Date: 2017-02-08
Type of information: Patent infringement lawsuit
Product name: Praluent® - alirocumab (SAR236553/REGN727)
Compound: alirocumab
Therapeutic area: Cardiovascular diseases - Genetic diseases - Metabolic diseases
Action mechanism: monoclonal antibody/RNAi/PCSK9 inhibitor.. Alirocumab is a subcutaneously administered, fully-human antibody targeting PCSK9 (proprotein convertase subtilisin/kexin type 9) in clinical development. By inhibiting PCSK9, a determinant of circulating LDL-cholesterol levels in the blood, REGN727 increases the number of free LDL receptors which can bind to circulating LDL and clear it from the bloodstream. REGN727 was created using Regeneron's pioneering VelocImmune® technology and is being developed by Regeneron in collaboration with Sanofi.
Company: Sanofi (France) Regeneron Pharmaceuticals (USA- NY)
Disease: adult patients with heterozygous familial hypercholesterolemia (HeFH) or patients with clinical atherosclerotic cardiovascular disease such as heart attacks or strokes, who require additional lowering of LDL cholesterol
Latest news: * On July 5, 2016, Sanofi and Regeneron Pharmaceuticals announced that the Ministry of Health, Labor and Welfare in Japan has granted marketing and manufacturing authorization for Praluent® (alirocumab) for the treatment of uncontrolled low-density lipoprotein (LDL) cholesterol, in certain adult patients with hypercholesterolemia at high cardiovascular risk. In Japan Praluent® is indicated for the treatment of patients with hypercholesterolemia and familial hypercholesterolemia (FH) who are at high cardiovascular risk and in whom treatment with statins (HMG-CoA reductase inhibitors) is not sufficient. Praluent® 75 mg and 150 mg will be available in Japan as a single-dose pre-filled pen and syringe. * On December 11, 2015, Regeneron Pharmaceuticals and Sanofi announced that UnitedHealth Group will provide preferred access to Praluent® (alirocumab) Injection through OptumRx and UnitedHealthcare for Commercial, Medicare, and Managed Medicaid patients. This decision, when combined with prior favorable coverage decisions at Express Scripts, Aetna and other insurers, provides for access to flexible dosing with Praluent on formularies covering more than 100 million patients in the United States. * On September 28, 2015, Regeneron Pharmaceuticals and Sanofi announced that the European Commission (EC) has granted marketing authorization for Praluent® (alirocumab) for the treatment of bad cholesterol, known as low-density lipoprotein (LDL) cholesterol, in certain adult patients with hypercholesterolemia. The EC approved Praluent® for the treatment of adult patients with primary hypercholesterolemia (heterozygous familial hypercholesterolemia [HeFH] and non-familial) or mixed dyslipidemia as an adjunct to diet: a) in combination with a statin, or statin with other lipid-lowering therapies in patients unable to reach their LDL-cholesterol goals with the maximally-tolerated statin or b) alone or in combination with other lipid-lowering therapies for patients who are statin intolerant, or for whom a statin is contraindicated. The effect of Praluent® on cardiovascular (CV) morbidity and mortality has not yet been determined. Praluent® is available in two starting doses as a single 1-milliter (mL) injection (75 mg and 150 mg) once every two weeks, offering two levels of efficacy. Praluent® will be available in a single-dose pre-filled pen that patients self-administer. The EC marketing authorization is based on data from 10 pivotal Phase 3 ODYSSEY trials, including five placebo-controlled and five ezetimibe-controlled. The data showed consistent, robust reductions in LDL-cholesterol for Praluent compared to placebo or ezetimibe, when added to current standard-of-care, which included maximally-tolerated statins. All trials met their primary efficacy endpoint, demonstrating significantly greater reductions from baseline in LDL-cholesterol at week 24, compared to placebo or ezetimibe. In the placebo-controlled trials, the average LDL-cholesterol reductions from baseline at week 24 for the Praluent group ranged from 46 to 61 percent. In the ezetimibe-controlled trial with Praluent added to background statins, the average change in LDL-cholesterol from baseline was 51 percent at week 24. In the ezetimibe trials with patients not on statins, the average LDL-cholesterol reduction from baseline in the Praluent group ranged from 45 to 47 percent at week 24. Additionally, significantly more patients achieved an LDL-cholesterol level of less than 70 mg/dL ( < 1.81 mmol/L) in the Praluent group compared to placebo or ezetimibe at week 12 and week 24. In eight trials, patients initially started on Praluent 75 mg every two weeks, and had their dose up-titrated to 150 mg every two weeks at week 12 if needed to reach protocol-specified LDL-cholesterol targets. Patients who initially started on Praluent 75 mg every two weeks experienced average LDL-cholesterol reductions from baseline ranging from 44.5 percent to 49 percent at week 12. The majority of patients achieved their pre-defined LDL-cholesterol target on the 75 mg dose, and maintained treatment at this dose. In two other trials where patients initially started on Praluent 150 mg every two weeks, the average LDL-cholesterol reduction from baseline was 63 percent at week 12. In ODYSSEY LONG TERM, the largest Phase 3 placebo-controlled trial evaluating Praluent to date, LDL-cholesterol reductions were sustained through 78 weeks. The ability of Praluent to reduce major CV events is being investigated in the ongoing ODYSSEY OUTCOMES trial, with results anticipated in 2017. In pre-specified final analyses of the ODYSSEY LONG TERM study, major CV events confirmed by adjudication were reported in 1.7 percent of patients in the Praluent group and 3.3 percent of patients in the placebo group. Hazard ratios were calculated post-hoc; HR=0.52 (95 percent CI, 0.31 to 0.90). In pre-specified analyses of pooled Phase 3 studies, major CV events were reported in 1.6 percent of patients in the Praluent group and 1.8 percent of those in the control group, which included either placebo or ezetimibe (HR=0.81; 95 percent CI, 0.52 to 1.25). Across the Phase 3 trials all-cause mortality was 0.6 percent in the Praluent group and 0.9 percent in the control group, with CV events being the primary cause of death in the majority of these patients. In clinical trials, Praluent was generally well-tolerated with an acceptable safety profile. Local injection site reactions including erythema/redness, itching, swelling or pain/tenderness where the injection is given were the most common events (6 percent with Praluent versus 4 percent with placebo) in clinical trials. Most injection site reactions were transient and of mild intensity. The discontinuation rate due to local injection site reactions was comparable between the two groups (0.2 percent Praluent and 0.3 percent control groups). Other common adverse events occurring more frequently in the Praluent group than placebo included upper respiratory tract signs and symptoms, and pruritus. * On July 24, 2015, the FDA approved Praluent® (alirocumab) injection, the first cholesterol-lowering treatment approved in a new class of drugs known as proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors. Praluent® is approved for use in addition to diet and maximally tolerated statin therapy in adult patients with heterozygous familial hypercholesterolemia (HeFH) or patients with clinical atherosclerotic cardiovascular disease such as heart attacks or strokes, who require additional lowering of LDL cholesterol. The efficacy and safety of Praluent® were evaluated in five placebo-controlled trials (Phase 3 ODYSSEY program), involving 2,476 participants exposed to Praluent. All participants had HeFH or were otherwise at high risk for heart attack or stroke, and were taking maximally tolerated doses of a statin, with or without other lipid-modifying therapies. Participants taking Praluent® had an average reduction in LDL cholesterol ranging from 36 to 59 percent, compared to placebo. Multiple clinical trials have demonstrated that statins lower the risk of having a heart attack or stroke. A trial evaluating the effect of adding Praluent® to statins on reducing cardiovascular risk is ongoing. The most common side effects of Praluent® include itching, swelling, pain, or bruising where injection is given, nasopharyngitis, and flu. Allergic reactions, such as hypersensitivity vasculitis (a skin rash usually appearing as purple-colored spots on the skin associated with inflammation of small blood vessels) and hypersensitivity reactions requiring hospitalization, have been reported with the use of Praluent®. Praluent® is the first and only PCSK9 inhibitor approved in the U.S. and is available in two different doses (75 mg and 150 mg). Both doses of Praluent are available in a single 1 milliliter (mL) injection delivered in a single-dose prefilled pen or syringe that patients self-administer every two weeks. The approval of Praluent® was based on data from the pivotal Phase 3 ODYSSEY program, which showed consistent, positive results compared to placebo, which included current standard of care therapy (statins). In the ODYSSEY LONG TERM trial which evaluated Praluent 150 mg every two weeks, Praluent reduced LDL cholesterol by 58 percent versus placebo at week 24 when added to current standard of care, including maximally tolerated statins. In ODYSSEY COMBO I, Praluent 75 mg every two weeks as an adjunct to statins reduced LDL cholesterol by an additional 46 percent compared to placebo at week 12. At week 24 in the same trial, Praluent reduced LDL cholesterol by 43 percent compared to placebo. In this study, if additional LDL cholesterol lowering was required based on pre-specified criteria at week 8, Praluent was up-titrated to 150 mg at week 12 for the remainder of the trial. Eighty-three percent of patients remained on their initial 75 mg dose. The U.S. Wholesale Acquisition Cost (WAC) price of Praluent is $40 per day ($1,120 every 28 days) for both the 75 mg and 150 mg doses, making Praluent the lowest priced patient-administered monoclonal antibody therapy on an annualized basis. Actual costs to patients, payers and health systems are anticipated to be lower as WAC pricing does not reflect discounts or rebates. Out-of-pocket costs to patients will vary depending on insurance status and eligibility for patient assistance. Sanofi and Regeneron will launch a comprehensive program that offers support, training and follow up for patients at every step of the process. The program will provide patient assistance to uninsured or underinsured patients, including providing free medicine to eligible patients, and can help identify coverage options for out-of-pocket costs. Additional services include educational information, clinical support for physicians, nurses and pharmacists, as well as reimbursement services, including co-pay support for eligible patients and information about insurance eligibility support. * On July 23, 2015, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for Praluent®, intended for the treatment of adult patients with primary hypercholesterolaemia (heterozygous familial and non-familial) and mixed dyslipidaemia. Praluent® will be available as 75 mg/ml and 150 mg/ml solution for injection in pre-filled syringes and prefilled pens. The benefits with Praluent® are its ability to reduce the levels of serum LDL-cholesterol in patients who are unable to control their cholesterol despite taking a maximum tolerated dose of statins or who cannot take statins. The most common side effects are upper respiratory tract signs and symptoms, pruritus and injection site reactions. The use of Praluent® may lead to very low cholesterol levels, the impact of which on long-term safety has not yet been established. The full indication is: "Praluent® is indicated in adults with primary hypercholesterolaemia (heterozygous familial and nonfamilial) or mixed dyslipidaemia, as an adjunct to diet: - in combination with a statin or statin with other lipid lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin or, - alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated.The effect of Praluent on cardiovascular morbidity and mortality has not yet been determined.” The efficacy of Praluent® was assessed in 10 phase III (late-stage) studies, involving close to 5,300 patients with hypercholesterolaemia (high blood cholesterol levels) and mixed dyslipidaemia (abnormal levels of fat in the blood, including high levels of LDL-cholesterol). Praluent® reduced LDL-cholesterol for these patient groups. Available evidence does not yet allow the longer term benefits of Praluent® for patients in reducing heart disease or death from heart disease to be determined. The Committee for Medicinal Products for Human Use (CHMP) also looked at safety information from over 3,300 patients treated with Praluent®. The Committee considered that the safety profile of Praluent® is acceptable, with few patients discontinuing treatment or showing serious adverse events. * On June 9, 2015, Regeneron Pharmaceuticals and Sanofi announced that the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) of the FDA recommended the approval of the investigational therapy Praluent® (alirocumab) Injection. The Committee voted 13 to three (with no abstentions) that Regeneron and Sanofi had sufficiently established that the low-density lipoprotein cholesterol (LDL-C, or bad cholesterol) lowering benefit of Praluent exceeds its risks to support approval in one or more patient populations. The Committee's recommendation was based on Praluent's benefit-risk profile, following review of efficacy and safety data from more than 5,000 patients across 10 pivotal Phase 3 double-blind trials ranging from six months to two years. Clinical data from the ODYSSEY Phase 3 program show consistent, positive results in reducing LDL-C. Common adverse events that were more frequently reported in patients treated with Praluent than the control groups included injection site reaction and pruritus (itching). The BLA for Praluent® was accepted for priority review by the FDA with a target action date of July 24, 2015. If approved by the FDA, Praluent® is expected to be the first fully human monoclonal antibody targeting PCSK9 (proprotein convertase subtilisin/kexin type 9) in the U.S. The Marketing Authorization Application for Praluent® in the European Union is currently under review by the European Medicines Agency (EMA). * On January 26, 2015, Regeneron Pharmaceuticals and Sanofi announced that the FDA has accepted for priority review the Biologics License Application (BLA) for Praluent® (alirocumab). Under the Prescription Drug User Fee Act (PDUFA), the goal for a priority review is six months, for a target action date of July 24, 2015. Alirocumab is an investigational monoclonal antibody targeting PCSK9 (proprotein convertase subtilisin/kexin type 9) that is intended for the treatment of patients with hypercholesterolemia.The BLA for Praluent® contains data from more than 5,000 patients, including 10 Phase 3 ODYSSEY trials. Together with additional ongoing studies including ODYSSEY OUTCOMES, the ODYSSEY clinical trial program will include more than 23,500 patients at more than 2,000 study centers in double-blind, randomized, placebo-and active-controlled trials ranging from 24 weeks to approximately 5 years. * On January 12, 2015, Regeneron Pharmaceuticals and Sanofi announced that the European Medicines Agency (EMA) has accepted for review the Marketing Authorization Application (MAA) for Praluent® (alirocumab). The MAA for Praluent®contains data from more than 5,000 patients, including 10 Phase 3 ODYSSEY trials.A biologics license application (BLA) for Praluent was submitted to the FDA in the fourth quarter of 2014. The EMA and FDA have conditionally accepted Praluent™ as the trade name for alirocumab. The safety and efficacy of alirocumab have not been fully evaluated by any regulatory authority. * On July 30, 2014, Regeneron Pharmaceuticals and Sanofi announced that the Companies intend to use a FDA rare pediatric disease priority review voucher in connection with the Biologics License Application (BLA) submission for alirocumab. The priority review voucher entitles the holder to designate a BLA for priority review, which provides for an expedited 6-month review from the filing date instead of the standard 10-month review. Regeneron Ireland, an indirect, wholly-owned subsidiary of Regeneron Pharmaceuticals, Inc., purchased the voucher from BioMarin GALNS Ltd., a direct, wholly-owned subsidiary of BioMarin Pharmaceutical, Inc., which had received it through the FDA's Rare Pediatric Disease Priority Review Voucher Program. Sanofi and Regeneron will equally share the purchase price of $67.5 million. Sanofi and Regeneron expect to submit U.S. and EU regulatory submissions for alirocumab before year end. The Pediatric PRV was created by the 2012 Food and Drug Administration Safety and Innovation Act (FDASIA) and is intended to encourage the development of treatments for rare pediatric diseases. Companies that receive a voucher may use it or transfer the voucher, including by sale, to other organizations.
Data from the global Phase 3 ODYSSEY trials showed consistent, robust reductions in LDL cholesterol for Praluent® compared to placebo, when added to current standard-of-care, which included maximally-tolerated statins. The Phase 3 ODYSSEY JAPAN trial evaluated the safety and efficacy of Praluent® 75 mg starting dose every two weeks, in comparison with placebo in 216 Japanese patients with primary hypercholesterolemia and LDL cholesterol of at least 100 milligrams/deciliter (mg/dL) (at least 2.59 millimoles per liter [mmol/L]). All study patients were on ongoing statin treatment with or without other lipid-lowering therapies. Average baseline LDL cholesterol levels in the randomized population were similar between the Praluent® (141 mg/dL / 3.6 mmol/L) and placebo groups (142 mg/dL / 3.7 mmol/L). Patients in the Praluent® group who did not achieve their pre-specified LDL cholesterol goals with Praluent® 75 mg at week 8 (2 out of 140 patients who continued treatment beyond week 12) were increased to Praluent 150 mg every two weeks at week 12.
In the ODYSSEY JAPAN trial, Praluent® reduced LDL cholesterol by 63 percent at week 24 on top of stable background statin therapy, compared to a 2 percent increase in the placebo group (p<0.0001, ITT analysis). Patients treated with Praluent maintained their LDL cholesterol reductions for the duration of the trial. By week 52 patients in the Praluent® group achieved an average LDL cholesterol of 53.4 mg/dL (1.38 mmol/L) compared to an average LDL cholesterol of 135.6 mg/dL (3.51 mmol/L) in the placebo group (ITT population).
In the trial, Praluent® was generally well-tolerated with an acceptable safety profile. Frequently reported adverse events included nasopharyngitis (46 percent Praluent versus 36 percent placebo); back pain (13 percent Praluent versus 6 percent placebo); and injection site reaction (13 percent Praluent versus 4 percent placebo). In ODYSSEY JAPAN, LDL cholesterol goals were defined according to the “Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012” published by the Japan Atherosclerosis Society (JAS) in which goals are set according to patients’ risk of cardiovascular events. The JAS guidelines define the risk of cardiovascular events as high when the patient has a history of coronary artery disease, a history of ischemic stroke (other than cardiogenic cerebral infarction), peripheral artery disease, diabetes mellitus, and chronic kidney disease, or in the presence of several risk factors for atherosclerosis.
In Japanese Phase 2 and 3 clinical trials, adverse events were observed in 17 percent (33 of 193) of patients on Praluent 75 mg or 150 mg. The most common adverse event was injection site reactions in 22 cases (11.4 percent).
Patents: * On February 8, 2017, Regeneron Pharmaceuticals and Sanofi announced that the United States Court of Appeals for the Federal Circuit has suspended the permanent injunction for Praluent® Injection pending the companies' appeal. Sanofi and Regeneron will continue marketing, selling and manufacturing Praluent® in the U.S. during the appeal process. The companies are challenging both the injunction ruling and validity judgment during the appeal process. They believe Amgen's asserted patent claims for antibodies targeting PCSK9 (proprotein convertase subtilisin/kexin type 9) are invalid in the ongoing U.S. patent infringement lawsuit. * On January 5, 2017, Amgen announced that the United States District Court in Delaware granted Amgen's request for a permanent injunction prohibiting Sanofi and Regeneron from infringing two patents that Amgen holds for Repatha® (evolocumab) by manufacturing, using, selling or offering alirocumab for sale in the United States . The judge's decision follows a jury verdict in March 2016 in Amgen's favor in a trial on the validity of two Amgen patents that describe and claim monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (PCSK9). Amgen has the ability to supply all potential Repatha patients and will work to ensure a smooth transition for patients who wish to switch to Repatha®. Sanofi and Regeneron Pharmaceuticals will appeal this injunction granted by the U.S. District Court for the District of Delaware preventing the marketing, selling or manufacturing of Praluent® in the U.S. during the term of two Amgen patents. The companies believe Amgen’s asserted patent claims are invalid and will also appeal a prior jury verdict upholding the validity of those patents. The injunction will not take effect immediately as the court has delayed its imposition for 30 days to allow defendants the opportunity to seek expedited review of this decision. Praluent continues to be available to patients at this time. * On March 16, 2016, Amgen announced that a Delaware jury delivered a verdict in Amgen's favor in a trial on the validity of two Amgen patents that describe and claim monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (PCSK9). Amgen brought the patent infringement action in Federal Court in Delaware against Sanofi and Regeneron Pharmaceuticals. Before trial, Sanofi and Regeneron acknowledged infringement of seven patent claims in U.S. Patent Numbers 8,829,165, and 8,859,741. The trial proceeded on Defendants' challenges to the validity of those seven claims. The jury found that Defendants had failed to prove the patents invalid for lack of written description and enablement. Prior to the case going to the jury, the Court dismissed Defendants' case on obviousness.
Regeneron Pharmaceuticals and Sanofi announced that the companies strongly disagree with this jury verdict that the asserted claims of two Amgen patents for antibodies targeting PCSK9 (proprotein convertase subtilisin/kexin type 9) are valid. Sanofi and Regeneron believe these Amgen patent claims are invalid in the ongoing U.S. patent infringement lawsuit and plan to appeal the judgment.
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: 2015-07-24
UE authorization: 2015-09-28
Favourable opinion UE: 2015-07-23
Favourable opinion USA: 2015-06-09
Orphan status USA:
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE: OTC status: Other news:
