Novartis CEO Cautions on Efficacy of Trump-Touted Covid-19 Treatment

Novartis CEO Cautions on Efficacy of Trump-Touted Covid-19 Treatment

Novartis’s (NVS) — Get Report CEO cautioned on Friday that it was “too soon” to know whether two of the company’s anti-malaria drugs could prove to be an effective treatment for the novel coronavirus, despite President Donald Trump touting them as a “game-changer.»

Speaking on CNBC, Novartis CEO Vas Narashimhan said that while two of the company’s drugs — Hydroxychloroquine and Chloroquine — are being tested to see whether they can reduce the severity of Covid-19 or even prevent it, conclusive evidence of their effectiveness is still at least a year and a half to two years away.

“With Hydroxychloroquine, what we know is in pre-clinical studies, the drug is quite active against the coronavirus but these are, of course, not in human beings — not in patients,” Narasimhan told the network on Friday.

“I do think it is too soon to know for sure until we have properly controlled randomized studies,” he said. “We hope over the next 18 months to two years, we can come back with a vaccine that will ultimately be the definitive way to deal with this pandemic.”

Chloroquine is a decades-old drug that was approved by the Food and Drug Administration in 1949 to treat malaria. Its derivative, Hydroxychloroquine, is often used by doctors to treat rheumatoid arthritis and lupus. Novartis is one of the main producers of the drug.

Speaking at a White House press briefing last week, Trump said that the two anti-malaria drugs were a “game-changer” in the global fight against the coronavirus pandemic, adding that they had shown “very, very encouraging results.″

“It’s shown very encouraging, very, very encouraging early results,” Trump told reporters. “And we’re going to be able to make that drug available almost immediately.”

As of Friday, more than 537,000 people around the world had contracted Covid-19, according to data compiled by Johns Hopkins University, with 24,110 deaths.

Novartis’s American depositary receipts were down 2.09% at $78.08 in New York trading on Friday.

The race to fight coronavirus

By Andy Extance 2020-02-11T14:30:00+00:00

While genome sequences enable testing and vaccine efforts, companies are donating existing antiviral drugs to explore repurposing

When the Chinese government published the genetic sequence for novel coronavirus 2019-nCoV, Inovio Pharmaceuticals was waiting. ‘By [the next day] we had a vaccine made from the sequence,’ says Jeff Richardson, the Pennsylvania, US, company’s vice president of strategic relations. Inovio’s story reflects how concern over 2019-nCoV has started a race among companies to develop drugs, vaccines and tests.

Inovio’s speed is remarkable. Following its initial isolation in Wuhan, the Chinese Center for Disease Control and Prevention (CCDC) had identified 2019-nCoV by 7 January 2020. The sequence was released on 10 January. On 30 January, the World Health Organization (WHO) declared the outbreak a global emergency as it continues to spread to at least 24 countries outside of China. As of 11 February, over 43,000 people have been infected globally and 1018 have died of the disease, officially named COVID-19 by the WHO. China and other nearby countries have imposed significant containment controls and are restricting people’s movement.

Government, university and commercial labs all over the world are working to develop tests and treatments for the nCoV-2019 virus

More people have now been infected in China than during the severe acute respiratory syndrome (Sars) coronavirus outbreak in the early 2000s. So far 2019-nCoV seems to be spreading faster but have a lower fatality rate than that outbreak. However, 2019-nCoV has already killed more people than the Middle East Respiratory Syndrome (Mers) outbreak that began in 2012, the most recent previous novel human coronavirus. Yet many details are still open to question that will be vital in determining whether it becomes as serious as the influenza outbreaks that kill hundreds of thousands of people per year worldwide. Nevertheless, authorities are already recognising that it’s too late to effectively contain the virus.

Having a vaccine to protect healthcare workers and people at risk will be critical

‘There are some indications that the virus can be spread from people who aren’t even showing symptoms,’ comments Kate Broderick, Inovio’s senior vice president for R&D. ‘Things like quarantine and isolation aren’t going to work, because you can’t intervene when somebody doesn’t appear to be sick.’ As such, Broderick says that 2019-nCoV ‘has hugely exceeded the need for a vaccine’. ‘The spread of the virus at the moment is particularly concerning,’ she says. ‘Having a vaccine to protect healthcare workers and target people we know are definitely at risk can be a critical tool.’

Coronaviruses have single-stranded RNA genomes wrapped in large protein envelopes. Everyone has experienced mild coronavirus infections as common colds, causing coughing and sneezing. Animals have their own coronaviruses, and sometimes one jumps into humans. 2019-nCoV is seemingly the latest example, thought to have originated in a Wuhan seafood market. Some patients rapidly develop viral pneumonia.

Testing times

As such, diagnosing the disease is important, yet few tests are available. One of the first commercial offerings comes from Primerdesign in Southampton, UK. It can distinguish 2019-nCoV from other coronaviruses. The company believes this differentiates it from rival tests, which are less specific and may also react to other related species giving rise to a false positive diagnosis.

Primerdesign has developed a highly specific PCR-based test kit, but it can only be used for research

2019-nCoV tests currently rely on the polymerase chain reaction (PCR) to amplify its RNA genome to detectable levels. Adam Herridge, Primerdesign product manager, explains that his company’s tests include multiple primer oligonucleotide sequences that can bind to 2019-nCoV. These give polymerase enzymes somewhere to bind and start replication. The tests also include a specific probe sequence can bind to the 2019-nCoV genes. The probe has a fluorescent structure at one end, but doesn’t glow on its own because it’s quenched by a structure at the other end. ‘When you’ve got a specific sequence that’s designed to be complementary to your probe – the novel coronavirus in this instance – it’s cleaved by an enzyme that has an exonuclease activity,’ Herridge explains. Separated from the quencher, the fluorescent structure emits light. Used in quantitative PCR, the resulting fluorescence ‘can quantify the number of copies of virus that were input in your original sample’.

Like Richardson, Herridge stresses the importance of moving fast on 2019-nCoV. Primerdesign’s test is based on sequence information released on 23 January, and was developed in less than two weeks. The sequence information is more up-to-date than sequences used by other tests, Herridge asserts. ‘That allows ours to be more specific, whereas the previous ones had more general sequences that are present in a wider family of coronaviruses,’ he says.

In these circumstances, where the situation is so serious, the only path to a solution is us all working together

Yet Primerdesign states that its test is intended for research use only. The limited availability of clinical tests means that diagnosis relies heavily on a few central government and academic labs. The World Health Organization has identified 15 such laboratories to provide reference testing support, but is working with them and commercial organisations to strengthen diagnostic capability. For example, in the US 2019-nCoV had been diagnosed only at the country’s Centers for Disease Control and Prevention (CDC) labs. But on 4 February, the US Food and Drug Administration issued an emergency use authorisation to enable clinical use of the CDC’s 2019-nCoV real-time PCR diagnostic panel. The test can now be used at qualified labs outside the CDC.

Among such efforts in China, health authorities and the government have been working with Swiss-headquartered Roche to ensure people can get access to screening and healthcare. In a statement the company says that it is ‘working to support the government and local health officials and hospitals in Hubei Province in dealing with the coronavirus’. It is providing diagnostic tests, medical supplies and financial support for the affected region. Roche’s coronavirus diagnostic tests are also PCR-based.

Antiviral efforts

Demand for Roche’s anti-flu medication Tamiflu (oseltamivir) has also forced Roche to stress in its statement that there are ‘currently no medicines to treat human coronaviruses’. ‘Roche medicines for the treatment of flu are designed to treat specific forms of flu viruses and it is extremely unlikely that they would be effective at treating the novel coronavirus,’ it says. Similarly, new antiviral small molecule drugs targeting coronaviruses would be almost impossible to develop in time to help with this outbreak. However, researchers are seeking to establish whether some existing drugs may be beneficial. For example, scientists in Wuhan, China, are using the HIV medicines lopinavir and ritonavir (sold together by US firm AbbVie as Kaletra) in a randomised, controlled trial.

Similarly US-headquartered multinational Johnson & Johnson (J&J) is donating its HIV medicines darunavir and cobicistat for investigational use in China to combat the novel coronavirus. ‘We believe we have a responsibility to step in and invest in solutions for global public health crises,’ says Hanneke Schuitemaker, global head of viral vaccines at Janssen (a J&J subsidiary). Yet J&J’s activities mostly reflect the fact that the chances for a more rapid response to 2019-nCoV come primarily down to a vaccine.

Chinese researchers are testing various antivirals — particularly anti-HIV drugs to see if they can be useful against coronavirus

The company’s vaccine development will exploit various technologies to rapidly scale up vaccine production. Its AdVac adenovirus vectors ‘can induce potent and long-lasting immune responses, enabling us to pursue vaccines for disease targets that are currently unpreventable or untreatable,’ Schuitemaker explains. This combines with the PER.C6 cell line that it uses to manufacture a wide variety of vaccines, enabling ‘fast and high-capacity production of biological components’, she adds.

When the Zika outbreak occurred, we went from viral sequence to the clinic in seven months. We are aiming to do coronavirus considerably faster than that

Like other companies, Schuitemaker says that J&J moved rapidly when the 2019-nCoV sequence was released. ‘We have initiated efforts to develop a vaccine candidate against the virus, which we hope can ultimately be deployed quickly and extensively to help combat this outbreak,’ she says. ‘We are also collaborating with other partners to screen our library of antiviral molecules, to identify potential treatments for rigorous research and development. We hope we can create a candidate vaccine for this virus and can start a Phase 1 clinical study within approximately 8–12 months. We started the work quickly because we want to be prepared.’

Schuitemaker stresses that even if successful, such a product should not be seen as the entire solution. ‘Vaccines and/or antivirals, if approved, should be used in combination with public health measures as outlined by the CDC, including use of protective equipment for health care workers in hospitals,’ she explains. ‘What we have learned from past epidemics such as Sars, and ongoing epidemics such as Ebola, is that coordination as a global community is critical to effectively containing, or eventually preventing these types of outbreaks.’

Ready in time?

Meanwhile, the Coalition for Epidemic Preparedness Innovations (CEPI) has initiated three programmes that should be well placed to develop vaccines against nCoV-2019. One is a new partnership in which CEPI will pay for US biotech firm Moderna to manufacture an mRNA-based vaccine developed by the US National Institute of Allergy and Infectious Diseases. The other two programmes will use rapid response platforms that CEPI already supports to advance nCoV-2019 vaccine candidates into clinical testing as quickly as possible.

In one, CEPI is paying the University of Queensland, Australia, up to $10.6 million to develop a vaccine platform that enables targeted and rapid vaccine production against multiple viral pathogens. The technology works by synthesising viral surface proteins, which attach to host cells during infection, and clamping them into shape. This makes it easier for the immune system to recognise them as the correct antigen, and was previously targeting Mers and flu. US-headquartered vaccine company Novavax is pursuing an nCoV-2019 product using a similar conformational stabilisation approach, delivering the proteins as nanoparticles, independently of CEPI.

The other platform that CEPI already supports is Inovio’s, with the rapid response to 2019-nCoV’s genetic sequence that Richardson outlines enabled by Inovio’s DNA Medicines platform. CEPI was already paying Inovio up to $56 million for vaccine candidates against Mers and Lassa fever using the technology, which delivers optimised synthetic antigenic genes into cells. Once inside, the cells translate the genes into protein antigens that activate a person’s immune system, stimulating targeted T cell and antibody responses. It’s easier to develop such vaccines fast, Richardson explains. That improves the chances that, even if this viral outbreak is seasonal, as is typical, they can develop a vaccine in time to help this season’s victims.

‘We have a track record of success of really rapidly responding to viral outbreaks,’ explains Broderick. ‘Three or so years ago, when the Zika outbreak occurred, we went from viral sequence to treating our first patient in the clinic in seven months. That was really an unprecedented speed. With this novel coronavirus development, we are aiming to do it considerably faster than that. It really puts us in a pivotal position, I believe, to respond to an outbreak like the one we’re seeing in China.’

Despite this confidence in being first to market, Broderick would welcome others delivering approved vaccines with similar speed. ‘I think in this sort of circumstance, where the situation is so serious, the only path to a solution is us all working together,’ she says. ‘Just getting a vaccine should be the goal of the scientific community.’

Can existing drugs slow Covid-19?

By Rebecca Trager 2020-03-31T09:30:00+01:00

The fastest route to treatments may be to repurpose existing drugs – if they work

More than a dozen companies worldwide are working to develop a vaccine against Covid-19 amid the worsening pandemic. But experts estimate that will take at least 12­–18 months, so doctors and companies are trying to repurpose existing drugs in the fight against the novel coronavirus.

The regulatory situation is evolving quickly. In many jurisdictions, doctors can exercise their discretion to use approved drugs off-label for other diseases, but widespread use should be backed up by evidence from quality clinical trials, and ideally approval of the regulators.

Antimalarials chloroquine (pictured here) and hydroxychloroquine have some antiviral effects and can be produced very cheaply

On that front, there is some confusion, as demonstrated when the US president, Donald Trump, recently proclaimed that the US Food and Drug Administration (FDA) has approved the antimalarial chloroquine and its derivative hydroxychloroquine to treat Covid-19 patients. That claim was immediately walked back by FDA chief Steven Hahn and US National Institute of Allergy and Infectious Diseases director Anthony Fauci. The drugs are approved by the FDA to treat malaria, lupus and rheumatoid arthritis, and the agency has allowed their ‘compassionate use’ against Covid-19 in dire cases. Hahn emphasised that there are, as yet, no approved treatments for Covid-19, while Fauci stressed the importance of large clinical trials to prove safety and efficacy.

Hope and hype

The clamour around chloroquine, hydroxychloroquine and combinations with other drugs is mostly based on in vitro laboratory tests and small, preliminary clinical studies.

For example, a French study of 20 Chinese Covid-19 patients provided early evidence in March that the combination of hydroxychloroquine and the antibiotic azithromycin might be effective against the virus. Those who received the drugs showed a reduction in viral load compared to controls, and their illness duration was reduced.

The situation is far from clear, however. In another trial involving 30 patients in China, hydroxychloroquine not did not appear to perform particularly well. Three US researchers have also issued a stark warning that the ‘anti-viral mechanisms of chloroquine remain speculative’. They asserted that ‘caution should be exercised when making premature interpretations’ because ‘clinical trials are still ongoing and interim trial data have not yet been made available.’

More about Covid-19 in our podcasts

Small trials of other antivirals have also been inconclusive. One study from China saw no significant differences between 44 patients receiving either the HIV drugs lopinavir and/or ritonavir, the Russian antiviral Arbidol (umifenovir), or no antiviral medication as the control. While another Chinese study showed that lopinavir and ritonavir did not result in any faster clinical improvement compared to patients who received standard care alone.

Avoiding ‘friendly fire’

Side effects need careful consideration in the search for drugs. An urgent guidance paper from researchers at the Mayo Clinic in Minnesota, US, including genetic cardiologist Michael Ackerman, warns that chloroquine, hydroxychloroquine, lopinavir and ritonavir could all cause ‘drug-induced sudden cardiac death’.

HIV combination drugs ritonavir (left) and lopinavir (right) are viral protease inhibitors that prevent the HIV virus from replicating. So far they do not appear particularly effective against Covid-19

These medications block one of the critical potassium channels in the heart, which increases the odds that a patient’s heart rhythm could degenerate, resulting in cardiac arrest. The same can be said for azithromycin, according to Ackerman.

Ackerman estimates that around 1% of Covid-19-positive patients would be at increased risk of such cardiac adverse events from taking these medicines. While no such incidents have been reported in any of the ongoing trials, Ackerman says there have been numerous such deaths in the FDA’s adverse event reporting system. ‘The possibility of drug-induced sudden cardiac death is not theoretical at all,’ he tells Chemistry World. ‘It will happen if we don’t identify the individuals that are at highest risk for this possibility.’

Ackerman calls the current treatment situation for Covid-19 patients ‘a total Wild West’, and says these sorts of tragic outcomes should not be accepted as ‘just part of the friendly fire in this war against coronavirus’.

Meanwhile, several drug companies across the world, including Novartis, Teva and Mylan, are ramping up production and donating tens of millions of tablets of chloroquine and hydroxychloroquine.

Remdesivir revival

Gilead Sciences’ intravenous antiviral drug remdesivir (originally developed for Ebola, but found to be ineffective) has also shown promise in laboratory studies against Covid-19 and related coronaviruses.

Developed as a treatment for Ebola and Marburg viruses, remdesivir interrupts replication of viral RNA and is one of the more promising agents being tested against the coronavirus

While a preliminary US human trial was inconclusive, there are randomised controlled trials of remdesivir underway in China and the US. Gilead has begun two of its own randomised, open-label, multicenter studies to evaluate the safety and efficacy of intravenous remdesivir for Covid-19 treatment. These trials will enrol approximately 1000 patients, primarily across Asian countries.

The FDA had granted remdesivir Orphan Drug status, which would give Gilead seven years of market exclusivity as well as grants and tax credits towards clinical drug testing costs. However, Gilead has now asked the FDA to rescind that decision. ‘Gilead is confident that it can maintain an expedited timeline in seeking regulatory review of remdesivir, without the orphan drug designation,’ the company said.

Getting a clearer picture

Fujifilm’s antiviral Avigan (favipiravir), which has been approved in Japan to treat various forms of influenza since March 2014, has also shown some effectiveness at accelerating viral clearance in a Chinese trial of 80 patients. A slightly larger trial in China, comparing umifenovir and favipiravir in 246 patients, also showed some benefit associated with favipiravir.

Favipiravir is approved for treating influenza in Japan, and is proposed to act by inhibiting a viral RNA polymerase enzyme, hence stopping the virus replicating its RNA

To generate robust data to show which treatments are the most effective against Covid-19, the World Health Organization (WHO) is leading a large international study called the Solidarity trial. The mega-trial will test four different drugs or combinations – remdesivir, a mixture of lopinavir and ritonavir, lopinavir and ritonavir plus interferon beta, and chloroquine – and compare their effectiveness to the standard of care in participating countries. The study will enrol thousands of patients across participating countries, including Argentina, Bahrain, Canada, France, Iran, Norway, South Africa, Spain, Switzerland and Thailand.

Influenza treatment umifenovir inhibits membrane fusion, preventing viruses from entering host cells, but its activity against Covid-19 appears limited

Expanding the options further

There are plenty of other avenues to explore. An international team has mapped the human proteins that viral proteins interact with. They identified 69 existing drugs and experimental compounds that bind to 66 druggable human proteins, and might therefore have some effect on the virus’s replication or transmission. A report from the American Chemical Society’s Chemical Abstracts Service (CAS), taking in patents and publications relating to Covid-19 and similar RNA viruses, identified 6 potential viral protein targets and 12 drugs to investigate for repurposing.

Meanwhile, scientists at Oak Ridge National Lab in Tennessee, US, used IBM’s Summit supercomputer to run more than 8000 simulations and identify 77 small-molecule drug compounds that might prevent the virus from infecting host cells. The researchers ranked those candidates in order of interest based in part on how likely they were to bind to the S-protein spike, which mediates virus entry into host cells.

Action on antibodies

Severe cases of Covid-19 infection cause a kind of pneumonia and significant lung inflammation. This has led to efforts to repurpose antibodies that dampen the body’s immune inflammation response. These include Roche’s Actemra (tocilizumab), whose approval has been extended to cover Covid-19 patients in China, and Sanofi–Regeneron’s Kevzara (sarilumab). Both drugs are beginning new clinical trials in Covid-19 patients.

Antibodies could also provide routes to stopping the virus from spreading. A preliminary study involving 28 Chinese patients suggests that meplazumab, a humanised anti-CD147 antibody, can improve outcomes in severe cases. The antibody binds to Basigin (CD147), which appears to be one of the proteins that the virus uses to attach to and enter cells.

‘The use of the antibody meplazumab for Covid-19 seems very positive,’ said Ian Jones, a virologist at the University of Reading, UK. ‘ It targets both the virus and the damage done by it during infection,’ he added. However, Jones noted that the treatment requires infusion while in hospital, and such drugs are not usually widely available.

Regeneron has identified hundreds of virus-neutralising antibodies and has also isolated antibodies from people who have recovered from Covid-19. The company is looking to develop a multi-antibody cocktail that can be administered preventatively before exposure or as treatment for those already infected.

Another promising lead is convalescent plasma, which the FDA has given permission for US doctors to use on critically ill Covid-19 patients. After people who have been exposed to the novel coronavirus recover and no longer have the virus in their blood, scientists could collect their blood, concentrate it, and then give it to other patients, he explained. Hahn suggested that the antibodies it contains could potentially provide a real treatment benefit.

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