Pollakisuria

A perplexing problem for people with recurring urinary tract infections (UTIs) is persistent pain, even after antibiotics have successfully cleared the bacteria. Now researchers have identified the likely cause -- an overgrowth of nerve cells in the bladder. A perplexing problem for people with recurring urinary tract infections (UTIs) is persistent pain, even after antibiotics have successfully cleared the bacteria. Now Duke Health researchers have identified the likely cause -- an overgrowth of nerve cells in the bladder. The finding, appearing March 1 in the journal Science Immunology, provides a potential new approach to managing symptoms of recurring UTIs that would more effectively target the problem and reduce unnecessary antibiotic usage. "Urinary tract infections account for almost 25% of infections in women," said senior author Soman Abraham, Ph.D., professor in the departments of Pathology, Molecular Genetics and Microbiology, Integrative Immunobiology, and Cell Biology at Duke University School of Medicine. "Many are recurrent UTIs, with patients frequently complaining of chronic pelvic pain and urinary frequency, even after a round of antibiotics," Abraham said. "Our study, for the first time, describes an underlying cause and identifies a potential new treatment strategy." Abraham and colleagues collected bladder biopsies from recurrent UTI patients who were experiencing pain despite no culturable bacteria in their urine. Using biopsies from people without UTIs as a comparison, they found evidence that sensory nerves were highly activated in the UTI patients, explaining the persistent sense of pain and urinary frequency. Further studies in mice revealed the underlying events, with unique conditions in the bladder that prompt activated nerves in the lining to bloom and grow with each infection. "Typically, during every bout of UTI, epithelial cells laden with bacteria are sloughed off, and significant destruction of nearby nerve tissue occurs," said Byron Hayes, lead author of the study and previously a postdoctoral fellow in Duke's Department of Pathology. "These events trigger a rapid repair program in the damaged bladder involving massive regrowth of destroyed nerve cells." This immune response, including repair activities, is led by mast cells -- which are immune cells that fight infection and allergens. Mast cells release chemicals called nerve growth factor, which drive overgrowth and increase sensitivity of nerves. The result is pain and urgency. The researchers were able to address these symptoms by treating study mice with molecules that suppress production of the mast-cell generated nerve growth factor. "This work helps illuminate a puzzling clinical condition that drives medical costs and affects the quality of life of millions of people, primarily women," Abraham said. "Understanding the crosstalk between mast cells and nerves is an essential step toward effective treatments for people suffering repeat urinary tract infections." In addition to Abraham and Hayes, study authors include Hae Woong Choi, Abhay PS Rathore,Chunjing Bao, Jianling Shi, Yul Huh, Michael W Kim, Andrea Mencarelli, Pradeep Bist, Lai Guan Ng, Changming Shi, Joo Hwan Nho, Aram Kim, Hana Yoon, Donghoon Lim, Johanna L Hannan, J Todd Purves, Francis M Hughes Jr, and Ru-Rong Ji. The study received funding support from the National Institutes of Health (K12-DK100024, R01-DK121969, R01-DK121032, R01-GM144606), the National Research Foundation of Korea (2020R1C1C1003257), and a Korea University grant.

New results from six patients with HGTa papillary tumors show five of six patients with HGRFS at Week 12 Data continue to support favorable tolerability of TARA-002 in patients with NMIBC As previously reported, anti-tumor activity observed in all three evaluable patients with CIS, including one heavily pre-treated BCG-unresponsive patient who achieved a complete response Company remains on track to report preliminary results from the expansion portion of the ADVANCED-1 trial in NMIBC patients with CIS in the first half of 2024 NEW YORK, Nov. 30, 2023 (GLOBE NEWSWIRE) -- Protara Therapeutics, Inc. (Nasdaq: TARA), a clinical-stage company developing transformative therapies for the treatment of cancer and rare diseases, today announced additional encouraging data from the Phase 1a dose-escalation component of its ongoing ADVANCED-1 clinical trial of TARA-002, the Company’s investigational cell-based therapy, for the treatment of patients with high-grade non-muscle invasive bladder cancer (NMIBC). In addition, the study design for its ADVANCED-2 trial will be presented. The data will be featured during a poster session at the 24th Annual Meeting of the Society of Urologic Oncology (SUO) being held in Washington, D.C. from November 28, 2023 through December 1, 2023. “We are pleased to share additional data from the ADVANCED-1 trial which continue to support the potential for TARA-002 to provide a meaningful benefit to patients with NMIBC,” said Jesse Shefferman, Chief Executive Officer of Protara Therapeutics. “We look forward to reporting preliminary results from the expansion portion of the ADVANCED-1 trial of TARA-002, which we expect in the first half of 2024, and remain focused on continuing to execute on the totality of our NMIBC program, including the ongoing ADVANCED-2 trial.” Study Results TARA-002 was generally well tolerated at all three dose levels evaluated in the trial, and no dose limiting toxicities were observed. While a maximum tolerated dose was not determined, the Company has selected the 40KE1 dose for use in subsequent clinical trials. The majority of reported adverse events were Grades 1 and 2 across all dose levels, and treatment-related adverse events, as assessed by study investigators, were in line with typical responses to bacterial immunopotentiation, and included fatigue, headache, fever, and chills. The most common urinary symptoms were urinary urgency, urinary frequency, urinary tract pain/burning, incomplete emptying, and bladder spasm. Most bladder irritations resolved soon after administration or in a few hours to a few days. A total of nine patients were enrolled in the study, including three patients with carcinoma in situ (CIS) who reached the three-month efficacy assessment. Of those three patients with CIS, one heavily pre-treated Bacillus Calmette-Guérin (BCG)-unresponsive patient achieved a complete response (CR) at the 20KE dose, and tumor regression was observed in the other two patients. New results from six patients with high-grade, non-invasive papillary (HGTa) tumors showed five of six patients with high-grade recurrence free survival (HGRFS) at week 12. The patient who did not achieve HGRFS was dosed at 10KE, the lowest dose of TARA-002 offered in the trial. The Company remains on track to report preliminary results from the expansion portion of the ADVANCED-1 trial in the first half of 2024. Supported by data from the Phase 1a study, the Company commenced ADVANCED-2 (NCT05951179), a Phase 2 open-label trial evaluating intravesical TARA-002 in up to 102 NMIBC patients with CIS (± Ta/T1) who are BCG-naïve (n=27) and BCG-unresponsive (n=75). Trial subjects received an induction with or without a reinduction course of six weekly intravesical instillations of TARA-002, followed by a maintenance course of three weekly installations every three months in the BCG-unresponsive cohort. Additional details on the trial design will be featured in a Trial in Progress poster at the SUO meeting. A copy of the SUO posters will be available in the Events and Presentations section of the Company’s website: . About Non-Muscle Invasive Bladder Cancer (NMIBC) Bladder cancer is the sixth most common cancer in the U.S., with NMIBC representing approximately 80% of bladder cancer diagnoses. NMIBC is cancer found in the tissue that lines the inner surface of the bladder that has not spread into the bladder muscle. Approximately 65,000 patients are diagnosed with NMIBC in the U.S. each year. About TARA-002 TARA-002 is an investigational cell therapy in development for the treatment of NMIBC and of LMs, for which it has been granted Rare Pediatric Disease Designation by the U.S. Food and Drug Administration. TARA-002 was developed from the same master cell bank of genetically distinct group A Streptococcus pyogenes as OK-432, a broad immunopotentiator marketed as Picibanil® in Japan and approved in Taiwan by Chugai Pharmaceutical Co., Ltd. Protara has successfully shown manufacturing comparability between TARA-002 and OK-432. When TARA-002 is administered, it is hypothesized that innate and adaptive immune cells within the cyst or tumor are activated and produce a strong immune cascade. Neutrophils, monocytes, and lymphocytes infiltrate the abnormal cells and various cytokines, including interleukins IL-2, IL-6, IL-8, IL-10, IL-12, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha are secreted by immune cells to induce a strong inflammatory reaction and destroy the abnormal cells. About Protara Therapeutics, Inc. Protara is committed to advancing transformative therapies for people with cancer and rare diseases. Protara’s portfolio includes its lead program, TARA-002, an investigational cell-based therapy being developed for the treatment of non-muscle invasive bladder cancer and lymphatic malformations, and IV Choline Chloride, an investigational phospholipid substrate replacement for patients dependent on parenteral nutrition. For more information, visit . References 1. Klinische Einheit, or KE, is a German term indicating a specified weight of dried cells in a vial. Forward-Looking Statements Statements contained in this press release regarding matters that are not historical facts are "forward looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. Protara may, in some cases, use terms such as “predicts,” “believes,” “potential,” “proposed,” “continue,” “designed,” “estimates,” “anticipates,” “expects,” “plans,” “intends,” “may,” “could,” “might,” “will,” “should” or other words or expressions referencing future events, conditions or circumstances that convey uncertainty of future events or outcomes to identify these forward-looking statements. Such forward-looking statements include but are not limited to, statements regarding Protara’s intentions, beliefs, projections, outlook, analyses or current expectations concerning, among other things: Protara’s business strategy, including its development plans for its product candidates and plans regarding the timing or outcome of existing or future clinical trials; statements related to expectations regarding interactions with the FDA; Protara’s financial position; statements regarding the anticipated safety or efficacy of Protara’s product candidates; and Protara’s outlook for the remainder of the year. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Factors that contribute to the uncertain nature of the forward-looking statements include: risks that Protara’s financial guidance may not be as expected, as well as risks and uncertainties associated with: Protara’s development programs, including the initiation and completion of non-clinical studies and clinical trials and the timing of required filings with the FDA and other regulatory agencies; general market conditions; changes in the competitive landscape; changes in Protara’s strategic and commercial plans; Protara’s ability to obtain sufficient financing to fund its strategic plans and commercialization efforts; having to use cash in ways or on timing other than expected; the impact of market volatility on cash reserves; the loss of key members of management; the impact of general U.S. and foreign, economic, industry, market, regulatory, political or public health conditions; and the risks and uncertainties associated with Protara’s business and financial condition in general, including the risks and uncertainties described more fully under the caption “Risk Factors” and elsewhere in Protara's filings and reports with the United States Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made and are based on management's assumptions and estimates as of such date. Protara undertakes no obligation to update any forward-looking statements, whether as a result of the receipt of new information, the occurrence of future events or otherwise, except as required by law. Company Contact: Justine O'Malley Protara Therapeutics Justine.OMalley@protaratx.com 646-817-2836

— Initial ALKS 2680 Data Demonstrated Dose-Dependent, Significantly Improved Sleep Latency Compared to Placebo in Narcolepsy Type 1 — — ALKS 2680 Was Generally Well Tolerated at All Doses Tested — — Pharmacokinetic Profile of ALKS 2680 Supports Once-Daily Dosing and Mimics the Natural Sleep/Wake Cycle — — Consistent, Dose-Dependent Effects Enable Dose Selection for Evaluation in Planned Phase 2 Study — DUBLIN, Oct. 23, 2023 /PRNewswire/ -- Alkermes plc (Nasdaq: ALKS) today announced preliminary results, including initial proof-of-concept data, from a phase 1 study evaluating ALKS 2680, the company's novel, investigational orexin 2 receptor (OX2R) agonist in development for the treatment of narcolepsy. The ongoing phase 1 study is evaluating the safety, tolerability, pharmacokinetics and pharmacodynamics of ALKS 2680 in healthy volunteers and patients with narcolepsy or idiopathic hypersomnia via once-daily, oral administration. Initial data from the single- and multiple-ascending dose evaluations in healthy volunteers and the first cohort of four patients with narcolepsy type 1 (NT1) will be presented today at the 2023 World Sleep Congress in Rio de Janeiro. The patients with NT1 were randomized to a crossover study in which each of them received 1 mg, 3 mg and 8 mg of ALKS 2680, and placebo, with washout periods between each treatment. Single administration of each dose strength of ALKS 2680 achieved statistically significant, clinically meaningful improvements compared to placebo in wakefulness, as measured by the maintenance of wakefulness test (MWT). In the four patients with NT1, treatment with ALKS 2680 demonstrated improved sleep latency compared to placebo at all doses tested, with a clear dose response. Following treatment with ALKS 2680, mean sleep latency in patients improved by 18 minutes, 30 minutes and 37 minutes from mean pre-treatment baseline sleep latency of three minutes at the 1 mg, 3 mg and 8 mg doses, respectively (least squares mean). Placebo treatment resulted in a one-minute reduction in mean sleep latency. The differences between ALKS 2680 and placebo were statistically significant for all doses: 1 mg (p<0.01), 3 mg (p<0.001), and 8 mg (p<0.001). Treatment with ALKS 2680 resulted in clinically meaningful improvements in MWT from baseline at all doses tested. At the 8 mg dose of ALKS 2680, patients maintained wakefulness for the full 40-minute MWT duration, up to 10 hours post-dose. MWT scores at 3 mg were comparable to the 8 mg scores for the first 6 hours post-dose, and treatment with both the 1 mg and 3 mg doses of ALKS 2680 resulted in improved MWT scores up to 8 hours post-dose. ALKS 2680 was generally well tolerated across all doses tested in the patients with NT1. Drug-related adverse events (AEs) were seen only at the 8 mg dose and were mild in severity. The AEs observed in >1 participant and deemed to be treatment-emergent at the 8 mg dose were insomnia (n=3), pollakiuria (urinary urgency or frequency) (n=2) and salivary hypersecretion (n=2). There were no serious AEs or AEs leading to discontinuation. Additionally, there were no clinically meaningful, treatment-emergent changes in hepatic and renal parameters, vital signs, or electrocardiogram (ECG) parameters. "The early proof-of-concept and safety data we've seen in this ongoing phase 1 study of ALKS 2680 in both healthy volunteers and four patients with narcolepsy type 1 are compelling. These data support further evaluation of ALKS 2680 as a potential treatment for narcolepsy," said Brendon Yee, Ph.D., Professor and Respiratory and Sleep Physician at the Woolcock Institute of Medical Research. "Orexin 2 receptor agonists such as ALKS 2680 represent an exciting new class of potential treatments for narcolepsy, with the opportunity to transform the treatment paradigm for people living with this disease." In healthy volunteers, ALKS 2680 was evaluated at single- and multiple-ascending doses. In the single-dose evaluation, ALKS 2680 was dosed from 1 mg to 50 mg. In the multiple-dose evaluation, participants received single daily doses of ALKS 2680 at 3 mg, 8 mg, 15 mg and 25 mg strengths for up to 10 days. ALKS 2680 was generally well tolerated across all doses tested and the maximum tolerated dose was not reached. Most AEs were mild, transient, and resolved without intervention or treatment interruption. In the single-ascending dose evaluation, AEs observed in >1 participant and deemed related to study drug were dizziness, pollakiuria, nausea and blurred vision, and most occurred at or above the 15 mg dose level. In the multiple-ascending dose evaluation, AEs observed in >1 participant and deemed related to study drug were insomnia, dizziness, pollakiuria and visual disturbances described as blurred or distorted vision, and most occurred at or above the 8 mg dose. There were no safety signals identified in vital signs, laboratory parameters or ECGs. In healthy volunteers, ALKS 2680 was observed to be centrally active and to have a pharmacokinetic and pharmacodynamic profile that supports once-daily, oral dosing. "Narcolepsy is a serious, chronic, neurological disease that impairs regulation of the sleep-wake cycle and negatively impacts daily life. There is significant unmet need for people with narcolepsy, as no currently available treatments address the underlying biology of the disease: orexin deficiency or dysfunction," said Craig Hopkinson, M.D., Chief Medical Officer and Executive Vice President of Research & Development at Alkermes. "These initial data support our design rationale for ALKS 2680 as a highly potent, orally bioavailable, selective orexin 2 receptor agonist designed to address the underlying pathology of narcolepsy. The consistent and dose-dependent effects observed in the initial proof-of-concept data enable dose selection for evaluation in phase 2. We look forward to sharing additional updates from the phase 1 study, and plan to initiate our phase 2 study of ALKS 2680, in the first half of 2024." About the ALKS 2680 Phase 1 Study The phase 1 study for ALKS 2680 includes single-ascending dose and multiple-ascending dose evaluations in healthy volunteers, and a double-blind, cross-over treatment in patients with narcolepsy type 1 (NT1), narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH). In the healthy volunteer phase of the study, each cohort included eight participants, six of whom were randomized to receive ALKS 2680 and two of whom received placebo. In the single-dose portion, ALKS 2680 was dosed from 1 mg to 50 mg. In the multiple-dose portion, participants received single daily doses of ALKS 2680 at 3 mg, 8 mg, 15 mg and 25 mg strengths for up to 10 days. The objectives of this part of the study were to assess ALKS 2680's safety, tolerability, pharmacokinetics and pharmacodynamics. The phase 1b proof-of-concept part of the study is enrolling patients with NT1, NT2 or IH, with up to eight patients for each such indication. Following an initial two-week washout period of existing medications, patients receive single doses of three active dose levels of ALKS 2680 and placebo in a randomized sequence in a four-way crossover design, with washout periods between each treatment in the sequence. The primary objectives are to assess safety and tolerability, and changes from baseline in the average sleep latency through the Maintenance of Wakefulness Test (MWT) at each cross-over, along with plasma PK, biomarkers such as quantitative electroencephalogram (qEEG) and event-related potential (ERP), and a cognitive test, the Sustained Attention to Response Task (SART). Data from the first four patients with NT1 will be presented at World Sleep Congress. About ALKS 2680 ALKS 2680 is a novel, investigational, oral, selective orexin 2 receptor (OX2R) agonist in development for the treatment of narcolepsy. Orexin neuropeptides are important regulators of the sleep/wake cycle through OX2R activation, and loss of orexinergic neurons in the brain is associated with excessive daytime sleepiness and cataplexy in narcolepsy.1 ALKS 2680 was designed to address the underlying pathology of narcolepsy with the goal of improving duration of wakefulness and providing cataplexy control. Once-daily oral administration of ALKS 2680 is currently being evaluated in a phase 1 study in healthy volunteers and people living with narcolepsy type 1, narcolepsy type 2 and idiopathic hypersomnia. About Alkermes plc Alkermes plc is a fully-integrated, global biopharmaceutical company developing innovative medicines in the fields of neuroscience and oncology. The company has a portfolio of proprietary commercial products focused on alcohol dependence, opioid dependence, schizophrenia and bipolar I disorder, and a pipeline of product candidates in development for neurological disorders and cancer. Headquartered in Dublin, Ireland, Alkermes has a research and development (R&D) center in Waltham, Massachusetts; a research and manufacturing facility in Athlone, Ireland; and a manufacturing facility in Wilmington, Ohio. For more information, please visit Alkermes' website at . Note Regarding Forward-Looking Statements Certain statements set forth in this press release constitute "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, but not limited to, statements concerning: the potential therapeutic and commercial value of ALKS 2680 for the treatment of narcolepsy; the company's expectations regarding plans and timelines for further clinical development activities for ALKS 2680, including dose selection, initiation of the phase 2 study and presentation of additional data from the phase 1 study. The company cautions that forward-looking statements are inherently uncertain. Although the company believes that such statements are based on reasonable assumptions within the bounds of its knowledge of its business and operations, the forward-looking statements are neither promises nor guarantees and they are necessarily subject to a high degree of uncertainty and risk. Actual performance and results may differ materially from those expressed or implied in the forward-looking statements due to various risks and uncertainties. These risks and uncertainties include, among others: whether ALKS 2680 could be shown to be ineffective or unsafe; whether preclinical and initial clinical results for ALKS 2680 will be predictive of results of further clinical studies or real-world results; potential changes in the cost, scope and duration of the ALKS 2680 development program; whether future clinical trials or future stages of ongoing clinical trials for ALKS 2680 will be initiated or completed on time or at all; and those risks and uncertainties described under the heading "Risk Factors" in the company's Annual Report on Form 10-K for the year ended Dec. 31, 2022 and in subsequent filings made by the company with the U.S. Securities and Exchange Commission (SEC), which are available on the SEC's website at . Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. Except as required by law, the company disclaims any intention or responsibility for updating or revising any forward-looking statements contained in this press release. 1 Nagahara T, Saitoh T, Kutsumura N, Irukayama-Tomobe Y, Ogawa Y, Kuroda D, Gouda H, Kumagai H, Fujii H, Yanagisawa M, Nagase H. Design and Synthesis of Non-Peptide, Selective Orexin Receptor 2 Agonists. J Med Chem. 2015 Oct 22;58(20):7931-7. doi: 10.1021/acs.jmedchem.5b00988. Epub 2015 Aug 26. PMID: 26267383. Alkermes Contacts: For Investors: Sandy Coombs, +1 781 609 6377 For Media: Gretchen Murphy, +1 781 609 6419 SOURCE Alkermes plc