Member Info for HotblackDesiato

Hi SOG - yup, it certainly adds a bit of sparkle to our shop window.

Your post on 20th Dec at 17:20 replying to Krone is worth a reread!

The BoD are definitely not just sitting back waiting for things to happen.

Example of deals in this area:

https://ir.biohaven.com/news-releases/news-release-details/biohaven-acquires-exclusive-license-oral-brain-penetrant-dual

"Terms of the Arrangement

Highlightll will receive $10 million in upfront cash and $10 million in BHVN equity, development and commercial milestone payments of up to $950 million, and tiered royalty payments ranging from mid-single digit to lower teens percentages. Biohaven and Highlightll will coordinate clinical development across global regions."

Hi JB, our value during the covid-mania that swept the bio/pharma markets was hopefully just a taste of what's to come -

1801 is showing good promise but more work required.

737 has been used clinically as monotherapy & in combo plus there are many research papers suggesting it's a strong candidate for further trials. A potential T/O may view 737 as an investment safety net with 1801 as their main target.

1802 still largely an unknown but from the same stable as 1801 so one to watch.

Aurora+Flt3 requires work, could be too difficult to crack.

SKIL sounds nifty but isn't the only kinase platform in town.

Taken as a whole, once 1801's tox results are in and 1802's translational studies are done, I'd expect the company to be at least on par with that pandemic valuation despite the intervening share dilution and whatever nonsense the sp is telling us.

Just to add, IF the BoD did have someone lined up to make a T/O offer once 1801 tox results are known, they're going to have to come up with some news in the intervening period otherwise the sp will erode further and certain shareholders will become more and more militant. So IF 737 is also a factor in that hypothetical T/O, that only leaves 1802. The BoD might have to finally announce the end of translational studies in the summer simply to keep people's interest until the end game appears.

I've never been right before so trolls and naysayers can save themselves some effort - I know I'm probably wrong!

Hi Celtic - I can only speculate here: the P1 trial was already designed and good to go until the MHRA blocked it. The BoD identified Oz as a good alternative and they accepted the paperwork with whatever was additionally required for their own rules. Pretty quick, pretty straight forward.

The extended tox study has required more 'components' to be put in place -

1. Talks with potential buyers made us pivot away from P1b trials so what are their expectations and were these negotiable?

2. We agree on extended tox trials - where will they take place and what preparations are required?

3. To placate regulatory bodies down the line, it's decided that a new batch of 1801 should be made but less pure than that used in Oz in order to increase the chances of seeing toxic effects and therefore indicating a max dose.

3a. Just how impure should this new batch be? Is it decided on a whim or does it take time to arrive at a value? Would 95% purity be just as effective as 97% pure therefore allowing acceptable toxicity without losing efficacy? What balance do you go for?

4. Not essential but JR writes up a paper on the Oz trial for publication. Before it gets published he has to ensure all patents are in place otherwise we may come unstuck if we subsequently try to add another patent (prior art and all that jazz).

5. Are the manufacturing and tox trial labs able to accomodate us right away or are they booked months ahead?

etc.

etc.

Think of it in terms of that Grand Designs programme - you say you can build a house in 12mths as you've got all the architect drawings and a builder ready to get cracking. Then winter sets in and a supplier goes bankrupt. Ah....

Regards.

Just musing.

I can almost see a scenario where someone wants the whole company but their offer is under a total NDA whilst awaiting extended tox results for 1801. We presume 1801 will sail through them but as we don't know what purity will be used in the tox study, we don't know what issues could arise (whether by design or not). IF a T/O is the BoD's preferred outcome then it could mean SP has to give the illusion he's trying his hardest to sell 737 whilst the reality is he's just treading water in order to sell all assets to the one buyer.

Terms and conditions apply. Always read the label. Keep away from children.

Hi Krone - I think SP's immediate focus is very much on 737. I asked a question (No. 4) at the IM event re how attractive 737 may still be to potental partners and the reply below suggests the BoD believe it still has a part to play in our future.

"The SRA737 patent gives us about nine years of protection – which is still attractive for partners since it's already at clinical stage and could reach market faster than a preclinical compound. While we're always looking at ways to extend protection, our main focus right now is finding the right partner or development path that can make the most of SRA737's existing clinical data and current patent life. With a clinical-stage asset, we believe there's still good time to create value within the current patent window."

Regards.

And yet Bizzi, quoting from the more recent study I posted about yesterday, "...ultimately SRA737 was selected for these preclinical experiments as it represented the current best candidate for future clinical development as a monotherapy and in combination with other therapies."

and

"...SRA737 demonstrated profound monotherapy activity and survival benefit in this PARPi-and platinum-resistant model. SRA737 also demonstrated efficacy in two highly treatment-resistant CCNE1amp HGSOC PDX models, with tumor regression observed in PDX #29, generated from a chemo naive patient who had rapidly progressive, fatal disease."

Cancer is a slippery customer so it's critical to apply the most appropriate treatment as early as possible. The Sierra studies were in patients who had run out of options as their cancers were so advanced. The preclinical work alluded to in the above quote strongly suggests 737 has a significant role to play if used under optimum conditions, in this instance models of ovarian cancer.

It ain't over 'til it's over.

Seems to all relate to this study they carried out in 2023 - https://www.explorationpub.com/Journals/etat/Article/1002193

"Tumour responses were noted in anogenital and other solid tumours, with an objective response rate in anogenital cancer of 25%. Partial tumour responses were also observed for a variety of other cancers, indicating SRA737’s anti-cancer activity in multiple indications. Many of the observed responses were associated with alterations in the Fanconi anaemia (FA)/BRCA network and factors involved in the repair of replication forks, and in tumours of intermediate to high mutational burden; providing clinical evidence of the effectiveness of LDG plus SRA737, justifying further study.

However, despite the positive reports of CHK1 inhibitors preclinically, overall, trial outcomes of CHK1 inhibitors have to date not lived up to expectation. This has included failure to substantially improve the standard treatment [40, 55], off-target effects [56], toxicity [57] and other contrary effects [58] or trial termination due to business reasons [59]. In addition, evidence of independence towards P53 has been observed in some studies and trials [59]. Thus, for CHK1 inhibition to ultimately progress, further new factors/biomarkers affecting the efficacy of CHK1 inhibitors need to be identified and translated to the clinic; with the perhaps most useful being those that allow for inhibitor-specific patient stratification criteria."

At least the mystery US-bio must have carried out some work beyond applying for the IND if their data has been added to the overall 737 data pack. Just curious why they were unable to start in-human trials given all the positive preclinical studies such as this one from last year looking at ovarian cancer:

https://www.cell.com/action/showPdf?pii=S2589-0042%2824%2901200-8

"At the time of study initiation, SRA737 was the only orally bioavailable CHK1-specific inhibitor in development. Prexasertib, a CHK1/2 inhibitor, is administered via I.V. and has high hematologic toxicities, which together limit its clinical utility as a monotherapy and in combination with novel agents. Other CHK1is, such as MK-8776 and AZD7762, were no longer in clinical development due to PK limitations and concerns of toxicities. Ultimately SRA737 was selected for these preclinical experiments as it represented the current best candidate for future clinical development as a monotherapy and in combination with other therapies.

Using the PDX drug-development platform, we demonstrated that SRA737 monotherapy is active in aggressive, drug resistant CCNE1amp HGSOC models. In an orthotopic PDX model (WO-19) established from a platinum-resistant CCNE1amp HGSOC patient, SRA737 demonstrated profound monotherapy activity and survival benefit in this PARPi-and platinum-resistant model. SRA737 also demonstrated efficacy in two highly treatment-resistant CCNE1amp HGSOC PDX models, with tumor regression observed in PDX #29, generated from a chemo naive patient who had rapidly progressive, fatal disease."

Regards all.

Hi Krone - anyone's guess if they'll RNS the report.

Looking at the numbers it's interesting that those given a single 1801 dose of 100mg daily all had some sort of adverse event yet the volunteers in MAD cohort D taking 70mg twice a day displayed no adverse events.

Referring back to the recent slide presentation, "SDC-1801 shows no effect on serum creatinine levels at doses equivalent to 100mg of brepocitinib". 1801 MAD cohort D (as mentioned above) gives a plasma exposure on par with brepocitinib's MAD 100mg per day trial.)

All looking good to me.

The key lesson is never trim your bush.

I think the most frustrating thing for the longer-term holders are the delays but delays appear in every aspect of life. Just watching the men's Oxford/Cambridge boat race which was delayed slightly by a log floating down the Thames (insert joke here).

Our time will come.

Celtic - also that's just the basic report. A more detailed one will probably be available to interested parties and referred to in the peer-review paper yet to be published.

Sounds like you're back on side after having a major wobble at the end of March.

Keep the faith.

I can't post a direct link but open the link below, scroll to the bottom of the page and open the pdf link in the section labelled 'attachment'.

https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=385663&isReview=true

"Serious Adverse Events

1 (8.3%) participant in the placebo group experienced 1 SAE of skin laceration caused by a hedge

trimmer that was considered not related to study drug. There were no SAEs in Parts 2 and 3."

Onwards!

No worries! In other news, have you noticed shares in Vagisil go up when those guys post? Cause and effect?

Hi Meg - I did imply that AI isn't the same as talking to an oncologist but I thought it might still be of interest to see if it could shed any light on potential benefits or negatives of a combo. I wouldn't like to mislead anyone to think if A is good and B is good then A+B must be even better. Medicine doesn't work like that, at least that's what my astrologer told me ;-)

A further query - How do the different forms of cellular stress created by each drug impact the effectiveness of the combined therapy?

"The cellular stress responses triggered by Capivasertib and SRA737 create a complex interplay that significantly impacts the effectiveness of combined therapy. Here's a detailed breakdown of these interactions:

Primary Stress Responses

Capivasertib-Induced Stress

Directly inhibits AKT signaling pathway

Creates metabolic stress through energy pathway disruption

Activates cellular protective mechanisms

May trigger adaptive responses in cancer cells

SRA737-Induced Stress

Generates DNA replication stress

Activates checkpoint responses

Creates genomic instability

Disrupts normal cell cycle progression

Interactive Stress Effects

Metabolic Pathway Interference

Capivasertib's AKT inhibition affects glucose metabolism

SRA737's checkpoint activation alters energy demands

Combined effect may exceed cellular compensation capacity

Risk of catastrophic failure of essential processes

Protein Homeostasis Disruption

Multiple stress pathways converge on proteasome function

Excessive protein misfolding triggers unfolded protein response

Potential for overwhelming cellular quality control systems

Risk of activating deleterious stress adaptation mechanisms

Impact on Therapeutic Effectiveness

Positive Interactions

Synergistic induction of lethal stress levels

Prevention of individual drug resistance mechanisms

Enhanced targeting of vulnerable cellular states

Potential for improved initial response rates

Negative Consequences

Risk of excessive toxicity

Activation of protective stress responses

Development of novel resistance mechanisms

Reduced therapeutic window

Clinical Implications

Treatment Optimization Challenges

Need for precise dosing to balance stress levels

Complex monitoring requirements

Potential for unexpected side effects

Necessity for careful patient selection

Resistance Development Risk

Multiple pathways for cancer cell adaptation

Potential for accelerated resistance evolution

Need for combination therapy sequencing strategies

Importance of biomarker development

This complex interplay of stress responses explains why seemingly complementary mechanisms require careful clinical evaluation. The success of combined therapy depends on finding the optimal balance between inducing sufficient cancer cell death while avoiding overwhelming normal cellular protective mechanisms."

Hope that's of some interest.

I asked AI if Capivasertib could be used with 737, some of the response is below. Obviously I'm no oncologist and neither is an AI chat tool so take things with a pinch of salt.

"Based on current information, while both Capivasertib and SRA737 show promise in treating certain types of cancer, there isn't enough data to determine whether combining them would create a more effective treatment for breast cancer."

When probed further -

"There are several compelling reasons why Capivasertib and SRA737 might not work well together, even if their mechanisms appear complementary. These concerns arise from multiple biological and clinical perspectives:

Cell Cycle Interference

Competitive Effects

Both drugs affect cell cycle checkpoints, potentially creating conflicting signals

Capivasertib's inhibition of AKT signaling could interfere with SRA737's ability to properly activate checkpoint responses

This competition might reduce the effectiveness of both drugs

Cellular Stress Overload

Each drug creates different forms of cellular stress

Combining these stresses could overwhelm cellular machinery

Resulting in unintended consequences rather than additive benefits

Signaling Pathway Complexity

Feedback Loop Disruption

AKT pathway inhibition by Capivasertib triggers complex feedback loops

These loops might alter the effectiveness of SRA737's checkpoint activation

Creating unpredictable outcomes due to pathway crosstalk

Apoptotic Threshold Issues

Different thresholds for triggering programmed cell death

Risk of either insufficient or excessive cell killing

Potential for selecting resistant clones

Clinical Safety Concerns

Enhanced Toxicity Risk

Overlapping toxicities in bone marrow suppression

Increased risk of severe adverse events

Potential for cumulative organ damage

Pharmacodynamic Interactions

Possible interference with drug metabolism

Altered bioavailability patterns

Changes in therapeutic windows

Development Challenges

Dosing Complexity

Need to balance competing requirements

Risk of underdosing one drug while overdosing the other

Complex titration requirements

Resistance Patterns

Potential for accelerated resistance development

Multiple escape routes for cancer cells

Reduced durability of response

These challenges highlight why seemingly complementary mechanisms don't guarantee successful combination therapy. Each concern represents a potential barrier to achieving the desired synergistic effect, emphasizing the importance of thorough preclinical and clinical testing before implementing such combinations in practice."

Regards.

Morning SOG - interesting stuff. When I posted the news about Capivasertib on another thread I did have it in the back of my mind about the other preclinical trial I mentioned that uses ultrasound + 737 to target breast cancer.

Sounds like we should arrange a meeting between AZ, SAR & the Chinese team...