In the latest edition of our Weekly COVID19 R&D Tracker, which has tracked progress and expected timelines of vaccines and treatments for COVID19 since late April, we highlight key developments that are impacting our assumptions.
As we move towards November, we are expecting major clinical readouts from several key vaccine candidates, and as we move towards this critical stage we are seeing good progress on most fronts. Although AstraZeneca‘s vaccine continues to be on clinical hold in the US, and J&J has also temporarily paused studies of its vaccine candidate, generally we are seeing positive momentum with rolling regulatory reviews commencing, as well as positive earlier-phase data. On the treatment front, meanwhile, we have seen disappointing data for Veklury (remdesivir) as well as a clinical hold on Lilly’s/AbCellera’s neutralizing monoclonal antibody candidate.
Latest developments for vaccines in the week ending 15 October from IHS Markit‘s COVID19 R&D Tracker:
A second Russian COVID-19 vaccine, the peptide subunit vaccine EpiVacCorona from the State Centre for Research in Virology and Biotechnology (Vektor), has received interim pre-Phase-III approval for public access in Russia, on the basis of limited Phase I/II data. The interim registration date is given as 13 October 2020, and permits “civil circulation” until 1 January 2021. The first batches of 60,000 doses will be produced shortly, at which point Vektor plans to initiate an in-parallel “post-registration” Phase III trial in 40,000 participants, in various regions of Russia, including a study in 150 people aged over 60.
Moderna has initiated a rolling review submission with Canadian regulatory authority Health Canada for its mRNA-based COVID-19 vaccine mRNA-1273. The company has also received written confirmation from the European Medicines Agency (EMA) that mRNA-1273 is eligible for a European Union rolling review filing.
The Australian Therapeutic Goods Administration (TGA) has granted a “provisional determination” to AstraZeneca’s COVID-19 vaccine candidate AZD1222, as the first step towards a rolling review filing for eventual authorisation of AZD1222 in Australia.
Pfizer/BioNTech’s COVID-19 vaccine candidate BNT162b2 has been accepted for a rolling regulatory submission process by Health Canada. Separately, the companies are planning to expand their US trials to include paediatric patients aged 12-15 towards the end of 2020.
Johnson & Johnson (J&J) has temporarily paused dosing in all clinical trials for its COVID-19 vaccine candidate, due to an unexplained illness in a study participant enrolled in the Phase III ENSEMBLE trial. The illness is being evaluated by the independent Data Safety Monitoring Board (DSMB) as well as J&J’s internal clinical and safety physicians, and it has not yet been confirmed whether the participant received the vaccine or placebo. J&J has described the suspension as a routine precautionary measure in the course of a large clinical trial.
Phase III clinical trials for the Gamaleya Institute’s vaccine candidate Sputnik V have been initiated in the UAE, as part of the Phase III Sputnik V vaccine study currently underway in Russia and Belarus, and including over 40,000 participants. Expansion of testing for the vaccine in Venezuela is currently being evaluated, according to Reuters. In addition, the Russian trial will be expanded to include around 110 older participants, aged over 60.
A Phase III clinical study of Bharat Biotech (India)’s inactivated whole-virion COVID-19 vaccine candidate Covaxin (BBV152) – which was expected to commence from mid-October 2020 – has been deferred by two weeks to the last week of October 2020.
The first 100 participants received the first dose of Oxford University and the Serum Institute of India’s Covishield vaccine, a slightly modified version of AstraZeneca’s AZD1222, on 8 October, with initial results for the Phase II study expected within a month. Following assessment of the initial data, the trial will be expanded to a Phase III trial and will include 1,600 participants; the final results may be released by January 2021. Participants will receive Covishield, placebo, or AZD1222 itself.
A third-in-line Russian vaccine project, confirmed to be an inactivated whole-virion vaccine from the Chumakov Centre of the Russian Academy of Sciences, initiated dosing in the Phase I portion of Phase I/II trials in 15 participants for this vaccine on 9 October. The trial is due to progress to the Phase II portion in another 285 volunteers on 19 October. Phase I/II completion, and potentially a third Russian interim approval, is expected by December.
Latest developments for key COVID-19 therapeutics in the week ending 15 October:
Eli Lilly and AbCellera have taken the precautionary step of pausing a Phase III (ACTIV-3) adaptive trial evaluating the neutralising monoclonal antibody candidate LY-CoV555 (bamlanivimab) in COVID-19 patients requiring hospitalisation. The decision to halt further enrolment is being taken to investigate a potential adverse safety event and is based on an independent data safety monitoring board (DSMB) recommendation, although the action appears to be a standard precautionary measure and not an indication of larger safety concerns.
South Korean firm Celltrion has received approval to start Phase III trials in South Korea of its neutralising antibody drug candidate, CT-P59, as a potential preventative treatment for COVID-19. The late-stage prophylaxis trial will investigate the use of CT-P59 in asymptomatic individuals who often have close contact with COVID-19 patients, such as frontline healthcare staff. About 1,000 volunteers are expected to be enrolled in the South Korea-based trial. South Korea’s Ministry of Food and Drug Safety has also recently approved Phase II/III trials of CT-P59 in mild-to-moderately affected COVID-19 patients. Celltrion has previously indicated that the company plans to seek conditional approval for CT-P59, under emergency use authorisation procedures, by the end of 2020.
UK firm AstraZeneca has announced plans to advance COVID-19-specific long-acting antibody (LAAB) cocktail AZD7442 into two global Phase III trials in over 6,000 participants. AZD7442 contains two monoclonal antibodies that have been engineered with AstraZeneca’s proprietary half-life extension technology to have prolonged therapeutic activity, potentially for 6-12 months following a single dose, and have also been designed to reduce the risk of resistance development by viral mutations over time, and reduced Fc receptor binding to avoid the risk of antibody-dependent enhancement. Two Phase III trials are planned for initiation in the coming weeks – one evaluating the safety and efficacy of AZD7442 in prophylaxis of infection for up to 12 months in around 5,000 participants, and the other evaluating post-exposure prophylaxis and pre-emptive treatment in about 1,100 participants. Additional trials are planned for treatment of COVID-19 in about 4,000 patients.
Relief Therapeutics and NeuroRx have reported positive top-line results from an open-label prospective study evaluating RLF-100 (aviptadil) in 21 patients admitted to an intensive care unit (ICU) with critical COVID-19 and respiratory failure. All patients in the open-label trial had severe comorbidities and were deteriorating despite treatment with approved therapies, making them technically ineligible for participation in an in-parallel randomised controlled Phase IIb/III trial. Treatment with aviptadil resulted in a significantly higher likelihood of survival beyond 60 days (81%) versus controls (17%) – a 9-fold increased probability of survival and recovery from respiratory failure. The majority of these highly comorbid patients treated with aviptadil have returned safely to their families. Detailed results from the randomised double-blind placebo-controlled trial in less severely comorbid patients are expected this quarter.
Gilead Sciences (US) has announced the publication of final results from NIAID’s international double-blind, placebo-controlled Phase III ACTT-1 trial evaluating a 10-day course of Veklury (remdesivir) placebo in 1,062 adults hospitalised with mild-to-moderate or severe COVID-19. The trial met its primary endpoint of shortening time to recovery through day 29 (10 days) on Veklury versus placebo (15 days), increasing the recovery rate by 29%. In patients requiring oxygen at baseline, recovery time was even more pronounced with Veklury (11 days) versus placebo (18 days). Patients were 50% more likely to have improved by day 15 when treated with Veklury compared with placebo, and this was maintained through day 29. The benefit of treatment was greater when given within 10 days of symptom onset, although benefit was still observed across more ranges of symptom duration. There was no significant effect of Veklury versus placebo on lowering mortality in the overall study population at day 15 and day 29, although a trend was observed. However, a post-hoc analysis of the data found that patients requiring low-flow oxygen at baseline achieved a significant 72% reduction in mortality at day 15 (3.1% versus 10.5%) and a significant 70% reduction in mortality at day 29 (4% versus 13%). Veklury treatment also reduced disease progression, resulting in fewer median days on oxygen support (13 days versus 21 days) and a significantly lower incidence of requiring new ventilation or ECMO (13%) compared with those on placebo (23%).
Eli Lilly has announced new data from the NIAID-sponsored ACTT-2 trial evaluating Olumiant (baricitinib) in combination with Veklury in hospitalised COVID-19 patients. Addition of Olumiant 4 mg to Veklury further reduced time to recovery and improved clinical outcomes versus Veklury alone, with the greatest benefit reported in patients requiring supplemental oxygen or high-flow oxygen/non-invasive ventilation at baseline. Treatment with Veklury and Olumiant significantly reduced the median time to recovery to seven days, compared with eight days with Veklury alone, meeting the study’s primary endpoint. The odds of improvement in clinical status at day 15 were 30% greater in patients treated with Veklury plus Olumiant compared with Veklury alone.
The US NIH has announced the initiation of a major placebo-controlled Phase III trial (ITAC) to test the safety, tolerability, and efficacy of a combination of the anti-viral remdesivir (Gilead Sciences) with concentrated COVID-19 hyperimmune intravenous immunoglobulin (hIVIG) from convalescent plasma. The ITAC study is being conducted in the US, Mexico, and 16 other territories across five continents in 500 hospitalised adults aged 18 or over who have had COVID-19 for up to 12 days, without life-threatening organ dysfunction or failure. COVID-19 hIVIG will be supplied by four companies under the CoVIg-19 Plasma Alliance – Emergent BioSolutions (US), Grifols (Spain), CSL Behring (US), and Takeda (Japan).
For vaccines against COVID-19, our baseline assumption is that we will likely have a fully approved, effective vaccine with access to large populations across several countries in the summer of 2021. This has been the working assumption since the launch of our weekly tracker at the end of April 2020, and is based on assessment of typical development and regulatory timelines, the potential for clinical failures, the build-up of necessary manufacturing and distribution channels, and the global demand to fast-track a vaccine approval. Until mid-2021, we are likely to see – and have already seen – conditional/emergency approvals of experimental vaccines in subset populations. Importantly, these emergency approvals do not change any fundamental assumptions around the trajectory of the disease, or the ability of countries to reopen broader parts of their economies. We have seen some approvals in China, Russia, and the United Arab Emirates (UAE) and pressure building in the United States for approvals before the end of 2020. These approvals are, however, limited in nature, based on vaccines with no evidence yet of protective effectiveness against real world infection. For treatments against COVID-19, our baseline assumption is that we will have no fully approved, effective treatment against COVID-19 until the first half of 2021. We have already seen some exceptional, emergency approvals for hydroxychloroquine (subsequently revoked), dexamethasone, remdesivir, and convalescent plasma, but we do not see these as particularly effective treatments according to the data to date.