Copyright©IBMI&RBMP

According to Clinical.gov, more than 700 new drugs against Covid-19 developed and registered by companies worldwide are undergoing Phase 2 and Phase 3 clinical trials. More than 500 clinical trials are underway around the globe with unprecedented competition. This article provides an overview of the current progress in drug development worldwide in three dimensions, including (1) FDA approvals, (2) oral dosage forms and (3) the R&D of new drugs in Taiwan’s bio-tech companies.

■ One durg with FDA approval, five with EUA, yet only one oral-administered

In May 2020, Gilead's Remdesivir became the first FDA-approved treatment of COVID-19 under EUA. Remdesivir, an RNA polymerase inhibitor, was originally developed against Ebola virus. During the epidemic, the Phase 3 clinical trials enrolled 4,891 patients with severe symptoms and 1,113 patients with moderate symptoms, and obtained approval for the drug’s use on hospitalized patients who are older than 12 or  are adult patients in October the same year. As for children with lower weights or younger age, the use is still in compliance with EUA.

For the time being, most enterprises granted EUA are well-known international pharmaceuticals, including Eli Lilly, which received two EUAs (Baricitinib, Bamlanivimab and Etesevimab); GSK, which collaborated with Vir Biotechnology to develop neutralizing antibody Sotrovimab to inhibit viral entry into the cell; Regeneron, a big biopharmaceutical company which received EUA for REGN-COV Antibody Cocktail, the combination of two monoclonal antibodies Casirivimab and Imdevimab. The latest EUA was granted to Genentech, a subsidiary of Roche, which developed the subcutaneous injection of IL-6 monoclonal antibody. The mechanism is to prevent the Cytokine Storm from happening and the deterioration in severe cases through inhibition of IL-6.

Currently, among most of the FDA-approved drugs and those authorized under EUA are old drugs in clinical use, antiviral drugs under development, immunomodulators and antibody drugs. Mostly, the drugs are injectable, only Baricitinib is administered orally.

Table 1. COVID-19 Drugs Approved and Authorized under an EUA

Source: FDA, official websites in different companies, compiled by IBMI & RBMP

Note
1.Baricitinib, which obtained EUA for the first time in November 11, 2020, should be taken with remdesivir for the treatment of hospitlazed patients with severe symptoms; afterwards, FDA announced revisions in July 28, 2121, to permit the use of baricitinib monotherapy under EUA.

2.FDA granted EUA to the use of Bamlanivimab plus Etesevimab for the treatment of patients with mild and moderate symptoms; later, due to the inactivity of Bamlanivimab plus Etesevimab against variants, EUA was paused; revisions were made to permit its use in regions where variants infect less than 5% of the population in August 27, 2021.

■ Front Runners in the R&D of New Oral Dosage Forms: Eli Lilly, Pfizer, Roche, and Merck Sharp & Dohme are in the last stage

For now, the number of Phase 3 clinical trials for Covid-19 launched by enterprises worldwide has exceeded 150, with most of them being injection dosage forms, only few are for oral dosage forms. The R&D of new Covid drugs focus on four dimensions, including (1) the treatment of hospitalized patients to prevent deterioration in severe cases, (2) the treatment of symptoms in severe cases, (3) the treatment of the infected to prevent from being hospitalized and severe cases, and (4) the disease prevention after exposure to virus.

Based on the progress of clinical trials, front-runners in the development of new oral drugs are still international well-renowned companies. Eli Lilly’s Baricitinib, which  is immunomodulatory drug originally for the treatment of rheumatoid arthritis and it is the fastest one to received EUA. In this June, it completed Phase 3 clinical trial which recuited 1,585 participants and mainly focused on the prevention of severe case among hospitalised adults.

Pfizer, which made the successful bid to develop vaccines with BNT, and Roche, the successful developer of Tamiflu in the past, both have their shares in the development of new covid drugs. PF-07321332 developed by Pfizer, and AT-527 co-developed by Roche and Atea, are protease inhibitor and RNA polymerase inhibitor respectively, whose mechanisms are both to inhibit viral replication. The developments all focus on the prevention of hospitalization, and severe cases after being infected, thus can be used for treating non-hospitalized patients. Pfizer CEO Albert Bourla said in this April, hoping that the use of PF-07321332 can be approved by the end of 2021, with the opportunity to become the first home-cure pill; as for Roche’s AT-527, the first participant was recruited in this April and other 1,386 participants are expected to be recruited by the end of August. It’s also worth mentioning that although the clinical trials of AT-527 still focus on patients with Covid-19, Atea believes that the results of healthy participants show that active metabolite of AT-527 can achieve enough concentration in lining fluid in the lungs, where SARS-CoV-2 replicates. Therefore, it has the potential to be used in disease prevention after exposure to virus, and the experiment in the future is indeed worth attention.

Molnupiravir, the treatment for non-hospitalized patients, mild and moderate cases in the early stage, was co-developed by Merck Sharp & Dohme and Ridgeback.Molnupiravir is a ribonucleoside analog, whose mechanism is to embed genes during the replication of Covid virus to cause mutation, and stop the replication. The U.S. government has agreed to an procurement deal in this June, and it shall come into effect upon Molnupiravir receiving EUA.

Proxalutamide, an androgen receptor antagonist used in the treatment of cancer by Kintor Pharmaceutical in China, was found to decrease the expression of ACE2 and TMPRSS2, further inhibit the entry of the virus into host cells, and stop viral replication. The results of Phase 3 clinical trials in 588 people in Brazil alone show the reduction of mortality rate by 92% in severe cases. More large-scale clinical trials are underway in various centers and countries globally.

The last one is Fujifilm Holdings Corporation’s Favipiravir developed in 1988 for flu, whose patent was expired in many countries. Counrtries around the globe like India, Russia, and China have all launched Phase 3 clinical trials, with a hope to take the lead in the market.

Table 2. Covid-19 Oral Drugs in Late-phase Clinical Trials

Source：Clinicaltrials.gov, official websites in different companies, global news agencies, complied by IMBI & RBMP

An Overview of R&D Progress of Covid-19 New Drugs in Taiwan

■ 9 enterprises in Taiwan has invested in the development of new drugs, and aimed at different markets with diversified drugs development

According to open data from domestic enterprises, those have announced the launch of development in new covid drugs include, PharmaEssentia, Senhwa Biosciences Inc., Foresee Pharmaceuticals Co., Ltd., Golden Biotechnology Corporation, SyneuRx, Oneness Biotech, Advagene Biopharma Co., Ltd., Taiwan Liposome Company, TaiMed Biologics. Immunomodulation and the inhibition of virus are the mainstream mechanisms, with the focus on treatment of mild, severe cases, and respiratory distress syndrome in severe cases. 4 of the drugs are oral dosage forms, which are the most, followed by 3 nasal dosage forms and 2 injection dosage forms. The development of various drugs is to enter different target markets.

• PharmaEssentia/P1101: a Pegylated interferon which seeks to treating polycythemia vera. It serves the purpose of boosting immune response, and  disrupting viral replication. Phase 3 clinical trials are underway in 5 hospitals in Taiwan. It is used for treating patients with mild to moderate symptoms, anticipating to recruit 318 patients.
  
  
• Senhwa Biosciences Inc/ Silmitasertib: Silmitasertib is an inhibitor of CK2, targeting SARS-CoV-2 induced CK2 that are overexpressed by blocking the pathway to replicate and spread virus to cells nearby whilst interfering downstream signaling pathways in order to calm the cytokine storm. Phase 2 trial is underway in the US. Silmitasertib is provided in Taiwan through compassionate use for patients with severe symptons.
  
  
• Foresee Pharmaceuticals Co., Ltd/ FP-025: approximately 10% of Covid-19 patients are hospitalized in the U.S., of 40% have Acute Respiratory Distress Syndrome, ARDS. For now, no treatments are available for ARDS and idiopathic pulmonary fibrosis. The mechanism of FP-025 is to reduce pulmonary imflammation and fibrosis through the inhibition of MMP-12. Phase 2/3 are underway in the U.S.
  
  
• SyneuRx/Pentarlandir: three mechanisms were found in preclinical development, including the inhibition of M-protease to prevent viral replication, the inhibition of human cells TMPRSS2 to block the virus entry into human body, and the function of anti-imflammation to avoid the deterioration in severe cases caused by Cytokine storm.
  
  
• Golden Biotechnology Corporation/ Antroquinonol: the new small molecule drug Antroquinonol, originally developed for cancer treatment, serves the purpose of inhibiting viral replication and anti-imflammation. FDA has approved Phase 2 clinical trials in various centers and contries, mainly for hospitalized patients with mild and moderate symptoms. Compassionate drug use is allowed in Taiwan for the said patient cohort.
  
  
• Oneness Biotech/ FB704A, SNS812: FB704A is Anti-IL6 monoclonal antibody. Because IL-6 is the key factor leading to the cytokine storm in severe cases, the drug’s mechanism is developed with the goal of inhibiting IL-6 and avoiding deterioration in severe cases. It has been approved by the FDA for Phase 2 clinical trials in patients with severe symptoms. Most recently with Genetech (Roche)’s EUA for its IL-6 Tocilizumab monoclonal antibody, Oneness Biotech had suspended the trial. The company has shifted its R&D focus towards the new nucleic acid drug SNS812, which can inhibit viral replication. At present, SNS812 has completed 6 animal tests, which can significantly reduce the motality rate of virus infection.
  
  
• Advagene Biopharma Co. Ltd.: AD17002-SC was developed on the LT adjuvant platform. It is administered through nasal spray to induce an immune response in the nasal mucosa and has showed the ability to improve respiratory tract inflammation and lungs inflammation after viral infection in previous animal tests. The drug is currently in Phase 2 human clinical trials in Taiwan with patients with mild symptons.
  
  
• Taiwan Liposome Company/ ISPM19: Hydroxychloroquine (HCQ) was once thought to be potential medication for the prevention of Covid-19. But due to the dosage availablility and cardiotoxicity, the results of clinical trials were found less positive and EUA was thus withdrawn. ISPM19 adopts Liposome co-encapsulation technique and delivers HCQ directly to the upper respiratory tract and lung target tissues in an inhaled form at a dose of nearly 1% of the oral dose to achieve an effective antiviral concentration locally while reducing cardiotoxicity. It is currently in Phase 1 clinical trial in Taiwan.
  
  
• TaiMed Biologics/ TMB-200: TMB-200 is a monoclonal antibody which targets the spike protein of severe SARS-CoV-2 to neutralize the virus and block viral entry into human cells, potentially preventing and/or treating COVID-19. Phase 1/2 trial was due to conduct in 2021, yet it suspended owing to commercial consideration.

Source: Clinicaltrials.gov, Center fo Drug Evaluation, official websites in different companies, global news agencies, compiled by IBMI & RBMP