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Thornogson. This is where the argument keeps slipping because you’re now stacking assumptions on top of assumptions and treating the result as proof.

You’ve effectively set up a straw man: “If AVA6000 hasn’t already shown vastly superior efficacy versus historical doxorubicin in STS (and hasn’t yet shown TNBC data), then it must be under-delivering because of its short half-life.” That conclusion simply doesn’t follow. Early-phase trials are not designed or powered to prove broad superiority versus SoC in anthracycline-sensitive tumours that are already close to an efficacy ceiling. Not seeing dramatic uplift at this stage is not evidence of PK failure.

You’re also quietly moving the goalposts. First the claim was that the 45-minute half-life means insufficient delivery. When it’s pointed out that tumour exposure is sustained and clinical activity is evident, the argument shifts to “well it hasn’t beaten historical dox yet, therefore something must be wrong.” That’s not new evidence , it’s inference.

Bottom line, this is intuition: short half-life → less drug → weaker efficacy. But drug delivery doesn’t work that way. Half-life limits systemic exposure, not tumour delivery and tumour exposure is determined by conversion efficiency and retention, which is exactly where AVA6000 has shown strength. From there you’re effectively adding 2 + 2 and getting 5.

I’ll happily agree with you on the factual points: AVA6000 efficacy in STS so far is not spectacular and TNBC data are still pending. What doesn’t follow is the leap from that to “the drug is under-delivering” or “the design was fundamentally compromised.” If that were true, you’d expect weak, short-lived responses everywhere, including SGC, which is not what’s being observed.

FAP-EXd may well have a higher ceiling and broader ambition. That’s fine. But different ceilings and different payload biology don’t retroactively turn AVA6000 into a failure. They just mean you’re judging an early-stage safety-optimised asset by endpoints it hasn’t even been built to answer yet.

At this point we’re not disagreeing on data, we’re disagreeing on what can legitimately be inferred from it and that’s where I’m comfortable stopping and letting the clinic, not your intuition, settle it.

Thornogson. We have all learned that different payloads need different half-lives , but you then assume that AVA6000’s shorter half-life means it was fundamentally flawed and should have been extended. That conclusion doesn’t actually follow.

First, AVA6000 is selective, not magically inert. There is always some very low level of off-tumour cleavage , Avacta’s own PK data show low but non-zero plasma exposure to released doxorubicin. That’s acceptable precisely because circulation time is short. If you extend plasma half-life from minutes to days, even tiny background activation becomes cumulative exposure and with an anthracycline that matters. This is why, in the Spotlight video, the scientists explicitly describe the short plasma half-life of faridoxorubicin as a benefit for safety, not a flaw they’re trying to fix.

Second and more importantly, I was led to beleive that a longer plasma half-life would actually make doxorubicin less effective, not more. The literature I've read over the years has suggested that doxorubicin works by delivering a high local hit in the tumour that causes acute DNA damage, with cancer cell death unfolding over many hours afterwards. That’s why it’s historically given as a bolus. Extending exposure into a slow drip reduces peak tumour concentration and blunts the very mechanism that makes doxorubicin work. Even if it were perfectly safe, that delivery profile would be biologically the wrong way to use an anthracycline.

A simple way to think about it: AVA6000 is a fast delivery van. It unloads a big payload into the tumour quickly, then leaves town because the cargo is dangerous if it hangs around systemically. The van leaving in 45 minutes doesn’t matter, the drug it delivered stays in the tumour doing its job for tens of hours. Keeping the van driving around for days wouldn’t improve delivery; it would increase risk and dilute impact.

This is also why the comparison with FAP-EXd breaks down. With 6103, the longer half-life reflects tumour retention, not prolonged systemic circulation. The molecule binds much more tightly to FAP and is held locally, releasing exatecan slowly in the tumour while blood levels fall away. Exatecan historically failed because exposure was too short, so sustained tumour exposure is exactly what it needs and it does not carry the same cumulative lifetime toxicity issues as doxorubicin. That’s not AVA6000 being “wrong”; it’s the platform doing what it’s designed to do: short half-life and high impact for doxorubicin, longer tumour-retained exposure for exatecan.

If AVA6000’s plasma half-life were genuinely impairing efficacy, you wouldn’t see durable disease control in the clinic, especially in SGC, where there is no standard of care. Yet that’s exactly what’s being observed. Learning that different drugs need different half-lives is platform evolution, not proof that AVA6000 was fundamentally compromised

I’ve started building a position in Winvia. Teddy Sagi is one of the very few serial entrepreneurs in the gambling/tech space who has repeatedly built billion-pound businesses from scratch. Playtech (founded from zero, taken to multi-billion valuation), SafeCharge (co-founded and sold for $889 million) — the track record speaks for itself. Very few operators have his combination of vision, execution and capital-allocation skill. That alone gives me huge confidence, even before looking at the assets.

The buy-and-build strategy here is already working in plain sight, and he has acquired the entire group for what now looks like an absurdly low price: BOTB was picked up for just £45.3 million in 2023 after the post-lockdown hangover crushed the share price. As Shearclass has already done (thank you) the H1 2025 standalone numbers (and remembering H1 is normally only 40–45 % of the full year), BOTB is on track for north of £60 million revenue and c. £12 million adjusted EBITDA this year — potentially a record year. Halving customer-acquisition costs and doubling LTVs through the Group’s proprietary tech stack is genuinely impressive and is driving a rapid turnaround. Click Competitions was added for £17.4 million and is already showing early synergies. With the same tech and marketing muscle applied, I expect it to scale nicely alongside BOTB.

The UK prize-draw market is currently worth £2+ billion, highly fragmented and growing at 12 % CAGR. There is no one I’d rather see consolidating it than Teddy Sagi, he will be extremely hard to compete with once the roll-up gains momentum. Low-multiple tuck-ins + tech-driven synergies is exactly the playbook that made Playtech a juggernaut.The Romanian gaming business is the perfect cash cow to fund the UK expansion: profitable, licence-protected, top-3 market share and already throwing off serious cash. It feels very reminiscent of the early Playtech cash-generating engine. Post-IPO balance sheet : £20 million of the net proceeds used to repay debt , leaves £15.6 million remaining debt and c. £29 million unrestricted cash (£32 million total cash including restricted prize funds) net cash position of £13–16 million and plenty of firepower for the next bolt-ons.

FY25 run-rate looks comfortably on track for £200–210 million revenue, £28–30 million adjusted EBITDA and £9–11 million PBT. At today’s £205 million market cap, you can make a credible case (as shearclass has) that BOTB alone justifies most or all of the valuation on its recovered run-rate — meaning the large, cash-generative Romanian business and Click are effectively in for free. All in all, a rare situation where the operator, the assets, the market opportunity and the price all line up. Happy to be on board.

The price action at PureTech is undeniably frustrating, but I’ve decided to stay calm, trusting that value will inevitably prevail. This optimism stems from our three most advanced clinical programs (SPT-300, LYT-100 & LYT-200) all in late-stage trials with massive potential. The SPT-300 Phase 2b trial for MDD, likely reading out in late 2026, could be registrational. Similarly, the LYT-100 Phase 3 trial, expected in 2028, is registrational, as is the LYT-200 Phase 2 for AML, assuming the mature Phase 1b data (13.2 mo OS) holds, also slated for 2028. Each represents a blockbuster opportunity, with FDA approval unlocking multi-billion-dollar valuations. Take LYT-100: Roche’s $8.3B purchase of pirfenidone in 2014 suggests that, if LYT-100 becomes the new standard of care, a comparable valuation could apply.

Before these readouts, I anticipate Seaport, Gallop, and Celea - housing these drugs - will follow Karuna’s path and float on Nasdaq. As readouts near, their valuations will soar; it’s illogical to think Celea, for instance, would be worth mere hundreds of millions pre-LYT 100 readout when a successful p3 readout could push it past a valuation of $10 billion. The market will assign values to these listed entities, making PureTech’s worth a simple sum of its parts. My only plea to management: halt any future drug discovery and redirect all cash into these founded entities. Our robust cash position offers key advantages: 1) no dilution fears from future raises, 2) shorts like Saba can’t spook the market over cash, 3) the weak share price won’t suffer from forced low-price raises, & 4) we can participate in future raises of our entities, minimizing dilution. Plus, our Cobenfy stake should bolster cash flow significantly in coming years, fueling further investment. As Ben Graham, Warren Buffett’s mentor, said, “In the short run, the market is a voting machine, but in the long run, it’s a weighing machine” - a perfect analogy here. Patience is key; one of these programs will hit big, and we’ll be poised to reap the rewards.

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