Archive for July, 2020

AstraZeneca And Oxford Surge To The Lead

Monday, July 20th, 2020

Lord knows, good news is hard to come by these days, but, H’Alleluia, we got some this morning.

Researchers from pharmaceutical giant AstraZeneca* and Oxford University’s Edward Jenner Institute for Vaccine Research announced promising results from a Phase 1/2 study of their COVID-19 vaccine candidate, known as AZD1222.

Researchers gave AZD1222 to about 500 volunteers and compared the results to those from around the same number getting a meningococcal vaccine.

For the AZD1222 vaccine, antibodies against the SARS-CoV-2 spike protein peaked by day 28 and remained elevated to day 56, the end of the study, indicating an immune response against the virus. Much has recently also been made of T cells, a type of white blood cell: Here, the vaccine levels of T cells peaked 14 days after vaccination and were still present two months later.

Ages in the study group ran from 18 to 55; the median was 35. This is much younger than the median age of the group that will need it the most: the elderly. Also, nobody in the study group had co-morbidities associated with heightened risk of bad outcomes.

There were side effects, but they were relatively minor: fevers, aches, headaches and fatigue, but acetaminophen, the active ingredient in Tylenol, alleviated these.

Phase 3 trials are now underway in the U.K., Brazil and South Africa and are due to start in the U.S.

The UK has already ordered 100 million doses of the unproven vaccine, which scientists from Oxford’s Jenner Institute have said could be ready for approval in September.

A word or two about the light speed of this vaccine’s development, as well as the roughly 100 others being developed around the world.

First, Oxford has been working toward developing a novel coronavirus vaccine for two or three years. After the 2014 Ebola epidemic, the British government invested  £120 million (about $149 million at the time) to create vaccines aimed at protecting against the 10 or 11 health threats deemed to be the most likely to threaten the country. Coronaviruses were on that list, and the government gave the Jenner Institute some of the money.

Once that happened, Oxford doctors Sarah Gilbert and Adrian Hill pioneered a way to put a bit of a novel coronavirus in a vaccine, but without the part that makes it replicate in humans. At that point it would be safe to inject in people. What Gilbert and Hill created was a platform that theoretically should work for many viruses and has been proven to be safe in vaccines for other diseases. And that methodology, called recombinant adenovirus vector, is what AstraZeneca and Oxford are making the foundation of their COVID-19 vaccine candidate.

So, because of the work of Gilbert, Hill and their Oxford team, Oxford and AstraZeneca had a head start on the COVID-19 vaccine derby. But still, AZD1222 entered its Phase 1 clinical trial the last week in March, 2020. If they succeed and have a vaccine ready for humanity by September, that will be six months from start to finish. This is way beyond unheard of!

Don’t believe me? Typically, and this is anything but, clinical trials go through four phases according to the FDA:

Phase 1: 

Study Participants: 20 to 100 healthy volunteers

Length of Study: Several months (For this example, let’s say 4)

Purpose: Safety and dosage

Result: Approximately 70% of drugs move to the next phase

Phase 2: (AZD1222’s Phase 1 and 2 were done in two months)

Study Participants: Up to several hundred people

Length of Study: Several months to 2 years (Let’s say 4 months to two years)

Purpose: Efficacy and side effects

Result: Approximately 33% of drugs move to the next phase

Phase 3: (This is what AZD1222 is beginning now)

Study Participants: 300 to 3,000 volunteers

Length of Study: 1 to 4 years

Purpose: Efficacy and monitoring of adverse reactions

Result: Approximately 25-30% of drugs move to the next phase

There is a Phase 4 with several thousand volunteers, but it appears the government may be combining Phase 3 and 4 as it did Phase 1 and 2.

If there is one thing Donald Trump and I can agree about it is that this is being done at Warp speed. If you do the math from above, you’ll see the fastest a drug typically makes it through the first three trials is 20 months, not six. Also, by rapid calculus, you’ll note that if we start with 100 drugs going into trials, five make it through Phase 3. We’re dealing with long odds here.

A couple of other things to think about.

First, drug discovery and development involves pre-clinical work that begins with mice, moves on to rats, guinea pigs, rabbits, pigs and non-human primates. Yes, monkeys. After all that, scientists apply for what’s called an Investigational New Drug Award, an NDI. If the FDA approves that, one can move into a Phase 1 trial. None of that has happened here, at least it hasn’t been reported as happening.

Second, even if good results happen from AZD1222’s Phase 3 trial, or one of the other vaccines under development, with such little longitudinal study how certain will we be that long-term immunity will result?

Finally, there are the old folks. One presumes they represent a cohort in the Phase 3 study. What happens if the vaccine succeeds beautifully in young people, but fails miserably in the elderly?

John Milton famously wrote, “Hope springs eternal.” But, frankly, I prefer the advice of my old commanding general in the mountains of Vietnam: “Hope for the best; prepare for the worst.”

 

* AstraZeneca is a British/Swedish company formed from the merger of Astra Pharmaceuticals, a British firm, and Zeneca, a Swedish one, in 1999. It’s headquarters are in Cambridge, England.