Overview of New Drugs Approved Globally in May 2019

In May 2019, the first batch of new drugs globally was mainly concentrated in the United States, the European Union, China, and Russia, totaling eight.

Among them, the U.S. Food and Drug Administration (FDA) approved one new molecular entity (NME), Alpelisib, for the treatment of breast cancer; and one newly approved biologic product, Onasemnogene abeparvovec, for the treatment of spinal muscular atrophy.

The European Medicines Agency (EMA) approved one new molecular entity, volanesorsen, for the treatment of familial chylomicronemia syndrome; and approved one biological product, autologous CD34+ cells encoding the βA-T87Q-globin gene, for the treatment of β-thalassemia.

The National Medical Products Administration (NMPA) approved two new molecular entities: PEG-Loxenatide for the treatment of type 2 diabetes and Benvitimod for the treatment of psoriasis vulgaris; it also approved one new monoclonal antibody, Camrelizumab, for the treatment of Hodgkin lymphoma.

Russian Ministry of Health (RMH): First New Monoclonal Antibody, Netakimab for the Treatment of Psoriasis

1. Alpelisib

Alpelisib, developed by Novartis and marketed under the brand name Piqray®, was approved by the FDA on May 24, 2019, for the treatment of HR-negative, HER2-negative, PIK3CA-mutated breast cancer in postmenopausal women and men. Additionally, alpelisib is currently in Phase III clinical trials for head and neck cancer, Phase II clinical trials for advanced non-small cell lung cancer, Phase I/II clinical trials for multiple myeloma, colorectal cancer, and esophageal cancer, Phase I clinical trials for rectal cancer, and preclinical studies for meningioma [1].

Breast cancer is the most common malignancy in women, with approximately 1.5 million women diagnosed globally each year. In 2015, around 570,000 women worldwide died from breast cancer, accounting for 15% of all cancer-related deaths in women [2]. PI3K kinase mutations promote tumor development and metastasis. The PI3K-AKT-mTOR signaling cascade is a key regulator of angiogenesis and can upregulate metabolic activity in tumor cells.

Alpelisib is a phosphatidylinositol 3-kinase (PI3K) inhibitor that primarily targets PI3Kα. It inhibits tumor growth by suppressing the phosphorylation activity of PI3Kα on downstream targets [3].

The approval of alpelisib was based on a Phase III clinical trial (NCT02437318, SOLAR-1), which enrolled a total of 572 patients with HR-positive, HER2-negative breast cancer. The median progression-free survival (PFS) for alpelisib combined with fulvestrant versus fulvestrant alone was 11.0 months (95% CI: 7.5–14.5) and 5.7 months (95% CI: 3.7–7.4), respectively; the overall response rates (ORR) were 35.7% and 16.2%, respectively [3].

2. Onasemnogene abeparvovec

Onasemnogene abeparvovec, developed by AveXis (acquired by Novartis), was approved by the FDA for marketing on May 24, 2019, for the treatment of spinal muscular atrophy (SMA), under the brand name Zolgensma® [4].

Spinal Muscular Atrophy (SMA) is a rare genetic disorder characterized by progressive muscle weakness and paralysis. Without treatment, most children with severe SMA will either become permanently dependent on mechanical ventilation for survival or ultimately die by the age of two [5]. In the United States, approximately 450 to 500 infants with SMA are born each year, necessitating early diagnosis and intervention to prevent irreversible loss of motor neurons [6].

Zolgensma® contains adeno-associated virus serotype 9 (AAV9) encoding the gene for human survival motor neuron (SMN) protein, with a cytomegalovirus enhancer and chicken β-actin hybrid promoter as regulatory elements. Zolgensma® treats SMA by transfecting cells to express normal SMN protein [7,8].

Clinical trials supporting the approval of Zolgensma® (N=15) demonstrated that after 24 months of treatment, one patient in the low-dose group (N=3) achieved permanent ventilation. Although no patients in the high-dose group (N=12) achieved permanent ventilation, all survived. Patients in the low-dose group were unable to sit, stand, or walk without support. In contrast, in the high-dose group, nine patients (75.0%) could maintain a sitting position for more than 30 seconds without support, and two patients (16.7%) could stand and walk without assistance [8].

3. Volanesorsen

Volanesorsen, developed by Akcea Therapeutics (a subsidiary of Ionis), was approved by the EMA for marketing on May 3, 2019, as an adjunct to diet in adult patients with familial chylomicronemia syndrome (FCS), under the brand name Waylivra® [9].

Familial Chylomicronemia Syndrome (FCS) is an extremely rare, debilitating disease. This condition is caused by impaired lipoprotein lipase (LPL) function, leading to acute pancreatitis and chronic complications such as long-term organ damage. It is estimated that there are approximately 3,000 to 5,000 patients with FCS worldwide, including over 1,000 in Europe [10].

Volanesorsen is an antisense oligonucleotide that binds to apoC-III mRNA, inducing its degradation and inhibiting the synthesis of apoC-III [11].

The APPROACH trial in patients with familial chylomicronemia syndrome (FCS) demonstrated that the least squares (LS) mean percentage change in triglyceride levels was -77% in the treatment group versus 18% in the placebo group, indicating effective reduction of lipid levels. The open-label extension study, APPROACH Open Label, is currently ongoing [11].

4. Autologous CD34+ cellsencoding βA-T87Q-globin gene

Zynteglo®, the autologous CD34+ cells encoding the βA-T87Q-globin gene developed by Bluebird Bio, was approved for marketing by the EMA on May 29, 2019, for the treatment of β-thalassemia [12].

Normal human hemoglobin is composed of two α-globin chains and two β-globin chains. Beta-thalassemia results from defects or mutations in the gene encoding β-globin, leading to reduced synthesis of β-globin. The excess α-globin forms inclusion bodies that induce erythrocyte apoptosis. The global incidence of this disease is 1/100,000, while in the European Union it is 1/10,000. The condition is most prevalent in countries and regions such as Cyprus (incidence rate of 14%), Sardinia (10.3%), and Southeast Asia [13]. Currently, the main treatment options are long-term transfusion combined with iron chelators, and hematopoietic stem cell transplantation; however, these approaches are limited by issues such as iron overload and difficulties in HLA matching, respectively.

Zynteglo® is a gene-modified autologous CD34+-enriched cell product containing hematopoietic stem cells (HSCs) transduced with the BB305 lentiviral vector (LVV) carrying the βA-T87Q-globin gene. After infusion into the body, the gene-modified CD34+ HSCs migrate to the bone marrow and differentiate into normal red blood cells expressing the βA-T87Q-globin [14].

The approval of Zynteglo® was based on four clinical trials involving 32 patients with non-β0/β0 transfusion-dependent beta-thalassemia (TDT). Two Phase I/II clinical trials (HGB-204 and HGB-205) demonstrated that 11 patients achieved transfusion independence (TI), with a median hemoglobin level of 10.51 g/dL (range: 9.3–13.2) during the TI period. For the three patients who did not achieve the clinical endpoint of TI, there were varying degrees of improvement in transfusion volume and frequency. In two ongoing Phase III clinical trials (HGB-207 and HGB-212), a total of 18 patients with non-β0/β0 TDT received Zynteglo® treatment. Among them, five entered the efficacy evaluation phase, and four achieved TI. For the one patient who did not achieve TI, transfusion volume and frequency decreased by 75.8% and 74.9%, respectively [14].

5. Camrelizumab

Camrelizumab, developed by Jiangsu Hengrui Medicine, was approved for marketing by the NMPA in May 2019 under the brand name Airuol® for the treatment of relapsed/refractory classical Hodgkin lymphoma (cHL) in patients who have received at least two prior lines of systemic therapy. Furthermore, clinical studies are ongoing for its use in various solid tumors and other indications, including relapsed or metastatic nasopharyngeal carcinoma, advanced esophageal cancer, advanced hepatocellular carcinoma, relapsed or refractory extranodal NK/T-cell lymphoma (nasal type), non-small cell lung cancer, advanced urothelial carcinoma, gynecologic malignancies, soft tissue sarcoma, gastroesophageal junction cancer, metastatic colorectal cancer, and small cell lung cancer [15].

Hodgkin Lymphoma (HL) is a distinct malignant disease of the lymphatic system, with a higher prevalence in males than females, exhibiting a male-to-female ratio of 1.3:1 to 1.4:1. In developed Western countries, the age of onset typically shows a bimodal distribution, with peaks at 15–39 years and after 50 years of age; whereas in East Asian regions, including China, the age of onset is predominantly between 30 and 40 years, showing a unimodal distribution. Classical Hodgkin lymphoma accounts for approximately 90% of HL cases [16].

Camrelizumab is a humanized monoclonal antibody targeting programmed cell death protein 1 (PD-1). By binding to PD-1, it blocks the inhibitory effect of PD-1 ligands on T cells, thereby enhancing the tumor-killing activity of T cells.

In an open-label, single-arm, randomized, multicenter Phase II clinical trial (CTR20170500, NCT03155425, SHR-1210-II-204), 75 patients aged 18 years or older with relapsed or refractory classical Hodgkin lymphoma (cHL) who had undergone autologous hematopoietic stem cell transplantation (auto-HSCT) or received ≥2 lines of systemic chemotherapy and were ineligible for hematopoietic stem cell transplantation were enrolled. Camrelizumab demonstrated robust efficacy in relapsed or refractory cHL, with an objective response rate (ORR) of 84.8% and a complete response (CR) rate of 30.3% as assessed by independent review committee (IRC), along with a significant reduction in tumor burden of target lesions. The investigator-assessed ORR and CR rates were 80.3% and 36.4%, respectively. Monotherapy with camrelizumab exhibited a favorable safety profile in patients with relapsed or refractory cHL, with adverse events being tolerable [17].

6. PEG-Loxenatide

PEG-Loxenatide (polyethylene glycol loxenatide), developed by Jiangsu Hansoh Pharmaceutical, was approved by the NMPA in May 2019 for the treatment of type 2 diabetes under the brand name Fulai Mei® [18].

China has a large population of individuals with diabetes, predominantly type 2 diabetes, while type 1 diabetes and other types are less common. According to the 2013 national survey, the prevalence of type 2 diabetes was 10.4%, higher in males than females (11.1% in males vs. 9.6% in females). The glucagon-like peptide-1 receptor (GLP-1R) is one of the primary targets for developing diabetes medications [19].

PEG-Loxenatide is a long-acting GLP-1 receptor agonist prepared by amino acid modification and polyethylene glycol (PEG)ylation based on the structure of exenatide.

Published Phase II clinical trial results showed that, compared with the placebo group, the changes from baseline in glycated hemoglobin (HbA1c, %) were −1.01, −1.34, and +0.12 in the 100 μg, 200 μg, and placebo groups, respectively; the proportions of subjects achieving HbA1c <7% were 50.0%, 60.5%, and 11.1%, respectively. Common adverse reactions were mild to moderate, dose-dependent gastrointestinal events [20].

7. Benvitimod

Benvitimod was approved by the NMPA in May 2019 for the topical treatment of mild-to-moderate stable plaque psoriasis in adults, under the brand name Xinbik® [21, 22].

Psoriasis, commonly known as "psoriasis vulgaris" or colloquially as "cowhide ringworm," is primarily characterized by erythematous skin lesions covered with white scales, and is noted for its tendency to recur and its chronic course. Approximately 1%–3% of the global population is affected by psoriasis. Among these cases, plaque psoriasis (psoriasis vulgaris) accounts for approximately 96%. The specific etiology of psoriasis remains unclear; it is generally believed to be associated with genetic factors, infections, metabolic disorders, immune dysfunction, and endocrine disturbances [23].

Benvitimod is a tyrosine protein kinase inhibitor that exerts its therapeutic effects by inhibiting T-cell tyrosine protein kinases, thereby interfering with or blocking the release of cytokines and inflammatory mediators, T-cell migration, and skin cell activation.

The Phase III clinical study (CTR20130379) demonstrated that 51.2% of patients in the benvitimod group achieved a ≥75% improvement in the Psoriasis Area and Severity Index (PASI75), compared with 37.9% in the calcipotriol group and 14.5% in the placebo group (p<0.001). Furthermore, 32.6% of patients in the benvitimod group achieved PASI90 after 3 months, versus 20.1% in the calcipotriol group (p<0.001) and 3.5% in the placebo group (p<0.001). The proportions of patients achieving an Investigator’s Global Assessment (PGA) score of 0 or 1 (clear or almost clear) were 66.3% in the benvitimod group and 63.9% in the calcipotriol group, nearly twice that of the placebo group (33.5%, p<0.010). Follow-up after discontinuation of benvitimod showed that 29 patients (49.2%) did not experience relapse, while 30 patients (50.8%) experienced relapse, with a median time to relapse of 36 weeks [24].

8. Netakimab

Netakimab, developed by Biocad, was approved by the Russian Ministry of Health (RMH) in May 2019 for the treatment of moderate-to-severe plaque psoriasis under the brand name Efleira® [25]. Netakimab is the first domestically developed monoclonal antibody drug marketed in Russia, and its development process has received significant attention from the RMH.

Netakimab is a chimeric IgG1 monoclonal antibody targeting IL-17, in which the heavy chain variable region (VH) is replaced by VHH from alpaca (Lama glama) featuring longer CDR regions [26]. IL-17 is an inflammatory cytokine that plays a crucial role in the body’s defense against bacterial and fungal infections [27]. However, overexpression of IL-17 can cause inflammatory damage, leading to autoimmune diseases such as psoriasis, psoriatic arthritis, rheumatoid arthritis, and systemic lupus erythematosus [28].

A multicenter Phase III clinical trial (BCD-085-7/PLANETA) conducted in Russia and Belarus enrolled 213 patients with moderate-to-severe psoriasis, with a treatment period and follow-up duration totaling three years. At the 12-week follow-up after treatment completion, 83.3% of patients achieved a 75% improvement in the Psoriasis Area and Severity Index (PASI 75), and one-third of patients achieved complete skin clearance. Biocad stated that with the market launch of netakimab, the cost of treating severe psoriasis would decrease by 25–30% [29].

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*Disclaimer: This article was written by an author contributing to Sina Medical News. The views expressed are solely those of the author and do not represent the position of Sina Medical News.