12 Immunomodulators and immunotherapy drugs
AimmuneTherapeutautics has achieved an important goal this year: Palforzia (Arachishypogaea allergen powder-dnfp) was approved by the FDA and listed for the first time. Palforzia is an oral allergen immunotherapy used to relieve allergic reactions, including immediate allergic reactions in sensitive individuals due to accidental consumption of peanuts. In the United States, about 1 million children are allergic to peanuts, and only 20% of them are no longer allergic to peanuts as adults. Even if patients with such diseases take a small amount of peanuts, their immune system will treat them as harmful foreign objects and attack them. The onset time and symptoms of allergic reactions caused by peanuts are unpredictable, and some individuals can cause severe allergic reactions even when eating very small amounts of peanuts. Physical symptoms can appear within seconds of being exposed to peanuts and may include skin reactions (for example, hives, redness, or swelling), gastrointestinal discomfort or more dangerous allergic reactions， for example, spasm and narrowing of the throat and airway, and insufficient blood supply to vital organs of the body. Antihistamines and epinephrine can be used to treat allergic reactions, but severe allergic reactions can be fatal even with proper and timely treatment. Palforzia was approved by the FDA’s fast track, and was recognized as a breakthrough therapy. The product was approved by the EC later in the same year and is suitable for the treatment of patients with peanut allergy diagnosed in patients aged 4-17 years. At the same time, peanut diet should be avoided. According to EC approval, patients ≥18 years of age can continue to use Palforzia. The company is currently planning to launch the drug for the first time in Europe (Germany and the United Kingdom) in May 2021.
Imlifidase (Indfirix) is an immunoglobulin G (IgG) degrading enzyme derived from Streptococcus pyogenes, developed by Hansa Biopharma, and is the first innovative drug for desensitization treatment of kidney transplant patients. Last year, Imlifidase received conditional approval from the European Commission for the desensitization treatment of highly sensitive patients who need a kidney transplant but may undergo rejection. Imlifidase can specifically target IgG and inhibit IgG-mediated immune response. Using Imlifidase is a new method to eliminate pathogenic IgG. The drug has a rapid onset of action and can cleave IgG antibodies and inhibit their immune reactivity within 24 hours after administration. The product was identified as an orphan drug and was approved by the European Medicines Agency for PRIME.
In patients with advanced COVID-19, immune dysfunction is a serious and potentially life-threatening complication. In the early or exudative stage of the disease course, the permeability of the pulmonary blood vessels increases, causing the alveoli and Interstitium to be filled with protein-rich edema fluid, and at the same time, it can trigger an inflammatory response. Pro-inflammatory cytokines trigger the lung or systemic inflammatory response and further promote its release throughout the body. This condition is sometimes called a “cytokine storm” (28). Alveolar macrophages release certain cytokines (IL-6, IL-10 and TNF-α), these cytokines can recruit and activate neutrophils in lung tissue, leading to inflammatory mediators (leukotrienes, antioxidants, Platelet activating factor and neutrophil elastase) are further released. All these substances have harmful effects on capillary endothelium and alveolar epithelium, thereby destroying the epithelial barrier between capillaries and alveoli. As a result, the alveoli and Interstitium are filled with edema fluid, protein, and cell debris. In the resulting cascade of events, the alveolar surfactants are destroyed and the alveoli collapse, causing an imbalance (“mismatch”) of ventilation/blood perfusion, leading to hypoxemia. As the main driving factor of the cytokine storm in COVID-19, IL-6 and its receptor are one of the first therapeutic targets to treat and prevent this harmful cascade. Levilimab (Ilsira; Biocad) is a monoclonal antibody that targets the IL-6 receptor (IL-6R). It was approved for marketing in Russia last year to prevent cytokine storms in hospitalized patients with severe SARS-CoV-2 infection (COVID-19). It is the world’s first drug approved for the treatment of this indication.
Other immune preparations (including several vaccines) were approved last year for emergency treatment and prevention of COVID-19. See the last section of this review for details.
In May 2018, the Democratic Republic of Congo (DRC) reported the first two cases of Ebola virus disease to the WHO. On August 1 of the same year, the government officially announced a new Ebola outbreak. The epidemic was concentrated in the two remote and war-torn provinces of North Kivu and Ituri, making it difficult for epidemic prevention materials to enter the region. Despite this, medical staff and anti-epidemic materials were quickly dispatched and distributed to these two areas; the materials included the first experimental drugs and vaccines distributed in history. The DRC epidemic was the second major outbreak of Ebola that has been officially reported in history. After the epidemic lasted for nearly two years, the WHO finally announced the end of the epidemic on June 25, 2020. The final total number of cases counted was 3,470, and the death toll was 2,287.
During the DRC outbreak, two new Ebola vaccines were successfully developed and tested on-site, namely the ervebo vaccine developed by Merck, which was approved by the FDA in 2019, and the 2-dose combination vaccine program Zabdeno (Ad26.ZEBOV)/mvabea (MVA-BN-Filo), which was approved by the EC in 2020. The preventive program includes the first injection of Ad26.ZEBOV based on Janssen’s AdVac viral vector technology, and about 8 weeks later, the second injection of MVA-BN-Filo booster vaccine based on Bavarian Nordic’s MVA-BN technology. The program is suitable for active immunization of individuals one year old and above to prevent Ebola virus disease caused by the Zaire Ebola virus genus. The vaccine combination contains two vaccines, and two marketing authorization applications (MAA) have been submitted to EMA. These two MAAs are supported by the following research data: Eleven phase I, phase II, and phase III clinical studies evaluated the safety and immunogenicity of the vaccine in more than 6,500 adults and children 1 year and older in the United States, Europe, and Africa, as well as 18 preclinical studies and comparisons, and immune bridging analysis of the results of clinical and preclinical effectiveness studies. After the accelerated review of MAA and the positive evaluation of EMA CHMP, the vaccine combination was approved for marketing under a special review model. With this approval, Janssen was cooperating with WHO on vaccine pre-certification, which will help accelerate the registration of its Ebola preventive vaccine in African countries. The vaccine program will be used to support preventive vaccination in countries with the highest risk of outbreaks and other high-risk groups. These high-risk groups include medical staff, BSL4 laboratory staff, military personnel dispatched to work in epidemic areas, airport staff, and visitors to high-risk countries.
In addition to vaccines, a monoclonal antibody cocktail therapy called Inmazeb (atoltivimab/odesivimab/maftivimab) produced by Regeneron was approved by the FDA last year for the treatment of adults and children infected with Zaire Ebola virus. This included newborns born to mothers who have tested positive for the virus. The drug is composed of three monoclonal antibodies with similar structures that can bind to different non-overlapping epitopes on the Zaire Ebola virus glycoprotein. These three antibodies can block the Ebola virus from invading the patient’s cells and/or recruit other immune cells to target the virus-infected cells, and remove these cells from the body, thereby achieving the effect of neutralizing the Ebola virus. This was the first time the FDA has approved a drug specifically for the treatment of Ebola virus disease. The PALM study initiated at DRC in 2018 confirmed the effectiveness of Inmazeb. This was a randomized, multi-center, controlled study that enrolled 681 patients. In 2019, after a preset interim analysis showed that Inmazeb was superior to other active drugs in the study (ZMapp and Remdesivir) in reducing mortality, the PALM study was terminated early. According to part of the agreement announced in July 2020, Regeneron would provide the U.S. Biomedical Advanced Research and Development Administration (BARDA) with an agreed amount of inmazeb within 6 years as part of the U.S. Department of Health and Human Services’ emergency preparedness plan for public health incidents.
Just before Christmas, Regeneron Pharmaceuticals’ Ebanga (Ansuvimab) was approved by the FDA. The drug is a human monoclonal antibody that targets the glycoprotein of the Zaire Ebola virus and is used to treat adults and children infected with the Zaire Ebola virus. Ansuvimab’s mechanism of action is to block the binding of the virus to the cell receptor, thereby preventing the virus from invading the cell. Ansuvimab, previously named mAb114, is an antibody isolated from a human survivor after the Ebola outbreak in Kikwit City, DRC, in 1995. Scientists and co-investigators from the National Institute of Allergy and Infectious Diseases (NIAID) Vaccine Research Center found that the survivor had retained anti-Ebola antibodies 11 years after being infected with the Ebola virus. After the team successfully isolated the antibody from the survivor, it conducted experiments in laboratory and non-human primate studies and found that the antibody was the most effective, so they chose the most promising Ansuvimab for clinical trials. In addition, Ansuvimab also showed good efficacy in the PALM study. In this study, patients were randomly assigned to the treatment group and the control group. Compared with the control group, the survival period of the MAb treatment group was significantly prolonged. The FDA has granted the MAb Orphan Drug and Breakthrough Therapy designation, and has conducted priority review.
Another major progress made last year was the launch of TwinRab (Docaravimab and Miromavimab), a cocktail of monoclonal antibodies, as a preventive drug after rabies virus exposure. The product was developed by ZydusCadila in accordance with an agreement with the World Health Organization to develop new rabies prevention and treatment drugs, replacing rabies immunoglobulin (RIG) made from serum. The product was developed by ZydusCadila in accordance with an agreement with the World Health Organization to develop new rabies prevention and treatment drugs to replace rabies immunoglobulin (RIG) made from serum. The reason is that RIG has several shortcomings, including limited supply, high cost, and the possibility of serious adverse reactions. TwinRab consists of two antibodies that can bind to two different non-overlapping epitopes on the rabies virus glycoprotein. In a randomized, open phase III study, TwinRab showed non-inferiority and good safety characteristics compared with human rabies immunoglobulin.
Fluad Quadrivalent is a new seasonal flu vaccine developed by Seqirus. It was approved in the United States in February 2020 and will be launched in time for the 2020-2021 flu seasons. The vaccine is suitable for adults 65 years and older, because these people are very susceptible to serious diseases. The effectiveness of the vaccine may be reduced due to age-related decline in immunity, but the vaccine contains MF59 adjuvant, which can induce a stronger immune response in this age group.
The seasonal influenza vaccine BCHT LAIV (Ganfog®; nasal spray freeze-dried live attenuated influenza vaccine; Changchun Biotech) was approved by the National Medical Products Administration (NMPA, formerly known as CFDA) in February 2020. The vaccine does not require injection. It is developed using BioDiem’s live attenuated influenza vaccine technology and would be launched in China later in the same year.
Vaccination against human papillomavirus (HPV) is a proven strategy to prevent cervical cancer. Last year, Xiamen Wantai Canghai Biotechnology Co., Ltd. launched the recombinant HPV bivalent (16, 18) vaccine Cecolin, which was launched in China for the first time. Cecolin is suitable for women aged 9-45 to prevent HPV infection.
Another vaccine to be marketed for the first time in China is the new varicella-zoster virus (varicella) vaccine developed by Kexing Biological. The vaccine was approved by China’s NMPA at the end of 2019 and would be launched in the first half of 2020. It is suitable for children aged 1-12 to prevent varicella-zoster virus infection.
Sanofi’s tetravalent meningococcal (groups A, C, Y and W) vaccine MenQuadfi was approved by the FDA in April 2020 and is suitable for the prevention of invasive meningococcal disease in people ≥ 2 years old. MenQuadfi aims to protect people with a wider age range. This approval makes it the only tetravalent meningococcal vaccine approved by the FDA for people aged 2-56 years and older. At the same time, MenQuadfi is also the first and only quadrivalent meningococcal vaccine that uses tetanus toxoid as a protein carrier to be marketed in the United States. The company said that this new vaccine will be on the market in 2021 to provide immune prevention for the population.