Remdesivir

from Wikipedia, the free encyclopedia
Structural formula
Structural formula of remdesivir
General
Non-proprietary name Remdesivir
other names
  • 2-Ethylbutyl- (2 S ) -2 - {[( S ) - {[(2 R , 3 S , 4 R , 5 R ) -5- (4-aminopyrrolo [2,1-f] [1,2 , 4] triazin-7-yl) -5-cyano-3,4-dihydroxytetrahydro-2-furanyl] methoxy} (phenoxy) phosphoryl] amino} propanoate ( IUPAC )
  • (2-Ethylbutyl) (N - {( S ) - [2 -C- (4-aminopyrrolo [2,1-f] [1,2,4] triazin-7-yl) -2,5-anhydro- D -altrononitril-6-O-yl] phenoxyphosphoryl} - L -alaninate) (WHO)
  • GS-5734 (Gilead Sciences)
  • RDV
Molecular formula C 27 H 35 N 6 O 8 P
External identifiers / databases
CAS number 1809249-37-3
ECHA InfoCard 100,302,974
PubChem 121304016
ChemSpider 58827832
DrugBank DB14761
Wikidata Q28209496
properties
Molar mass 602.585 g · mol -1
safety instructions
GHS labeling of hazardous substances
08 - Dangerous to health

Caution

H and P phrases H: 373
P: ?
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Remdesivir (manufacturer: Gilead Sciences ) is a drug that has been in clinical trials for the treatment of the SARS-CoV-2 virus- induced disease COVID-19 since February 2020 . After it was initially used in compassionate use applications, there are now special approvals in the USA, Japan and the EU .

The nucleotide analog was because of his virostatic originally for use against properties Ebola and Marburg virus infections developed, did not reach there but the maturity for therapeutic use.

It has been marketed under the Veklury brand since mid-2020 .

Spectrum of activity

The substance remdesivir was first synthesized by Gilead Sciences. During the Ebola virus epidemic from 2014 to 2016 , Gilead carried out tests of the substance on primates. The tests took place in laboratories of the USAMRIID biological protection level IV . It could be shown that the active ingredient penetrates the tissues of the brain, eyes and testicles that serve as a retreat for virus replication. In clinical tests on monkeys infected with the Ebola virus, the intravenous administration of the active substance was able to suppress replication of the virus in six out of six cases. Laboratory chemical and clinical signs of disease decreased and there was no fatal course of the disease. Another study in primates was conducted in 2019. The active ingredient prevented infection by the Nipah virus , while the animals in the control group died from the infection. In cell cultures , Remdesivir showed activity against other human pathogenic RNA viruses . These included the Marburg virus , Lassavirus , MERS-CoV , SARS-CoV , influenza virus A , Paramyxoviridae (such as human parainfluenza virus 3 , Nipah virus , Hendra virus , measles virus and mumps virus ) and Pneumoviridae (such as respiratory syncytial virus ). It also acts against the murine hepatitis virus (MHV), which infects mice. An inhibition of virus replication by SARS-CoV-2 in cell cultures was also demonstrated.

Mechanism of action

Remdesivir is a 1′-cyano 4-aza-7,9-didesazaadenosine-C analogue of adenosine . It is a Monophosphoramidat - prodrug ( "protide" ), the GS-441 524 is transferred from the metabolism to the active form. GS-441524 inhibits the viral RNA polymerase and prevents the virus from replicating further in the infected cells by breaking the chain during RNA replication. The EC 50 of Remdesivir is 0.03 μM for the murine hepatitis virus (MHV) in cell culture from DBT cells.

Analytics

The reliable qualitative and quantitative determination of Remdesivir succeeds after appropriate sample preparation by coupling the HPLC with the mass spectrometry .

Therapeutic use

Remdesivir has so far been approved as a medicinal product under special regulations, but not yet without restrictions in any country in the world .

Ebola fever

2016 was a Scottish nurse who in West Africa with the Ebola virus had infected, treated successfully with Remdesivir. After nine months she had a relapse with renewed viral replication, which clinically manifested itself as meningoencephalitis . The virus, which was only mutated in two non-coding base pairs, was again successfully treated with the substance and corticosteroids .

In a randomized controlled study that took place during an Ebola outbreak in the Democratic Republic of the Congo between November 2018 and August 2019, a combination of ZMapp and remdesivir was found to be significantly inferior to the combination of the antibodies MAb114 and REGN-EB3 . In the ZMapp / Remdesivir group, around half of the patients died, and around a third in the group with the two antibodies. As a result, for ethical reasons, the study was only continued with the two antibodies.

COVID-19

The mechanism of action of remdesivir is known and plausible. It works against coronaviruses in cell cultures and animal models .

In an expert survey by the World Health Organization (WHO) carried out at the end of January 2020 , remdesivir was considered the most promising therapy option. A research group classified remdesivir in in-vitro tests at the beginning of February as highly antiviral. According to a publication presented at the end of March, Remdesivir effectively inhibits not only the polymerases of SARS-CoV and MERS-CoV, but also those of SARS-CoV-2 ('new coronavirus') in insects .

In a comparative study on 2x6 rhesus monkeys presented in mid-April , the remdesivir-treated group was less affected by shortness of breath than the control group , showed less lung infiltration, a significantly lower amount of virus and less lung damage. Viral antigens were detected in all twelve animals after one week, regardless of treatment .

Clinical trials

At the beginning of April, five studies on the efficacy and tolerability of remdesivir were running, and four more were planned.

The Chinese National Medical Products Administration approved remdesivir in February 2020 for testing on a total of 761 patients suffering from the new coronavirus SARS-CoV-2 . One study evaluated severely ill patients, and another mild to moderately ill patients. The randomized controlled clinical trial was conducted under the direction of Friendship Hospital and the Chinese Academy of Medical Sciences . Due to a lack of new cases, the study with seriously ill patients with 237 participating patients was ended on April 10th. Two thirds received remdesivir for ten days, one third a placebo. The clinical condition was assessed after up to 28 days. The remdesivir-treated group recovered somewhat faster, but the effect was not significant , with the same mortality . The partial study with ultimately 308 moderately ill patients was interrupted; Results are expected on April 27, 2020.

Gilead Sciences is conducting two phase III studies of its own as part of the so-called SIMPLE studies . Five and ten day treatments are compared with each other. The Food and Drug Administration (FDA) fast-tracked this in late February. These multicenter studies have been running since March 2020 on around 1000 patients worldwide in medical centers, mainly in Asian countries. Half of around 400 seriously and around 600 moderately ill adults should be given the drug intravenously over five or ten days. In a group of around 400 seriously ill patients, all should receive Remdesivir as a supplement to the previous standard treatment. In the group of moderately ill patients, one third should receive the drug for five or ten days as a supplement to the standard treatment, one third only receive the standard treatment. In both groups, tolerability and efficacy should be assessed two weeks after the first administration. By mid-April, 2,400 seriously ill people in 152 locations had been included in the study; the group of moderately ill patients comprised 1,600 patients in 169 facilities worldwide. As of mid-April, an expansion to 6000 or 1600 sick people is planned. Gilead published the first results from the group of the seriously ill on April 29, 2020 and announced a peer-reviewed publication soon . The manufacturer expects results from the study with moderately ill patients in May 2020.

Results of a placebo-controlled study coordinated by the US National Institute of Allergy and Infectious Diseases (NIAID) were presented in late April. The study had reached its primary endpoint by this point, according to Gilead . On April 29, 2020, NIAID published a press release about preliminary study results from the ACTT study. Preliminary results showed a 31% shorter recovery time in the remdesivir group compared to the placebo group or a median recovery time of 11 days in the remdesivir group compared to 15 days in the placebo group. This difference was statistically significant. The interim result of the mortality rate was not statistically significant: 8.0% in the remdesivir group, 11.6% in the placebo group.

Remdesivir is also part of the “Solidarity” study launched by the WHO in March 2020, which also tests chloroquine / hydroxychloroquine , lopinavir / ritonavir (partly in combination with beta interferon ). It is also part of the “Discovery” large-scale study, which began at the end of March 2020, in which remdesivir, hydroxychloroquine and lopinavir / ritonavir are to be compared with previous treatment in more than 3000 Covid-19 patients in eight European countries.

Remdesivir should not be administered simultaneously with chloroquine or hydroxychloroquine, since in vitro -Untersuchungen antagonistic revealed effects of chloroquine on the intracellular metabolic activation and antiviral activity of Remdesivir.

In Germany, the Federal Institute for Drugs and Medical Devices (BfArM) approved two clinical phase III trials with remdesivir as an investigational drug on March 10, 2020. The aim is to treat patients with severe or moderate COVID-19 disease. Eight clinical centers are involved in Germany, including the Munich Clinic Schwabing , the University Medical Center Hamburg-Eppendorf and the University Medical Center Düsseldorf . By April 10, the BfArM had approved three clinical trials, all three of which include moderately to seriously ill and inpatients. In addition, a study by the World Health Organization in Germany is to be approved by the BfArM in mid-April, in which the effectiveness of Remdesivir will be compared with hydroxychloroquine.

The United States Department of Defense is making Remdesivir available to soldiers and civilian workers as part of its own study.

In early July 2020, Gilead announced the initiation of a phase 1 study with an inhaled dosage form in around 60 healthy volunteers. The FDA approved the study in June. It is hoped that remdesivir will be more beneficial when used in the early stages of Covid-19 disease, when the patients have not yet been hospitalized. Inhalative administration is possible on an outpatient basis.

Gilead announced in early July 2020 that, according to retrospective cohort studies , remdesivir not only shortens the duration of illness, but also lowers mortality . This must be verified in further studies.

Emergency use approvals

The FDA approved remdesivir for emergency use on May 1, 2020. The Emergency Use Authorization (EUA) includes children and adults who suffer from COVID-19, are being treated in hospital and have a severe course. According to the EUA, the disease is severe if the oxygen saturation in room air is less than 95% or if oxygen is required, or if artificial ventilation or extracorporeal membrane oxygenation (ECMO) is necessary. Distribution in the United States under the EEA is under the control of the US government.

On May 7, 2020, the Japanese Ministry of Health, Labor and Social Welfare issued rapid approval for the drug called Veklury . The South Korean Ministry of Food and Drug Safety approved remdesivir in June 2020.

On July 3, 2020, the European Commission granted Member States the conditional approval of Remdesivir for the treatment of COVID-19 in adults and adolescents aged 12 and over with pneumonia who require supplemental oxygen, which the European Medicines Agency recommended in June. The application for approval was received at the beginning of June, but the assessment of the preparation had already started at the end of April 2020 as a rolling review ("continuous review").

Remdesivir is available as a concentrate and as a lyophilisate for the preparation of a solution for intravenous administration.

Individual attempts at healing

Apart from the clinical studies, the manufacturer, Gilead Sciences, has been providing Remdesivir for suitable Covid-19 patients on a compassionate use basis as an emergency treatment since January 25 . The active ingredient is released for a specific patient for ten days of treatment. On March 22, 2020, the company announced that, in view of the many individual inquiries, it wanted to switch to a broader program ("expanded access") to facilitate access to Remdesivir. This should enable medical institutions and treating physicians to apply for Remdesivir for several patients at the same time. On March 23, the FDA granted orphan drug status reserved for rare diseases in the United States . Several expanded access locations in the United States went into operation on March 27, with more to follow. New compassionate use applications may temporarily only be submitted for severe Covid 19 cases in minors and pregnant women. By the beginning of April, the manufacturer had sold Remdesivir to over 1,700 patients on a compassionate use basis. The German BfArM approved a corresponding compassionate use program for remdesivir with effect from April 3, 2020 for one year.

On April 3, the European Medicines Agency issued recommendations for criteria and boundary conditions for compassionate use programs in the member states. It recommends the use in ventilated patients with adequate kidney function and other criteria. On May 11, the EMA extended the approval to hospitalized patients who a. only receive supplemental oxygen, non-invasive ventilation, or ECMO.

Initial experiences from compassionate use were published in the New England Journal of Medicine on April 10, 2020 . Of 61 treated patients, 36 patients showed an improvement in oxygen levels during the observation period, 25 were discharged and seven died. Eight patients dropped out of the study for other reasons. Of 30 patients with mechanical ventilation, thirteen were still on ventilation at the end of the study. The informative value of the publication is controversial because of the small patient population, the lack of a control group and the direct involvement of the manufacturer.

Production and availability

According to the manufacturer, 1.5 million doses of Remdesivir were available in April or about to be completed. In January 2020, doses for 5000 patients were in stock, in March already doses for 10-day treatment of 30,000 patients. 140,000 treatments should be possible by the end of May 2020, more than half a million by October 2020 and more than a million by the end of 2020. If necessary, several million patients could be treated in 2021. Since, according to the manufacturer, a five-day treatment was sufficient from the end of April, more patients could be treated.

According to the manufacturer, the production of Remdesivir originally took nine to twelve months and has since been shortened to around six months. The synthesis comprised a sequence of steps that sometimes took weeks. Substances are also required that are only available to a limited extent on the world market. Further optimizations are in the works. Changed formulations , forms of administration and combination therapies are being examined.

According to Gilead Sciences, it will invest more than $ 1 billion in the production of remdesivir in 2020. According to the company from the beginning of August 2020, the production network now includes more than 40 companies in North America, Europe and Asia. Compared to January 2020, production has increased fifty-fold and global demand is expected to be satisfied from October 2020. Doses for more than two million treatments are expected to be produced by the end of 2020.

In April 2020, British pharmacologist Andrew Hill estimated the minimum production cost for a daily dose of remdesivir to be 0.93 US dollars or 93 cents

The company gave its stash of remdesivir free in May, with about 40 percent (doses used to treat 78,000 patients) going to the United States. The company says it is considering granting free licenses to produce Remdesivir for the period until at least 2022, including the necessary technology transfer . Beyond this period, Indian and Pakistani generic drug manufacturers are expected to produce Remdesivir for use in developing countries. By August 2020, the company had allowed nine generic drug manufacturers to produce Remdesivir to supply 127 developing and emerging countries.

Therapy costs

On June 30, 2020, Gilead Sciences put the drug cost for a five-day treatment of severely COVID-19 patients in the United States - based on a retail price of $ 390 per ampoule - at $ 2,340 (equivalent to about 2,000 euros). This net price is also planned for Germany. For privately insured persons, the price in the USA is 3120 US dollars. For countries in need, the company wants to make a cheaper variant available and has granted licenses to nine generic drug manufacturers in India, Pakistan and Egypt, who can set the sales price themselves. The licenses are free until the WHO declares the end of the pandemic or, alternatively, another drug for the treatment or prevention of COVID-19 is approved.

Individual evidence

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