

Qudexy XR has been available in the United States since June 2014.


NEXT: Promacta stimulates platelet production in CITP pediatric patients



FDA has approved eltrombopag (Promacta, Novartis) for the treatment of children aged 6 years and older with chronic immune thrombocytopenia (cITP).

Related: FDA approves first spray-dried sealant to stop bleeding

Immune thrombocytopenia (ITP) is a bleeding disorder in which a person’s immune system attacks their own platelets. Due to a low number of platelets, the blood does not clot as it should and consequently, people with ITP can bruise of bleed more easily than normal.  ITP affects as many as 5 in 100,000 children each year, and up to 30 percent of those affected experience persistent disease for more than 6 months and are diagnosed with chronic ITP. Patients with chronic ITP are at an ongoing risk of significant bleeding.

Promacta is a once-daily thrombopoietin receptor agonist that interacts with the thrombopoietin receptor to increase platelet production. It is now approved to treat children aged 6 years and older with chronic ITP, when corticosteroids, immunoglobulins, or splenectomy have not been successful. It was approved in 2008 for use in adults with the same condition.

Related: Pediatric migraine drug gets FDA green light

“[The] FDA approval of Promacta for children with chronic ITP, a rare and potentially serious blood disorder, gives new hope to patients and their families,” said Bruno Strigini, president, Novartis Oncology. “All patients are important, but when we can help children, we are especially gratified. This approval underscores our expertise in benign hematologic disease and our commitment to provide treatments for rare diseases.”

The drug's approval was based on 2 double-blind, placebo-controlled trials, including the largest phase 3 clinical trial in this patient population. Results from the PETIT and PETIT2 trials showed that Promacta significantly increased and sustained platelet count among some pediatric patients with chronic ITP, and some patients who were taking other ITP medications were able to reduce or discontinue the use of these medications.

It is not known if Promacta is safe and effective in ITP patients younger than age 6 years. Separate applications were submitted to FDA earlier this year to include chronic ITP patients aged 1 year and older.  Upper respiratory tract infection, nasopharyngitis, and rhinitis were the most common adverse reactions associated with the use of Promacta in chronic ITP patients aged 6 years and older. 

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