LIVE BLOG: R&D response to COVID-19 pandemic (archived)

Pharming has announced top line results from two randomised, open label clinical trials of its immune-modulating drug Ruconest in the treatment of patients hospitalised with COVID-19.

The aim was to show the product prevented severe SARS-CoV-2 infection. In one study held in the US, patients treated with Ruconest plus standard of care had statistically significant lower disease severity scores at day seven, compared to patients who received standard of care alone.

However, in the second, investigator-led study, conducted in Switzerland, Brazil and Mexico, and funded through the Swiss National Research programme in COVID-19 of the National Science Foundation, there was no difference in disease severity at day seven between Ruconest treated patients and those receiving standard of care alone.

Leiden-based Pharming said the results of the Swiss study are difficult to interpret because there was a significant difference in disease severity at baseline, with patients in the Ruconest arm having more severe disease.

Anurag Relan, Pharming’s Chief Medical Officer said the results support the initial hypothesis on the need to control hyper-inflammatory processes in patients with severe COVID-19 infection. “It is unfortunate we cannot draw many conclusions from the investigator-led study, due to the imbalance between the Ruconest-arm and the control group at the start of the trial. We will analyse the full results of these studies as we design future clinical trials with Ruconest for the treatment of COVID-19,” Relan said.

French biotech Valneva said it is continuing phase III development of its COVID-19 vaccine after the UK government cancelled its order for 100 million doses.

The UK government alleges Valneva is in breach of its obligations under the contract between the two, something the company “strenuously denies”.

No details of the exact nature of the dispute were disclosed. The cancellation was unexpected, given the UK government’s investment in Valneva’s manufacturing facility in Livingston, Scotland, where commercial supplies of the vaccine are already being made. The government investment was due to be recouped once vaccine started to be supplied under the contract.

Valneva also has received UK government support with the clinical development of the vaccine, which is the only one in Europe using a whole, inactivated SARS-CoV-2 virus. This was seen as a key technology and an important way of spreading the risk in vaccines in development at the point Valneva was awarded the contract, worth up to €1.4 billion, a year ago.

The phase III clinical testing of the vaccine is ongoing under the supervision of Public Health England, with results expected to be available early in the fourth quarter of 2021. Last month, Valneva said it had started submission of data for the conditional approval of the vaccine with the UK Medicines and Healthcare products Regulatory Agency, and was expecting initial approval could be granted in late 2021.

Valneva said it has, “has worked tirelessly, and to its best efforts” on the collaboration with the UK government and will continue to develop the vacccine.

The European Medicines Agency has listed the rare autoimmune disorder, Guillain-Barre syndrome as a possible side effect of the AstraZeneca COVID-19 vaccine, following the latest review of reports of adverse events following administration of the product.

The information leaflet will be updated to reflect this. Pains in the legs and arms or stomach and influenza-like symptoms have also been included in the product information as side effects.

This follows the addition of a warning to raise awareness of cases of Guillain-Barré syndrome in July, since when EMA has been keeping reports of the syndrome under close monitoring. In a meeting earlier this week it assessed additional data supplied by AstraZeneca and the results from a scientific literature review.

A total of 833 cases of Guillain-Barré syndrome were reported with the vaccine worldwide up to 31 July 2021, at which point more than 592 million doses had been administered.

Based on the assessment of the data, and taking into account advice from neurological experts, EMA has now concluded that a causal relationship between the AstraZeneca vaccine and Guillain-Barré syndrome is at least a reasonable possibility and that the syndrome should therefore be added to the product information as a side effect.

The global picture of access to COVID-19 vaccines is “unacceptable” according to the organisations leading the Covax initiative, which was set up to ensure equitable distribution, in their latest supply forecast.

To date, only 20% of people in low- and lower-middle-income countries have received a first dose of vaccine compared to 80% in high- and upper-middle income countries, according to a joint statement by the Coalition for Epidemic Preparedness Innovations, Gavi, the Vaccine Alliance and the World Health Organisation.

Covax’s ability to protect the most vulnerable continues to be hampered by export bans, the prioritisation of bilateral deals by manufacturers and countries, ongoing challenges in scaling up production by some key producers, and delays in filing for regulatory approval, the statement says.

According to the supply forecast, Covax expects to have access to 1.425 billion doses of vaccine in 2021. Of these doses, approximately 1.2 billion will be available for lower income economies, enough to protect 20% of the population, or 40% of all adults, in 92 countries. The key Covax milestone of two billion doses released for delivery is now expected to be reached in the first quarter of 2022.

Covax says it is working closely with governments to ensure the conditions are in place to ensure successful rollout of vaccines. It is now calling on donors and manufacturers to recommit their support and prevent further delays to equitable access.

Manufacturers are asked to deliver vaccine supplies in accordance with firm commitments and provide transparency on timelines, to allow countries to plan in advance.

Countries which are ahead of Covax in manufacturer queues and that have already achieved high vaccination coverage, are asked to give up their places in the queue to Covax.

EMA has started evaluating an application for the use of a booster dose of the Pfizer/BioNTech COVID-19 vaccine, to be given six months after the second dose in people aged 16 years and older.

The booster doses would be given to vaccinated people to restore protection after it has waned.

EMA said it will carry out an accelerated assessment of data, including results from an ongoing clinical trial in which around 300 adults with healthy immune systems received a booster dose approximately six months after the second dose.

The outcome of this evaluation is expected within the next few weeks.

Separately, EMA is also assessing data from the literature on the use of an additional, third dose of an mRNA vaccine in severely immunocompromised people who do not achieve an adequate level of protection from standard primary vaccination and may need another dose as part of their primary vaccination.

Although EMA and the European Centres for Disease Control say they don’t consider the need for COVID-19 vaccine booster doses to be urgent,  EMA is evaluating the application for boosters to ensure evidence is available to support further doses as necessary.

Advice on how vaccinations should be given remains the prerogative of the national immunisation advisory groups.

AstraZeneca and the European Commission reached an agreement to end legal proceedings over the advance purchase agreement for the delivery of the COVID-19 vaccine.

Under the agreement, AstraZeneca has said it will deliver 60 million doses of the vaccine by the end of the third quarter 2021, 75 million by the end of the fourth quarter 2021 and 65 million by the end of the first quarter 2022. Member states will be provided with regular deliveries and there will be rebates in the event of any delays.

“We are fully committed to manufacture [the vaccine] for Europe following the release for supply of more than 140 million doses to date at no profit,” said Ruud Dobber, executive vice president of Biopharmaceuticals at AstraZeneca.

Legal proceedings by the European Commission against AstraZeneca were initiated in Brussels on 21 April 2021, and court hearings were scheduled for the end of September 2021.

To date, AstraZeneca and its partners have supplied more than 1.1 billion doses of vaccine to over 170 countries; approximately two thirds have gone to poorer countries.

Moderna announced it has started submission to the U. Food and Drug Administration (FDA) for the evaluation of a booster dose of its COVID-19 vaccine and expects to submit data to the European Medicines Agency and other regulatory authorities around the world in the coming days.

The submitted data shows “robust antibody responses against the Delta variant,” said Stéphane Bancel, CEO of Moderna.

The phase II study of the vaccine was amended to offer a booster dose to interested participants six months following their second dose, with 344 volunteers taking up the offer. Neutralising antibody levels had waned significantly prior to boosting. The booster dose raised neutralising levels significantly.

After a third dose, a similar level of neutralising antibodies was seen across age groups, notably in older adults aged 65 and above. The safety profile following dose three was similar to that observed for the second dose.

People who catch SARS-CoV-2 despite having received one or two doses of vaccine have significantly lower odds of severe disease or hospital admission than unvaccinated people, according to a large-scale study investigating COVID-19 breakthrough infections.

Researchers also found that the odds of experiencing Long COVID, with symptoms lasting 28 days or more after a positive test were cut in half for people who received two vaccines doses, in the study published in The Lancet Infectious Diseases journal.

Those most vulnerable to a breakthrough infection after their first vaccine dose included frail older adults aged 60 years and above, and older adults living with underlying conditions such as obesity, heart disease, kidney disease, and lung disease.

In all age groups, people living in deprived areas, such as densely populated urban settings, were more likely to experience a breakthrough infection.

“We are at a critical point in the pandemic as we see cases rising worldwide due to the Delta variant,” said co-author Claire Steves of King’s College London. The Delta variant is now causing most infections in Europe and the rest of the world, and other data shows vaccines are less effective against it.

“Breakthrough infections are expected and don’t diminish the fact that these vaccines are doing exactly what they were designed to do - save lives and prevent serious illness,” Steves said.

The researchers used self-reported data collected by the UK COVID symptom social media app. Of 1.2 million adults who reported to the app who received at least one dose of any vaccine between 8 December 2020 to 4 July 2021, fewer than 0.5% reported a breakthrough infection more than 14 days after their first dose. Of those who had received who received two doses, fewer than 0.2% experienced a breakthrough infection more than seven days after the second dose. In total, there were 2,370 positive cases after 971,504 second vaccine.

Among those who did experience a breakthrough infection, the odds of that infection being asymptomatic increased by 63% after one vaccine dose and by 94% after the second dose. Researchers also found that the odds of hospitalisation were reduced by approximately 70% after one or two doses, and that the odds of experiencing severe disease, defined as having five or more symptoms in the first week of illness, were lessened by approximately one third. In addition, the odds of Long COVID, having symptoms for 28 days or more after infection, were reduced by 50% after two doses.

Based on current evidence, there is no urgent need for the administration of booster doses of vaccines to fully vaccinated individuals in the general population, according to a technical report issued by the European Centre for Disease Prevention and Control (ECDC).

However, additional doses should be considered for people with severely weakened immune systems as part of their primary vaccination.

Evidence on vaccine effectiveness and duration of protection shows that all vaccines authorised in the EU are currently highly protective against COVID-19-related hospitalisation, severe disease and death.

At the same time, about one in three adults over 18 years is still currently not fully vaccinated. “In this situation, the priority now should be to vaccinate all those eligible individuals who have not yet completed their recommended vaccination course,” the European Medicines Agency said in a statement.

EMA is currently assessing data on booster doses, and said while it does this member states “may consider preparatory plans for administering boosters.”

The first of the so-called second wave of COVID-19 vaccines, which have been designed from the ground up to be more accessible and affordable, has started a phase III clinical trial.

The vaccine, GBP510, developed by South Korean biotech SK Bioscience, will be administered in combination with an adjuvant from GlaxoSmithKline (GSK), which is intended to increase the immune response.

The randomised global trial will enrol around 4,000 participants from a range of countries to evaluate GBP510's safety and immunogenicity compared to the AstraZeneca/Oxford University COVID-19 vaccine. The study will be one of the first global phase III trials to directly compare two different COVID-19 vaccines.

"We are grateful that we were able to advance to the phase III study with the unprecedented support of global initiatives, including GSK, the Coalition for Epidemic Preparedness Initiative (CEPI), and the Bill & Melinda Gates Foundation,” said Jaeyong Ahn, CEO of SK Bioscience.

“While many countries have made good progress with vaccination, there remains a need for accessible and affordable COVID-19 vaccines to ensure equitable access and to protect people across the world,” said Thomas Breuer, chief global health officer at GSK.

The move to phase III follows positive interim phase I/II data which showed that all participants who received the adjuvanted vaccine developed strong neutralising antibody responses, demonstrating a 100% seroconversion rate. Neutralising antibody levels were between five and a maximum of eight times higher than in people who had recovered from COVID-19.

The vaccine is being developed by SK Bioscience in collaboration with the Institute for Protein Design at the University of Washington, with $213 million funding from the Gates Foundation and CEPI as part of the 'Wave 2' vaccine investment project to develop more accessible and affordable COVID-19 vaccines.

Results from the phase III study are expected in the first half of 2022.