Vibegron: a ß3-adrenergic agonist for the treatment of overactive bladder.

Overactive bladder (OAB) is an extremely common condition in adults of both sexes. It is characterized by an urgent need to micturate often accompanied by incontinence. The condition may also increase the number of micturitions in a 24-hour period as well as nocturia. The syndrome is not due to a urinary infection or other obvious pathology. In terms of drug treatment of OAB, there are two main approaches. One is the use of anticholinergic drugs that reduce the effect of the parasympathetic nervous system on the bladder. The other involves the use of drugs that are agonists at ß3-adrenergic receptors in the bladder. These drugs increase the capacity of the bladder and cause reductions in the number of daily micturitions and nocturia and also importantly reduce the frequency of urinary urgency and urinary urgency incontinence. Vibegron is the second ß3-adrenergic agonist to be approved for the treatment of OAB.

Remimazolam: a short-acting benzodiazepine for procedural sedation.

The ultra-short-acting opioid analgesic remifentanil provided the approach that was used in the synthesis of remimazolam. A carboxylic ester was incorporated into the benzodiazepine structure providing a resultant compound that is rapidly broken down in the body into a breakdown product that is inactive, thus ensuring a very short-acting benzodiazepine. Remimazolam is highly selective in its action, only having activity at the GABAA receptor. It has been shown to be highly effective in providing sedation for bronchoscopy and colonoscopy without having a prolonged duration of action, therefore having a short effect until patients are fully awake and ready for discharge.

Satralizumab: an interleukin-6 (IL-6) receptor antagonist for the treatment of neuromyelitis optica spectrum disorders.

Neuromyelitis optica spectrum disorders (NMOSD) consist of a rare autoimmune disorder in which patients suffer from relapses that affect the optic nerve, spinal cord or brainstem. Few have a full recovery. NMOSD is more common in women, the age of onset being around 30-40 years of age depending on race. The prevalence of the condition varies from 0.5-4.4 per 100,000 population. About 80% of patients have antibodies directed against the aquaporin-4 (AQP4) protein that form membrane-bound water transporters in the central nervous system (CNS). This protein is highly expressed in those areas of the CNS often targeted in NMOSD relapses. Satralizumab is a humanized monoclonal antibody that binds to the interleukin-6 (IL-6) receptor and thus inhibits IL-6 signaling. Two recent phase III studies have demonstrated that satralizumab significantly reduced the relapse rate in NMOSD by 76-79%. This beneficial effect was apparently confined to patients who have anti-AQP4 antibodies and satralizumab did not reduce the rate of pain or fatigue in NMOSD patients.

Apomorphine hydrochloride: a sublingual tablet for the OFF episodes in Parkinson's disease.

Parkinson's disease is one of the commonest neurodegenerative disorders, particularly in those over 60 years of age. Although the introduction of levodopa was a tremendous advance in its treatment, the condition is a progressive one. It has been found that the longer patients have the condition and are treated with levodopa, the more likely they are to develop OFF episodes in which their ability to do things becomes increasingly limited. The development of a sublingual apomorphine hydrochloride film (APL-130277, Kynmobi) was designed to alleviate this OFF condition by allowing the patients to experience rapid relief of their OFF episodes up to 5 times a day.

Bempedoic acid: effect of ATP-citrate lyase inhibition on low-density lipoprotein cholesterol and other lipids.

Bempedoic acid is a new, first-in-class oral ATP-citrate lyase (ACLY) inhibitor that has to be converted to its CoA thioester before it inhibits ACLY. This conversion only occurs in the liver and not in skeletal muscle. This may explain why, unlike the statins, bempedoic acid does not cause myalgia. Bempedoic acid given at a dosage of 180 mg orally once daily produces a highly significant reduction in low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol, total cholesterol, apolipoprotein B and importantly also in high-sensitivity C-reactive protein. It has recently been approved by both the Food and Drug Administration (FDA) and the European Commission for use in adult patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease who require additional lowering of LDL-C, and for the treatment of adults with primary hypercholesterolemia (heterozygous familial and nonfamilial) or mixed dyslipidemia, respectively.

Drospirenone: a novel progestogen used as an oral contraceptive without an estrogen component.

Drospirenone (DRSP) was synthesized as an analogue of spironolactone with the aim of producing a fourth-generation progestogen that differed from earlier progestogens in that it had antiandrogenic and little or no androgenic activity and lacked estrogenic effects while retaining some antimineralocorticoid activity. Since then, DRSP has been included in several oral contraceptive preparations together with an estrogen. However, increasing evidence has demonstrated that DRSP 4 mg on its own inhibits ovulation. It was thus a logical development to determine the efficacy of a tablet that only included DRSP 4 mg as an oral contraceptive. This proved successful and this product has now been approved by the Food and Drug Administration (FDA).

Istradefylline: adenosine A2A receptor antagonist to reduce "OFF" time in Parkinson's disease.

Parkinson's disease (PD) is an extremely common degenerative disease with a progressive course. Unfortunately, the longer patients are treated with levodopa, the more likely they are to suffer from increasingly long periods of immobility or "OFF" time. For over 30 years Kyowa Kirin Co., Ltd. (formerly Kyowa Hakko Kirin Co., Ltd.) has been researching the possibility of finding drugs that affect adenosine receptors and that can be used successfully as additional drugs in the treatment of PD. Istradefylline is an adenosine A2A receptor antagonist that significantly reduces the "OFF" time and improves the motor function of patients with PD, as measured by the Unified Parkinson's Disease Rating Scale (UPDRS) Part III, while increasing the time without troublesome dyskinesia. It was approved for use in PD in Japan in 2013 and in the United States in 2019.

Risankizumab.rzaa: an interleukin monoclonal antibody antagonist binding to the p19 subunit of human IL-23 cytokine.

Plaque psoriasis is the commonest form of psoriasis affecting about 85% of those patients with the condition. Risankizumab was developed as a high-affinity humanized monoclonal antibody specific for the p19 subunit of interleukin-23 (IL-23p19). Clinical trials demonstrated that risankizumab was very effective in patients with moderate to severe plaque psoriasis causing total clearing of the condition as evidenced by Psoriasis Scalp Severity Index (PSSI100) and static Physician's Global Assessment (sPGA) of 0 in more than 50% of patients after 52 weeks of treatment. Risankizumab has been approved by the Food and Drug Administration (FDA) for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy as a dose of 150 mg administered by subcutaneous injection at week 0, week 4 and every 12 weeks thereafter.

Contraceptive vaginal ring containing segesterone acetate and ethinyl estradiol: long-acting, patient-controlled, procedure-free, reversible prescription birth control.

The Food and Drug Administration (FDA) approved on August 10, 2018, a soft, reusable, flexible silicone ring (56 mm diameter) containing segesterone acetate and ethinyl estradiol as the first contraceptive vaginal ring (CVR) that can be used for a year and that is totally under the control of the woman using it. The vaginal ring releases segesterone and ethinyl estradiol at estimated rates of 150 mcg/day and 13 mcg/day, respectively. The CVR is inserted into the upper two-thirds of the vagina and left in place for 21 days, then removed for 7 days. The same ring can be used for 13 cycles for a total of a year's contraception. The CVR was found to be 97.5% effective in preventing pregnancy with a Pearl Index of 2.98. The adverse effects in women using the ring were similar in nature and frequency to those reported during the use of other hormonal contraceptives. The one exception was the occurrence of venous thromboembolism, which was reported more often than expected. Because of this, the FDA has required a postmarketing study to determine the true incidence of this adverse effect. The CVR was developed by the Population Council, is known as Annovera, and will be marketed by TherapeuticsMD in the U.S.

Tafamidis: a selective transthyretin stabilizer to treat wild-type ATTR amyloidosis and hereditary ATTR amyloidosis with cardiomyopathy.

Plasma protein transthyretin (TTR) can undergo conformational change resulting in the formation of amyloid fibrils that can then cause amyloidosis. This can occur spontaneously in individuals over the age of 70-80 resulting in wild-type transthyretin amyloidosis (ATTR) (with cardiomyopathy). This then progresses to fatal cardiac failure. TTR can also undergo conformational change in individuals who have a genetic abnormality in the structure of TTR resulting in hereditary ATTR amyloidosis. This is usually first manifested as polyneuropathy but can progress to cardiomyopathy with time. Until recently, there has been no specific treatment for these conditions. However, a detailed search for compounds that stabilize TTR resulted in the discovery of tafamidis. This compound stabilizes TTR and has been found to significantly reduce the progression of both wild-type ATTR amyloidosis and hereditary ATTR amyloidosis.

Estradiol vaginal inserts (Imvexxy): effective in genitourinary syndrome of menopause without increasing systemic estrogen levels.

Many women suffer from the genitourinary syndrome of the menopause (GSM), in particular pathological changes that occur in the vagina due to the reduction in their production of estrogens. TherapeuticsMD has developed Imvexxy, small softgel capsules that contain solubilized estradiol and that are inserted vaginally by women twice a week, every 3 to 4 days. These vaginal inserts have been found to readily supply estradiol to the vagina and to result in significant improvement in the GSM signs and symptoms these women had been experiencing. At the same time, pharmacokinetic studies have demonstrated that the small doses of estradiol used do not increase systemic blood levels of estrogens above baseline values, thus greatly reducing the likelihood of unwanted systemic effects of estradiol. The placebo used in clinical trials, which only contained the 'inactive' ingredients in Imvexxy, had partial efficacy, the result either of a placebo effect or of the use of MIGLYOL 812 N to keep the estradiol in solution.

Tildrakizumab: monoclonal antibody against IL-23p19 for moderate to severe psoriasis.

Tildrakizumab is a monoclonal antibody that binds to the p19 subunit of interleukin (IL)-23. Studies examining affected skin in psoriatic patients showed significant changes in the cellular, cytokine and gene expression profiles of psoriatic lesions as a result of treatment with tildrakizumab, as well as significant changes in clinical measures of disease activity. These studies demonstrated significant clinical responses in psoriasis with significant improvements found in the percentage of patients achieving a Physician Global Assessment score of 0 or 1, and a 75%, 90% or 100% improvement in the Psoriasis Area and Severity Index (PASI 75, PASI 90, PASI 100). These changes were accompanied by a low frequency of adverse effects. This combination of efficacy and safety led to the approval of tildrakizumab in 2018 by the U.S. Food and Drug Administration (FDA) for use in adult patients with moderate to severe psoriasis.

Guselkumab: human monoclonal antibody against interleukin-23 for moderate to severe psoriasis.

Guselkumab is an antibody designed to bind to the p19 subunit of interleukin-23 (IL-23). Detailed studies of affected skin in patients with psoriasis demonstrated that guselkumab induced significant changes in the cellular, cytokine and gene expression profiles of psoriatic lesions accompanied by significant changes in clinical measures of disease activity. The significant clinical response in psoriasis was demonstrated in these studies by significant improvement as reflected in the percentage of patients achieving a Physicians Global Assessment score of 0 or 1, and a 90% or 100% improvement in the Psoriasis Area and Severity Index (PASI 90, PASI 100), as well as changes in quality of life measures. These changes were accompanied by a low frequency of adverse effects. The combination of efficacy and safety led to its approval by the Food and Drug Administration (FDA) for use in patients with moderate to severe psoriasis.

Dupilumab: human monoclonal antibody against IL-4Rα for moderate to severe atopic dermatitis.

Atopic dermatitis (AD) is one of the most common skin disorders with a prevalence of about 20% in children and affecting adults in significant numbers. Moderate to severe AD significantly impairs a patient's quality of life with severe pruritus as a major issue that impairs sleep and contributes to major psychological disturbances. Detailed studies of its pathogenesis have revealed that immune mechanisms are involved including activation of T helper type 2 cells (Th2). Dupilumab is a fully human Ig4 monoclonal antibody directed against the interleukin-4 receptor subunit α (IL-4Rα) of IL-4 and IL-13 receptors. In clinical studies it has been demonstrated to significantly reduce the molecular signature in the skin of patients with AD and to significantly reduce the clinical manifestations of moderate to severe AD. It also very importantly significantly reduces the pruritus of moderate to severe AD thus improving the patients' quality of life. Dupilumab is administered by subcutaneous injection every other week. It was approved by the FDA in March 2017 for the treatment of moderate to severe AD.

Nusinersen: antisense oligonucleotide to increase SMN protein production in spinal muscular atrophy.

Patients with spinal muscular atrophy (SMA) have an autosomal recessive disease that limits their ability to produce survival motor neuron (SMN) protein in the CNS resulting in progressive wasting of voluntary muscles. Detailed studies over several years have demonstrated that phosphorothioate and 2'-O-methoxyethyl- modified antisense oligonucleotides (ASOs) targeting the ISS-N1 site increase SMN2 exon 7 inclusion, thus increasing levels of SMN protein in a dose- and time-dependent manner in liver, kidney and skeletal muscle, and CNS tissues only when administered intrathecally. On a dose basis, nusinersen was found to be the most potent ASO for SMN2 splicing correction in the CNS of adult mice. After nusinersen was found to increase levels of SMN protein in the CNS of mice and subhuman primates without causing significant adverse events, it was advanced into clinical studies in patients with SMA. These trials in SMA patients have demonstrated significant improvements in various measures of motor function and in progression to movement developments not normally seen in SMA patients. In addition, there have been significant extensions in life expectancy. These findings led to the U.S. and European approval of nusinersen for use in SMA patients of all ages.

Crisaborole: Phosphodiesterase inhibitor for treatment of atopic dermatitis.

Atopic dermatitis (AD) is an extremely common condition affecting as many as 10-20% of children and 2-10% of adults. A particularly distressing symptom of AD is pruritus. One of the important aspects of AD is inflammation associated with increased activity of phosphodiesterase 4 (PDE4), resulting in decreased intracellular levels of cyclic adenosine monophosphate, which in turn causes increased production of inflammatory cytokines. Crisaborole was developed as a small-molecule, boron-based, selective PDE4 inhibitor that can be used topically. Clinical trials have demonstrated its efficacy in treating patients with mild to moderate AD, resulting in significant relief of pruritus. Unlike PDE4 inhibitors that act systemically, crisaborole does not cause significant gastrointestinal adverse effects. The most common adverse effect has been temporary stinging and burning in about 4% of patients upon application of the 2% ointment. To date there is no evidence of atrophy, telangiectasia or hypopigmentation resulting from its use. Crisaborole is the first topically applied PDE4 inhibitor to be approved by the FDA for use in AD.

Nebivolol/valsartan: Fixed-dose combination for treatment of hypertension.

Clinical trials demonstrated that a fixed-dose combination (FDC) of the beta-blocker nebivolol (5 mg) and the angiotensin II antagonist valsartan (80 mg) produced a significant reduction of both diastolic and systolic blood pressure in patients with hypertension. Both nebivolol and valsartan contributed to this effect, partial additivity of 86.6% and 82.2% being observed for diastolic and systolic blood pressure, respectively. These values are very similar to the additivity ratios of other recently approved FDCs for hypertension. Use of the FDC nebivolol 5 mg/valsartan 80 mg formulation was associated with a low incidence of treatment-related adverse effects and of serious adverse effects. There was no evidence of adverse effects due to beta2-adrenoceptor blockade. The FDC (Byvalson) was approved and launched in 2016 in the U.S. for the treatment of hypertension.

Deutetrabenazine: Treatment of hyperkinetic aspects of Huntington's disease, tardive dyskinesia and Tourette syndrome.

Deutetrabenazine is a derivative of tetrabenazine in which two trideuteromethoxy groups substitute two methoxy groups. The active metabolites of deutetrabenazine have a longer half-life than those of tetrabenazine, together with a greater overall absorption. However, the peak plasma concentrations are lower. Because of these pharmacokinetic differences, deutetrabenazine can be given twice daily, thus improving compliance. The lower peak concentrations may account for a lower incidence of some unwanted adverse effects. Unlike tetrabenazine, deutetrabenazine has no effect on the QT interval. Treatment with deutetrabenazine significantly improved chorea in Huntington's disease, the hyperkinetic features of tardive dyskinesia, and tics in Tourette syndrome. In all three conditions, deutetrabenazine produced an acceptable level of overall adverse effects without causing any severe adverse effects.

Lifitegrast: First LFA-1/ICAM-1 antagonist for treatment of dry eye disease.

Dry eye disease is an extremely common condition affecting millions worldwide. The underlying pathophysiological mechanism is thought to be localized inflammation of the ocular surface resulting in the localization of T cells at this surface followed by their activation and subsequent liberation of cytokines. This effect on T cells results from the binding of lymphocyte function-associated antigen-1 (LFA-1) located on T cells to intercellular adhesion molecule 1 (ICAM-1) expressed on inflamed epithelium and endothelium, and on T cells. Lifitegrast is a T-cell integrin antagonist designed to mimic ICAM-1, thus blocking the interaction of LFA-1 and ICAM-1. Lifitegrast enters the systemic circulation to a limited extent thus reducing the likelihood of unwanted systemic reactions. Clinical trials in over 2,500 subjects with dry eye disease have shown that 5.0% lifitegrast given by ocular instillation causes a significant reduction in objective and subjective signs and symptoms of the disease. These beneficial effects are associated with a relatively low incidence of unwanted effects, almost all local in nature. In light of these findings, lifitegrast was approved by the Food and Drug Administration (FDA) in 2016 for the treatment of dry eye disease, the first drug with this mechanism of action to be so approved.

Sebelipase alfa: enzymatic replacement treatment for lysosomal acid lipase deficiency.

Sebelipase alfa was approved for use in 2015 for patients suffering from lysosomal acid lipase deficiency in either of its two forms. The more severe, early-onset form, Wolman disease, occurs in young infants in whom it is normally fatal within the first year of life. Sebelipase alfa has allowed a small number of such infants to achieve a relatively normal growth rate and to survive for 2 or more years. In older children and adults, the enzyme has corrected their dyslipidemia and produced significant improvement in markers of hepatic function. Important unanswered questions remain, such as to what extent treatment with sebelipase alfa alters the long-term cardiovascular and hepatic consequences of this rare recessive genetic disorder. Further research is also required to determine the true frequency of the disorder in different populations and ethnic groups. The high cost of treatment with sebelipase alfa also poses a very significant obstacle for many health plans.