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The FDA accepted for review a new drug application for the steroidogenesis inhibitor levoketoconazole for the treatment of endogenous Cushing’s syndrome, according to an industry press release. “We are pleased with the FDA’s acceptance for filing of the Recorlev new drug application,” John H. Johnson, CEO of Strongbridge Biopharma, said in the release. “We believe this decision reflects the comprehensive clinical evidence that went into the NDA submission, including the positive and statistically significant efficacy and safety results from the multinational phase 3 SONICS and LOGICS studies evaluating Recorlev as a potential treatment option for adults with endogenous Cushing’s syndrome. We are advancing our commercial readiness plans and look forward to potentially bringing a new therapeutic option to the Cushing’s syndrome community in the first quarter of 2022.” As Healio previously reported, top-line findings from the LOGICS study demonstrated that levoketoconazole (Recorlev, Strongbridge Biopharma) improved and normalized morning urinary free cortisol concentrations for adults with endogenous Cushing’s disease compared with placebo. The drug was generally well tolerated, with safety data mirroring those from the earlier phase 3 SONICS trial. Endogenous Cushing’s syndrome — caused by chronic hypercortisolism — is rare, with estimates ranging from 40 to 70 people per million affected worldwide, according to the National Institute of Diabetes and Digestive and Kidney Diseases. The FDA set a Prescription Drug User Fee Act target action date of Jan. 1, 2022, for levoketoconazole, according to the company. The FDA letter made no mention of a plan to hold an advisory committee meeting. From https://www.healio.com/news/endocrinology/20210513/fda-accepts-nda-for-novel-cushings-syndrome-treatment-
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~ RECORLEV® (levoketoconazole) New Drug Application is Supported by Previously-Reported Positive and Statistically Significant Results from the Phase 3 SONICS and LOGICS Studies ~ ~ Nearly 40 Percent of Prescription-Treated Endogenous Cushing’s Syndrome Patients in the U.S. Are Not Well-Controlled, Underscoring Need for New, Safe and Effective Pharmaceutical Options to Help Regulate Cortisol Levels ~ ~ If Approved Following a Projected 10-Month Review Cycle, RECORLEV is Anticipated to Launch in First Quarter of 2022 ~ DUBLIN, Ireland and TREVOSE, Pa., March 02, 2021 (GLOBE NEWSWIRE) -- Strongbridge Biopharma plc, (Nasdaq: SBBP), a global commercial-stage biopharmaceutical company focused on the development and commercialization of therapies for rare diseases with significant unmet needs, today announced that it submitted a New Drug Application (NDA) for RECORLEV® (levoketoconazole) for the treatment of endogenous Cushing’s syndrome to the U.S. Food and Drug Administration (FDA). The submission is supported by previously reported positive and statistically significant results of the SONICS and LOGICS trials: two Phase 3 multinational studies designed to evaluate the safety and efficacy of RECORLEV when used to treat adults with endogenous Cushing’s syndrome. “The submission of the New Drug Application for RECORLEV® (levoketoconazole) represents not only a significant milestone for Strongbridge but also for the Cushing’s syndrome community as a whole. As an organization focused on developing treatments for underserved rare disease patient populations, we are one step closer to helping address the needs of the estimated 8,000 Cushing’s syndrome patients in the U.S. who are treated with prescription therapy, many of whom, as we learned in our market research, are not well-controlled with current therapies,” said John H. Johnson, chief executive officer of Strongbridge Biopharma. “We look forward to working with the FDA through their review of our application, and we are actively preparing for the potential launch of RECORLEV in the first quarter of 2022, if approved.” RECORLEV, the pure 2S,4R enantiomer of the enantiomeric pair comprising ketoconazole, is a next-generation steroidogenesis inhibitor being investigated as a chronic therapy for adults with endogenous Cushing’s syndrome. Two Phase 3 studies have demonstrated substantial evidence of efficacy and safety in a combined study population of 166 patients that was representative of the adult drug-treated U.S. population with Cushing’s syndrome. The SONICS study met its primary and key secondary endpoints, demonstrating a statistically significant rate of mean urinary free cortisol normalization after six months of maintenance therapy without a dose increase (detailed results here). LOGICS, a double-blind, placebo-controlled randomized-withdrawal study, which also had statistically significant primary and key secondary endpoints, confirmed that the long-term cortisol-normalizing efficacy demonstrated in SONICS was due to use of levoketoconazole specifically (detailed results here). The long-term open-label extension study, OPTICS, is contributing safety information to the NDA. “We want to thank the patients, their families, investigators, collaborators, and employees who have contributed to the RECORLEV clinical program leading to this important regulatory milestone,” said Fredric Cohen, M.D., chief medical officer of Strongbridge Biopharma. RECORLEV has received orphan drug designation from the FDA and the European Medicines Agency for the treatment of endogenous Cushing's syndrome. Strongbridge will host a conference call tomorrow, Wednesday, March 3, 2021 at 8:30 a.m. ET to discuss the Company’s fourth quarter and full-year 2020 financial results and recent corporate highlights, including the RECORLEV NDA submission. About Cushing’s Syndrome Endogenous Cushing’s syndrome is a rare, serious and potentially lethal endocrine disease caused by chronic elevated cortisol exposure - often the result of a benign tumor of the pituitary gland. This benign tumor tells the body to overproduce high levels of cortisol for a sustained period of time, and this often results in undesirable physical changes. The disease is most common among adults between the ages of 30 to 50, and it affects women three times more often than men. Women with Cushing's syndrome may experience a variety of health issues including menstrual problems, difficulty becoming pregnant, excess male hormones (androgens), primarily testosterone which can cause hirsutism (growth of coarse body hair in a male pattern), oily skin, and acne. Additionally, the internal manifestations of the disease are potentially life threatening. These include metabolic changes such as high blood sugar, or diabetes, high blood pressure, high cholesterol, fragility of various tissues including blood vessels, skin, muscle and bone, and psychologic disturbances such as depression, anxiety and insomnia. Untreated, the five-year survival rate is only approximately 50 percent. About the SONICS Study SONICS is an open-label, Phase 3 study of RECORLEV as a treatment for endogenous Cushing’s syndrome that enrolled 94 patients at centers in North America, Europe and the Middle East. Following a screening phase, SONICS has three treatment phases: (1) Dose Titration Phase: Patients started RECORLEV at 150 mg twice daily (300 mg total daily dose) and titrated in 150 mg increments with the goal of achieving a therapeutic dose – a dose resulting in mUFC normalization – at which point titration was stopped; (2) Maintenance Phase: The dose was fixed and should not have been changed other than for safety reasons or loss of efficacy. At the end of the six-month maintenance phase, the mUFC response rate was measured; and (3) Extended Evaluation Phase: Patients continued on RECORLEV for another six months to evaluate long-term safety and tolerability and explore efficacy durability. About the LOGICS Study The Phase 3, multinational, double-blind, placebo-controlled, randomized-withdrawal study, LOGICS, randomized Cushing’s syndrome patients with baseline mean urinary free cortisol (mUFC) at least 1.5 times the upper limit of normal (ULN) following completion of a single-arm, open-label treatment phase of approximately 14 to 19 weeks, with RECORLEV individually titrated according to mUFC response. A total of 79 patients were dosed during the open-label titration-maintenance phase, 7 of whom had previously received RECORLEV during the SONICS study, and 72 who had not previously received RECORLEV. At study baseline, the median mUFC was 3.5 times the ULN, indicative of significant hypercortisolemia. A total of 44 patients (39 who had completed the titration-maintenance phase and five who directly enrolled from the SONICS study), were randomized to either continue RECORLEV (n=22) or to have treatment withdrawn by receiving a matching placebo regimen (n=22) for up to 8 weeks, followed by restoration to the prior regimen using blinded drug. Of the 44 patients randomized, 11 patients (25 percent) had previously received RECORLEV during the SONICS study. Patients who required rescue treatment with open-label RECORLEV during the randomized-withdrawal phase were considered to have lost mUFC response at the visit corresponding to their first dose of rescue medication. Patients who did not qualify for randomization were removed from open-label treatment prior to randomization and excused from the study. About RECORLEV RECORLEV® (levoketoconazole) is an investigational cortisol synthesis inhibitor in development for the treatment of patients with endogenous Cushing’s syndrome, a rare but serious and potentially lethal endocrine disease caused by chronic elevated cortisol exposure. RECORLEV is the pure 2S,4R enantiomer of ketoconazole, a steroidogenesis inhibitor. RECORLEV has demonstrated in two successful Phase 3 studies to significantly suppress serum cortisol and has the potential to be a next-generation cortisol inhibitor. The Phase 3 program for RECORLEV includes SONICS and LOGICS: two multinational studies designed to evaluate the safety and efficacy of RECORLEV when used to treat endogenous Cushing’s syndrome. The SONICS study met its primary and secondary endpoints, demonstrating a statistically significant normalization rate of urinary free cortisol at six months. The LOGICS study, which met its primary endpoint, is a double-blind, placebo-controlled randomized-withdrawal study of RECORLEV that is designed to supplement the long-term efficacy and safety information supplied by SONICS. The ongoing long-term open label OPTICS study will gather further useful information related to the long-term use of RECORLEV. RECORLEV has received orphan drug designation from the FDA and the European Medicines Agency for the treatment of endogenous Cushing's syndrome. About Strongbridge Biopharma Strongbridge Biopharma is a global commercial-stage biopharmaceutical company focused on the development and commercialization of therapies for rare diseases with significant unmet needs. Strongbridge’s rare endocrine franchise includes RECORLEV® (levoketoconazole), a cortisol synthesis inhibitor currently being studied in Phase 3 clinical studies for the treatment of endogenous Cushing’s syndrome, and veldoreotide extended release, a pre-clinical next-generation somatostatin analog being investigated for the treatment of acromegaly and potential additional applications in other conditions amenable to somatostatin receptor activation. Both RECORLEV and veldoreotide have received orphan drug designation from the FDA and the European Medicines Agency. The Company’s rare neuromuscular franchise includes KEVEYIS® (dichlorphenamide), the first and only FDA-approved treatment for hyperkalemic, hypokalemic, and related variants of primary periodic paralysis. KEVEYIS has orphan drug exclusivity in the United States. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the federal securities laws. The words “anticipate,” “estimate,” “expect,” “intend,” “may,” “plan,” “potential,” “project,” “target,” “will,” “would,” or the negative of these terms or other similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. All statements, other than statements of historical facts, contained in this press release, are forward-looking statements, including statements related to data from the LOGICS and SONICS studies, the potential advantages of RECORLEV, the anticipated timing for potential approval of a marketing authorization for RECORLEV and for the potential launch of RECORLEV, Strongbridge’s strategy, plans, outcomes of product development efforts and objectives of management for future operations. Forward-looking statements involve risks and uncertainties that could cause actual results to differ materially from those expressed in such statement, including risks and uncertainties associated with clinical development and the regulatory approval process, the reproducibility of any reported results showing the benefits of RECORLEV, the adoption of RECORLEV by physicians, if approved, as treatment for any disease and the emergence of unexpected adverse events following regulatory approval and use of the product by patients. Additional risks and uncertainties relating to Strongbridge and its business can be found under the heading “Risk Factors” in Strongbridge’s Annual Report on Form 10-K for the year ended December 31, 2019 and its subsequent Quarterly Reports on Form 10-Q, as well as its other filings with the SEC. These forward-looking statements are based on current expectations, estimates, forecasts and projections and are not guarantees of future performance or development and involve known and unknown risks, uncertainties and other factors. The forward-looking statements contained in this press release are made as of the date of this press release, and Strongbridge Biopharma does not assume any obligation to update any forward-looking statements except as required by applicable law. Contacts: Corporate and Media Relations Elixir Health Public Relations Lindsay Rocco +1 862-596-1304 lrocco@elixirhealthpr.com Investor Relations Solebury Trout Mike Biega +1 617-221-9660 mbiega@soleburytrout.com From https://www.biospace.com/article/releases/strongbridge-biopharma-plc-announces-submission-of-new-drug-application-for-recorlev-levoketoconazole-for-the-treatment-of-endogenous-cushing-s-syndrome-to-the-u-s-food-and-drug-administration/
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Patients with endogenous Cushing’s syndrome who stopped using Recorlev (levoketoconazole) and moved to a placebo in a study started having their urine cortisol levels rise in response to lack of treatment, compared with those who remained on Recorlev, according to top-line data from the Phase 3 LOGICS trial. Based on these findings and data from a previous Phase 3 trial of Recorlev called SONICS (NCT01838551), the therapy’s developer, Strongbridge Biopharma, is planning to submit a new drug application requesting its approval to the U.S. Food and Drug Administration (FDA) early next year. If approved, Recorlev could be available to patients in the U.S. in 2022. “We are delighted to announce the positive and statistically significant top-line results of the LOGICS study, which add to the growing body of evidence supporting the potential of Recorlev (levoketoconazole) as an effective and well tolerated cortisol synthesis inhibitor to treat Cushing’s syndrome,” Fredric Cohen, MD, chief medical officer of Strongbridge Biopharma, said in a press release. Recorlev, also known as COR-003, is an investigational oral treatment for endogenous Cushing’s syndrome that inhibits the production of cortisol, the glucocorticoid hormone that is overly produced in patients with the disorder. The safety, tolerability, effectiveness, and pharmacological properties of Recorlev in people with endogenous Cushing’s syndrome are currently being assessed in the LOGICS trial (NCT03277690). LOGICS enrolled patients who had never been treated with Recorlev, as well as those given the medication in SONICS. The study included an initial withdrawal phase, in which patients were assigned randomly to either Recorlev (up to a dose of 1,200 mg), or to a placebo for about 8 weeks. This was followed by a restoration phase, lasting approximately the same time, in which all patients received Recorlev in combination with a placebo. With this design, patients initially assigned to Recorlev continued treatment in the study’s second phase, while those originally assigned to a placebo switched to Recorlev. Before enrolling in the study’s initial randomized-withdrawal phase, patients completed an open-label titration and maintenance phase lasting 14 to 19 weeks, which determined the best dose of Recorlev they should receive later. Of the 79 patients who entered the open-label titration and maintenance phase, 44 enrolled in the randomized-withdrawal phase, and 43 completed this initial portion of the trial. Top-line data now announced by the company showed the proportion of patients having their urine cortisol levels rise by the end of the randomized-withdrawal phase was 54.5% higher among those on a placebo than among those treated with Recorlev (95.5% vs. 40.9%). All 21 patients who lost their initial treatment response in the open-label portion of the study, and saw their cortisol levels rise after moving to a placebo (withdrawal phase) were given early rescue treatment. Their cortisol levels started to drop after a median of 22 days. The percentage of patients whose urine cortisol levels were within normal range by the end of the withdrawal phase was 45.5% higher among those treated with Recorlev, compared with those given a placebo (50.0% vs. 4.5%). In addition to losing benefits related to cortisol control, patients receiving a withdrawal-phase placebo also lost the therapy’s positive cholesterol-lowering effects. “The Phase 3 LOGICS results complement the long-term efficacy and safety data supplied by the Phase 3 SONICS study, which was published in The Lancet Diabetes & Endocrinology, by confirming that the effects of Recorlev (levoketoconazole) were responsible for the therapeutic response when treatment was continued compared to withdrawing patients to placebo,” said Maria Fleseriu, MD, FACE, professor of Medicine and Neurological Surgery and director of the Oregon Health Sciences University Pituitary Center, and principal investigator of the study. “The LOGICS findings — which build upon the long-term benefit shown during open-label treatment in SONICS — provide robust evidence to support the use of RECORLEV as an important treatment option for this life-threatening rare endocrine disease,” Fleseriu added. Recorlev was found to be safe and well-tolerated in LOGICS. Of the 79 patients who entered in the study’s open-label titration and maintenance phase, 19% discontinued due to side effects in this phase, and none of the 44 who proceeded to the withdrawal phase stopped treatment for these reasons. The most common side effects observed during the first two parts of LOGICS included nausea (29%), low blood potassium levels (28%), headache (21%), high blood pressure (19%), and diarrhea (15%). Some patients saw the levels of their liver enzymes rise above normal levels — a sign of liver inflammation and damage — during the study. However, this and other side effects of special interest, including those associated with adrenal insufficiency, resolved by either lowering the dose or stopping treatment with Recorlev. The proportion of patients experiencing these side effects was similar to that seen in SONICS. These findings are part of a subset of data from a planned interim analysis of LOGICS. Final study data requires analyses of additional datasets. Adapted from https://www.globenewswire.com/news-release/2020/09/08/2089872/0/en/Strongbridge-Biopharma-plc-Announces-Positive-and-Statistically-Significant-Top-Line-Results-from-the-Pivotal-Phase-3-LOGICS-Study-of-RECORLEV-levoketoconazole-for-the-Treatment-of.html
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Strongbridge Biopharma released additional positive results from a Phase 3 trial evaluating whether the company’s investigational therapy Recorlev (levoketoconazole) is safe and effective for people with endogenous Cushing’s syndrome. The latest results were presented in the scientific poster “Safety and Efficacy of Levoketoconazole in Cushing Syndrome: Initial Results From the Phase 3 SONICS Study,\” at the 18th Annual Congress of the European NeuroEndocrine Association (ENEA), which took place in Wrocław, Poland, last month. The SONICS study (NCT01838551) was a multi-center, open-label Phase 3 trial evaluating Recorlev’s safety and effectiveness in 94 patients with endogenous Cushing’s syndrome. The trial consisted of three parts: a dose-escalation phase to determine the appropriate Recorlev dose that achieved normalization of cortisol levels; a maintenance phase in which patients received the established dose for six months; and a final extended phase, in which patients were treated with Recorlev for an additional six months, with the possibility of dose adjustments. Its primary goal was a reduction in the levels of cortisol in the patients’ urine after six months of maintenance treatment, without any dose increase during that period. Among secondary goals was a reduction in the characteristically high risk of cardiovascular disease in these people, through the assessment of multiple cardiovascular risk markers. Strongbridge announced top-line results of the SONICS study in August, which showed that the trial had reached its primary and secondary goals. It concluded last month. After six months of maintenance therapy, Recorlev successfully lowered to normal the levels of cortisol in 30% of patients without a dose increase. It also led to statistically and clinically significant reductions in cardiovascular risk biomarkers, including blood sugar, cholesterol levels, body weight, and body mass index. Maria Fleseriu, MD, director of the Oregon Health Sciences University Northwest Pituitary Center, presented additional and detailed results of SONICS at the congress. Additional analyses showed that among the 77 patients who completed the dose-escalation phase and entered the study’s maintenance phase, 81% had their cortisol levels normalized. At the end of the six months of maintenance treatment, 29 (53%) of the 55 patients who had their cortisol levels assessed at the beginning of the study and at the end of the maintenance phase had achieved normalization of cortisol levels, regardless of dose increase. Among all patients who completed maintenance treatment (including patients with some missing data) and regardless of dose increase, 38% had achieved normalization of cortisol levels and 48% recorded a 50% or more decrease or normalization. The results also highlighted that Recorlev substantially reduced patients’ cortisol levels regardless of their levels at the study’s beginning (which were on average about five-fold higher than the upper limit of normal). In those patients with the highest levels of cortisol in their urine, Recorlev led to a median reduction of more than 80%. As previously reported, Recorlev was found to be generally well-tolerated, with no new safety concerns, and only 12 participants (12.8%) stopped treatment due to adverse events. Ten patients had three- or five-fold increased levels of alanine aminotransferase — a liver enzyme used to assess liver damage — which were fully resolved without further complications. These liver-related adverse events “were all noted in the first 60 days, thus suggesting a timeline interval for monitoring,” Fleseriu said in a press release. “We continue to be encouraged by the positive efficacy results of SONICS and the overall benefit-to-risk profile of Recorlev and look forward to sharing additional planned analyses from the study in the near future,” said Fredric Cohen, Strongbridge’s chief medical officer. From https://cushingsdiseasenews.com/2018/11/01/new-data-from-phase-3-trial-supports-recorlev-ability-to-safely-treat-cushings-syndrome/
