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TP53 mutation.

Last one from me, taking a break for a while, unless anything new is disclosed, or I find anything noteworthy.

Given the high N of TP53 mutant patient numbers (41% r/r) in the single-arm Bexmab trial, the Overall Survival and Response Rates were highly likely suppressed, given the dire prognosis in this mutation population, with the overall prevalence of TP53 in the high risk MDS population estimated at 15-20%.

In Farons upcoming randomised phase 3 trial, which will be stratified for TP53, as Dr. Zeidan suggested yesterday, ie patients with that specific mutation are evenly distributed across both the AZA / placebo and AZA / Bex arms, respectively, the true performance of Bexmarilimab will be highlighted, in light of its effect over AZA, the current standard of care.

In Abbvies phase 2 Front Line Venetoclax / AZA MDS trial, the modified overall response rate was recently reported as 80.4%, however when IWG 2023 guidance is followed, the component of mCR, marrow complete response, is no longer valid, and would reduce this figure to just 29.9%.

https://www.hematologyadvisor.com/news/myelodysplastic-syndrome-mds-venetoclax-azacitidine-shows-efficacy/

Furthermore, as presented yesterday, the overall survival of AZA / VEN in r/r MDS, in the TP53 population was 3 months, compared to 9 months in AZA / Bex. Again, highlighting the superior performance of Bex.

None-the-less, Abbvie have took it upon themselves to run the phase 3 Verona trial, of the same doublet, AZA / VEN versus AZA alone, in a randomised (placebo controlled) pivotal study in the Front Line population.

I suspect, infact, easily arguably ‘know’, Abbvie will be looking very carefully at the Bexmab data, given the likelihood Bex blows Venetoclax out of the water for ORR’s, Survival & safety / tolerability in combination with AZA in both r/r and FL given the aforementionedZ

Furthermore, there is huge scope for combination with Ven, Bex & AZA.

If Abbvie don’t move to maintain its lead in both MDS & likely AML, a number of other major players will be looking at Abbvies lucrative AML / MDS franchise, with bated breath…

2/2 As mentioned yesterday by Dr Zeidan- the IDH1 drug, ivosidenib, which is only applicable to less than 5% of MDS patients, was approved with only 18 adults with relapsed or refractory MDS and a confirmed IDH1 mutation.

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ivosidenib-myelodysplastic-syndromes?utm_source=chatgpt.com

Elzonris (tagraxofusp) for Blastic plasmacytoid dendritic cell neoplasm (BPDCN)

Single arm Phase 1/2 with only ~65 patients and Efficacy: 54% CR + CRc (in treatment-naïve)

OS ~15 months

Rationale: No alternative treatment; very poor prognosis

https://www.fda.gov/drugs/fda-approves-tagraxofusp-erzs-blastic-plasmacytoid-dendritic-cell-neoplasm

🔹 Blenrep (belantamab mafodotin) – GSK

• Indication: Relapsed/refractory multiple myeloma

• Approval: Accelerated Approval in 2020

• Trial: DREAMM-2 Phase 2 trial, only 97 patients

• Efficacy: ORR ~31%; median DOR ~11 months

https://www.gsk.com/en-gb/media/press-releases/fda-approves-gsk-s-blenrep-belantamab-mafodotin-blmf-for-the-treatment-of-patients-with-relapsed-or-refractory-multiple-myeloma/

To me, this increases the chances of getting an accelerated approval and / or emergency use access in r/r MDS, perhaps first granted to TP53 patients, given the highly unfavourable prognosis, even worse than standard r/r MDS.

While there is no guarantee of emergency approval coming to pass, the likelihood of accelerated approval, given this has already been discussed and a study preliminarily outlined by the FDA via project front runner, this increases the likelihood of partnering which is likely to come before the year is out at the latest and offers the potential of FL approvals, following phase 3 interim readout (full r/r approvals at the same time) and phase 3 completion (full FL population approvals).

There is plenty to look forward to here and Bex’s strong safety credentials will work heavily in our favour as we help address this devastating disease with limited options…!

GLA.

(1/2) Morning all.

Whilst the SP has been disappointing (I too have added this morning) I think we need to put the convertible loan dilution into perspective. The number of shares being issued in this 2 monthly amortisation, including interest is 0.3% of the total shares in issue posts dilution- a very small number.

My take is there is some pressure being put on, likely via a short position, to try and shake holders out and help somebody acquire shares, I realise that’s a cliche on AIM, but we have a lot to look forward to which could catch the traders out with their pants around their ankles, imo.

1. The company will be submitting for breakthrough therapy designation, which would pretty much give us the full-house on accelerated approval pathway designations.

2. Anticipating the EOP2 meeting, the likelihood of a successful outcome given data and unmet need and pre-positioning for what should be a positive outcome.

3. Partnering / deal making - any whiff of a deal should see us re-rate heavily, imo.

4. The strong potential here for accelerated approval / emergency access. I believe our new CBO RH has experience in this area, and I’m sure will be pushing all the regulatory buttons he can, while discussing this with potential partners. There are a number of precedents where very small numbers of patients have lead to early approvals, particularly in sub sets of disease, and in diseases which have no therapeutic options following failure on existing treatments. See below…

5. The visibility we now have following the global ASCO audience & subsequent news articles / press releases could lead to hedge funds / institutions / experts taking positions from anywhere in the world.

6. It could be that it takes a very specialised audience to understand the investment here, it’s a little easier when you are quite knowledgable on the company as most here likely are.

7. Imo, potential partners / suitors will know the importance of the approval pathways / dire unmet need, and the importance and likelihood for getting this to patients ASAP, thus potentially leading someone to make a bid / seal a partnership before a phase 3 is fully outlined & others enter the deal making process which prefer more certainty, following the EOP2 meeting.

8. The new cCR, composite Complete Response and its prediction for overall survival designed by Dr Zeidan who yesterday presented the data at yesterdays webcast now known as the new IWG 2023 criteria which has a high correlation with overall survival offering certainty for partners, a surrogate endpoint for early approval and increasing the likelihood of success given Farons data.

Some examples of early approvals briefly touched on above, in high unmet need blood cancer indications:

As mentioned yesterday by Dr Zeidan- the IDH1 drug, ivosidenib, which is only applicable to less than 5% of MDS patients, was approved with only 18 adults with relapsed or refractory MDS and a confirmed IDH1

I asked ChatGPT the Significance of high TP-53 mutation patent inclusion and its implication for valuation…

Great observation — the mention of >40% TP53-mutant (TP53m) patients in the BEXMAB trial is very significant, both scientifically and commercially.

Let’s break this down:

⸻

🧬 Why is TP53 mutation rate high in this trial?

1. Relapsed/refractory MDS is enriched for TP53m:

• Patients who fail HMAs (like azacitidine) often have underlying high-risk genetics, and TP53 mutations are one of the worst prognostic markers.

• In real-world cohorts of r/r MDS, TP53 mutation frequency can be as high as 30–50%.

2. Frontline HR-MDS population skewed to high-risk:

• The “HR” designation means patients were selected based on IPSS-R/IPSS-M high or very high risk, which also coincides with higher TP53m rates.

3. Not excluded: Unlike some trials, BEXMAB didn’t exclude TP53m patients, so the >40% figure is likely naturalistic and reflects real clinical practice.

⸻

📈 Does this support an increased valuation?

Yes — very strongly. Here’s why:

1. TP53m patients are underserved with no effective therapies

• These patients:

• Respond poorly to HMAs, venetoclax, and even investigational agents like sabatolimab.

• Have extremely short survival: 5–6 months in r/r MDS with TP53m is common.

• If bexmarilimab shows meaningful response and durability in this subgroup, it represents a breakthrough therapy potential.

2. Regulatory and market value upside

• FDA and EMA are highly receptive to drugs showing activity in TP53m:

• Magrolimab was fast-tracked largely because of early TP53m signal.

• Decitabine/cedazuridine, eprenetapopt (APR-246), sabatolimab — all tried and failed or plateaued here.

• Bexmarilimab may be eligible for:

• Accelerated approval pathways

• Breakthrough designation

• Premium pricing

3. Smaller trials may suffice for approval

• If a focused subgroup (e.g., TP53m HR-MDS) shows strong efficacy and safety, it may support a smaller, faster registrational trial.

• This could reduce development costs and timelines, increasing NPV and strategic attractiveness in a sale.

⸻

🧠 Summary Takeaway

A >40% TP53m rate, combined with strong ORR (63% r/r, 72% frontline) and survival (13.4 mo in r/r), makes bexmarilimab one of very few agents ever to show this level of promise in a biologically hard-to-treat and clinically urgent population.

📌 Yes — this supports a significantly higher valuation. Bidders would likely assign platform value not just to MDS, but specifically to TP53m AML/MDS, with optional registrational paths and premium pricing potential.

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