09 Endocrine drugs
Eli Lilly’s Lyumjev is a fast-acting insulin used to improve blood glucose control in adults with type 1 and type 2 diabetes. It was approved in the European Union, Japan and the United States last year. Lyumjev is a new formulation of insulin lispro (marketed under the trade name of Humalog since 1996), which aims to accelerate the absorption of insulin into the blood and reduce the level of glycosylated hemoglobin (HbA1C). The approval of the drug is based on the data from the Phase III studies PRONTO-T1D and PRONTO-T2D. These two studies were randomized, positive-controlled and standard treatment studies (NCT03214367 and NCT03214380) comparing Lyumjev and Humalog in adult patients with type 1 and type 2 diabetes, respectively. Both studies reached the primary end point, which was medication at meals. At the 26th week of treatment, Lyumjev was non-inferior to Humalog in terms of A1C reduction relative to baseline. In addition, the trial adjusted the key endpoint indicators to perform multiple tests, including the comparison of blood glucose changes one hour after a meal and two hours after a meal. In the two studies, the Lyumjev group had higher blood glucose peak drops at 1 hour and 2 hours after the study meal was ingested than in the Humalog group. In the phase III study, Lyumjev and Humalog had similar in safety and tolerability. Lyumjev was first launched in Japan in June.
The triple oral hypoglycemic drug TrijardyXR (enpagliflozin/linagliptin/metformin) was approved by the FDA in January 2020 to improve the blood glucose control of adult patients with type 2 diabetes based on diet and exercise. The drug was jointly developed by Boehringer Ingelheim and Eli Lilly. It is a sustained-release tablet, each containing an SGLT-2 inhibitor, a DPP-IV inhibitor and metformin. The drug has been on the market in the first quarter of 2020.
In August 2020, after submitting a public application, Novartis’s product octreotide acetate (Sandostatin) was approved in Japan for a new indication for the treatment of congenital hyperinsulinemia-related hypoglycemia. Newborns and infants are the main patients with this rare disease. In Japan, 25-30 children suffer from this disease every year, and the children suffer from severe hypoglycemia due to excessive insulin secretion. In addition to glucose infusion and liquid diet, the treatment can also be given by oral diazoxide and other drugs; if such treatment is ineffective, pancreatectomy may be required. The Japanese Society of Pediatric Endocrinology held a meeting for the treatment of unapproved drugs and off-label drugs for diseases whose medical needs are far from being met. After the review, Novartis was encouraged to develop drugs for this new indication.
Cushing’s syndrome is a rare endocrine disease with multiple system symptoms. Its pathogenesis is the excessive secretion of the adrenal hormone cortisol or cortisol-like glucocorticoids, which leads to long-term and excessive exposure of body tissues to these hormones, and in turn causes pathological changes. In early 2020, both the EC and FDA approved the 11β-hydroxylase (CYP11B1) inhibitor Osilodrostat (Isturisa; Recordati Rare Disease Company) for the treatment of Cushing’s syndrome in adults. CYP11B1 is an enzyme that plays a role in the last step of adrenal cortisol synthesis. Osilodrostat was launched in France in June 2020 and was recognized as an orphan drug in both markets.
Somapacitan (Sogroya) is a long-acting human growth hormone (hGH) analog developed by Novo Nordisk. It was approved for marketing in the United States in September 2020. Somapacitan is used as a replacement therapy for endogenous growth hormone to treat adult growth hormone deficiency. Unlike previous growth hormone (GH) replacement therapy, which must be administered daily, Somapacitan only needs to be administered by subcutaneous injection once a week. The efficacy of the drug was confirmed in the REAL1 study (NCT02229851). The study was a randomized, double-blind, placebo-controlled phase III trial in 301 patients with growth hormone deficiency who have never received GH treatment or have stopped other GH preparations treatment at least three months before the study. Patients were randomly assigned to receive Somapacitan injections (once a week), placebo injections (once a week), or growth hormone (another FDA-approved growth hormone, once a day). The effectiveness of the study drug was determined by the percentage change in trunk fat. Trunk fat refers to the fat that accumulates in the trunk or the central area of the body, which is regulated by GH and may be associated with serious medical problems. At the end of the 34-week treatment period, patients who received Somapacitan each week had a 1.06% reduction in trunk fat mass, while the placebo group had an increase of 0.47%.
About 40% of Graves disease patients suffer from thyroid Ophthalmopathy (TED), also known as Graves Ophthalmopathy or Graves orbital disease. Patients with this type of disease manifest as inflammation of the fatty tissue and muscles around the eyes, leading to protruding eyes. For a long time, the only treatment for TED was corticosteroid therapy, and the route of administration was oral or periorbital injection. Last year, Teprotumumab (Tepezza; Horizon Therapeutics), the first anti-insulin-like growth factor-1 receptor (IGF-1R) monoclonal antibody specifically designed to treat TED, was approved for marketing in the United States. Teprotumumab was originally developed as a potential anti-tumor drug. The reason for the development of this drug for TED indications is that it has been found that fibroblasts, T cells and B cells in the orbit of TED patients can upregulate the IGF-1R signaling pathway, leading to overexpression of IGF-1R.
The progesterone receptor agonist Dinagest (Dinagest; Mochida Japan) was approved for marketing in Japan last year for the treatment of dysmenorrhea, a new indication. Dienogest has been used to treat endometriosis since its launch in 2008, and it has been used to relieve pain caused by Adenomyosis since 2016. Dienogest can selectively activate progesterone receptors, thereby inhibiting ovarian function and the proliferation of endometrial cells.
In May 2020, AbbVie and NeurocrineBiosciences announced that the FDA has approved their new combination product Oriahnn (elagolix/estradiol/norethindrone acetate capsules, packaged as elagolix capsules), and the approved treatment lasted up to 24 months. Oriahnnn is the first oral, non-surgical treatment approved by the FDA for the treatment of menorrhagia associated with uterine fibroids in premenopausal women. Oriahnn would be launched in the United States in June 2020.
Last year, EvofemBiosciences’ Phexxi (lactic acid, citric acid and potassium bitartrate) vaginal gel formulation was also approved for marketing in the United States as an on-demand contraceptive method for fertile women. Phexxi is the first contraceptive and it does not contain hormones, can be used on demand and can adjust the vaginal pH. Phexxi can maintain the vaginal pH within the normal range of 3.5-4.5. This acidic environment is not suitable for sperm survival.
10 Dermatology drugs
The cytokine signaling pathway mediated by Janus kinase/signal transducer and activator of transcription (JAK/STAT) is related to the pathogenesis of a variety and increasing number of immuno-inflammatory diseases (including atopic dermatitis). Last year, Janus kinase inhibitor Delgocitinib (Corectalim; Coretim; Japan Tobacco/Torii Pharmaceutical) was approved for marketing in Japan as a local treatment for atopic dermatitis. This is the first drug to treat the disease with such a mechanism of action. Soon afterwards, Eli Lilly’s JAK1/2 inhibitor Baricitinib (Olumiant) was also approved in the EU and marketed in the UK for new indications for the treatment of moderate to severe atopic dermatitis. The drug was once approved for marketing as a rheumatoid arthritis drug.
In August 2020, the androgen receptor inhibitor Clacoterone (Winlevi; Cassiopea) was approved by the US FDA. The drug is the first acne treatment drug with a new mechanism of action in 40 years. Kracotone acts on the androgen receptor in the area of acne, which is contained in both men and women. This androgen receptor inhibitor can inhibit the role of these hormones in promoting sebaceous gland secretion and inflammation. The drug is expected to be launched in the United States in early 2021.
The microtubule inhibitor Tirbanibulin (Klisyri) was approved by the FDA in mid-December 2020 for the treatment of actinic keratosis (AK) in the face or scalp area. AK is a kind of precancerous lesion with high prevalence. In the United States, AK is the second most common disease diagnosed in dermatology. The approval was based on data from two pivotal, randomized, double-blind, vehicle-controlled Phase III studies (the KX01-AK-003 and KX01-AK-004 studies). These two studies evaluated the effectiveness and safety of Tirbanibulin ointment in 702 adult patients with actinic keratosis of the face or scalp area (NCT03285477 and NCT03285490). On the 57th day of treatment, patients in the Tirbanibulin treatment group had significantly more cases of complete clearance of AK lesions in the face or scalp area than in the vehicle group. In the KX01-AK-003 study, 44% of patients in the Tirbanibulin treatment group observed complete clearance of the lesion, while this ratio was only 5% in the vehicle group. In the KX01-AK-004 study, 54% of patients in the Tirbanibulin treatment group observed complete clearance of the lesion, compared to 13% in the vehicle group. The most common adverse events were pruritus and pain at the site of local application. The incidence in the two groups was 9% and 10%, respectively. The drug will be launched in the United States in the first quarter of 2021 by the developer Athenex and its development and distribution partner Almirall.
According to data reported by the International Hyperhidrosis Society, approximately 365 million people worldwide (equivalent to 5% of the global population) suffer from hyperhidrosis (excessive sweating). Hyperhidrosis is mainly divided into two types: primary focal hyperhidrosis refers to hyperhidrosis that is not caused by other diseases or side effects of drugs, and the hyperhidrosis is a typical sweating site (armpits, hands, feet, head and face); secondary systemic hyperhidrosis refers to excessive sweating over a large area of the body caused by a certain disease or treatment. Last year, Japan approved the anticholinergic drug Sofpironium bromide (Ecclock; Kaken), providing a new treatment option for hyperhidrosis patients. Acetylcholine causes sweating by binding to muscarinic receptors in sweat glands. Sofpironium bromide inhibits the binding of acetylcholine to receptors by competitively binding with muscarinic receptors in eccrine glands that cause hyperhidrosis, thereby reducing sweating. This product is a gel preparation and is directly applied to the armpit area once a day. It is the first medicine used to treat the disease in Japan.
Hereditary angioedema (HAE) is a rare, autosomal dominant genetic disease characterized by sudden onset, severe localized subcutaneous and submucosal edema without itching, which may involve any skin or mucosal surface, including face, arms, legs, hands, feet, genitals, gastrointestinal tract and throat. he most common pathogenesis of HAE is the lack of antigenic and functional C1 esterase inhibitor (C1-INH) in plasma. The inhibitor is a naturally occurring molecule in the human body and has an inhibitory effect on plasma Kallikrein and other serine proteases in the blood. Kallikrein is a key enzyme in the inflammatory cascade and has been identified as an important therapeutic target for HAE. Plasma Kallikrein can release bradykinin, which is a molecule that promotes the penetration of local body fluids from blood vessels into tissues and can cause swelling and pain associated with HAE. In early December 2020, the FDA approved BioCryst’s plasma Kallikrein inhibitor Berotralstat hydrochloride (Orladeyo) for the prevention of HAE attacks in adults and children above 12 years. Berotralstat was HAE’s first approved once-a-day oral preparation, and it was on the market within a few weeks after approval.
Pyoderma gangrenosum (PG) is a rapidly progressing inflammatory skin disease, divided into ulcer type, bullous type, pustular type, proliferative type and periostoma type. Ulcerative PG is the most common type, manifested as lower limb pain, pustules, papules and nodules, especially in the calf area, and can progress further to form raised ulcer skin lesions with infiltration on the edges. The process of ulcer formation is accompanied by severe pain, which is known to severely affect the quality of life of patients. Last year, AbbVie and Eisai’s anti-TNF-α monoclonal antibody Adalimumab (Humira) was approved in Japan for the treatment of pyoderma gangrenosum. Adalimumab has been on the market for more than a dozen indications. However, this approval marks that Adalimumab has become the world’s first drug for the treatment of PG. This indication was approved based on data from a phase III trial in Japan for patients with active ulcers with PG who were diagnosed with PG but were ineffective or unsuitable for local treatment. At the 26th week of dosing, 54.5% (12/22) of the patients reached the primary endpoint, that is, pyoderma gangrenosum ulcer area reduction (PGAR) reached 100% (target PG ulcer healed completely). Among patients receiving study drug treatment, the most common adverse drug reaction was bacterial skin infection. For this indication, Adalimumab is recognized as an orphan drug in Japan. According to reports, the annual incidence of PG in Japan is 0.3 per 100,000.