Global approval of new drugs in December 2019
Release date: 2020-01-14 Views: 0
In December 2019, the first global approval of new drugs was concentrated in the United States and China. The U.S. Food and Drug Administration (FDA) has approved five new molecular entities (NMEs): Golodirsen for Duchenne muscular dystrophy, Lumateperone for schizophrenia, and Lemborexant for insomnia , Brilliant Blue G for inner limiting membrane staining, Ubrogepant for migraine. The National Drug Administration (NMPA) approved one NME drug: Remimazolam Tosylate for sedation. In addition, the FDA approved two new biological products, Enfortumab Vedotin for urothelial cancer and Fam-trastuzumab deruxtecan for HER2-positive metastatic breast cancer. NMPA approved one monoclonal antibody: Tislelizumab for the treatment of Hodgkin's lymphoma; approved one new vaccine: Human papillomavirus 16/18 vaccine recombinant bivalent (Xiamen Innovax) for the prevention of human papilloma virus infection and cervical cancer.
Golodirsen was developed by Sarepta Therapeutics and approved by the FDA on December 12, 2019 under the trade name Vyondys 53® for the treatment of Duchenne muscular dystrophy (DMD)  .
DMD is the most common X-chromosome-associated genetic disease, which is characterized by progressive muscle atrophy and is accompanied by cardiac and respiratory complications. It is caused by the loss of anti-dystrophin caused by mutations in the DMD gene, which can disrupt the reading frame of the anti-dystrophin transcription process  .
Vyondys 53® is an antisense oligonucleotide of the diphosphophosphate morpholino oligomer (PMO) subclass, which can target the mRNA that binds to the dystrophin precursor, allowing the precursor mRNA to shear Exon 53 jumps in, producing a truncated but still functional anti-dystrophin dystrophin. PMO is a synthetic molecule in which the five-membered nucleofuranyl ring in natural DNA and RNA is replaced by a six-membered morpholino ring. Each morpholino ring is connected by an uncharged diaminophosphate moiety, and each diaminophosphate The morpholino subunits all contain a heterocyclic base in DNA  .
The approval of Vyondys 53® is based on an evaluation study of the efficacy of DMD patients. The first part of the study is a double-blind, placebo-controlled, dose titration experiment for 12 patients with DMD. The patients were tested in a 2: 1 ratio. Receive Vyondys 53® or placebo. The second part included 13 additional patients who had not been treated with the drug. In the study, by week 48, the average anti-dystrophin level of patients treated with Vyondys 53® increased from 0.10% (SD 0.07) of the normal value to 1.02% (SD 1.03) of the normal value. The increase was 0.92% (SD 1.01) of normal value (p <0.001); the median change was 0.88% of normal value  .
The accelerated approval of Vyondys 53® demonstrates that the FDA has recognized the urgent needs of patients with DMD. Currently Sarepta Therapeutics has approved two DMD exon skipping therapy drugs for marketing.
02 Enfortumab Vedotin
Enfortumab Vedotin was jointly developed by Agensys (a subsidiary of Astellas) and Seattle Genetics. It was approved by the FDA on December 18, 2019 and is marketed under the trade name Padcev3®.It is used to treat PD-1 or PD-L1 inhibition. Agent and platinum-containing chemotherapy for patients with locally advanced or metastatic urothelial cancer  .
Patients with advanced urothelial cancer have a poor clinical prognosis. Few patients can live more than 5 years after diagnosis. First-line chemotherapy based on cisplatin can improve overall survival. . After the failure of cisplatin-based first-line chemotherapy, there is no unified model for the further treatment of patients with locally advanced or metastatic urothelial cancer  .
Enfortumab vedotin is an antibody-conjugated drug that targets Bindingin 4. It consists of 3 parts: 1) recombinant fully human IgG1 kappa monoclonal antibody enfortumab; 2) cleavable linker molecule of mc-val-cit-PABC , Namely maleimidocaproyl-valyl-citrullinyl-p-aminobenzyloxycarbonyl type; 3) small molecule drug MMAE (monomethyl auristatin E). MMAE is coupled to the cysteyl of the monoclonal antibody via Linker, and the average ratio of DAR to the drug is 3.8: 1  .
Padcev® approval is based on a single-arm, multicenter clinical study. A total of 125 patients with locally advanced or metastatic urothelial cancer were included in this study. The objective response rate was 44% (35.1, 53.2) and the duration of response was 7.6 (6.3, NE).
Padcev® is the first antibody-conjugated drug approved for the treatment of locally advanced or metastatic urothelial cancer through the FDA accelerated approval program. It is an advanced urothelial cancer patient whose disease has progressed after receiving chemotherapy and immunotherapy Treatment offers a new paradigm.
Lumateperone was originally developed by Bristol-Myers Squibb. In 2005, development rights for the compound to treat neurological disorders were awarded to Intra-cellular. Lumateperone was approved by the FDA on December 20, 2019 for use in the treatment of adult patients with schizophrenia under the trade name Caplyta®  .
Lumateperone is a serotonin 2A receptor and dopamine D2 receptor antagonist. The specific mechanism of action is still unclear  .
Caplyta® approval is based on two four-week, randomized, double-blind, placebo-controlled, multicenter clinical studies. Study 1 enrolled 335 subjects, divided into Caplyta® 42 mg, Caplyta® 84 mg, and placebo. The results showed that patients treated with Caplyta® 42 mg had an average decrease in the PANSS index of 13.2 from the beginning to the 28th day, which was a significant decrease compared to the placebo group (7.4). A total of 450 patients included in Study 2 were randomized to Caplyta® 28 mg, Caplyta® 42 mg, or placebo. Results From the beginning to the 28th day, the average decrease in the PANSS index of patients treated with Caplyta® 42 mg was 14.5, which was significantly lower than that of the placebo group (10.3)  .
Schizophrenia is a chronic, lifelong, complex disease. Intra-cellular believes that Caplyta® will provide doctors with a new, safe and effective treatment for schizophrenia.
Lemborexant was approved by the FDA for marketing on December 20, 2019. It was developed and marketed by Eisai under the trade name Dayvigo®. It is used to treat adult insomnia patients who have difficulty initiating and maintaining sleep  .
Lemborexant is an orexin receptor antagonist that can block the binding of orexin A and B to its receptors OX1R and OX2R  .
Dayvigo® approval is based on two clinical studies in patients with sleep onset or difficulty maintaining sleep. Study 1 is a 6-month, randomized, double-blind, placebo-controlled, multicenter trial. The study subjects were adult patients who met the criteria for DSM-5 insomnia, and were randomly divided into the placebo group (n = 325), the Dayvigo® 5 mg group (n = 323), or the Dayvigo® 10 mg group (n = 323). As a result, the main efficacy indicators of the Dayvigo® 5 mg group and the Dayvigo® 10 mg group were 0.7 (0.6, 0.8) and 0.7 (0.6, 0.8), respectively. The ratio of sleep latency (sSOL) to the placebo group was significantly better than the placebo. group. Study 2 is a 1-month, randomized, double-blind, placebo, positive control, multicenter clinical trial. The study subjects were women over 55 years and men over 65 years who met the DSM-5 insomnia disorder criteria. The patients were randomly divided into placebo (n = 208), Dayvigo® 5 mg (n = 266), and Dayvigo® 10 mg Group (n = 269) or positive control group (n = 263). The main efficacy indicators of the Dayvigo® 5 mg and Dayvigo® 10 mg groups were 0.8 (0.7, 0.9) and 0.7 (0.6, 0.8) in the ratio of continuous sleep delay (LPS) to LPS in the placebo group, which was significantly better than the placebo group [ 10] .
Dayvigo® is the first drug approved by the FDA to report safety data within 12 months and data on sleep initiation and sleep maintenance efficacy within 6 months in key clinical data. At the same time, Eisai submitted new drug applications for Lemborexant in Japan (March 2019) and Canada (August 2019).
05 Fam-trastuzumab deruxtecan
Fam-trastuzumab deruxtecan was approved by the FDA for marketing on December 20, 2019. It was developed and sold by Daiichi Sankyo under the trade name Enhertu®. Treatment of adult patients with breast cancer  . Breast cancer is the leading cause of cancer-related deaths in women. The proto-oncogene HER2 / neu or its protein receptor HER2 is overexpressed in nearly 25-30% of breast tumors  .
Fam-trastuzumab deruxtecan is an antibody coupling drug targeting HER2, consisting of 3 parts: 1) recombinant humanized IgG1 kappa anti-HER2 monoclonal antibody trastuzumab; 2) cathepsin B cleavable tetrapeptide GGFG molecule Linker; 3) The payload is a camptothecin derivative with topoisomerase I inhibition. The payload is conjugated to the cysteyl of the monoclonal antibody via a linker, and the average ratio of DAR to the drug is 8  .
Enhertu® approval is based on a multicenter, single-arm experiment. A total of 184 women with HER2-positive, unresectable, or metastatic breast cancer were included in the trial. These patients received 2 or more anti-HER2 treatments. The median objective response rate was 60.3% (52.9, 67.4), and the median response duration was 14.8 (13.8, 16.9)  .
Fam-trastuzumab deruxtecan has been advancing all the way, and even directly challenged HER2-positive metastatic breast cancer that was not treated with HER2 target therapy drugs (trastuzumab, pertuzumab, and T-DM1). At the same time, Fam-trastuzumab deruxtecan has also shown very good results in the treatment of other HER2-positive tumors (such as gastric cancer and lung cancer)  .
06 Brilliant Blue G
Brilliant Blue G was approved by the FDA on December 20, 2019, and was developed by Dutch Ophthalmic Research under the trade name TissueBlue®. The drug can selectively stain the inner limiting membrane of the retina, but does not stain the preretinal membrane and the retina. After use, the membrane can be visualized for removal  .
Ubrogepant was approved by the FDA on December 23, 2019. It was developed and marketed by Allergan under the trade name Ubrelvy® for the treatment of acute migraine in adults. Ubrogepant was originally developed by Merck and licensed to Allergan in 2015  .
Ubrogepant is a calcitonin gene-related peptide (CGRP) receptor antagonist. Migraine is related to dysfunction of the trigeminal vascular system. CGRP is a related peptide released by trigeminal nerve fibers. It plays an important role in the pathophysiology of migraine and is the current target for the treatment of migraine  .
Ubrelvy® approval is based on two randomized, double-blind, placebo-controlled trials. The main efficacy analysis was performed in the treatment of patients with moderate to severe migraine. Efficacy was judged by its effect on freedom of pain and most annoying symptoms (MBS) two hours after administration. Pain freedom is defined as moderate to severe headache relief to pain, and MBS freedom is defined as MBS without awareness. Among patients with MBS, photophobia (56%) was most commonly followed, followed by phobia (24%) and nausea (19%). In Study 1, subjects who took Ubrelvy® 50 mg had a pain-free and MBS-free response rate that was 7.4% and 10.8% higher than those in the placebo group, and those who took Ubrelvy® 100 mg responded to both indicators. 9.4% and 9.9% higher than the placebo group, respectively. In Study 2, subjects who took Ubrelvy® 50 mg had a pain-free and MBS-free response rate that was 7.5% and 11.5% higher than the placebo group after 2 hours, respectively. In both studies, the therapeutic effect of Ubrogepant was significantly better than placebo  .
Ubrelvy® quickly eliminates the most annoying migraine symptoms in two hours. Unlike subcutaneous injections of Erumab-aooe, Ubrelvy® as an oral CGRP receptor antagonist will provide more treatment options for patients with acute migraine.
08 Remimazolam Tosyla te
Remazolam tosylate was approved by the NMPA in December 2019. It was developed and marketed by Jiangsu Hengrui under the trade name Rebinin® as a sedative injection for routine gastroscopy. Remazolam tosylate is a salt-forming compound of remazolam (developed by Paion, Germany), which has higher stability. The drug is a short-acting GABAa receptor agonist and is a benzodiazepine-type central nervous system drug  .
Gastroscopy is one of the most widely used methods of digestive endoscopy in clinical practice, but conscious gastroscopy often brings different degrees of pain and discomfort to the patient, and sedation with gastroscopy can eliminate or alleviate patients during the gastroscopy. Subjective pain and discomfort such as pain, nausea and vomiting can especially eliminate the patient's fear of re-examination, improve the patient's acceptance of gastroscopy, and at the same time create better conditions for diagnosis and treatment of endoscopic physicians  .
Remazolol tosylate for injection is the sixth innovative drug approved by Hengrui Medicine. The launch of this product will further consolidate its advantageous position in the field of surgical medicine and meet the needs of patients for comfortable diagnosis and treatment. In addition, the production of sedative indications for colonoscopy has been declared in August 2019, and has been included in the priority review process by NMPA due to its obvious therapeutic advantages.At the same time, the drug is also undergoing phase III of general anesthesia indications. Clinical Trials.
09 Tislelizumab (Tislelizumab)
Tislelizumab was approved by NMPA on December 27, 2019. It was developed by BeiGene and marketed under the trade name Baizeran®.It is used to treat classic Hodgkin that relapses or is refractory after receiving at least two previous treatments. Lymphoma. Tislelizumab is a IgG4-type monoclonal antibody that targets programmed death receptor 1 (PD-1). It binds to PD-1 on the surface of T cells and blocks cancer cells from immunosuppressing T cells through PD-1. Function  .
Classic Hodgkin's lymphoma usually has a good prognosis, but patients with relapsed / refractory classic Hodgkin's lymphoma still have difficulty obtaining long-term remission and survival. Reed-Sternberg cells of classic Hodgkin's lymphoma have 9p24.1 chromosomal abnormality, which leads to over-expression of programmed death ligand-1 (PD-L1) and programmed death ligand-2 (PD-L2) Combines with PD-1 on the surface of T cells to induce immune tolerance. PD-1 or PD-L1 antibodies can block the PD-1 / PD-L1 pathway, reverse immune tolerance, and exert antitumor effects  .
Baizean®'s approval is based on the results of a clinical trial of a single-arm, multi-center pivotal phase 2 clinical trial in China. Patients included in the study's efficacy analysis set had a follow-up period of at least 12 months and a median follow-up period of 14 months. The objective response rate (ORR) evaluated based on the Independent Review Committee (IRC) was 76.9%, of which the complete response (CR The rate is 61.5%  .
Baizeran® has achieved promising clinical results and safety results in the treatment of patients with relapsed or refractory classic Hodgkin lymphoma. People are also looking forward to its subsequent development in a series of other solid tumor and hematological indications.
10 Human papillomavirus 16/18 vaccine recombinant bivalent (Xiamen Innovax)
Recombinant human papilloma virus 16/18 type bivalent vaccine (Xiamen Wantai Canghai) was approved for listing by NMPA in December 2019. It was developed and marketed by Xiamen Wantai Canghai Biotechnology Co., Ltd. under the trade name Xinconin®. It is suitable for the prevention of human papillomavirus infection and cervical cancer in women aged 9-45 years  .
The drug is the first domestic human papillomavirus vaccine approved. Human papillomavirus vaccine (HPV) is commonly known as cervical cancer vaccine. There are currently three types of HPV vaccines that have been marketed globally. They are the bivalent vaccines for HPV16 and 18 produced by GlaxoSmithKline in the United Kingdom, and HPV6 for Merck in the United States. Tetravalent vaccines of types 11, 11, 16, 18 and nine-valent vaccines against HPV 6, 11, 16, 18, 31, 33, 45, 52, 58 types. The bivalent human papilloma virus vaccine (E. coli) approved this time is the first batch of HPV vaccines to be produced in China, and has been included in the national special new drug innovation and special support  .
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