Overview of Global approval of New drugs in July 2019

In July 2019, the world’s first approval of new drugs was concentrated in the United States. The FDA (US Food and Drug Administration) approves three new molecular entity drugs (NME), such as selinexor, which is used for the treatment of multiple myeloma. Cilastatin sodium/imipenem/relebactam, a new compound drug for the treatment of complex urinary tract infections (including pyelonephritis) and complex abdominal infections, in which relebactam was approved as NME for the first time; darolutamide in the treatment of castrated prostate cancer.


Developed by Karyopharm Therapeutics, Selinexor was approved by the FDA priority review on July 3, 2019, the product name is Xpovio®. The drug is used in multiple myeloma that is still ineffective for at least two proteasome inhibitors or two immunomodulators and CD38 monoclonal antibodies after four treatments. In 2014, selinexor was qualified as an orphan drug for FDA and EMA, respectively. In addition, selinexor is also in the clinical stage of liposarcoma and endometrial cancer, metastatic breast cancer, small cell lung cancer, metastatic prostate cancer, squamous cell carcinoma, bone marrow dysplasia and other diseases.

According to the National Cancer Institute (NCI), multiple myeloma is the second highest incidence of blood cancer in the United States. There are 130000 patients in the United States, with 32000 new cases each year. At present, patients will still have recurrence after receiving a variety of treatment, and there are no effective treatment measures. It is estimated that 13000 patients will die of multiple myeloma in the United States in 2019.

Selinexor can inhibit the nuclear export process of tumor inhibitory protein (TSPs), growth regulator and Oncogene protein mRNA by binding to nuclear export protein receptor XPO1. The inhibition of XPO1 eventually led to the accumulation of TSPs in the nucleus and the down-regulation of c-myc and cyclin D1, which induced cell cycle arrest and apoptosis. In vitro, selinexor also showed apoptosis-promoting effects on multiple myeloma cell lines, tumor samples from patients and mouse xenotransplantation models.

Selinexor was approved based on a phase II clinical trial, STORM (KCP-330-012; NCT02336815), in which 122 patients were treated with selinexor (80 mg) combined with dexamethasone (20 mg) twice a week. Of these, 83 patients were still recurrent after previous fourth-line treatment. The main end point ORR (total remission rate) was 25.3%. The median first response time was 4 weeks and the median duration was 3.8 months.

Cilastatinsodium/imipenem/relebactam, developed by Merck, was approved by FDA on July 16, 2019, for the treatment of complex urinary tract infections (cUTI, including pyelonephritis) and complex abdominal infections caused by certain Gram-negative bacteria (cIAI). The product is called Recarbrio®. Among them, relebactam was approved for the first time as a form of NME.

Complex abdominal infection is usually caused by gastrointestinal perforation caused by the spread of infection, including appendicitis, cholecystitis, abdominal abscess and peritonitis, clinical treatment options include surgery and antibiotics. Complex urinary tract infection is characterized by abnormal structure and function of genitourinary system, which is mainly treated with antibiotics. However, antibiotic resistance is becoming a difficult problem in the treatment of multi-pathogenic microbial infection, and the development of new antimicrobial agents is urgent.

Recarbrio® is a compound preparation consisting of penicillene drug imipenem, renal dehydrodipeptidase inhibitor cilastatin and β-lactamase inhibitor relebactam. Cilastatin can inhibit the metabolism of imipenem in kidney and has no antibacterial activity in itself.Imipenem interferes with the synthesis of cell wall by binding to penicillin binding proteins PBP 2 and PBP 1B of Enterobacteriaceae and Pseudomonas aeruginosa (Pseudomonas aeruginosa). Relebactam also has no antibacterial activity, but acts as an enzyme inhibitor to protect imipenem from degradation of some types of serine β-lactamases.
The approval of Recarbrio® is based on previous data on the clinical efficacy and safety of imipenem/cilastatin. The contribution of relebactam to efficacy is mainly reflected in vitro and animal model tests. Recarbrio® randomized, blind, positive controlled multicardial trials for cIAI and cUTI and pyelonephritis provided only limited data on efficacy and safety.

  • Darolutamide


Darolutamide was approved by FDA on July 30, 2019 for the treatment of non-metastatic castrated resistant prostate cancer. (nmCRPC), trade name is Nubeqa®. The drug was first developed by Orion, and in June 2014, Bayer was authorized to develop and commercialize the drug for prostate cancer.
In 2018, 1.2 million of prostate cancer was diagnosed worldwide and 358000 died. Prostate cancer mainly occurs in men over 50 years old. Surgery, radiotherapy and hormone suppression are common clinical treatments. However, there is still recurrence after hormone suppression therapy, manifested as castrated resistant prostate cancer (mCRPC). In 2019, it is estimated that more than 73000 of American men will be diagnosed with mCRPC. About 40% of the patients were accompanied by high levels of prostate specific antigen (PSA) and the cancer cells did not spread to other parts of the body, namely nmCRPC. Within 2 years, about one third of nmCRPC patients will develop metastatic cancer.

Darolutamide is a non-steroidal androgen receptor (AR) inhibitor through competitive inhibition of androgen binding, nuclear transfer of AR and AR-mediated transcription. In vitro test and mouse xenotransplantation model, darolutamide could reduce the proliferation of prostate cancer cells in vitro and the size of mass in mouse transplantation model.
Darolutamide was approved based on a multicenter, double-blind, placebo-controlled phase III clinical trial, ARAMIS (NCT02200614). The main outcome measures were metastasis-free survival time (MFS), that is, obvious metastasis or death within 33 weeks after admission to the last scan. The median MFS was 40.4 months in the treatment group and 18.4 months in the control group (p< 0.0001). The overall survival rate of the secondary index, OS, was immature, and the progress of pain was delayed compared with the placebo group. In addition, the blood-brain barrier transmittance of Darolutamide is low, and the side effects are small, which provides more drug options for the clinical treatment of nmCRPC.