FDA Approves Wakix (pitolisant), a First-in-Class Medication for the Treatment of Excessive Daytime Sleepiness in Adult Patients with Narcolepsy

Harmony Biosciences, LLC (Harmony) announced the U.S. Food and Drug Administration (FDA) approval of Wakix (pitolisant) for the treatment of excessive daytime sleepiness (EDS) in adult patients with narcolepsy. Wakix is the first and only treatment approved for patients with narcolepsy that is not scheduled as a controlled substance by the U.S. Drug Enforcement Administration (DEA).

“We are extremely proud to bring Wakix to market for those living with narcolepsy, a chronic, debilitating, rare neurologic disorder,” said Harmony’s Chairman and Chief Executive Officer, John C. Jacobs. “At Harmony we share a vision to develop novel treatment options for people living with rare diseases, with a focus on those that affect the central nervous system. The approval of Wakix strengthens our commitment to making that vision a reality.”

Wakix, a first-in-class medication, is a selective histamine 3 (H₃) receptor antagonist/inverse agonist that works through a novel mechanism of action to increase the synthesis and release of histamine, a wake-promoting neurotransmitter in the brain. Wakix is administered orally once daily in the morning upon wakening.

“The approval of Wakix provides healthcare professionals managing people living with narcolepsy a new and important treatment option for their patients,” said Harmony’s Chief Medical Officer, Jeffrey Dayno, M.D. “Additionally, Wakix is the only non-scheduled treatment option approved for adult patients with narcolepsy, and it offers an important benefit/risk profile to address the unmet medical need that exists in people living with narcolepsy.”

The efficacy of Wakix for the treatment of EDS in adult patients with narcolepsy was evaluated in two multicenter, randomized, double-blind, placebo-controlled studies (HARMONY 1 and HARMONY 1bis). These studies included a total of 261 patients who were randomized to receive Wakix, placebo, or active control; these patients had a median age of 37 (HARMONY 1) and 40 (HARMONY 1bis). Treatment duration was eight weeks, with a three-week dose titration phase followed by a 5-week stable dose phase; 75% to 80% of the patients in these studies had a history of cataplexy. In both of these studies, WAKIX demonstrated a statistically significant improvement in EDS as measured by the Epworth Sleepiness Scale (ESS) score. In the placebo-controlled trials conducted in patients with narcolepsy with or without cataplexy, the most common adverse reactions (occurring in ≥5% of patients and at twice the rate of placebo) with the use of WAKIX were insomnia (6%), nausea (6%), and anxiety (5%).

Wakix will be commercially available to healthcare professionals and appropriate patients in the U.S. in the fourth quarter of 2019.

About Wakix (pitolisant)

Wakix is a first-in-class medication approved for use in the U.S. for the treatment of excessive daytime sleepiness in adult patients with narcolepsy. It was granted orphan drug designation for the treatment of narcolepsy in 2010. WAKIX is a selective histamine 3 (H₃) receptor antagonist/inverse agonist. The mechanism of action of Wakix is unclear; however, its efficacy could be mediated through its activity at H₃ receptors, thereby increasing the synthesis and release of histamine, a wake promoting neurotransmitter. WAKIX was designed and developed by Bioprojet Societe Civile de Recherche (Bioprojet), who has marketed the product in Europe since its approval by the European Medicines Agency in 2016. Harmony has an exclusive license from Bioprojet to develop, manufacture and commercialize pitolisant in the United States.

INDICATION AND USAGE

Wakix (pitolisant) is approved for the treatment of excessive daytime sleepiness (EDS) in adult patients with narcolepsy.

IMPORTANT SAFETY INFORMATION

Do not use Wakix if you have severe liver disease.

Tell your healthcare provider about all your medical conditions, including if you have heart rhythm irregularities, were born with a heart condition, or the levels of electrolytes in your blood are too high or too low. Wakix has an effect on the electrical activity of the heart known as QT/QTc prolongation. Medicines with this effect can lead to disturbances in heart rhythm, which are more likely in patients with risk factors such as certain heart conditions, or when taken in combination with other interacting medicines. Tell your healthcare provider about all the other medicines you take.

The risk of QT prolongation may be greater in patients with liver or kidney disease. Wakix is not recommended in patients with end stage kidney disease.

The most common side effects seen with Wakix were insomnia, nausea and anxiety. Other side effects included headache, upper respiratory infection, musculoskeletal pain, heart rate increased, and decreased appetite. These are not all the possible side effects of Wakix. Tell your healthcare provider about any side effect that bothers you or that does not go away.

Tell your healthcare provider about all the medicines you take or plan to take, including prescription and over-the-counter medicines. Some medicines can increase the amount of Wakix that gets into your blood and some medicines can decrease the amount of Wakix that gets into your blood. The dosage of Wakix may need to be adjusted if you are taking these medicines.

Wakix can also decrease the effectiveness of some medicines, including hormonal birth control methods. You should use an alternative non-hormonal birth control method during treatment with Wakix and for at least 21 days after discontinuation of treatment.

Tell your healthcare provider if you are pregnant or planning to become pregnant. There is a pregnancy exposure registry that monitors pregnancy outcomes in women who are exposed to Wakix during pregnancy. You are encouraged to enroll in the Wakix pregnancy registry if you become pregnant while taking WAKIX. To enroll or obtain information from the registry, call 1-800-833-7460.

The safety and effectiveness of Wakix have not been established in patients less than 18 years of age.

https://pubchem.ncbi.nlm.nih.gov/compound/Pitolisant#section=2D-Structure

FDA Approves Boxed Warning About Increased Risk of Blood Clots and Death with Higher Dose of Tofacitinib (Xeljanz, Xeljanz XR)

In continuation of my update on tofacitinib 

The U.S. Food and Drug Administration has approved new warnings about an increased risk of blood clots and of death with the 10 mg twice daily dose of tofacitinib (Xeljanz, Xeljanz XR), which is used in patients with ulcerative colitis. In addition, the approved use of tofacitinib for ulcerative colitis will be limited to certain patients who are not treated effectively or who experience severe side effects with certain other medicines. We approved these changes, including adding our most prominent Boxed Warning, after reviewing interim data from an ongoing safety clinical trial of tofacitinib in patients with rheumatoid arthritis (RA) that examined a lower and this higher dose of the medicine.

The 10 mg twice daily dose of tofacitinib is not approved for RA or psoriatic arthritis (PsA). This dose is only approved for ulcerative colitis for initial treatment and for long-term use in limited situations. While the increased risks of blood clots and of death were seen in patients taking this dose for RA, these risks may also apply to those taking tofacitinib for ulcerative colitis.

Tofacitinib works by decreasing the activity of the immune system; an overactive immune system contributes to RA, PsA, and ulcerative colitis. Tofacitinib was first approved in 2012 to treat adult patients with RA who did not respond well to the medicine methotrexate. In RA, the body attacks its own joints, causing pain, swelling, and loss of function. In 2017, we approved the medicine to treat patients with a second condition that causes joint pain and swelling, PsA, who did not respond well to methotrexate or other similar medicines. In 2018, we approved tofacitinib to treat ulcerative colitis, which is a chronic, inflammatory disease affecting the colon.

Patients should tell your health care professionals if you have a history of blood clots or heart problems, and talk to them about any questions or concerns. Stop taking tofacitinib and seek emergency medical attention right away if you experience any unusual symptoms, including those that may signal a blood clot such as:

• Sudden shortness of breath
• Chest pain that worsens with breathing
• Swelling of a leg or arm
• Leg pain or tenderness, or red or discolored skin in the painful or swollen leg or arm

Do not stop taking tofacitinib without first talking to your health care professional, as doing so can worsen your condition.

Health care professionals should discontinue tofacitinib and promptly evaluate patients with symptoms of thrombosis. Counsel patients about the risks and advise them to seek medical attention immediately if they experience any unusual symptoms, including those of thrombosis listed above. Reserve tofacitinib to treat ulcerative colitis for patients who have failed or do not tolerate tumor necrosis factor (TNF) blockers. Avoid tofacitinib in patients who may have a higher risk of thrombosis. When treating ulcerative colitis, use tofacitinib at the lowest effective dose and limit the use of the 10 mg twice daily dosage to the shortest duration needed (See Additional Information for Health Care Professionals for more recommendations).

When FDA first approved tofacitinib in 2012, we required a postmarketing clinical trial in patients with RA on background methotrexate, to evaluate the risk of heart-related events, cancer, and infections. The trial is studying two different doses of tofacitinib (5 mg twice daily, which is the currently approved dose for RA, and a higher, 10 mg twice daily dosage) in comparison to a TNF blocker. An interim analysis of the trial’s results found an increased occurrence of blood clots and of death in patients treated with tofacitinib 10 mg twice daily compared to patients treated with tofacitinib 5 mg twice daily or a TNF blocker. Based on these results, the 10 mg twice daily treatment was stopped and patients were allowed to continue treatment on 5 mg twice daily.

This safety trial is ongoing. Patients in the 5 mg twice daily group and the TNF blocker group continue to be followed. FDA will reassess these safety issues when the trial has completed and final, verified data are available. We will update the public when additional information is available.

The interim results of the trial, as of January 2019, have identified the following:

• 19 cases of blood clots in the lung out of 3,884 patient-years of follow-up in patients who received tofacitinib 10 mg twice daily, compared to 3 cases out of 3,982 patient-years in patients who received TNF blockers
• 45 cases of death from all causes out of 3,884 patient-years of follow-up in patients who received tofacitinib 10 mg twice daily, compared to 25 cases out of 3,982 patient-years in patients who received TNF blockers

https://en.wikipedia.org/wiki/Tofacitinib

FDA Approves Recarbrio (imipenem, cilastatin, and relebactam) for the Treatment of Complicated Urinary Tract and Complicated Intra-Abdominal Bacterial Infections

  

Imipenem (Primaxin)                      Cilastatin                                     Relebactam

Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved Recarbrio (imipenem, cilastatin, and relebactam) for injection, 1.25 grams, a new combination antibacterial. Recarbrio is indicated in patients 18 years of age and older who have limited or no alternative treatment options, for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis, caused by the following susceptible Gram-negative microorganisms: Enterobacter cloacae, Escherichia coli, Klebsiella aerogenes, Klebsiella pneumoniae, and Pseudomonas aeruginosa.

Recarbrio is also indicated in patients 18 years of age or older who have limited or no alternative treatment options, for the treatment of complicated intra-abdominal infections (cIAI) caused by the following susceptible Gram-negative microorganisms: Bacteroides caccae, Bacteroides fragilis, Bacteroides ovatus, Bacteroides stercoris, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Fusobacterium nucleatum, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Parabacteroides distasonis and Pseudomonas aeruginosa.

Approval of these indications is based on limited clinical safety and efficacy data for Recarbrio.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Recarbrio and other antibacterial drugs, Recarbrio should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Relebactam received FDA’s Qualified Infectious Disease Product (QIDP) designation for the treatment of cUTI and cIAI. The New Drug Application (NDA) for Recarbrio received Priority Review designation from the FDA. Merck anticipates making Recarbrio available later this year.

Recarbrio is contraindicated in patients with a history of known severe hypersensitivity (severe systemic allergic reaction such as anaphylaxis) to any component of Recarbrio. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with beta-lactams. Central nervous system (CNS) adverse reactions, such as seizures, confusional states, and myoclonic activity, have been reported during treatment with imipenem/cilastatin, a component of Recarbrio, especially when recommended dosages of imipenem were exceeded. These reactions have been reported most commonly in patients with CNS disorders (such as brain lesions or a history of seizures) and/or compromised renal function. Concominant use of Recarbrio, with valproic acid or divalproex sodium may increase the risk of breakthrough seizures. Additionally, Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including imipenem/cilastatin plus relebactam and may range in severity from mild diarrhea to fatal colitis. See Important Safety Information below.

Recarbrio is a combination of imipenem/cilastatin and relebactam. Imipenem is a penem antibacterial drug, cilastatin sodium is a renal dehydropeptidase inhibitor, and relebactam is a beta lactamase inhibitor. Cilastatin limits the renal metabolism of imipenem and does not have antibacterial activity. The bactericidal activity of imipenem results from binding to PBP 2 and PBP 1B in Enterobacteriaceae and Pseudomonas aeruginosa and the subsequent inhibition of penicillin binding proteins (PBPs). Inhibition of PBPs leads to the disruption of bacterial cell wall synthesis. Imipenem is stable in the presence of some beta lactamases. Relebactam has no intrinsic antibacterial activity. Relebactam protects imipenem from degradation by certain serine beta lactamases such as Sulhydryl Variable (SHV), Temoneira (TEM), Cefotaximase-Munich (CTX-M), Enterobacter cloacae P99 (P99), Pseudomonas-derived cephalosporinase (PDC), and Klebsiella-pneumoniae carbapenemase (KPC).

“Recarbrio provides an important addition to our toolkit in the ongoing fight against infections caused by certain Gram-negative pathogens,” said Dr. Keith Kaye, professor of medicine and director of research for the division of infectious diseases, University of Michigan Heath System, and a principal investigator in the clinical program. “Recarbrio offers an additional treatment option for patients with cIAI and cUTI who have limited and, in some cases, no alternative therapeutic options.”

“Today’s announcement is a great example of Merck’s longstanding commitment to infectious diseases research and development, as we continue to search for novel ways to approach difficult-to-treat pathogens,” said Dr. Nick Kartsonis, senior vice president, infectious diseases and vaccines, Merck Research Laboratories.

https://en.wikipedia.org/wiki/Imipenem

https://www.drugbank.ca/drugs/DB01597

https://en.wikipedia.org/wiki/Relebactam