Products

Date: 2016-12-16

Type of information: Product launch

Product name: Juxtapid®/Lojuxta®

Compound: lomitapide

Therapeutic area: Rare diseases - Genetic diseases - Metabolic diseases

Action mechanism: protein inhibitor/microsomal triglyceride transfer protein (MTP) inhibitor. Lomitapide is a small molecule, microsomal triglyceride transfer protein inhibitor, or MTP-I. HoFH is a rare genetic disorder inherited from both parents, and characterised by significantly elevated low density lipoprotein cholesterol (LDL-C) levels. HoFH patients have LDL receptors that are either non-functional or are defective in their functioning. Patients diagnosed with HoFH typically have as much as three to six times the normal amount of LDL-C while on a variety of lipid-lowering drug treatments, putting them at risk for a major cardiovascular event. Most other drug treatments such as statins work by increasing the number of LDL-receptors and if these are defective or negative, the drugs that work by these mechanisms typically have limited effectiveness in HoFH patients. Inhibition of MTP reduces lipoprotein secretion and circulating concentrations of lipoprotein-borne lipids including cholesterol and triglycerides.

Company: Aegerion Pharmaceuticals (USA - MA), a Novelion Therapeutics' subsidiary (Canada)

Disease: homozygous familial hypercholesterolemia (HoFH)

Latest news:

• • On December 16, 2016, Novelion Therapeutics announced that subsidiary Aegerion Pharmaceuticals completed the first commercial shipment of Juxtapid® (lomitapide) to a patient in Japan . In September 2016 , Juxtapid® was approved by Japan's Ministry of Health, Labor & Welfare (MHLW) for patients with homozygous familial hypercholesterolemia (HoFH). The MHLW based its approval of Juxtapid® on Aegerion's Phase III study in Japanese patients, which evaluated the safety and efficacy of the medicine to reduce LDL-C levels in nine patients with HoFH. The findings were consistent with the known safety and efficacy profile of Juxtapid®.
• • On November 20, 2015, Aegerion Pharmaceuticals announced that the Régie de l'Assurance Maladie du Québec (RAMQ) has added Juxtapid™ (lomitapide) capsules for the treatment of homozygous familial hypercholesterolemia (HoFH) to its formulary effective November 20, 2015. The listing was based on a recommendation from l'Institut National d'Excellence en Santé et en Services Sociaux (INESSS) and is subject to a Listing Agreement between the Quebec Minister of Health and Social Services and Aegerion Pharmaceuticals. The Listing Agreement is based on Aegerion's price for Juxtapid™ in Canada, which is a fixed daily cost irrespective of the dose prescribed and strengths dispensed.
• * On April 30, 2015, AOP Orphan announced that the company is launching Lojuxta® into the Austrian market. Lojuxta® was authorized by the EMA in July 2013. Under the distribution agreement with Aegerion Pharmaceuticals, AOP Orphan has rights to Lojuxta in Austria, and in several Eastern European countries.
• • On February 10, 2014, Aegerion Pharmaceuticals announced that Health Canada has granted a Notice of Compliance (NOC) approving Juxtapid®/Lojuxta® as an adjunct to a low-fat diet and other lipid-lowering drugs, with or without LDL apheresis, to reduce low-density lipoprotein cholesterol (LDL-C) in adult patients with homozygous familial hypercholesterolemia (HoFH). Based on the risk of liver toxicity, Juxtapid®/Lojuxta® is subject to a risk management plan in Canada. Due to its benefit-risk profile, the prescribing of Juxtapid®/Lojuxta® should be limited to physicians experienced in the diagnosis and treatment of familial hypercholesterolemia.
• • On January 20, 2014, Aegerion Pharmaceuticals announced that the Mexican Federal Commission for the Protection against Sanitary Risk (COFEPRIS) has approved Juxtapid®/Lojuxta® as an adjunct treatment to a low-fat diet and other lipid-lowering treatments, including LDL apheresis where available, to reduce low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein B (apo B) and non-high-density-lipoprotein cholesterol (non-HDL) in patients with homozygous familial hypercholesterolemia (HoFH).
• • On August 1, 2013, Aegerion Pharmaceuticals has announced that the European Commission has approved Lojuxta® (lomitapide) hard capsules as an adjunct to a low-fat diet and other lipid-lowering medicinal products with or without low density lipoprotein (LDL) apheresis in adult patients with homozygous familial hypercholesterolemia (HoFH). The Summary of Product Characteristics  describes that genetic confirmation of HoFH should be obtained whenever possible, and that other forms of primary hyperlipoproteinemia and secondary causes of hypercholesterolemia (e.g., nephrotic syndrome, hypothyroidism) must be excluded.
• The European Commission's decision is based on a favorable benefit-risk assessment from Aegerion's Phase 3 study which evaluated the safety and efficacy of the medicine to reduce LDL-C levels in 29 adult patients with HoFH. When added to the existing lipid-lowering therapy of the HoFH patients in the study, Lojuxta® significantly reduced LDL-C from a baseline average of 336 mg/dL to 190 mg/dL (40% reduction) at Week 26 in the intent-to-treat population. LDL-C was reduced by an average of 50% in the 23 patients who completed the study through Week 26. After Week 26, during the safety phase of the study, adjustments to concomitant lipid-lowering treatments, including apheresis, were allowed. Average reductions in LDL-C were sustained during chronic therapy and no additional dropouts were seen.
• The most common adverse reactions in the Phase III trial were gastrointestinal, reported by 27 (93%) of 29 patients. Diarrhea occurred in 79% of patients, nausea in 65%, dyspepsia in 38%, and vomiting in 34%. Other reactions reported by at least 20% of patients include abdominal pain, abdominal discomfort, abdominal distension, constipation, and flatulence. Elevations in liver enzymes and hepatic (liver) fat were also observed. Ten of the 29 patients in the study had at least one elevation in liver enzymes greater than or equal to three times the upper limit of normal, including four patients who experienced liver enzymes greater than or equal to five times the upper limit of normal. Liver enzyme elevations were managed through dose reduction or temporary discontinuation of dose. There were no clinically meaningful elevations of total bilirubin, international normalized ratio (INR) or alkaline phosphatase, which are other markers of potential harmful effects on the liver. Hepatic fat increased from a baseline of one percent to a median absolute increase of six percent at 26 and 78 weeks.
• Aegerion has adopted a risk management plan to help educate physicians on the safety information for Lojuxta® and appropriate precautions to be followed by healthcare professionals and patients. In addition, as part of Aegerion's post-marketing commitment to both the FDA and the EMA, the Company will conduct an observational cohort study to generate more data on the long-term safety profile of lomitapide, the patterns of use and compliance and the long-term effectiveness of controlling LDL-C levels.
• • On 30 May 2013, the Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion, recommending the granting of a marketing authorisation for Lojuxta® (lomitapide), 5mg, 10mg, 20mg hard capsules intended as an adjunct to a low fat diet and other lipid lowering medicinal products with or without low density lipoprotein (LDL) apheresis in adult patients with homozygous familial hypercholesterolaemia. The benefits with Lojuxta® are its ability to consistently reduce LDL-cholesterol levels by approximately 40% in HoFH patients. The CHMP, on the basis of quality, safety and efficacy data submitted, considers there to be a favourable benefit-to-risk balance for Lojuxta® and therefore recommends the granting of the marketing authorisation under exceptional circumstances.
• • On December 24, 2012, the FDA has approved Juxtapid® (lomitapide) capsules as an adjunct to a low-fat diet and other lipid-lowering treatments, including LDL apheresis where available, to reduce low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein B (apo B) and non- high-density-lipoprotein cholesterol (non-HDL) in patients with homozygous familial hypercholesterolemia. The FDA based its approval on Aegerion's pivotal Phase III study, which evaluated the safety and effectiveness of the medicine to reduce LDL-C levels in 29 adult patients with HoFH. The study was a multinational, single-arm, open-label, 78 week trial that was recently published in the November 2, 2012 online version of the Lancet. In this study, Juxtapid® was initiated at 5 mg daily and gradually escalated to doses of 10 mg, 20 mg, 40 mg, up to 60 mg, based on tolerability and acceptable liver enzymes levels. When added to the existing lipid-lowering therapy of the HoFH patients in the study, Juxtapid® significantly reduced LDL-C from a baseline average of 336 mg/dL to 190 mg/dL (40% reduction) at Week 26 in the intent-to-treat population with last observation carried forward for the patients who discontinued prematurely. LDL-C was reduced by an average of 50 percent for the 23 patients who completed the study through Week 26. After Week 26, during the safety phase of the study, adjustments to concomitant lipid-lowering treatments were allowed. Average reductions in LDL-C were sustained during chronic therapy.
• The most common adverse reactions in the Phase III trial were gastrointestinal, reported by 27 (93%) of 29 patients. Adverse reactions, which were reported by more or equal to 8 patients (28%) in the HoFH clinical trial, included diarrhea, nausea, vomiting, dyspepsia and abdominal pain. Other common adverse reactions, reported by 5 to 7 (17-24%) patients, included weight loss, abdominal discomfort, abdominal distension, constipation, flatulence, increased ALT, chest pain, influenza, nasopharyngitis, and fatigue. Elevations in liver enzymes and hepatic (liver) fat were also observed. Ten of the 29 patients in the study had at least one elevation in liver enzymes greater than or equal to three times the upper limit of normal, including four patients who experienced liver enzymes greater than or equal to five times the upper limit of normal. Liver enzyme elevations were managed through dose reduction or temporary discontinuation of dose. There were no clinically meaningful elevations of total bilirubin, international normalized ratio (INR) or alkaline phosphatase, which are other markers of potential harmful effects on the liver. Hepatic fat increased from a baseline of 1 percent to a median absolute increase of 6 percent at 26 and 78 weeks.Because of the risk of liver toxicity, Juxtapid® is available only through a restricted program called the Juxtapid® Risk Evaluation and Mitigation Strategy (REMS) Program. Aegerion will certify all health care providers who prescribe Juxtapid® and the pharmacies that will dispense the medicine. To further understand Juxtapid®'s long-term safety and effectiveness, Aegerion has made a commitment to the FDA to conduct a post-approval, observational cohort study.
• • On October 17, 2012, Aegerion Pharmaceuticals has announced that the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) of the FDA determined by a vote of 13 to 2 that Aegerion has presented sufficient safety and efficacy data to support marketing of its product, lomitapide, for the treatment of patients with HoFH when used as an adjunct to a low-fat diet and other lipid-lowering therapies. The FDA has assigned a Prescription Drug User Fee Act (PDUFA) action date of December 29, 2012, for completion of its review of the New Drug Application (NDA) for lomitapide.
• • On March 20, 2012, Aegerion Pharmaceuticals has announced that the European Medicines Agency (EMA) has accepted for review the Marketing Authorization Application (MAA) for lomitapide, a once-daily, oral treatment for HoFH. Lomitapide will be evaluated through the EU's Centralized Procedure with an official start date of March 21, 2012. If approved, lomitapide will gain marketing authorization for all EU Member States simultaneously. Lomitapide holds orphan drug designation for the treatment of HoFH in the United States, and for the treatment of familial chylomicronemia (FC) in the U.S. and EU.

Patents:

Submission of marketing authorization application USA :

Submission of marketing authorization application UE:

Withdrawal of marketing authorization application USA:

Withdrawal of marketing authorization application UE:

US authorization: 2012-12-21

UE authorization: 2013-07-31

Favourable opinion UE: 2013-05-30

Favourable opinion USA: 2012-10-17

Orphan status USA: 2007-10-23

Orphan status UE: 2010-12-17

Pediatric exclusivit _USA:

Pediatric exclusivity UE:

OTC status:

Other news:

Is general: Yes