β1-adrenergic receptor

BHV-1300 achieved deep lowering of targeted IgG, with reductions > 60% in the lowest subcutaneous dose tested in the MAD. Subcutaneous BHV-1300 achieved rapid and progressive lowering of IgG within hours of each weekly dose administration, and pharmacodynamic effects were sustained relative to baseline over the four-week period. The optimized subcutaneous formulation also showed substantially less inter-patient variability in the MAD compared to the previously reported intravenously administered BHV-1300. BHV-1300 has been safe and well tolerated across the ongoing Phase 1 without any dose limiting toxicity to date. All AEs have been mild, with no SAEs or discontinuations related to study drug. Dose escalation continues with the optimized subcutaneous formulation to explore the full range of IgG reductions possible with BHV-1300. Additional Phase 1 data will be presented upon completion of the remaining subcutaneous cohorts in 1Q25. Laboratory data from the MAD confirm a differentiated safety profile compared to competitor agents as BHV-1300 has had no clinically significant reductions in albumin, liver function test abnormalities or increases in cholesterol at week 4 relative to baseline. Further enhancing the competitive safety profile, BHV-1300 was rationally designed to spare IgG3 with plasma IgG3 levels over the course of the MAD preserved through the end of study week 4 to allow for healthy immune effector functioning. Submitted new drug application (NDA) to US FDA for troriluzole in spinocerebellar ataxia (SCA), following completion of pre-NDA meeting in 4Q 2024. Troriluzole has Orphan Drug and Fast-Track designations and qualifies for potential Priority Review. Announced completion of enrollment during 4Q 2024 in the BHV-7000 pivotal 3-week, Phase 2/3 bipolar trial, several months ahead of timelines. Expanded and advanced the molecular degraders of extracellular proteins (MoDE) clinical program to include next-generation autoantibody specific degraders that selectively remove pathogenic antibodies while preserving healthy immune functioning, with regulatory acceptance of 3 novel drug candidate INDs and/or CTAs in 4Q24: IgA nephropathy: Initiated Phase 1 dosing with BHV-1400, a novel IgAN investigational therapy designed to selectively degrade pathogenic galactose deficient IgA1 (Gd-IgA1) while sparing normal IgA. In addition to rapid and sustained lowering of Gd-IgA1, BHV-1400 is expected to result in less potential for respiratory, mucosal or central nervous system infections compared to broader IgA lowering or immunosuppressive strategies in development by competitors. Autoimmune cardiomyopathy: Initiated Phase 1 dosing with BHV-1600, a novel investigational therapy designed to selectively degrade b1 adrenergic receptor (b1AR) autoantibodies. Biohaven also completed an INTERACT meeting with FDA regarding BHV-1600 in 4Q 2024 and gained alignment for the study design to pursue an accelerated approval pathway in peripartum cardiomyopathy (PPCM), a rare autoimmune life-threatening disease with no approved therapy. IgG mediated diseases: IND opened for BHV-1310, an optimized and selective IgG1, IgG2, and IgG4 degrader in 4Q 2024 with first dosing planned for 1Q 2025. Entered into an agreement with Ypsomed to develop and manufacture BHV-1300 in an easy-to-use, autoinjector for self-administration. Ypsomed is a leading provider of autoinjector technology used in commercialized products for convenient patient use. The Ypsomed device is expected to be used across all MoDE programs through development and commercial use, derisking this aspect of the development program as well as providing seamless transitions and allowing for significant data generation on the device in advance of future NDA filings. NEW HAVEN, Conn., Dec. 16, 2024 /PRNewswire/ -- Biohaven Ltd. (NYSE: BHVN) ("Biohaven"), a global clinical-stage biopharmaceutical company focused on the discovery, development, and commercialization of life-changing therapies to treat a broad range of rare and common diseases, today highlighted the achievement of several clinical and regulatory milestones across its proprietary Molecular Degrader of Extracellular Proteins (MoDE™) platform as well as its glutamate modulation and ion channel programs. Figure 1: BHV-1300 easy-to-use autoinjector for pivotal trials in 2025, developed and manufactured in collaboration with Ypsomed. Ypsomed, a Swiss device maker and global leader in the development of innovative injection systems, is well-known for its design, development and production of user-friendly injectors for self-medication in various diseases including the treatment of metabolic disorders. This device is expected to be used across all MoDE programs through development and commercialization, providing seamless transitions and allowing for significant data generation on the device in advance of future NDA filings. Figure 2: (A) IgA nephropathy is caused by excess production of galactose deficient IgA1 and deposition in the renal glomerulus, setting off an inflammatory cascade and renal damage. Figure 2: (B) BHV-1400 degrades galactose deficient IgA1 (red) in vivo in preclinical models. With BHV-1400 administration compared to vehicle administration, galactose deficient IgA1 clears from the renal glomerulus (inset) over hours. BHV-1400 was designed with precision to remove the pathogenic driver of IgA nephropathy and preserve components of the immune system crucial to fighting infections, such as meningitis. Figure 3: Autoantibodies target the b1-adrenergic receptor (b1AR) to cause cardiac dilation and heart failure.1 BHV-1600 selectively removes autoantibodies to b1AR, and has been dosed in humans, with recent FDA alignment on a clinical development program to most efficiently deliver a potentially transformative therapeutic to patients with peripartum cardiomyopathy. Subcutaneously administered BHV-1300 achieved deep lowering of targeted IgG, with reductions > 60% in the lowest subcutaneous dose tested in the ongoing multiple ascending dose (MAD) study. Subcutaneous BHV-1300 achieved progressive reduction in IgG within hours of each weekly dose administration in the MAD, and pharmacodynamic effects were sustained relative to baseline over the four-week study period. BHV-1300 has been safe and well-tolerated across the Phase 1 study. There were no clinically significant effects on albumin or liver function, and no increases in cholesterol were noted. Further enhancing the competitive safety profile and as intentionally designed, plasma IgG3 levels were preserved through the end of study week 4 to allow for healthy immune effector functioning. All AEs were mild, any drug-related AE resolved, and there were no discontinuations due to study drug related AEs. The optimized subcutaneous formulation in the MAD also showed substantially less inter-patient variability compared to previously reported intravenous BHV-1300. Escalating dose level cohorts of subcutaneous BHV-1300 are ongoing to explore the full range of IgG reductions possible with BHV-1300 for a wide range of future disease indications. Tova Gardin MD, MPP, Biohaven's Chief Translational Officer, commented, "The results of subcutaneously delivered BHV-1300 from the first and lowest MAD dose cohort represent a monumental step forward for our MoDE platform with deep and rapid reduction in targeted IgG. Our results highlight the selectivity and precision of BHV-1300 in potentially treating IgG mediated immune diseases while the regulatory acceptance of three next generation degraders showcases the future of the MoDE technology in autoantibody disease. With speed, selectivity, and depth of lowering, BHV-1300 has the potential to transform the treatment of autoimmune disease and has paved the way for rapid innovation across the degrader platform. With the mechanistic validation of BHV-1300 and performance of the optimized subcutaneous formulation in Phase 1, we have begun the manufacturing of a convenient autoinjector that will further differentiate our approach in the clinic. The early autoinjector development to ensure a commercial ready, patient-administered device for BHV-1300 was important to derisking this aspect of our MoDE development program." Biohaven licensed the MoDE technology from Yale University with high potential differentiation for the treatment of autoimmune diseases, including rapid degradation of targets within hours, deep reductions that can be titrated by dose level and frequency, simple-to-use patient administration, excellent tolerability without deleterious effects on albumin or cholesterol, and the flexibility to be used in conjunction with Fc-containing biologics (unlike other IgG lowering agents). Additionally, BHV-1300 is unique with its selective removal of targeted IgG (IgG1, IgG2 and IgG4 over IgG3). IgG3 plays a critical role in the immune response and in activating effector functions crucial for combating bacteria, parasites, and viruses. BHV-1300 was designed to spare IgG3 to avoid the broad immunosuppression associated with other IgG lowering approaches and to allow for an immune response to combat potential infections while delivering therapeutic actions in autoimmune disease. Results of the ongoing Phase 1 trial validate the selectivity of BHV-1300 and the adaptability of the platform to engage targets of interest with precision. In addition to the new Phase 1 data with BHV-1300, Biohaven also announced regulatory acceptance of three INDs and/or CTAs for its next-generation MoDE molecules to target other immune mediated diseases. Two of these novel MoDEs, BHV-1400 and BHV-1600, represent the platform's first autoantibody specific degraders, sparing the body's healthy antibodies (IgG, IgA, etc.) to function normally while clearing disease-causing antibodies. Dosing in humans has been initiated for BHV-1400, a novel IgA nephropathy (IgAN) investigational therapy designed to selectively degrade galactose deficient IgA1 (Gd-IgA1) without immunosuppression. IgAN is a rare disease affecting approximately 60,000 individuals in the United States. It is often diagnosed in the second or third decade of life, progresses over decades, and can result in kidney failure leading to the need for hemodialysis. Approved therapies broadly suppress the immune system or target the downstream consequences of immune damage without targeting the autoimmune cause of disease. For a disease which is diagnosed in young adults and treatment may be required over the lifespan, BHV-1400 is highly differentiated, engineered to clear the pathogenic nidus of disease, Gd-IgA1, and preserve the individual's immunoglobulins (IgG, IgA, IgE, IgM), immune cells, and complement system (Figure 2). Thus, BHV-1400 is expected to result in less potential for respiratory, mucosal or central nervous system infections compared to broader IgA lowering or immunosuppressive strategies in development. Additionally, IgAN clinical trials have a well-established pathway for accelerated approval. Biohaven also initiated dosing in humans with BHV-1600 in 4Q 2024. BHV-1600 is a MoDE engineered to rapidly degrade pathogenic autoantibodies to the b1-adrenergic receptor (b1AR). BHV-1600 is the first rationally designed investigative treatment in development for peripartum cardiomyopathy (PPCM), a rare type of heart failure that occurs during pregnancy or soon after birth that has no currently approved therapy. In b1AR autoantibody-driven cardiomyopathy, autoantibodies bind b1AR and induce cardiomyocyte toxicity and heart failure (Figure 3).1 PPCM affects mothers at an incredibly vulnerable period: previously healthy, individuals with PPCM develop profound heart failure, struggling with new symptoms as their child experiences its first days and often first years of life. Without disease-specific therapies, women with PPCM can develop heart failure and may emergently require left ventricular assistive devices or heart transplant. Given PPCM is a life-threatening disease with no current treatment and the potential for BHV-1600 to rapidly degrade pathogenic b1AR autoantibodies, Biohaven completed an INTERACT meeting with the FDA in 4Q 2024 and gained alignment on a clinical development program to pursue an accelerated approval pathway for BHV-1600 in PPCM. An IND has also been accepted for BHV-1310, an optimized and selective IgG1, IgG2, and IgG4 degrader. Dosing is expected in humans in 1Q 2025. In addition to key updates in the MoDE clinical development program, Biohaven also announced critically important advances related to its late-stage glutamate and ion channel platforms. A new drug application (NDA) was submitted to the US FDA for troriluzole in the treatment of all genotypes of spinocerebellar ataxia (SCA), following the completion of a pre-NDA meeting in 4Q 2024. Troriluzole was previously granted Orphan Drug and Fast-Track designations by FDA, and qualifies for potential Priority Review. Biohaven recently reported positive topline pivotal results in SCA in September 2024, demonstrating that troriluzole slowed disease progression by 50-70% over the 3-year study period. SCA is a rare, life-threatening, progressively debilitating neurodegenerative disease that affects approximately 15,000 people in the US, and 24,000 in Europe and the United Kingdom. Troriluzole has been safe and well-tolerated in over 8 years of clinical trial experience. There are no FDA approved treatments for SCA and troriluzole is the first investigational agent to show disease slowing in its clinical development program. Biohaven further announced the completion of enrollment in a pivotal BHV-7000 Phase 2/3 trial in bipolar disorder in 4Q 2024. BHV-7000 is a selective activator of Kv7 potassium channels that offers a novel and compelling mechanism of action for the treatment of bipolar disorder and an excellent tolerability at all doses evaluated in previous studies without the central nervous system adverse effects, such as somnolence and other CNS-related effects, that typically limit the use of other mood stabilizing medications. The trial completed enrollment several months ahead of anticipated timelines, reflecting the high unmet need for new treatments in bipolar disorder. The Phase 2/3 double-blind, placebo-controlled study enrolled approximately 256 patients. Patients were randomized to receive BHV-7000 75 mg once daily or placebo over a 3-week treatment period. The primary outcome measure of the study is the change from baseline to week 3 in mania symptom severity, as measured by the Young Mania Rating Scale (YMRS). Secondary objectives include response and remission rates, early onset of efficacy, depression symptom severity as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS), and safety. Irfan Qureshi MD, Chief Medical Officer of Biohaven, commented, "Biohaven continues to propel cutting edge science into reality in the clinic. Biohaven's proprietary MoDE degrader platform is a technology that has the potential to revolutionize precision treatment of a spectrum of common and rare autoimmune diseases. Targeted removal of IgG, b1AR autoantibodies and galactose deficient IgA1 has the potential to transform the treatment of rheumatoid arthritis, myasthenia gravis, autoimmune cardiomyopathy, IgAN, and many other immune mediated disorders. While advancing new compounds in immunology and inflammation, our R&D teams have also delivered important milestones for our ion channel and glutamate modulating agents. We are proud to have completed enrollment in the pivotal bipolar study with BHV-7000, months ahead of timelines and eagerly await topline results. And, our NDA submission for spinocerebellar ataxia represents the culmination of over 8 years of innovation, research, and commitment to patients with this devastating neurodegenerative disease. We believe troriluzole is a transformative breakthrough that offers new hope to individuals and families suffering from SCA who currently have no therapeutic options to alter the course of this relentless disease." Dr. Qureshi added, "We are extremely excited about the rapid progress across the portfolio and optimistic about the opportunities we have to make a positive impact on patients' lives and create value in 2025 and beyond." About Biohaven Biohaven is a biopharmaceutical company focused on the discovery, development, and commercialization of life-changing treatments in key therapeutic areas, including immunology, neuroscience, and oncology. Biohaven is advancing its innovative portfolio of therapeutics, leveraging its proven drug development experience and multiple proprietary drug development platforms. Biohaven's extensive clinical and nonclinical programs include Kv7 ion channel modulation for epilepsy and mood disorders; extracellular protein degradation for immunological diseases; TRPM3 antagonism for migraine and neuropathic pain; TYK2/JAK1 inhibition for neuroinflammatory disorders; glutamate modulation for OCD and SCA (spinocerebellar ataxia); myostatin inhibition for neuromuscular and metabolic diseases, including SMA and obesity; antibody recruiting bispecific molecules and antibody drug conjugates for cancer. For more information, visit . Forward-looking Statements This news release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. The use of certain words, including "continue", "plan", "will", "believe", "may", "expect", "anticipate" and similar expressions, is intended to identify forward-looking statements. Investors are cautioned that any forward-looking statements, including statements regarding the future development, timing and potential marketing approval and commercialization of development candidates, are not guarantees of future performance or results and involve substantial risks and uncertainties. Actual results, developments and events may differ materially from those in the forward-looking statements as a result of various factors including: the expected timing, commencement and outcomes of Biohaven's planned and ongoing clinical trials; the timing of planned interactions and filings with the FDA; the timing and outcome of expected regulatory filings; complying with applicable U.S. regulatory requirements; the potential commercialization of Biohaven's product candidates; and the effectiveness and safety of Biohaven's product candidates. Additional important factors to be considered in connection with forward-looking statements are described in Biohaven's filings with the Securities and Exchange Commission, including within the sections titled "Risk Factors" and "Management's Discussion and Analysis of Financial Condition and Results of Operations". The forward-looking statements are made as of the date of this news release, and Biohaven does not undertake any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law. MoDE is a trademark of Biohaven Therapeutics Ltd. Investor Contact: Jennifer Porcelli Vice President, Investor Relations [email protected] +1 (201) 248-0741 Media Contact: Mike Beyer Sam Brown Inc. [email protected] +1 (312) 961-2502 SOURCE Biohaven Ltd. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Researchers have figured out how to turn ordinary white fat cells, which store calories, into beige fat cells that burn calories to maintain body temperature. New UCSF study shows that suppressing a protein turns ordinary fat into a calorie burner and may explain why drug trials attempting the feat haven't been successful. Researchers at UC San Francisco have figured out how to turn ordinary white fat cells, which store calories, into beige fat cells that burn calories to maintain body temperature. The discovery could open the door to developing a new class of weight-loss drugs and may explain why clinical trials of related therapies have not been successful. Until now, researchers believed creating beige fat might require starting from stem cells. The new study published July 1 in the Journal of Clinical Investigation, showed that ordinary white fat cells can be converted into beige fat simply by limiting production of a protein. "A lot of people thought this wasn't feasible," said Brian Feldman, MD, PhD, the Walter L. Miller, MD Distinguished Professor in Pediatric Endocrinology and senior author of the study. "We showed not only that this approach works to turn these white fat cells into beige ones, but also that the bar to doing so isn't as high as we'd thought." A fat transformation Many mammals have three "shades" of fat cells: white, brown and beige. White fat serves as energy reserves for the body, while brown fat cells burn energy to release heat, which helps maintain body temperature. Beige fat cells combine these characteristics. They burn energy, and unlike brown fat cells, which grow in clusters, beige fat cells are embedded throughout white fat deposits. Humans and many other mammals are born with brown fat deposits that help them maintain body temperature after birth. But, while a human baby's brown fat disappears in the first year of life, beige fat persists. Humans can naturally turn white fat cells into beige ones in response to diet or a cold environment. Scientists tried to mimic this by coaxing stem cells into becoming mature beige fat cells. But stem cells are rare, and Feldman wanted to find a switch he could flip to turn white fat cells directly into beige ones. "For most of us, white fat cells are not rare and we're happy to part with some of them," he said. Of mice and humans Feldman knew from his earlier experiments that a protein called KLF-15 plays a role in metabolism and the function of fat cells. With postdoctoral scholar Liang Li, PhD, Feldman decided to investigate how the protein functioned in mice, which retain brown fat throughout their lives. They found that KLF-15 was much less abundant in white fat cells than in brown or beige fat cells. When they then bred mice with white fat cells that lacked KLF-15, the mice converted them from white to beige. Not only could the fat cells switch from one form into another, but without the protein, the default setting appeared to be beige. The researchers then looked at how KLF-15 exerts this influence. They cultured human fat cells and found that the protein controls the abundance of a receptor called Adrb1, which helps maintain energy balance. Scientists knew that stimulating a related receptor, Adrb3, caused mice to lose weight. But human trials of drugs that act on this receptor have had disappointing results. A different drug targeting the Adrb1 receptor in humans is more likely to work, according to Feldman, and it could have significant advantages over the new, injectable weight-loss drugs that are aimed at suppressing appetite and blood sugar. Feldman's approach might avoid side effects like nausea because its activity would be limited to fat deposits, rather than affecting the brain. And the effects would be long lasting, because fat cells are relatively long-lived. "We're certainly not at the finish line, but we're close enough that you can clearly see how these discoveries could have a big impact on treating obesity," he said. Liang Li is also an author of this study. This work was funded by NIH grant R01DK132404.

Asthma is a chronic respiratory disease characterized by chronic inflammation of the airways and reversible airway obstruction. Individuals with asthma have sensitive airways that can narrow when exposed to triggers, leading to difficulties in breathing, wheezing, coughing, and a feeling of chest tightness. Asthma patients experience recurrent episodes of breathing difficulties and wheezing that vary in severity and frequency over time. Globally, as many as 262 million people are affected by asthma, with about 25 million in the United States alone. These patients face the risk of severe exacerbations regardless of the severity of their condition, adherence to treatment, or level of control. It is estimated that there are 136 million exacerbations of asthma annually worldwide. These exacerbations pose a physical threat and emotional impact on many patients and can be fatal. Many patients with asthma symptoms use short-acting β2-adrenergic receptor agonists, such as albuterol, as rescue medications. However, the use of short-acting β2-adrenergic receptor agonists alone does not address the underlying inflammation, leaving patients at risk of severe exacerbations which can lead to decreased quality of life, hospitalization, and frequent use of oral corticosteroids. Additionally, risks of adverse health outcomes are associated with 1-3 short courses of oral corticosteroid treatment of exacerbation, including type 2 diabetes, depression/anxiety, renal impairment, cataracts, cardiovascular disease, pneumonia, and fractures. In January 2023, AstraZeneca's official website announced that Airsupra (albuterol/budesonide, PT027), the first and only rescue medication approved in the United States for as-needed use to reduce the risk of asthma exacerbation, has been authorized in the U.S. for as-needed treatment or prevention of bronchospasm, and to lower the risk of asthma exacerbation in patients aged 18 years and older. The approved Airsupra is a pressurized metered-dose inhaler (pMDI) and fixed-dose combination rescue medication, co-developed by AstraZeneca and Avillion, containing the short-acting β2-adrenergic agonist albuterol and the anti-inflammatory inhaled corticosteroid budesonide. Based on the results of a clinical study (MANDALA trial) published in the New England Journal of Medicine in May 2022, the combination therapy of Airsupra was shown to significantly reduce the risk of severe exacerbations in patients with moderate to severe asthma when used as-needed as a rescue medication, compared to the use of albuterol alone. Importantly, at the approved dose (90 mcg albuterol/80 mcg budesonide), Airsupra significantly reduced the average annualized total systemic corticosteroid exposure, a key secondary endpoint, compared to albuterol. According to statistics from the Synapse database, there are 1,565 investigational drugs and 148 marketed drugs globally for the treatment of asthma. The β2-adrenergic receptors and glucocorticoid receptors mentioned in this article are the most important therapeutic targets for asthma. In addition, other popular targets include the H1 histamine receptor, acetylcholine receptor, IgE, CysLT, IL-5, etc. Among them, monoclonal antibody drugs targeting IgE (Omalizumab), IL-5 (Mepolizumab, Reslizumab), and TSLP (Tezepelumab) have been approved and launched on the market in recent years. β2AR and Compound Asthma MedicationThe β2 adrenergic receptor (β2AR) is one of the most classic members of the GPCR family. Due to its extensive distribution in lung tissues, it plays a critical role in the pathogenesis and treatment of asthma. Activation of β2 adrenergic receptors results in an increase in intracellular cAMP levels, which in turn activates protein kinase A. The activation of protein kinase A leads to relaxation of smooth muscles, particularly the relaxation of bronchial smooth muscles. This effect aids in the dilation of airways, reduction of respiratory resistance, and improvement of ventilation capacity. In asthma patients, the bronchial smooth muscles are more sensitive to various stimuli, causing airway constriction. Activation of β2 adrenergic receptors helps to mitigate this airway constriction and improve breathing by promoting the relaxation of the bronchial smooth muscles. Therefore, β2 adrenergic receptor agonists are commonly used medications for the treatment of asthma. β2 agonists are divided into two categories: short-acting and long-acting. Short-acting β2 agonists are primarily used for emergency relief to quickly alleviate acute asthma symptoms. Long-acting β2 agonists are usually used for the long-term control of asthma and can help prevent the occurrence of symptoms. More than half of the drugs that target β2 adrenergic receptors worldwide, either in clinical research or approved for clinical use, are related to the treatment of asthma. This includes asthma, chronic obstructive pulmonary disease (COPD), mild asthma, allergic asthma, and more. In addition to the development of non-selective or selective agonists targeting β2 adrenergic receptors alone, β2 adrenergic receptors are often paired with other asthma targets for the development of combination formulations. Common combinations include those with GR (glucocorticoid receptors), mAChRs (muscarinic acetylcholine receptors), H1R (histamine receptor 1), β1AR (beta-1 adrenergic receptors), DRDs (dopamine receptors), and others. Combination asthma medications are designed to control asthma symptoms more comprehensively through different mechanisms of action. Compared to single-component β2 agonists, combination asthma medications better meet patients' needs and offer a more comprehensive treatment effect. Inhaled corticosteroids: Inhaled corticosteroids (such as fluticasone, budesonide, etc.) are commonly used drugs for controlling asthma inflammation. They can reduce the inflammatory response within the airways and decrease mucus production, thereby helping to alleviate airway obstruction. Leukotriene modifiers: For example, montelukast is a leukotriene modifier that can block the actions of leukotrienes, reducing the inflammatory response and lowering airway hyperresponsiveness. Some combination asthma medications combine these different types of drugs to simultaneously relieve asthma symptoms through multiple pathways. Such combinations can enhance therapeutic efficacy to some extent, reduce the frequency of medication use, and improve patient compliance.