Oxford/AZ Vaccine Efficacy Data

 by  Derek Lowe 

As of this morning, we have a first look at the Oxford/AstraZeneca vaccine’s efficacy in clinical trials via press releases from both organizations. The number in the headlines says about 70% efficacy, but there’s more to the story.

Here’s the landscape so far: we have results from Pfizer and from Moderna, both of them developing mRNA-based coronavirus vaccines, and both showing efficacy in the 90 to 95% range. The Oxford effort is a different platform, though, with key similarities and key differences. It relies on another virus (a chimpanzee-derived adenovirus) that has had its original DNA genetic payload removed and substituted with the appropriate DNA to produce the full-length Spike protein of the coronavirus. In this construct, the original viral “leader sequence” at the beginning of this DNA has been replaced with another, the leader sequence found for the human tissue plasminogen activase (TPA) protein, because this gave better expression and a better immune response. These adenovirus particles can’t replicate – they don’t have the DNA to express the proteins needed to do that. But they do have all the viral machinery needed to infect a human patient’s cells and force them to express the coronavirus Spike protein, which will set off an immune response that should provide protection against later exposure to the real coronavirus.

So both the adenovirus vector and the mRNA vaccines hijack the protein expression capabilities of a vaccinated person’s own cells, making them produce SARS-Cov-2 Spike protein constructs and thus setting off the immune system. The Pfizer and Moderna mRNA vaccines we’ve seen so far actually express a form of the Spike protein that has a couple of proline residues mutated to make it more stable, whereas the Oxford/AZ vaccine is using the straight wild-type Spike sequence – there’s one difference. Another big one is of course that the Oxford/AZ vaccine is using a completely difference virus to deliver a DNA sequence, whereas the mRNA vaccines are skipping up to a later stage in protein production and slipping messenger RNA directly into the cells.

What was announced today is that they have quite different results for two different dosing regimens. This interim analysis was run when 131 cases had been accrued across trials in the UK, Brazil, and South Africa across about 24,000 trial participants (treatment and control groups). In the treatment group, 8,895 participants received two full doses of the vaccine, spaced one month apart, and 2,741 patients got a half dose at first, followed by a full dose a month later. And the efficacy rates for these two dosing regimes were very different: 62% for the two-full-dose group and 90% for the half/full group. I do not see a breakdown of how those 131 cases partitioned across the two groups, but the overall N has to be higher for the first, doesn’t it? I’d like to know what the statistics are for the 90% efficacy number, for sure.

Why might there be such a significant split in efficacy? My own wild guess is that perhaps the two-full-dose protocol raised too many antibodies to the adenovirus vector itself, and made the second dose less effective. This has always been a concern with the viral-vector idea. It is, in fact, why this effort is using a chimpanzee adenovirus – because humans haven’t been exposed to it yet. Earlier work in this field kicked off with more common human-infective adenoviruses (particularly Ad5), but there are significant numbers of people in most global populations who have already had that viral infection and have immune memory for it. Dosing people with an Ad5 vector would then run into patients whose immune systems slap down the vaccine before it has a chance to work. That’s not the case for a chimpanzee-infecting form, naturally (few if any people have ever been exposed to that one!) but the two-dose regime may have run into just that problem. Immunology being what it is, though, there are surely other explanations, but that’s the one that occurs to me. Update: there’s always the outside nasty chance that the smaller N in the 90% group is giving a number that won’t hold up. I would hope this isn’t the case, but without a better look at the statistics, it’s not possible to rule that out.

Now, I’ve seen people speculating this morning that these numbers may be better than they look, because they believe that these trials monitored patients by PCR tests rather than by symptoms. If that were the case, then yes, that’s a finer net than the Pfizer and Moderna trials used and it would certainly affect the efficacy readouts. But I don’t think it is: looking at the published trial protocol for the US trial, the cases are defined as “SARS-CoV-2 RT-PCR-positive symptomatic illness”, and the patients have to show symptoms of the disease (see Table 13). Update: I have been unable to find published protocols for the UK/Brazil/South Africa trials that went into today’s numbers, but I have no reason to think that they differ on this point. So I don’t think we can explain the lower efficacy by saying that they were finding asymptomatic people as well: the trial excludes asymptomatic people from its endpoint definition. The rate of asymptomatic cases in the treatments and controls will be determined in these trials (see section 8.5.2.1 of the protocol) but those aren’t the numbers we’re seeing today.

So from an efficacy standpoint, the choice is clear: if this vaccine is going to be deployed, the half-dose/full-dose regime is the obvious choice, since otherwise you can do the same amount of work dosing your population, use up more vaccine. doing it, and get notably worse results. How about from the safety side of things? The Oxford release says just that “No serious safety events related to the vaccine have been identified”, and the AZ one says “No serious safety events related to the vaccine have been confirmed”. I would have preferred to hear more about local and systemic reactions, as we did with the Pfizer and Moderna releases, but that seems to be it. Readers will recall that a participant in the UK trial developed transverse myelitis, and that the trial was stopped in the US for about a month. (Note: the US trial is the two-full-dose version). Update: they say now that they’re going to ask to switch to the apparently more effective dosing regime in the US trial.

Overall, I would have to think that Oxford and AZ are disappointed with the results from the two-full-dose regime and will be actively trying to track down the reason for the better performance in the the half/full dosing, which one would expect to be the way the vaccine is eventually used. How many of the other trials that are being run are using that protocol, one wonders? This could still be an effective weapon in the pandemic, but the stories are starting to differentiate. Pfizer (very effective, tough distribution and storage), Moderna (very effective, easier distribution/storage than Pfizer, but perhaps stronger safety reactions), and now Oxford/AZ (widely varying efficacy depending on dosing, easier distribution/storage, safety details TBD). The next vaccine effort to report efficacy will be J&J, another adenovirus vector, and this time with a one-shot dose. The landscape is starting to fill in a bit!

https://blogs.sciencemag.org/pipeline/archives/2020/11/23/oxford-az-vaccine-efficacy-data

Ionis announces 3rd investigational antisense med to treat NASH

 

• Ionis Pharmaceuticals (NASDAQ:IONS) announces today that the biopharmaceutical company AstraZeneca has licensed ION455, an investigational antisense medicine being developed as a potential treatment for nonalcoholic steatohepatitis.
• ION455 is the second medicine for the treatment of NASH that Ionis has partnered with AstraZeneca.
• NASH is the most severe form of nonalcoholic fatty liver disease and is related to the epidemic of obesity, pre-diabetes and diabetes.
• Separately, Ionis is also developing a wholly owned NASH program.
• "Today, there are no FDA-approved medicines to specifically treat nonalcoholic steatohepatitis. However, due in large part to the progress made by our cardio-metabolic franchise, three Ionis-discovered novel medicines are now in development. These are encouraging advances that we hope will one day bring therapeutic benefit to patients who have limited treatment options," said Brett P. Monia, Ph.D., CEO.
• Press Release
• https://seekingalpha.com/news/3638893-ionis-announces-third-investigational-antisense-medicine-to-treat-nash

The pandemic response roars on

 Vaccines against Covid-19 are generating very impressive data, but there remains a pressing need for effective treatments for people already suffering from the infection. In response, the US FDA has now granted five emergency use authorisations to experimental therapies; drugs from Regeneron and Eli Lilly became the latest recipients last week.

Despite this progress, it is clear that big pharma considers the search for potential treatments far from over. This morning Merck & Co announced the $425m buyout of Oncoimmune’s lead Covid-19 therapy, a recombinant fusion protein that generated very encouraging data in an early look at an ongoing phase III trial.

The interim analysis – conducted on 75% of the trial’s 270 participants – found that severe or critically ill patients treated with CD24Fc had a 60% higher chance of achieving clinical recovery than those in the placebo group (p=0.005). The median time to recovery was 6 days for CD24Fc patients compared with 10 days in the placebo group, while the risk of death or respiratory failure was cut by more than 50%.

Final results from the Oncoimmune phase III trial are expected by the end of the year, and Merck is presumably hoping to see a clear signal of a mortality benefit. Only dexamethasone has achieved this so far: in the Recovery trial the generic steroid cut deaths by 35% in ventilated patients and by 20% in those receiving oxygen.

Merck told Evaluate Vantage that it was “too early to speculate” whether the trial might be sufficient to support an EUA application. However, it seems likely that this is the hope. The spanner in the works could be Oncoimmune’s manufacturing capacity – being able to manufacture at scale is a requirement of any regulatory approval – thus the decision to sell up to a large partner with deep pockets and expertise to oversee a quick ramp-up makes sense.

Oncoimmune should certainly be applauded for making the most of this opportunity. The $425m fee is all about CD24Fc: Oncoimmune’s other assets are being spun out into a new entity, which will be owned by the company’s existing shareholders, and in which Merck will buy a $50m stake.

FDA emergency use authorisations for Covid-19 so far
Date	Product (company)	Setting	Ongoing or confirmatory trials
Nov 20	Casirivimab and imdevimab (Regn-COV2; Regeneron)	Patients with mild-to-moderate disease at high risk of progressing to severe Covid-19 and hospitalisation	Subcutaneous formulation; prevention; confirmatory in mild to moderate; hospitalised.
Nov 19	Olumiant (Lilly) in combination with Veklury (Gilead)	Hospitalised patients requiring oxygen, ventilation or ECMO	Hospitalised patients (monotherapy); Tacit-R (academic trial); ACTT-4 (+Veklury, yet to start)
Nov 9	Bamlanivimab (Lilly)	Patients with mild-to-moderate disease at high risk of progressing to severe Covid-19 and hospitalisation	Prevention study (Blaze-2); + LY-CoV555, mild to moderate
Aug 23	Convalescent plasma (various providers)	Hospitalised patients	-
May 1	Veklury (Gilead)	Certain hospitalised patients	Outpatient setting; paediatric trial
Source: FDA, clinicaltrials.gov.

Interestingly, the primary thrust of CD24Fc’s clinical development was graft-versus-host disease, before the pandemic prompted a pivot. Another GvHD treatment, Incyte and Novartis’s Jak inhibitor Jakafi, is also being trialled in hospitalised Covid-19 patients; an Incyte-sponsored study is explicitly striving to demonstrate a mortality benefit.

And of course Olumiant, one of the EUA’s issued by the FDA last week, is another Incyte Jak inhibitor, albeit sold for rheumatoid arthritis by Lilly. The Covid-19 approval was on the back of the NIH-funded trial ACTT-2, which found that adding Olumiant to Veklury sliced a day off median time to recovery, over Veklury monotherapy.

In real terms this was eight versus seven days respectively; a hazard ratio of 1.15 and 95% confidence interval of (1.00, 1.31) “indicated a statistically significant effect”, the FDA said. Other measures, including odds of clinical improvement and patient progression also favoured the combination arm, while 29-day mortality was 4.7% for Olumiant plus Veklury versus 7.1% for placebo plus Veklury.  

If these results seem underwhelming, a Lilly-sponsored trial should show more clearly what Olumiant is capable of here, and help tease out exactly what the Gilead antiviral is contributing.

Regeneron too is running several confirmatory studies with Regn-Cov2, a combo of casirivimab and imdevimab that also just won an EUA on the back of data that still leave room for improvement.

Approval was granted on results in 799 non-hospitalised patients with mild-to-moderate disease, showing that viral load reduction was larger in patients treated with the antibody combo than those on placebo, at day seven. Most important, the agency stated, were data on a secondary endpoint of hospitalisations and emergency room visits; these medical visits occurred in 3% of the treated group and 9% of placebo-treated patients.

Sales forecasts for Regn-Cov2 show that the financial community expects better treatments to come along – and for the vaccine rollout to diminish need, of course. With big pharma willing to jump in on projects like CD24Fc, hopefully this greater efficacy is not too far behind.

https://www.evaluate.com/vantage/articles/news/deals/pandemic-response-roars

5 questions for Astrazeneca on its Covid-19 vaccine

 The third set of phase III Covid-19 vaccine data are in – and the market reaction was disappointment. Despite Astrazeneca talking up a lack of severe Covid-19 cases and hospitalisations in a pooled analysis of its UK and Brazil studies of AZD1222, the group’s stock was down 3% today.

Astra has suffered from the fact that the average efficacy of AZD1222 in preventing Covid-19 infections, at 70%, is less impressive than the 95% seen with Pfizer/Biontech’s and Moderna’s candidates. But the Astra release, encompassing different data with two different dosing strategies, was also confusing.

In short, there are more questions than answers on AZD1222. Here are some of the key points that need to be clarified.

Why might a lower priming dose work better, and is this a real effect?

The pooled analysis involved the phase II/III COV002 trial in the UK and the phase III COV003 study in Brazil, and included over 23,000 participants. The interim analysis was carried out once 131 cases of Covid-19 had occurred.

However, the results looked very different with two different dosing regimens. 

Across the UK and Brazil trials, 8,895 people received a full-dose (5x1010 viral particles) primer and booster at least a month apart. In these patients, efficacy at preventing Covid-19 was an unimpressive 62%.

However, in a subgroup of 2,741 participants in the UK study receiving a half-dose (2.5 x1010 viral particles) primer followed by a full-dose booster, efficacy was 90%. The addition of a half-dose regimen appeared to have come about because of a dosing error, according to Berenberg analysts.

“We think that by giving a smaller first dose we’re priming the immune system differently – we’re setting it up better to respond,” said Professor Andrew Pollard, head of the Oxford Vaccine Group, during a media call today to discuss the data. However, he conceded that more work needed to be done to verify this theory.

Professor Pollard was confident that the effect was real rather than just a function of the small numbers of participants involved in this analysis. There is also speculation that the full-dose primer might have raised too many antibodies to the adenovirus vector itself, and made the second dose less effective.

However, Leerink’s Geoffrey Porges was scathing about this claim: “The suggestion by the inventors that the small sample given the lower priming dose was evidence of superior efficacy only brings discredit to the programme,” he wrote.

For which does(s) will Astra be seeking approval?

This ultimately appears to be down to the regulators, with Mene Pangalos, head of biopharmaceuticals R&D for Astra, saying the discussion would be around whether one dosing schedule, or both, could get the nod.

“The pooled analysis is sufficient for approval, we think, across a variety of regions including the EU and UK,” he added. Astra has already started rolling reviews with the EU and UK regulators.

Can Astra use these data to file for emergency use authorisation in the US?

The situation in the US is much less clear. The FDA seems unlikely to accept data from studies that do not include any US patients as the basis for an emergency use authorisation, especially following the strong results with Pfizer/Biontech’s BNT162b2 and Moderna’s mRNA-1273.

Mr Pangalos was cagey about AZD1222’s chances in the US, admitting that a scenario in which AZD1222 was available worldwide but not yet approved in the US was “possible”.

One complication is that the group’s phase III US study does not currently include the half-dose/full-dose regimen. This is something that Astra hopes to remedy by adding a new cohort to the trial “within weeks”, Mr Pangalos said.

The company will need to move fast here, especially if BNT162b2 and/or mRNA-1273 are authorised soon, as people might not want to run the risk of getting a placebo in a clinical trial once marketed vaccines are available. Pfizer and Biontech submitted an EUA request on Friday.

Mr Pangalos told the media briefing that Astra would start talking to the FDA this week: this will initially involve sharing the latest data and firming up plans for the US pivotal trial, and then “interacting with them about the potential for submission or not”.

Astra will face a delay if it is has to wait for US data. The company was forced to put its phase III programme on hold after a serious adverse event in the UK trial, thought to be transverse myelitis. The US study only restarted in late October. Around 10,500 US participants have now been dosed, Mr Pangalos said today; the target recruitment is around 40,000, up from 30,000 previously.

For his part, Leerink’s Mr Porges believes that AZD1222 “will never be licensed in the US”.

What about safety?

Astra was not giving much away today about safety, saying only that no serious adverse events related to the vaccine had been confirmed. Given the trial pause, this comment is unlikely to satisfy those who remain sceptical about the project's safety profile. 

During the call, Mr Pangalos said that both dosing regimens had been well tolerated, with the main adverse events being things like sore arms, headache and fatigue. Safety looks set to remain a big focus when the full data are published.

How did AZD1222 perform in older patients?

It is also unclear how AZD1222 performed in older adults; the investigators have not had a chance to crunch these numbers yet. Generating an immune response here has long been a concern with Covid-19 vaccines because immune function declines with age.

However, even when full data are available they might not provide a comprehensive answer: only around 20% of participants in the UK and Brazil trials are over the age of 55, Mr Pangalos said.

Astra was keen, once again, to talk up the relatively simple storage requirements for AZD1222, as well as its manufacturing capabilities – the company has the capacity to make around three billion doses in 2021.

However, if the vaccine cannot get the go-ahead in the US it might come to be seen as a second-best option.

https://www.evaluate.com/vantage/articles/news/trial-results/five-questions-astrazeneca-its-covid-19-vaccine

AstraZeneca Analyst Flags Lack Of Details In Interim COVID-19 Vaccine Data

 AstraZeneca plc 

AZN 1.43% announced Monday interim Phase 3 data for its coronavirus vaccine candidate AZD1222 from studies conducted in the U.K. and Brazil, showing efficacy ranging between 62% and 90%.

The AstraZeneca Analysts: SVB Leerink analyst Geoffrey Porges has an Outperform rating on AstraZeneca with a $65 price target. 

BofA Securities analyst Sachin Jain maintained a Buy rating and $69 price target.

Data Disclosure Premature, Insufficient, SVB Leerink Says: The average 70% efficacy after 132 infection events reported by AstraZeneca in the pivotal trial is likely to be criticized, Porges said in a Monday note.

The company did not disclose information on any actual safety event and said "no serious safety events related to the vaccine have been confirmed," the analyst said. 

The company tried to project the 90% efficacy in a relatively small sub-set of subjects — 2,741 participants — who received a half dose of vaccination, followed by a full dose four weeks later, he said. 

AstraZeneca's disclosure was short on details such as the exact number of events in each study or how the company calculated the blended 70% efficacy for the full cohort of 11,636 subjects and efficacy in sub-populations such as the elderly, high risk or minority populations, Porges said. 

"We regard the data disclosure as premature and insufficient, and is likely to attract a raft of criticism," the analyst said.

Related Link: The Week Ahead In Biotech: Moderna Vaccine And Roche, Revance, Rhythm, Liquidia FDA Updates

The company is positioning the product as suitable for use in less-developed countries, where the relatively favorable storage conditions may be advantageous.

AstraZeneca's vaccine will never be licensed in the U.S. due to pivotal trial designs that are not in conformity with standards set by the FDA, and the occurrence of severe safety events that resulted in an extended clinical hold on enrollment into the trials in the U.S., according to SVB Leerink. 

The firm said it is not very positive on the outlook for an adenovirus-based COVID vaccine, as it appears that the occurrence of pre-existing or post-vaccination immunity to the vector has a significant dampening effect on the efficacy of the vaccines.

These products are likely to be regarded as relatively marginal suppliers in the COVID-19 vaccine market of the future, Porges said.

Vaccine Needed Globally In 2021, BofA Says: Efficacy at the "first dose as half-dose" regimen of 90% is comparable to the 94%-95% efficacy seen with Pfizer Inc. PFE 0.68% and Moderna Inc MRNA 3.43%, Jain said in a note. 

The efficacy for the normal dose is at 62%, the analyst said. 

"We look for further details on whether the event split is similar to the split in patients at the two regimens (c25% of patients at the "half-dose" implying only c35 events at this dose), & explanation for better efficacy at lower dosing," he said. 

Beyond efficacy and safety, AstraZeneca's vaccine supply is likely required for global vaccination in 2021, Jain said.

It also has easier logistics than the vaccine candidates from Pfizer and Moderna, the analyst said. 

https://www.benzinga.com/analyst-ratings/analyst-color/20/11/18493523/astrazeneca-analyst-flags-lack-of-details-in-interim-covid-19-vaccine-data

Schrödinger upgraded by BofA after collaboration with BMY

 

• Schrödinger (SDGR +13.4%) upgraded by BofA analyst Michael Ryskin to Buy from Neutral.
• The price target remains unchanged at $74.
• Th upgrade was announced after the multi-target collaboration with Bristol-Myers Squibb (NYSE:BMY)
• The analysts sees this deal as "a major validation" of the company's platform and model and a major step forward for the business.
• He adds, under the pact Schrodinger will receive $55M in an upfront payment and up to $2.7B in various milestones, as well as sales-based payments.
• He also points to the $1.6B in research and development milestones as "noteworthy" given his view that "these are typically more 'realistic' than long-term commercial targets.
• https://seekingalpha.com/news/3638810-schrodinger-stock-scales-upgraded-bofa-after-collaboration-bmy

J&J sized up favorably after positive medical devices update

 

• Bank of America has a positive read-through on Johnson & Johnson (JNJ -1.5%) from the company's medical devices update last week.
• "JNJ’s comments at their medical device focused analyst day last week suggest that the recent spread of COVID has had less of an impact on surgical procedure volumes than we anticipated. Checks also indicate capital trends remain solid. JNJ stated that, in their top ten markets, device revenue has been over 100% of last year’s levels over the last three weeks. JNJ also gave a breakdown of growth by geography which suggests JNJ’s total device growth is probably down slightly year over year currently. These JNJ comments seem to us encouraging but we remain cautious near term as COVID’s spread continues especially in the US which could pressure surgical volumes over the next six weeks."
• BofA keeps a Buy rating on Johnson & Johnson.
• https://seekingalpha.com/news/3638793-johnson-johnson-sized-up-favorably-after-positive-medical-devices-update