The latest Investing Matters Podcast with Jean Roche, Co-Manager of Schroder UK Mid Cap Investment Trust has just been released. Listen here.
Just spotted the final bullet point got cut off, it said:
- First anti-microbial study for antibiotics coming soon, ORPH's 'extensive range' of challenge studies is being expanded further
Questions
Whys and wheres of becoming CEO rather than Exec Chairman?
- Company still small by US standards. Some non-exec board members who might make good replacement Exec Chairman. CF has one eye on a billion-dollar spin off with which he wants some 'hands-on' involvement as a non-exec chairman. ORPH will not be leaving AIM and going to Nasdaq, but one of the spin offs will list on AIM with a dual listing on Nasdaq to follow. CF dodged question about which asset this was referring to, but suggested we look at orphpharma.com
Hard lock-in period - is this til June 2021 or 2022?
- Technically end of June 2021 but "more or less" hard lock in for another 12 months as CF has inside information. CF wants to increase his position in ORPH if possible. Also mentioned £500k of his own money to go into one of the spin outs.
Would you consider taking a stake in Codagenix?
- Unfortunately Codagenix don't need cash, already have very wealthy shareholders (e.g. Jim Simons) in addition to two big pharmas. ORPH doing all their Phase I work and Codagenix has the potential to be bigger than the Oxford/Astra vaccine - very exciting to be involved.
Any time frame on DIM?
- Imutex divestment is slower than CF would like as ORPH doesn't have controlling stake. DIM has the potential to "build a very big cake" and be spun out into ORPH Data - will take time but ORPH has full ownership.
Does billion dollar target include spin offs or just core ORPH business?
- Includes spin offs, ORPH is only circa £250m mcap currently. Timeframe a year or two
Where do you see ORPH in a year?
- Bigger, better, stronger, doing more of the same and more exciting things. Billion dollar target within a year is a good one to go for
I couldn't watch live tonight as I was out but I had a quick look at the messages on here as I was heading back to my car and it made me drive a bit faster!
Made some notes as I was watching, please add anything I missed or noted down incorrectly.
- Invesco have now gone - institutions tend to take profit when SP increases; many institutions still on board but below 3% threshold
- CF's shareholding is 6.69%, and he would like to increase in weeks and months ahead
- CF "absolutely not leaving company any time soon"
- ORPH has lots of cash and balance is increasing
- Within April, at least one, possibly two non-core spinouts if all goes to plan
- Influenza Immune Modulator will be bundled with 'other' non-core assets when divested (very keen to know what these other assets are!)
- Imutex and PrepBio to be divested individually
- Again mentioned RenaltyxAI spinout from EKF and how quickly this reached $1bn mcap
- CF now CEO rather than Exec Chairman as he needs to keep a hands-on role in one of the spinouts as a non-exec chairman
- "Definite" update in April on non-core asset(s) divestments and dividends in specie, all three before the end of the summer if all goes to plan; cash dividend to follow later this year
- Mentioned new screening centre in St Pancras to handle "burgeoning" number of volunteers coming through
- Last RNS for RSV was £7.5m, recruitment started immediately and all revenue recognised this year
- "No safety concerns presented" for first Covid-19 challenge study volunteers who have been discharged - a world first, with UK Gov as partner
- New volunteers to be infected with Covid-19 every week for the foreseeable future, brings down vaccine testing time significantly compared to standard trials
- "Pandemic more or less over", UK to begin looking at Covid the same as influenza
- Annual update to Covid vaccines, similar to current flu vaccines
-More Covid vaccine work to come despite the pandemic gradually petering out
- Hvivo "will be put on the world map" later this year if intranasal Codagenix vaccine is adopted for the developing world
- Aware investors are getting impatient regarding DIM, it is "almost close now" to a standalone business and is now patented
- Rather than do a "quickie deal" for DIM, CF is taking his time as it is his belief that it is better as a fourth non-core asset to be divested
- Imutex's Flu-v vaccine is Phase III-ready and could be repurposed as a *universal* Covid vaccine (Is this the first time this has been stated? CF has previously said that Imutex's divestment has been delayed because they potentially had a *seasonal* Covid vaccine) and is 49% ORPH-owned
- PrepBio is moving faster re: divestment
- CF described the Immune Modulator as "the big one" (I was surprised by this)
- UK is fabulous place for ORPH's planned expansion with MHRA and UK Gov both on side
- First anti-microbial study for antibiotics coming soon, ORPH's '
I didn't see Eskers had already shared that article last night, I got a Google News alert for it by email. Great news regardless to see some progress on Flu-v.
Given the recent success of mRNA vaccines for COVID-19, there is a growing interest in this approach too — a team at the University of Pennsylvania in the United States has developed an mRNA vaccine that encodes for the full HA protein, which was able to induce high levels of stalk antibodies?[9]?.
Future prospects
For ConserV, the current challenge is not identifying the vaccine targets, but defining a regulatory pathway since there is currently no process for approving a flu vaccine with a specific broad spectrum or indeed universal designation.
“Commercially, it’s not viable if we come out of phase III, with the same label that an annual flu vaccine has, we can’t compete,” says Duncan.
Krammer agrees that regulatory issues need attention, but there are inherent difficulties.
“In animals [we] can easily prove that a vaccine is universal, by challenging them with all kinds of subtypes, but how do we prove that in humans?”
A broad-spectrum designation will likely require trials over multiple flu seasons, and “[it takes] a lot of money to do that,” says Krammer.
Although a truly universal vaccine is currently a long way off, McCauley sees the potential for a better seasonal one within a “reasonable time frame”.
ConserV is currently in discussions with the US Food and Drug Administration to submit plans for a two-year, phase III trial of Flu-v.
And, Krammer hopes that if the current stalk-focused strategies continue to be successful, a broad-spectrum vaccine should be available within five years.
Even though we can now produce vaccines quicker than ever before, COVID-19 has shown us that millions of people can still die in the time that it takes — and a universal vaccine could prevent this. Bearing recent events in mind, Pleguezuelos argues that now is certainly not the time for complacency.
“This is what we’re trying to do with influenza — we don’t want to wait until there is a pandemic.”
[sorry to clog up the board, didn't realise how long that article was!]
“[Our] model is suggesting [that], rather than there being this continuous arms race, where flu is slowly and incrementally altering the epitopes that it presents to the immune system, it is actually mutating very quickly, but it only has a small number of possibilities within each epitope region,” explains Gupta.
So far, the pair have identified four epitopes that provide immunity to all historical flu strains in mice, while BLU Water vaccines based in Cincinnati, Ohio, is developing a vaccine which would contain a ****tail of those epitopes from a number of flu subtypes?[7]?.
Currently delayed owing to the COVID-19 pandemic (see Box), Gupta is hopeful that phase I trials can start in the near future.
T-cell vaccines and other approaches
Predicting how viral surface proteins will mutate still comes with considerable uncertainties, so researchers are also exploring other avenues.
“There is more to immunity than just stopping infection [with antibodies] … in fact, it may well be that [other mechanisms of] immunity may attenuate the disease process, for example, through cytotoxic T cells,” says McCauley.
Inducing a T-cell response by vaccination has been the aim of recent vaccine research for diseases like HIV and malaria. Bioscience is taking this approach with its vaccine, FLU-v.
T cells are white blood cells that are programmed to attack specific antigens; they also produce signalling molecules, called cytokines, that stimulate a further immune response. This means that vaccines that stimulate a T-cell response can be more effective than those that just stimulate antibody production.
ConserV was able to identify epitopes from proteins inside the virus that activate a T-cell immune response. Its synthetic peptide vaccine is designed to provide broad protection, including against avian and swine flu strains that pose the greatest pandemic risk.
“We focus on segments of proteins that do not evolve over succeeding generations of viral strains or as they jump from animals to humans, so we are antipandemic, by the nature of our design,’” explains Kimbell Duncan, chief executive of ConserV.
As well as testing against a broad range of circulating strains, ConserV has successfully completed a phase IIb intranasal challenge study in 153 healthy adults?[8]?.
Trial participants are directly exposed to the 2009 H1N1 flu strain to see the different responses in vaccinated and unvaccinated groups.
“We vaccinated people and then we put them all sort of in a flu hotel,” explains Pleguezuelos.
“This is the first time that a vaccine of this type has shown efficacy [in a human study].”
The trial showed that a single dose of the vaccine led to a larger proportion showing no disease at all compared to those unvaccinated (67.5% versus 45.2%)?[8]?.
Other strategies being investigated include using the surface protein, NA, in addition to HA.
Continued...
To do this, Krammer and his team made new versions of HA by combining parts from different subtypes (chimeras). Specifically, they engineered proteins made from the heads of ‘exotic subtypes’ like H5 or H8, which are unfamiliar to the human immune system, but kept an H1 stalk, which is more familiar.
This means that, once vaccinated, the host immune system is primed to create more broadly protective antibodies that target regions on the HA stalks of the virus.
“The stalk approach is still the one that is the most promising, just because these [stalk] antibodies do exist [naturally in humans],” says Krammer.
In December 2020, Krammer’s first clinical study showed that the vaccine effectively stimulates antibodies against one group of HA in humans and the team is now planning further trials?[5]?.
Another similar strategy uses just the stalk of the HA protein — an approach being taken by scientists at the US National Institute of Allergy and Infectious Disease Vaccine Research Centre in Bethesda, Maryland.
Their vaccine — H1ssF_3928, based on the H1 protein — displays multiple stalks on the surface of a nanoparticle made from the protein ferritin. Ferritin is useful as a vaccine platform because it forms particles that can display multiple influenza HA spikes on its surface, mimicking the virus itself.
However, there may be problems with these strategies because recent results show that the HA stalk can mutate in some strains.
“We have looked at the potential for mutations in one of the sites in the HA stalk that we are interested in for design of a universal vaccine,” says Ian Wilson, a structural biologist from Scripps Research in California.
“It was clear that, compared to the more antigenic HA head, there’s less mutational ability, but there is some that can lead to escape mutations,” he adds. This occurred with one of most common flu sub-types, H3N2?[6]?.
Creating immunity against multiple flu viruses is complicated by the concept of “original antigenic sin”, or imprinting, Wilson adds.
“Each of us is primed to respond to influenza virus based on what we saw with our first infection as a child … [meaning] that each of us responds differently, depending on our first exposure.
“So, to try to get a completely new response, over a recall response, is more problematic with a virus that circulates in a new form every year.”
Gupta and Craig Thompson, a virologist at the University of Oxford, have developed an approach using a combination of bioinformatics and structural biology to find conserved epitopes in the HA protein head — these are regions of the flu protein recognised by the immune system that have remained constant throughout historic flu strains.
Continued...
This means that current seasonal flu vaccines have, on average, an efficacy of only 40%. There have been some industry advances, such as the new quadrivalent vaccine, which is designed to protect against four different flu viruses; and newer cell-based vaccines. However, for a long time, improving the flu vaccine was not a priority.
“Industry does not make huge amounts of money out of flu vaccines … there’s no blockbusting in this,” explains John McCauley, director of the Worldwide Influenza Centre at the Francis Crick Institute in London.
However, according to Florian Krammer, a microbiologist at the Icahn School of Medicine at Mount Sinai, New York, things started to change in 2009 after it was discovered that some of the antibodies humans make in response to influenza can neutralise multiple flu subtypes.
“That really catalysed it because that gave us a hope that we can do this with the human immune system,” he says.
By 2018, the United States National Institute for Allergy and Infectious Diseases had taken up the challenge and released a strategic plan for a universal flu vaccine and funded a US$51m collaborative network to drive its development?[3,4]?.
Some researchers refer to “more broadly protective” vaccines, indicating a vaccine that may protect against the antigenic drift of existing strains and provide broader coverage to flu subtypes already in circulation.
A truly universal vaccine would also protect against any new subtypes that may emerge from the animal kingdom — sometimes called an ‘antigenic shift’ — which is much more difficult.
Also, according to Olga Pleguezuelos, chief scientific officer at the UK biotechnology company ConserV Bioscience: “You will never demonstrate universality because you don’t know what’s coming next year.”
In 2020, US vaccine development company Novavax started a phase III trial for its quadrivalent NanoFlu vaccine, which — although not universal — showed “significant improvements against four drifted H3N2 strains”.
However, the creation of broader vaccines is hugely challenging and several attempts have failed.
In January 2020, Oxford-based biotechnology company Vaccitech announced that phase IIb data for its universal flu vaccine — VTP-100 — had shown it had not achieved reductions in infections compared with the seasonal vaccine and that it would discontinue the trial.
Then, after 15 years of research, Israeli biotech BiondVax Pharmaceuticals announced in October 2020 its phase III study of universal flu vaccine — M-001 — showed no significant protection above placebo.
Universal strategies
One of the most promising approaches to developing a universal vaccine currently involves stimulating immunity against the parts of the mushroom-shaped HA protein that remain unchanged across strains — specifically the ‘stalk’ of the mushroom rather than the ‘head’ (see Figure).
Continued...
I was able to load the article initially but it now seems to be behind a paywall, so here's the text in full in case anyone can't access it.
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Preventing the next pandemic: the search for a universal flu vaccine
With each new strain of the influenza virus — like the bird flu identified in Russia in 2021 — comes the potential risk of a pandemic. Now, amid the global COVID-19 crisis, a vaccine that can protect against multiple flu strains has never been more important.
Social distancing and lockdown measures put in place across the UK to limit the spread of COVID-19 have also led to a huge drop in the levels of influenza.
However, while we continue to battle the COVID-19 pandemic, it is important not to become complacent about the risks posed by the yearly emergence of new strains of flu. The virus’s ability to mutate rapidly means that when a new strain appears, immunity is low, protection from seasonal vaccines is limited and the risk of a pandemic is high.
The 1918 Spanish flu infected 500 million people — about a third of the world’s population at that time — and killed an estimated 50 million, and the most recent flu pandemic in 2009 is estimated to have infected around 24% of the global population and killed over 284,000 in its first year?[1,2]?.
Looking at these data, it is clear that developing a universal flu vaccine to protect against multiple flu strains is more important than ever.
An arms race
The challenge with the flu virus lies in its ability to alter its surface proteins — the parts of the virus the human immune system usually targets first, which enables it to continue reinfecting the same host population over time.
“It is engaged in a kind of evolutionary process … that one could describe as an arms race,” says Sunetra Gupta, a theoretical epidemiologist and vaccine developer from the University of Oxford.
The flu virus exists in many types and subtypes: both influenza A and B can cause epidemic seasonal infections. Influenza B is typically only found in humans, but influenza A subtypes are found in many other species, particularly in birds, and if these subtypes transfer to humans the risk of a pandemic increases.
We are also battling against what immunologists call ‘antigenic drift’ within current flu subtypes, owing to rapid changes in the surface glycoprotein haemagglutinin (HA).
Influenza viruses are named after the 18 possible HA subtypes (which can be split into two broadly similar groups) and the 11 different subtypes of another surface protein, neuraminadase (NA). Subtypes found in humans are usually H1N1 or H3N2 but there have also been a handful of deadly outbreaks of H5N1 and H7N9 influenzas.
It is changes to the HA protein, which occur even in familiar circulating subtypes, which necessitate updating flu vaccines every year.
“You have to race to make the vaccine,” explains Gupta: “And very often there is a mismatch.”
Continued...
Interesting article published yesterday about universal flu vaccines, with a lot of focus on ConserV Bio and Flu-v:
https://pharmaceutical-journal.com/article/feature/preventing-the-next-pandemic-the-search-for-a-universal-flu-vaccine
In the 'future prospects' section towards the end, the article notes:
"Although a truly universal vaccine is currently a long way off, [John McCauley, director of the Worldwide Influenza Centre at the Francis Crick Institute in London] sees the potential for a better seasonal one within a 'reasonable time frame'. ConserV is currently in discussions with the US Food and Drug Administration to submit plans for a two-year, phase III trial of Flu-v."
Great to hear that discussions are in progress with the FDA for the next stage of clinical trials on Flu-v as news on this seemed to have gone pretty quiet.
https://www.londonstockexchange.com/news-article/ORPH/holding-s-in-company/14919948
There's a 100+ bed student halls building right across the road from that screening centre too, wonder if CF has had his eye on it!
CF said in the Proactive presentation that they're aiming for before June, and that all he can say at this stage is that "the results are nice".
Just published by The Times:
https://www.thetimes.co.uk/article/test-yourself-for-covid-twice-a-week-public-to-be-urged-7b3nt7s53
"All adults will be encouraged to test themselves for Covid-19 twice a week to help us ease of out lockdown, The Times understands.
Getting the public into the habit of regular swabs is viewed as a vital way to stop people breaking the rules if they test negative and an advertising campaign will urge people to “play their part” by regularly checking they are not infectious.
Testing chiefs hope that isolating more infectious people without symptoms, alongside vaccination, can drive the virus to low levels this summer.
Nationwide sewage monitoring will then be used to check for areas where Covid-19 clusters are emerging with the aim of using “surge testing” — currently targeted at dangerous variants — to snuff out any outbreaks."
Obviously wouldn't complain about a takeover approach, but personally I'd be a little bit disappointed if ORPH got bought out in its entirety before at least a couple of the non-core assets are spun out, particularly Imutex.
Questions
Confirm, ORPH is only company with challenge study capability for Covid?
- Yes, people thought we couldn’t do it or get approval, but we have and we should be proud
Still locked in til June 2022?
- Yes, and CF wants to increase his stake
Invesco selling down – dividend cut off dates might help get rid of them earlier?
- Invesco have been approached to buy their stake. They have refused multiple times. Strategic ‘overseas’ investors want to buy from Invesco off-market; they have continued to decline. The following months will be ‘quite rewarding’ regardless. ‘World is watching’ challenge trials with North America specifically mentioned. CF has to be careful what he says as vaccine taskforce colleagues will be watching, but there will be an appropriate announcement soon
Listing in US?
- One spinoff in particular will go to Nasdaq. All spinoffs will ideally go to public vehicles.
Trading update?
- Working on trading update, will be RNS’d as soon as it’s available. Aiming for earlier than June. “All we can say is that the results are nice.”
China, N America – work in progress. Any update or timescales? Any Chinese partners?
- Can’t say too much, China very focused on vaccine development, some Chinese media coverage for Hvivo recently. Chinese companies want to get into challenge studies, ‘we are going to help them and it will cost them a lot of money’
Any difficulty recruiting as non-vaccinated population decreases?
- If we were dependent solely on UK then maybe, but we are looking west to Ireland for recruitment where there are more unvaccinated volunteers. France also a possibility. Won’t have a problem finding volunteers. Already have 100k-strong contact list of volunteers.
If recruiting in Europe, where will challenge trials be carried out?
- As much in UK as possible, but haven’t ruled out elsewhere in Europe. Customers are based all over the world. UK is wonderful place to develop vaccines – regulators and government all on side, happy where we are
Still aiming to double SP every 6 months?
- Only at 200m mcap currently. Billion dollars is the goal, £750m sterling – not a double, it’s a triple!
What are you most excited about?
- CF has moved to UK from Dublin, excited about everything ORPH. New surprises every day, business has never been in better shape. Proving doubters wrong. Excited to be doing world-first Covid trials. Excited for dividends in specie and delivering for all shareholders.
Made a few notes as CF was presenting and asking questions just now, please add anything I missed. Sounding positive as ever, just more patience needed for some big news.
Main presentation:
- clear intentions that this company could get into the 'billion dollar club'
- one of the non core divestments getting much closer to 'something exciting'
- CF suggested we look at EKF’s spin off of Renalytix Ai - within 2 years, it’s worth a billion dollars
- one spinoff could be a cash dividend (but later said ideally they would all be spun out into public companies)
- Britain going to be doing a lot more work in vaccine space
- Contracts for Venn values not published but they are ‘significant’
- Had a reason to pause Hvivo contract announcements due to needing approval but plenty more coming up
- First gen vaccines may not protect as effectively against new variants of Covid + have storage issues with deep freeze required in some cases
- Second gen vaccines may give 5 – 7 years immunity, protect against new variants, be intranasal and single dose rather than needle-based with boosters required, have easier storage – and will require human challenge studies
- Covid challenge studies have commenced
- In very near future, a number of Covid trial contracts will be announced, all £10m+
- Screening centres being looked at across Europe, in addition to new ones in Manchester and Whitechapel already announced
- CF still locked in til June 2022, wants to increase stake, can’t see a safer investment right now
- New Whitechapel hotel unit is full, will be full until at least the end of the year
- DIM deals are in progress, will be delivered, on a recurring, annual subscription basis, extremely valuable to the company, could hypothetically be a fourth spinout
- Imutex – work in progress, “working consistently on it”.
- SEEK is now ConserV, as soon as Imutex can be commercialised it will be granted as a dividend in specie into a publically listed company
- One asset much closer to monetisation than the others (wasn’t sure here if CF meant one asset within Imutex or Imutex itself?)
- PrepBio and Modulator will each go into separate vehicles and be spun off
- “At least one of our spinouts worth a billion dollars, plus parent company getting bigger and bigger”
- Raglan is CF’s family investment vehicle; bought MOGP “but don’t read too much into it”
- It wasn’t CF’s intention to go over percentage threshold for notification, but given that ORPH is looking for shell companies, “no harm in having an eye on shell companies”
- “Cinderella is now at the ball” referring to investment in vaccine development!
He's now deleted his whole account. Very strange.
Looks like it's been deleted - was hoping they'd reply to the tweet asking for a source.