AstraZeneca’s fast-growing BTK inhibitor Calquence is already challenging class leader Imbruvica from Johnson & Johnson/AbbVie in the treatment of chronic lymphocytic leukaemia (CLL). Now, AZ has new data suggesting its drug is less likely to cause a serious cardiac side effect.
The latest study in AZ’s ELEVATE trial series showed that Calquence (acalabrutinib) matched Imbruvica (ibrutinib) on keeping adults with previously treated, high-risk CLL alive without disease progression.
It also showed that AZ’s drug was significantly less likely to be associated with atrial fibrillation (AF), an irregular heart rate that can increase the risk of stroke, heart failure and other cardiovascular complications.
Two years ago, a study by the Cleveland Clinic in the US suggested that around 9% of patients treated with Imbruvica developed AF within a year of starting the drug, which was in the middle of other reviews suggesting the rate varied from around 4% to 16%. The authors suggested that it could generally be managed safely with drugs like beta blockers.
According to AZ, the ELEVATE-RR trial is the first phase 3 study to compare two BTK inhibitors head to head in CLL, which is the most common form of leukaemia in adults. So far only the top-line outcome has been released, without any supporting data.
First approved for mantle cell lymphoma (MCL) in 2017, Calquence sales have rocketed since its approval for CLL towards the end of 2019, rising more than 200% to reach $340 million in the first nine months of 2020.
It is however still dwarfed by J&J and AbbVie’s blockbuster, which made around $5.6 billion in 2019 from half a dozen indications, including CLL and MCL. AZ has said is seeing swift growth for its brand in CLL thanks to its “outstanding efficacy and a favourable tolerability profile”.
That allowed the drug to capture around 35% of new patient starts in the US in the third quarter of 2020, according to the drugmaker.
That came ahead of the approval of Calquence for CLL in Europe, which was secured last November, as well registration of the drug in the last few days for relapsed or refractory CLL in Japan, based ono the results of the ASCEND trial.
“With over forty months of follow-up, today’s results confirm that Calquence…displays superior safety in atrial fibrillation without compromising efficacy,” said the company’s head of oncology José Baselga.
“The totality of the data confirm our confidence in the favourable benefit-risk profile of Calquence.”
AZ meanwhile is running trials to try to position Calquence as an alternative to Imbruvica in other indications, including diffuse large B-cell lymphoma, Waldenström’s macroglobulinaemia, and follicular lymphoma.
https://pharmaphorum.com/news/az-says-calquence-is-a-safer-drug-than-imbruvica/
Pharmaceutical giant Merck said on Monday that it was discontinuing the development of two Covid-19 vaccine candidates after early clinical trial data showed an "inferior" immune response.
Merck said in a statement posted on its website the decision to scrap the two vaccine candidates followed its review of findings from Phase 1 clinical studies.
The company said the studies showed that both candidates were generally well tolerated, but the immune responses were inferior to those seen following natural infection and those reported for other Covid-19 vaccines.
Evidence is growing that some coronavirus variants could evade immune responses triggered by vaccines and previous infections. Researchers are trying to make sense of a tsunami of lab studies released this week that raise concerns about some emerging variants and mutations.
“Some of the data I’ve seen in the last 48 hours have really scared me,” says Daniel Altmann, an immunologist at Imperial College London, who worries that some of results could portend a reduction in the effectiveness of COVID-19 vaccines.
But the picture is murky, Altmann and other scientists emphasize. The studies — which examined the blood of small numbers of people who had recovered from COVID-19 or received a vaccine — probed only their antibodies’ capacity to ‘neutralize’ variants in laboratory tests, and not the wider effects of other components of their immune response.
Neither do the studies indicate whether the changes in antibody activity make any difference to the real-world effectiveness of vaccines or the likelihood of reinfection. “Are these changes going to be important? I really don't know,” says Paul Bieniasz, a virologist at the Rockefeller University in New York City, who co-led one of the studies.
Much of the concern centres around a variant that researchers identified in South Africa in late 2020. A team led by Tulio de Oliveira, a bioinformatician at the University of KwaZulu-Natal in Durban, South Africa, linked the variant — called 501Y.V2 — to a fast-growing epidemic in Eastern Cape province that has since spread across South Africa and into other countries1. The lineage carries many mutations in the SARS-CoV-2 spike protein — the immune system’s prime target, which allows the virus to identify and infect host cells — including some changes linked to weakened antibody activity against the virus2,3.
The Eastern Cape was hit hard by South Africa’s first COVID-19 wave, and researchers wondered whether the rapid spread of 501Y.V2 could be partly explained by its ability to elude previously established immune responses.
To investigate this, de Oliveira, virologist Alex Sigal at the Africa Health Research Institute in Durban and other colleagues isolated 501Y.V2 viruses from people infected with the variant4. They then tested the variant samples against serum — the antibody-containing portion of blood — taken from six people who had recovered from COVID-19 caused by other versions of the virus. This convalescent serum tends to contain neutralizing, or virus-blocking, antibodies that can prevent infection. The researchers found that the convalescent serum was much worse at neutralizing 501Y.V2 than at neutralizing variants that circulated earlier in the pandemic. Some people’s plasma performed better against 501Y.V2 than did others’, but in all cases, the neutralizing power was substantially weakened, says de Oliveira. “It’s extremely worrying.”
In a separate study5, a team led by virologist Penny Moore at the National Institute for Communicable Diseases and the University of the Witwatersrand in Johannesburg, South Africa, probed the effects of convalescent serum on various combinations of spike mutations found in 501Y.V2. They did this using a ‘pseudovirus’ — a modified form of HIV that infects cells using the SARS-CoV-2 spike protein.
These experiments showed that 501Y.V2 contains mutations that blunt the effects of neutralizing antibodies that recognize two key regions of spike: its receptor-binding and N-terminal domains. Pseudoviruses with the full package of 501Y.V2 mutations were fully resistant to convalescent serum from 21 out of 44 participants, and were partly resistant to the vast majority of people’s sera, Moore’s team found.
There is now proof of several reinfections with 501Y.V2 in South Africa, says de Oliveira. It seems increasingly likely that the variant’s ability to spread in places hit hard by earlier waves of COVID-19 is being driven, in part, by its capacity to evade immune responses that developed in response to earlier versions of the virus.
“It becomes virtually inescapable that that’s what’s happening,” says Bieniasz, noting that variants identified in Brazil and the United Kingdom carry some of the same spike mutations.
Both South African teams will soon test the 501Y.V2 variant with serum from people who participated in COVID-19 vaccine trials, and similar studies are under way at labs worldwide. A team co-led by Bieniasz found that mutations in the receptor-binding domain of 501Y.V2 caused a modest drop in the potency of antibodies from people who had received either the Pfizer or Moderna mRNA vaccines6. That’s “a reassuring finding”, says Moore, but it will be important to test the consequences of other mutations in 501Y.V2.
Whether these could lessen the effectiveness of vaccines is still uncertain, says Volker Thiel, an RNA virologist at the University of Bern in Switzerland. Most COVID-19 vaccines elicit high levels of antibodies that target diverse regions of the spike protein, so some of the molecules are likely to be able to block variants of the virus. And other components of the immune response, such as T cells, might not be affected by 501Y.V2. “Although the vaccines target only the spike gene, they should still mount an immune response that is diverse enough that these new variants should be covered,” Thiel says. “But experimental studies need to be done.”
Data from ongoing efficacy trials and national vaccine rollouts should be able to uncover the effects of the variants. Several vaccines are still being trialled in South Africa, and researchers will be watching for any drop in their ability to prevent COVID-19 that’s linked to the rise of 501Y.V2.
A dampened antibody response to variants such as 501Y.V2 might not be much of a problem in practice, says Marion Koopmans, a virologist at the Erasmus Medical Center in Rotterdam, the Netherlands. “You can see some change in a lab assay, which does not have an effect in a person because that person still has enough antibodies to neutralize the infection.” It can also be difficult to disentangle whether reinfections are due to waning immune responses triggered by the first infection, or to the effects of a mutation, she adds.
Clues are also beginning to emerge about the behaviour of a fast-spreading variant identified in the United Kingdom, known as B.1.1.7. In pseudovirus experiments, researchers at biotech firm BioNTech in Mainz, Germany, found that B.1.1.7’s spike mutations had little effect on sera from 16 people who had received the vaccine the company developed with Pfizer7. Meanwhile, a team led by virologist Ravindra Gupta at the University of Cambridge, UK, looked at the sera of 15 people who had received the first of two doses of the same immunization8; the team found that 10 people’s sera was less effective against B.1.1.7 than against other versions of SARS-CoV-2. These changes shouldn’t make a difference to the vaccine’s effectiveness now, says Gupta, but they could as antibody levels wane over time.
What this week’s results mean for battling the pandemic are not yet clear. It is a top priority for researchers to determine whether mutations in 501Y.V2 are responsible for reinfections. If they are, says de Oliveira, “the whole idea of herd immunity would become a pipe-dream, at least from natural infection”.
Paul Bieniasz didn’t mince words in a sarcastic New Year’s Day statement he tweeted. If he wanted to create a new, vaccine-resisting version of the pandemic coronavirus, the Rockefeller University virologist wrote, “having developed a remarkable two-dose vaccine, [I’d] … ADMINISTER IT TO MILLIONS OF PEOPLE – BUT DELAY THE SECOND DOSE. … If we let immunity wane for a little while, say 4 to 12 weeks, we just might hit the sweet spot”—and create a virus that could foil the vaccine.
Bieniasz was reacting to the United Kingdom’s 30 December 2020 decision to allow up to 12 weeks between doses of two authorized vaccines, rather than the 3 or 4 weeks tested in the vaccines’ clinical trials. Desperate to tame a massive surge in cases and alarmed by the spread of a new, more contagious variant of the virus, U.K. vaccine experts were aiming to quickly get at least some protection into the arms of as many people as possible.
In a similar tactic to stretch scarce vaccine supplies, on Monday Russia revealed it would test its two-dose Sputnik V vaccine to see whether just one dose—“Sputnik Light”—would be efficacious. And yesterday, the Trump administration announced it would no longer withhold 50% of the available vaccine supply in the United States to ensure timely second doses.
But Bieniasz and other virologists worry that extending the dosing interval might result in millions of people with only partial immunity as they wait for their second dose—a potential breeding ground for vaccine-resistant mutations. “If we end up with everybody just getting one dose with no doses available for a timely boost, that would in my opinion, be a problem,” says Florian Krammer, a virologist at the Icahn School of Medicine at Mount Sinai.
Experts don’t agree, however, on how big of a risk a long delay between doses poses, especially when weighed against the current out-of-control spread of the pandemic coronavirus, SARS-CoV-2, in many places. “It’s carnage out there,” says Andrew Read, an evolutionary microbiologist at Pennsylvania State University, University Park. “Twice as many people with partial immunity has got to be better than full immunity in half of them.”
Yet the record case counts also create an exceptional milieu—with untold billions of viral replications occurring every second—for mutations to arise as the virus makes errors in copying its genetic alphabet. One viral variant, first spotted in South Africa, has evolved two mutations that block the effectiveness of antibodies used to treat COVID-19, raising the specter that they could also block vaccine-induced antibodies.
One of those mutations reduced by 10-fold or more the ability of antibodies from some recovered COVID-19 patients to neutralize viruses expressing the coronavirus spike protein, according to a recent preprint by Jesse Bloom and Allison Greaney of the Fred Hutchinson Cancer Research Center and their colleagues.
Virologists worry lengthening the dosing interval from, say, 3 weeks to 3 months, could speed the emergence of such mutants by creating a pool of subimmune people who have enough antibodies to slow the virus and avoid developing symptoms—but not enough to wipe it out. Those people might incubate viruses with mutations that allow them to dodge vaccine-induced antibodies—for example, by changing the amino acid sequence at a site where antibodies previously bound, preventing the virus from invading cells and replicating. Because most COVID-19 vaccines generate immunity to just one protein, the spike protein on the virus’ surface, the new vaccines might be easier for mutant viruses to evade than other vaccines that evoke broader immunity, Read notes.
Some data support the possibility that partial immunity could spawn new variants. For example, a case study published recently in The New England Journal of Medicine reported how, in a prolonged, ultimately fatal case of SARS-CoV-2 in an immunocompromised man, the virus kept mutating at a rapid rate compared with virus circulating in the general population.
But evolutionary biologists who use computer modeling to generate scenarios of viral “escape” from vaccines say there aren’t enough data yet to compute this still-hypothetical risk, and any single mutation is unlikely to send vaccine effectiveness plummeting. Bloom notes that “even [the] worst mutations” seen so far only partially eroded the effectiveness of antibodies from recovered patients’ blood.
“Most people I know who do dynamical modeling in public health and evolution think [vaccine escape] is a secondary … concern. That it’s more important just to immunize broadly right now. I’m in that camp,” says Sarah Cobey, an epidemiologist and evolutionary biologist at the University of Chicago.
Historically, few viruses have managed to evolve resistance to vaccines, with the notable exception of seasonal influenza, which evolves so rapidly on its own—without vaccine pressure—that it requires a newly designed vaccine every year. The poliovirus mutates much more rapidly than the new coronavirus, yet polio vaccines remain highly effective. The measles virus mutates about twice every million times it replicates. But the virus cannot end run its highly effective vaccine, made from live, attenuated virus, according to a preprint published in October 2020, in part because the vaccine arouses such a broad array of antibodies that no single mutation has much impact.
If over time the novel coronavirus does mutate significantly, researchers can update the vaccines, says Lucy Van Dorp, a computational geneticist at University College London. She notes that the messenger RNA vaccines made by Pfizer and Moderna “are very well suited to updates.” The chief executive of BioNTech, which first developed Pfizer’s vaccine, recently told The Financial Times that “we could manufacture a new vaccine within 6 weeks.”
Still, scientists would like to resolve their theoretical debate with data. Lab studies are examining how well antibodies from vaccinated people neutralize various strains of the virus. And data expected soon from late-stage vaccine trials in South Africa, which began before the concerning new strain appeared in that country, should illuminate that strain’s ability to escape these vaccines.
In the meantime, a live experiment in lengthening the dose interval is underway in the United Kingdom. Bieniasz says he can’t say with any certainty whether vaccine-resisting viral strains will result. “But if that was my goal this is how I would do it.”
By Derek Lowe
We have some more data on the vaccine front that’s worth looking at. J&J has published a bit more on their trials of their adenovirus-vector candidate, with data on the immunogenicity of the vaccine in patients. They have several cohorts evaluated: a single shot of low dose, single shot of high dose, two shots of low dose and two shots of high dose. This article at STAT sums it up: it’s clear that the vaccine generates neutralizing antibodies at both low and high doses, that the higher doses do indeed tend to give higher antibody levels, that the two-dose regime leads to higher antibody titers overall, and that these titer rise over time (present at day 29 after injection and actually higher at day 57).
So far, so good. But what we still don’t know are the correlates of protection: which of these antibody levels are enough to keep a person from getting the coronavirus and to what extent? The same goes, of course, for the T-cell data. The paper shows levels of both CD4+ and CD8+ T cells after vaccination, but how these relate to protection is an open question. And for all of these, such numbers might be different in different patient groups (particularly older versus younger patients). Fortunately, we should soon (within two weeks, I’d say) be getting actual efficacy data from the single-dose trial, so I’m not going to spend much energy speculating.
There’s another thing to watch: the New York Times reported yesterday that J&J has told the US government that they might have fallen as much as two months behind on their production schedule for the vaccine. No word as to what the problem might be. Adenovirus vectors have vulnerabilities of their own, with a whole set of manufacturing steps that are distinct from the other types. What you gain in not having everything reliant on a single pathway, you can lose when unique problems crop up. But overall it’s still far better to have a diverse set of things under development than not.
Now for another vaccine candidate, the inactivated virus one from SinoVac. I discussed that one here after an earlier publication, and when last heard from there was an odd report from Turkey of 90% efficacy in a small trial with no data to back it up. Then just a few days ago there was a figure of 78% efficacy from the trial in Brazil, but that has now been revised to 50%. Meanwhile, Indonesia says that a preliminary analysis shows about 65% efficacy – the government there has approved the vaccine, but the rollout is apparently not going well. To be honest, these are about the efficacy numbers one could expect from an inactivated-virus vaccine. It’s an old technology, and it doesn’t always work that well. The chaotic release of these data (and the lack of comment from SinoVac themselves about any of these numbers) does not build confidence, with the consequences that you can see in that last link.
But that takes us back around to what the true efficacy of another vaccine is: the Oxford/AZ one. The statistics on that are a mess too, and their public presentation has been a mess, and we can only hope that things come into better focus when their US trial reports (other data are coming as well). But at the moment, I wouldn’t be prepared to put money on how much better it is than the SinoVac one. To be sure, a 50% or 60% effective vaccine (with a reasonable safety profile) is surely better than no vaccine at all. But it means that you have to vaccinate a lot more people before you start to make a dent in a pandemic like this one, which is a significant real-world limitation. Of course, here in the US we’re not doing that great a job in rolling out the 95% effective ones, either, if we want to talk real world effects!
Update: let’s compare these numbers with the immunity that a person can get from just being infected with the coronavirus itself. That’s been a matter for speculation, but we now have some numbers from the NHS in the UK. In their SIREN study they’ve been looking at a large cohort of health care workers, monitoring them for infections and antibodies. Out of over six thousand who have had the virus, there have been about 42 re-infections. Comparing that to the cohort of people who were never infected, that comes out to 83% efficacy. So there’s your comparison number – which means that being vaccinated with either of the mRNA agents provides better protection than being infected with the real coronavirus can.
https://blogs.sciencemag.org/pipeline/archives/2021/01/14/johnson-and-johnson-sinovac-and-more
PDF: https://www.thelancet.com/action/showPdf?pii=S2589-5370%2820%2930464-8
