11 Anti-infective drugs
The 2020 COVID-19 pandemic will linger in everyone’s memory forever. In this year, Remdesivir (Veklury; Gilead), as the first anti-viral treatment of the disease, obtained rapid development and approval, which is a major progress in this field. The most specific target in inhibiting RNA viruses (such as the SARSov-2 virus that causes COVID-19) is RNA-dependent RNA polymerase (RdRp), which regulates the replication and transcription of the viral genome. The RdRp inhibitor Remdesivir was originally studied as a therapeutic drug for Ebola, so it was determined to have anti-coronavirus potential in the early stages of the COVID-19 outbreak. After evaluating several large-scale clinical trials, including the ACTT-1 trial sponsored by NIAID, the FDA granted emergency use authorization (EUA) for Remdesivir in the United States in May 2020, allowing authorized medical institutions to distribute and use the drug for adult and pediatric patients who were severely hospitalized due to COVID-19. In May of the same year, the Ministry of Health, Labour and Welfare (MHLW) of Japan approved Remdesivir as a therapeutic drug for SARS-CoV-2 infection through a special review route. However, it was worth noting that Japan’s review process did not include emergency use clauses. In July 2020, the European Medicines Agency granted conditional marketing authorization to Remdesivir for the treatment of adults and teenagers 12 years and older with COVID-19 patients who need supplemental oxygen. The license allowed Remdesivir to be listed in all EU countries and in the United Kingdom in September of the same year. In October 2020, Remdesivir was officially approved by the FDA for the treatment of COVID-19 patients with a body weight of 40kg or more and children 12 years and older who need to be hospitalized. In contrast, the World Health Organization (WHO), based on the results of the Solidarity study published in October, issued a conditional recommendation on November 20 to oppose the use of Remdesivir in hospitalized patients regardless of the severity of the disease, and pointed out that there was no evidence that Remdesivir could improve the survival and other outcomes of these patients. Relevant evidence included no significant impact on mortality, the need for mechanical ventilation, time to clinical improvement, and other outcomes that are important to patients. The WHO emphasized the need for further clinical evaluation of anti-viral drugs.
Favipiravir was a nucleoside analogue for the treatment of influenza A and B introduced by Toyama Chemical Co., Ltd. in Japan in 2017. The drug can also inhibit the RNA-dependent RNA polymerase of a variety of RNA viruses; in addition to influenza virus, it can also inhibit the replication of yellow fever virus, Ebola virus, norovirus and chikungunya virus. Although Favipiravir did not have high anti-viral activity against SARS-CoV-2 in vitro, due to its commercial availability and good tolerability, it was reasonable to carry out clinical trials to evaluate the efficacy of the drug in patients with early COVID-19. In June 2020, the generic Favipiravir (FabiFlu) produced by Glennmark Pharmaceuticals received accelerated approval in India for the treatment of mild to moderate COVID-19. The approval set a restriction on the use of the drug, which required each patient to sign an informed consent form before receiving treatment. Favipiravir developed by R-Pharm and Russian Pharmaceutical Investment and R&D Group was officially approved in Russia in September and November 2020, respectively. R-pharm’s Coronavir is suitable for the treatment of mild to moderate COVID-19, while the Russian Pharmaceutical Investment and R&D Group’s Fapilavir (Avifavir) is suitable for the treatment of severe COVID-19. Favipiravir is provided to patients free of charge by the Russian government.
In the past year, several COVID-19 treatment drugs and biologics have been approved globally. Most of them are authorized drugs for emergency use, see the last section of this report for details.
Hepatitis D is a serious inflammatory disease of the liver caused by infection with a hepatotropic pathogen (named hepatitis D virus HDV or hepatitis D). HDV is a defective RNA virus: without the assistance of hepatitis B virus (HBV), HDV can only replicate but cannot release virus particles. The viral particle assembly process also requires hepatitis B surface antigen (HBsAg) and host cell proteins to assist its replication. Therefore, hepatitis D can only cause infection in individuals with previous chronic HBV infection (ie dual infection) or individuals who are infected with both viruses at the same time (ie co-infection). As of 2020, the standard treatment for hepatitis D is long-term (≥48 weeks) use of Peginterferon alpha-2a or -2b. This therapy can only successfully eradicate HDV in 1/3 of patients, and this therapy has potentially serious adverse effects. Because of this, the successful development of the viral invasion inhibitor Bulevirtide (Hepcludex; MYR Pharmaceuticals) represents a significant progress in this therapeutic area. Bulevirtide is a sodium taurocholic acid cotransport polypeptide (NTCP) inhibitor with high specificity and stability, and NTCP is an indispensable hepatocyte surface receptor for the binding of HBV and HDV. The drug can induce the virus to enter another pathway that does not cause the virus to multiply, thereby preventing cell infection. In August 2020, Bulevirtide received conditional approval from the European Commission and was identified as an orphan drug and a priority review drug (PRIME). Bulevirtide was first launched in Germany, France and Austria in September.
Last year, a new treatment for hepatitis C was launched in China. Hepatitis C (HCV) is a viral hepatitis with a higher prevalence rate. Chronic hepatitis C patients in China account for 14% of the total number of patients worldwide. Lavidavir Hydrochloride (Asclevir) is a non-structural protein 5A (NS5A) inhibitor developed by Golly Pharmaceutical Co., Ltd. It was approved by the China National Medical Products Administration in July 2020 and was launched later in the same year. The drug is suitable for combination with serine protease NS3/nonstructural protein 4A (NS3/NS4A) inhibitor Danorevir to treat genotype 1 HCV patients.
ViiV Healthcare and Janssen announced in March 2020 that Health Canada had approved Cabenuva (cabotevir/ripivirin sustained-release injection suspension) as the first and only complete long-acting program that only requires monthly dosing. The drug is used to treat HIV-1 infected adult patients who have reached virological stability and suppression (HIV-1 RNA<50 copies/mL), and replace the current antiretroviral (ARV) regimen. Cabenuva uses a combination package that contains two injections, Janssen’s Ripavirin and ViiV Healthcare’s cabotwe, which are jointly developed by the two companies. Health Canada has also approved Vocabria (Cabotvir) oral tablets, combined with Cabenuva, for short-term use. This is the first time that Cabenuva and Vocabria have been approved globally. Cabenuva’s approval is based on the pivotal Phase III ATLAS study (NCT02951052) and FLAIR study (NCT02938520), and two studies included more than 1,100 subjects from 16 countries. Before starting the administration of Cabenuva, the oral administration of Cabotevir and Lilpivirin was carried out for about one month to evaluate the tolerability of Cabotevir and Lilpivirin. The study showed that during the 48-week study period, the monthly buttock intramuscular injection of Cabenuva had the same effect in maintaining viral suppression compared to continuing the daily oral antiretroviral regimen. Cabenuva and Vocabria would be launched in Canada in September 2020. The European Union, Switzerland and Australia are also reviewing the long-acting treatment plan. The Committee on Medicines for Human Use (CHMP) gave a positive review of the program in October 2020.
Fostemsavir (Rukobia) is the first anti-HIV drug developed by ViiV Healthcare and was approved by the FDA last year. It is for use in combination with other anti-retroviral drugs (ARV) for multi-drug resistant adult HIV-1 infected patients who have received multiple drug treatments in the past but have failed current antiretroviral therapy due to drug resistance, intolerance or safety issues. Fostemsavir is a prodrug that can be converted into Temsavir with therapeutic activity after oral administration. Temsavir exerts antiviral activity by directly attaching to the gp120 subunit on the surface of the virus, thereby blocking the attachment of HIV to the CD4+ T cells of the host immune system, and preventing the virus from infecting these cells and proliferating.
Last year, two new antibiotic drugs developed by Walkhart of India were approved for marketing in India, namely Emrok (levonadifloxacin arginine salt, intravenous injection) and Emrok O (alalevonadifloxacin mesylate, oral preparation). It was used to treat acute bacterial skin and skin structure infections, including diabetic foot infections and complications of bacteremia. The approval of these two new drugs was based on a phase III study conducted in 500 patients in 40 research centers in India. These two new drugs have strong bactericidal effects against gram-positive bacteria, bacteria sensitive to quinolones, gram-negative bacteria, anaerobic bacteria and atypical bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Clinical and non-clinical studies have found that Emrok and Emrok O had better safety characteristics than the MRSA drugs that have been on the market (including vancomycin, teicoplanin, daptomycin and linezolid).
The quinolone antibacterial drug Lakufloxacin hydrochloride (Lasvic; Kyorin) was approved by the Japanese MHLW in 2019 and was launched in January 2020 for the treatment of respiratory tract and ear-nose-throat infections. The drug’s indications include pharyngitis, stomatitis, tonsillitis, acute bronchitis, pneumonia, secondary infections of chronic respiratory diseases, otitis media and sinusitis. It is also suitable for the treatment of infections caused by sensitive strains such as From Staphylococcus, Streptococcus, Pneumococcus, Moraxella catarrhalis (Branhamella), Klebsiella, Enterobacter, Haemophilus influenzae, Legionella pneumophila, Prevotella, Mycoplasma pneumonia, etc.
Cefadil (Fetroja) developed by Shiono Yoshino Pharmaceutical Co., Ltd. was launched in the United States in February 2020 for treatment of adult patients aged 18 and older who have limited or no other treatment options. The drug’s indications include the treatment of complex urinary tract infections (cUTI) caused by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa and Enterobacter cloacae, including pyelonephritis. Cefadil is a cephalosporin drug, which can act as a siderophore by binding to free iron outside the cell. In addition to passive diffusion through the porin channel, Cefadil can also actively pass through the outer cell membrane of bacteria into the periplasmic space through the iron uptake mechanism of siderophores. The drug inhibits the biosynthesis of bacterial cell walls by binding to penicillin binding protein, thereby showing a bactericidal effect. Cefadil obtained the QIDP qualification granted by the FDA, thereby obtaining the fast track certification and priority review qualification. Later in the same year, the FDA approved a Supplemental New Drug Application (sNDA) for Cefadil for the treatment of hospital-acquired bacterial pneumonia caused by susceptible Gram-negative bacteria in patients 18 years of age and older.
African trypanosomiasis (commonly known as sleeping sickness) is a parasitic disease caused by Trypanosoma brucei gambiae and transmitted to humans through the bite of an infected tsetse fly. This parasite can invade the central nervous system of humans, so patients with sleeping sickness are usually fatal if they are not diagnosed and treated in time. In early 2020, the anti-trypanosomal drug Fexinidazole Winthrop was launched in the Democratic Republic of Congo (DRC), becoming the first direct oral treatment for this neglected tropical disease. The WHO has included Fexinidazole in the list of essential medicines for adults and children. The drug is used to treat sleeping sickness in the first stage (hemolymphatic stage) and second stage (neural stage). Fexinidazole was originally developed by the German pharmaceutical company Hearst (now a Sanofi company); however, the company abandoned the development plan after abandoning the tropical disease project in the 1980s. In 2005, the compound was redeveloped. In May 2009, Sanofi authorized this drug candidate to the Neglected Disease Drug Development Initiative (DNDi) for development, production and distribution for the treatment of human African trypanosomiasis. Promoted by DNDi, a new drug development model was used to develop Fexidazole. Finally, 15 partners from governments, private companies and civil society groups joined the development project. Among them, Sanofi is the main partner from pharmaceutical companies.
Abametapir (Xeglyze; Dr. Reddy’s laboratory) is a metalloprotease inhibitor that has the effects of killing lice eggs and lice. It was approved in the United States in July 2020 for local treatment of the head of patients 6 months and older. Since most existing treatment methods cannot kill lice eggs, the successful launch of this product represented a major advancement in this treatment field. As an inhibitor of metalloproteinases (MMP-2, -8 and -9), Abametapir can target metalloproteinases required for lice egg hatching and nymph development (26). The product was discovered and developed by Hatchtech, a start-up company in Melbourne, Australia. Hatchtech has authorized Dr. Reddy’s laboratory to commercialize the drug in most major markets, including the United States.