01 Nervous system drugs
The drug paroxysmal sleep disease of nervous system is a kind of chronic nervous system disease which makes people weak, which is characterized by excessive daytime sleepiness (EDS) and the inability to regulate sleep wake cycle normally. It is estimated that one in 2,000 people in the United States has paroxysmal sleep sickness, which is usually first developed in childhood or adolescence. γ- Hydroxybutyrate (GHB, sodium hydroxybutyrate) is the standard treatment for paroxysmal sleep disease. GHB is a natural neurotransmitter and neuromodulator, and it is suspected that GABAB can be stimulated and dopaminergic neurons can be inhibited through proprietary receptors. Large randomized clinical trials have shown that GHB can control all the main symptoms of paroxysmal sleep disorders, including sudden fall, EDS, irresistible sleep and nocturnal sleep disorders. Last year, FDA approved the Xywav oral solution developed by Jazz Pharmaceuticals Public Limited Company, a new GHB preparation for the treatment of sudden falls or EDs in patients 7 years old and older. Compared with the drugs previously listed, Xywav contains the same concentration of hydroxybutyrate, but the sodium content is 92% lower than the drug already on the market, which significantly reduces the amount of sodium taken by patients when taking hydroxy acid salt treatment drugs, which may help patients to meet the standards recommended by the American Heart Association.
Calcitonin gene-related peptide (CGRP) is a vasodilator neuropeptide composed of 37 amino acids. CGRP is widely distributed in the central and peripheral nervous system and cardiovascular system. In these systems, CGRP plays a series of biological effects and physiological functions, and plays an important role in the pathophysiological mechanism of migraine, including neuroregulation and vasodilation. Anti CGRP monoclonal antibodies and CGRP receptor antagonists are the latest therapies for migraine. Three such drugs have been launched in 2018. Last year, three other drugs were approved and all of them were listed in the United States, namely, anti CGRP monoclonal antibody Eptinezumab (Vyepti; H. Lundbeck A/S) and small molecule CGRP antagonist Ubrogepant (Ubrelvy; Allergan) and Rimegepant (Nurtec; Biohaven). Monoclonal antibodies must be administered by injection, while small molecule antagonists have the advantage of oral administration.
The first new drug, 5-HT1F receptor agonist, lasmiditan succinate (Reyvow; Eli Lilly) is a new neuroactive anti migraine drug (NAAMA). Previous generations of anti-migraine drugs were involved in the mechanism of action of vasoconstriction, and NAAMA drugs can play a role without causing vasoconstriction. Lasmiditan can selectively target 5-HT1F receptor in trigeminal pathway. In October 2019, the drug was approved by FDA for acute treatment of adult migraine (with or without aura).Eli Lilly and Company has launched the drug in early 2020 after it was reviewed by the Drug Enforcement Administration (DEA).
Sanbexin is a new fixed dose compound preparation containing free radical scavenger Edaravone and D-camphenol. It is developed by Simcere Pharmaceutical Group for the Chinese market. The curative effect of the compound preparation in patients with acute ischemic stroke is significantly higher than that of Edaravone monotherapy. Last year, the company was approved for listing in China.
Kynmobi is a new sublingual membrane of apomorphine, a standard anti-parkinson drug. It was approved in the United States last year for the treatment of short-term (acute) and intermittent “off period” attacks in patients with Parkinson’s disease. Developed by Synovion and funded by the Michael J. fox Parkinson’s disease research foundation (MJFF), this new fast acting preparation has provided a convenient way for patients to quickly improve their motor disorders and better control their motor symptoms when necessary.
Cenobamate (Xcopri) is a new anticonvulsant drug discovered and developed by SK Biopharmaceuticals of South Korea. It was launched in the United States in May last year and its indication is adult partial seizures. The drug exerts anti-convulsant effect through a dual mechanism: Cenobamate can not only inhibit the continuous flow of sodium ions into cells through voltage-gated sodium channels, but also can act as an allosteric regulator of non-benzodiazepine GABAA channels. The efficacy and safety of Cenobamate were studied in clinical trials worldwide, including two randomized, double-blind, placebo-controlled studies (study 013 and study 017) and a large, multicenter, open safety study (study 021). All three studies enrolled adult patients with uncontrolled focal epilepsy who were taking 1-3 other antiepileptic drugs at the same time. In the randomized study, compared with placebo, Cenobamate significantly reduced the frequency of seizures, and up to 1/5 patients achieved zero seizures during maintenance treatment.
Fenfluramine, an amphetamine derivative, has been on the market for decades as a treatment for adult obesity, but it has been withdrawn from the market due to serious side effects (including pulmonary hypertension, valvular heart disease and myocardial fibrosis) and abuse tendency. However, during clinical application, it has been found that low-dose Fenfluramine was very effective in the treatment of severe spastic diseases (such as Dravet syndrome and Lennox Gastaut syndrome), and had good risk benefit characteristics. Although it is known that Fenfluramine can regulate the activity of serotonin in the brain, its mechanism in the treatment of epilepsy remains unclear. Fenfluramine not only interferes with the storage of 5-HT in neuronal vesicles, but also inhibits the reuptake of 5-HT. The dosage of the drug in the treatment of epilepsy is much lower than that previously used for appetite suppression, and studies have shown that it is safe and effective in young patients with Dravet syndrome. In June 2020, based on two studies involving 202 subjects aged 2-18, FDA approved Fenfluramine hydrochloride (Fintepla；Zogenix) is used to treat Dravet syndrome patients ≥ 2 years old. These studies measured changes in seizure frequency from baseline. In both studies, the reduction in seizure frequency during the trial was significantly lower in the Fenfluramine group than in the placebo group. A decrease in seizure frequency was observed at 3-4 weeks of treatment and maintained for 14-15 weeks. Fenfluramine has been identified as an orphan drug for the treatment of Dravet syndrome.
Anti-CD20 monoclonal antibody ofatumumab (Kesimpta; Genmab/Novartis) was approved in the United States last year for the treatment of adult relapsing multiple sclerosis (MS), including clinically isolated syndrome, relapse remission MS and active secondary progressive MS. MS is a new indication of orfamuzumab, which was launched in 2009 and was initially used for the treatment of chronic lymphoblastic leukemia.
Another good news for MS patients is that ozanimod (Zeposia; Bristol-Myers Squibb Company), an agonist of sphingosine 1-phosphate receptor (S1PR1 and S1PR5) has been approved for listing in the United States. The drug is the third drug on the market to alleviate the condition of MS with this relatively new mechanism. It is suitable for the treatment of adult multiple sclerosis, including clinical isolated syndrome, relapse remission MS and active secondary progressive MS. The same indication of the drug has been approved in the European Union.
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease, which mainly occurs in childhood, involving motor neurons in spinal cord and brain stem. SMA is a rare disease, which has been found all over the world. The incidence rate of live births in this disease is about 1/11,000, and the carrying rate is about 1/50. No drug was approved for this indication five years ago. It was not until FDA approved the first SMA treatment drug in 2017 that this situation changed. The drug, nusinersen, is an antisense oligonucleotide, which can enhance the expression of SMN2 gene on the full length of SMN protein. It is suitable for the treatment of type I spinal muscular atrophy. In 2019, Onasemnogeneabeparvovec, the first gene replacement therapy for SMA, was approved in the United States. In 2020, the third therapeutic drug of SMA has been approved; the drug is risdiplam (Evrysdi) developed by Genentech Inc., which is a small molecule oral drug of SMN2 splicing modifier. The drug was approved based on data from two clinical studies designed to broadly represent patients with SMA: the FIREFISH study in symptomatic infants 2-7 months of age (NCT02913482) and the SUNFISH study in children and adults 2-25 years of age (NCT02908685). In both studies, Risdiplam improved motor function in patients of all ages and different severity (types I, II and III). The drug has helped baby patients get rid of permanent dependence on ventilators and has given them the ability to sit and stand without support.
Muscular dystrophy (MD) is a group of congenital neuromuscular diseases with heterogeneity in clinical symptoms, genetics and biochemistry. It is characterized by progressive muscle atrophy and muscle weakness (starting from the micro changes of muscle); at present, more than 30 kinds of MD have been found, the most common type is Duchenne muscular dystrophy (DMD). The initial symptoms of DMD patients (usually male, aged 3-5 years) are lower extremity muscle weakness, pseudohypertrophy of gastrocnemius and typical gait instability. Most of the patients begin to use wheelchairs in early adolescence; many patients die in late adolescence or early adulthood. Children’s intellectual development and academic performance may be damaged to a certain extent. Ten years ago, no drug for any type of MD was approved in any country. Since Ataluren was launched in 2014, the prospects of patients with DMD and their families have rapidly improved; at present, there are five kinds of such drugs on the market. In 2020, a new member of the drug family, Viltalarsen (Viltepso; Nippon Shinyaku) was approved in Japan in March and launched in Japan in May. As the first exon skipping therapy drug developed for Japanese market, Viltalaren is suitable for the treatment of DMD patients with confirmed DMD gene mutation and suitable for exon 53 skipping therapy. Viltalarsen was approved and launched in the United States in the second half of 2020. It is the first and only DMD drug for children under 4 years old.
Neuromyelitis Optica Spectrum Disorders (NMOSD), also known as Devic’s disease, is a rare chronic autoimmune disease with the main symptoms of optic neuritis (optic neuritis) and myelitis (myelitis) and involving the brain and spinal cord. Optic neuritis can cause pain and loss of vision, while myelitis may affect some or all of the motor, sensory and autonomic nervous functions of the lower part of the body. According to the U.S. organization for rare diseases, 1-10 out of every 100,000 people in the world suffer from NMOSD. In NMOSD patients, the positive rate of AQP4 antibody is about 80%. These anti AQP4 autoantibodies are secreted by CD19 + B cells and mainly bind to astrocytes in the central nervous system. It is generally believed that anti-AQP4 antibody can form membrane attack complex after binding with nerve cells of central and peripheral nervous system, thus causing damage to optic nerve, spinal cord and brain tissue. Until 2019, treatment options for patients with the disease were limited to immunosuppressants or corticosteroids. In 2019, Eculizumab, a complement inhibitor, was approved for the treatment of NMOSD; In 2020, two new drugs has been approved.
In June 2020, FDA approved the humanized anti-CD19 monoclonal antibody Inebilizumab (Uplizna) developed by Viela Bio, Inc. for the treatment of adult NMOSD patients with positive anti-AQP4 antibody. The treatment plan is maintenance treatment after initial administration, twice a year. Part of the reason for the drug’s approval is based on the results of a key, placebo-controlled n-momentum study (NCT02200770) worldwide involving 213 anti AQP4 antibody positive patients and 17 anti AQP4 antibody negative patients. This study has shown that Inebilizumab can significantly reduce the risk of NMOSD attack, thus reaching the primary endpoint. Specifically, at 6 months of treatment, 89% of patients in the anti AQP4 antibody positive group did not relapse, compared with 58% in the placebo group. Inebilizumab also yielded significant benefits in key secondary endpoints, including a reduction in the number of hospitalizations associated with NMOSD. In addition, the drug has good safety and tolerability characteristics. Inebilizumab has been certified as an orphan drug and breakthrough therapy and has been available in the United States in the summer of 2020.
Also in June, regulatory agencies in Japan and Canada approved the anti-interleukin-6 receptor (IL-6R) monoclonal antibody Aatralizumab (Enspring; Chugai/Genentech). As monotherapy or as an additional therapy based on immunosuppressive therapy, it is used to treat AQP4 IgG seropositive NMOSD adult and adolescent patients. The FDA subsequently approved Satralizumab in August. Satralizumab is the only approved drug targeting and inhibiting the activity of IL-6 receptor in the treatment of NMOSD. It is believed that Satralizumab plays an important role in the treatment of NMOSD related inflammation. Compared with the traditional technology, the new recycling antibody technology can prolong the duration of antibody recycling, and the administration scheme is subcutaneous once every four weeks. Satralizumab was first listed in Japan in August 2020.
Neurofibromatosis type 1 (NF1) is another rare hereditary disease of the nervous system. The first drug for the disease was approved in 2020. NF1 is caused by a mutation in a gene called NF1 on chromosome 17, which affects one in every 2,500-3,000 newborns. NF1 gene is responsible for regulating the production of neurofibroma protein, which is considered to be a tumor suppressor. The disease is characterized by multiple benign tumors of the skin and nerves, i.e. plexiform neurofibroma (PN), and abnormal pigmentation on the surface of the skin. NF1 patients may also have macrosomia and/or relative short stature, as well as other abnormal symptoms, such as epilepsy, learning and attention deficit, speech difficulties, and skeletal abnormalities. There may be great individual differences in the range and severity of related symptoms and other abnormal manifestations. Although most NF1 patients have normal intelligence, about 50% of the affected children have learning disabilities. In April 2020, FDA approved the MEK1/2 inhibitor Selumetinib sulfate (Koselugo; AstraZeneca/MSD) is used to treat children with NF1 who have symptoms and whose plexiform neurofibroma cannot be resected surgically. This is the first drug approved for the treatment of NF1 PN. The drug was approved based on the positive results of sprint stratum 1 phase II study. The results showed that the total response rate (ORR) was 66% (n = 33 / 50) in children with symptomatic NF1 and unresectable plexiform neurofibroma treated with Selumetinib twice daily. ORR was defined as the proportion of patients who confirmed complete or partial remission (tumor volume reduction of at least 20%). 33 patients with remission were confirmed to have achieved partial remission. The drug was identified as an orphan drug in the United States, and was launched immediately after approval.