Member Info for BuenaVista

No. Previously he's always returned the big beautiful vase so that the world can fill it with flowers again. This time he's smashed the vase.

Approximately 20 to 22.5 million barrels of oil and petroleum products are normally exported from the Persian Gulf every day, about 20% to 25% of the total seaborne oil trade worldwide.

The UAE operates the Abu Dhabi Crude Oil Pipeline (ADCOP), also known as the Habshan-Fujairah pipeline, which diverts oil across the country to bypass the Strait of Hormuz. The 360-400 km pipeline carries up to 1.8 million barrels per day from Habshan in Abu Dhabi to the Fujairah port on the Gulf of Oman, allowing exports to bypass the strategic chokepoint. So some 8.5% of the amount shipped through the Gulf. Not enough.

It's not just oil though that is being held up. It is also LNG, literally floating bombs on the water, and — very importantly — fertilisers that are needed for the coming planting season. There is the distinct possibility of poor harvests this autumn and next year and hence famine and mass starvation if the fertilisers aren't delivered in time.

Just finished reading this thread. My view is that the situation in the Persian Gulf is a lot more involved, complex and nuanced than is being appreciated here. It's not just oil/LNG being held up and facilities destroyed, it's also fertilisers (think famines), metals, and other resources. It will take weeks to unwind the shipping backlog and the economies of the Gulf states are fooked as they are fundamentally unsafe areas in which to live, holiday and do business. As regards Trump pulling out... then what? Iran is demanding reparations and the removal of all US bases from the Gulf area. Iran holds the cards.

I highly commend the What's Going on With Shipping? YouTube channel - https://www.youtube.com/@wgowshipping - and particularly yesterday's "Strait of Hormuz 3-Week Recap | What is the Status of the Ships, Transits and Escort Mission?" - https://www.youtube.com/watch?v=q64cOs7GN_4

Another good source of information and comment is the The Rest Is Politics channel - https://www.youtube.com/@restispolitics - with Alistair Campbell and Rory Stewart, the latter of whom has a lot of contacts with knowledge of the Gulf region.

I'll be buying a small initial stake in L&G if the share price goes below 210 in the next 10 days or so. I don't think the dividend is in danger.

Ah, it seems someone is craving narcissistic supply this Sunday lunchtime.

Well, Bayer's ATR (ataxia-telangiectasia and Rad3 related protein) inhibitor BAY1895344 started Phase 1 in July 2017 and completed in September 2023. That was 6yrs 2mths: https://clinicaltrials.gov/study/NCT03188965

The AVA6000 trial has been going since July 2021, which is 4yrs 8mths (with completion due August 2026, so after 5yrs 1mth): https://clinicaltrials.gov/study/NCT04969835

This would have been shorter with:

• Access to more cash initially

• Clinician recognition of Avacta and the platform

• Better planning

• Greater experience of the trial process

• Greater knowledge of the platform MoA

• A MTD found

Why do you call it a straight when it's clearly a bend?

Nah. Don't like that. The Spitfire was a design classic, like the Mini, just beautiful. That one looks like the Mondeo of fighter planes.

Getting a message since before 7am that HL are carrying out 'routine maintenance' on their app. Seems a strange and inconvenient time for 'routine' maintenance. Accounts on the website are unavailable due to 'technical issues'. Pretty poor, really.

You omitted to mention that this is your only start-up biopharma investment, or you'd know what to expect.

I stopped reading at "Speculation on X "

VS wrote on Wednesday:

"That's what Monday's RNS was about??"....Not exactly. On Monday the site was open but it emphasised " not yet recruiting". Today it changed to " Recruiting"

I explained that Avacta submitted a change of status on Monday and the updated record was published yesterday.

I was looking for some deeper meaning but there was indeed no issue, just a misunderstanding by VS about the process.

Change of status was submitted on Monday, 16th, the day of the RNS, and the updated record was published yesterday, 18th.

There's nothing new or different here from what we already knew - my point. I don't see what VS's issue is.

So VS, is today's clinicaltrials site update materially different from Monday's RNS? Has it added anything new?

The orginal NCT07454642 record had nothing for Contacts/Locations, Monday's RNS said the two sites were open for recruiting, and today's NCT07454642 update reflects that change. Nothing here we didn't already know other than the contact details and that no international dialling code is required for US phone numbers.

Courtesy of an alert by Tom-the-Bomb: https://www.fiercebiotech.com/biotech/hitting-regulatory-roadblock-bicycle-pumps-brakes-lead-program-and-deflates-headcount-30

Pipeline (updated - zelenectide pevedotin and BT7480 affected): https://www.bicycletherapeutics.com/pipeline/pipeline/

This AI response is history now, but... Gemini: Bicycle Therapeutics's PDCs

Bicycle Therapeutics is a clinical-stage biopharmaceutical company developing a novel class of medicines known as Bicycles®, which are fully synthetic, short peptides constrained into two loops to form a bicyclic structure. These molecules act as Peptide–Drug Conjugates (PDCs)—or more specifically, Bicycle Toxin Conjugates (BTCs™)—combining the high affinity and selectivity of antibodies with the small molecular weight and fast renal clearance of peptides.

Key Advantages of Bicycle PDCs

• Rapid Tumor Penetration & Retention: Due to their small size (~2 kDa), Bicycles penetrate solid tumors more effectively than larger antibodies.

• Rapid Renal Clearance: Unlike Antibody-Drug Conjugates (ADCs), Bicycle PDCs are excreted through the kidneys, which may minimize liver and gut toxicities.

• Fully Synthetic: This allows for precise engineering, scalable manufacturing, and reduced immunogenicity.

Primary PDC Pipeline Candidates

Bicycle Therapeutics is currently focusing its pipeline on oncology, targeting high-unmet medical needs:

• Zelenectide pevedotin (BT8009): A second-generation BTC targeting Nectin-4, a validated tumor antigen, conjugated with monomethyl auristatin E (MMAE). It is currently in Phase I/II trials, with an expedited development plan for a registrational trial (Duravelo-2) in metastatic bladder cancer.

• Nuzefatide pevedotin (BT5528): A second-generation BTC targeting EphA2, which is overexpressed in many solid tumors, including breast, lung, and ovarian cancers. It is currently undergoing Phase I/II evaluation.

• BT7480: A Bicycle TICA™ (Tumor-Targeted Immune Cell Agonist) that targets Nectin-4 and agonizes CD137. It is designed to act as an immune stimulant within the tumor microenvironment without systemic toxicity.

• BT1718: A BTC targeting MT1-MMP, which is being investigated in a Phase I/IIa trial sponsored by Cancer Research UK.

Clinical Development and Collaborations

• Clinical Progress: As of April 2024, the company reported significant progress in Phase I/II trials for BT8009, BT5528, and BT7480, with strong cash reserves to support operations.

• Bayer Collaboration: In May 2023, Bicycle entered a strategic collaboration with Bayer to develop Bicycle Radioconjugates (BRCs) for oncology, aiming to target specific tumors with radiation rather than toxins.

• Novartis Collaboration: In March 2023, the company announced a partnership with Novartis to develop radiopharmaceutical cancer treatments.

Bicycle Therapeutics is headquartered in Cambridge, UK, with operations in Cambridge/Lexington, MA.

With this link you can play around and view its 3D structure: https://pubchem.ncbi.nlm.nih.gov/compound/Elimusertib#section=Structures

It went very quiet on AVA6000 in high-grade soft-tissue sarcoma didn't it?

Until "This study shows single agent and combinatorial activity of AVA6000 (Faridoxorubicin, FAP-Dox), in pancreatic cancer and liposarcoma, cancer associated fibroblast co-culture models. ... Further, we tested the effects of the combination of an ATR inhibitor BAY1895344 in combination with AVA6000 in the coculture system."

...r for the first deal.

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Gemini: Do ATR inhibitors work with anthracyclines?

Yes, ATR (Ataxia telangiectasia and Rad3-related) inhibitors work effectively in combination with anthracyclines (such as doxorubicin, epirubicin, and idarubicin), with numerous studies indicating a synergistic effect that enhances cancer cell killing.

Anthracyclines induce DNA damage, specifically double-strand breaks (DSBs) and replication stress. Cancer cells typically respond to this damage by activating the ATR-Chk1 pathway to repair the lesions and survive. Inhibiting ATR blocks this repair mechanism, forcing the cancer cells into a premature, fatal mitosis (mitotic catastrophe).

Key Mechanisms and Findings

• Synergistic Cytotoxicity: Combining ATR inhibitors (e.g., VE-822, AZD6738) with doxorubicin has been shown to significantly reduce cell viability and increase apoptosis (programmed cell death) compared to either treatment alone.

• Overcoming Resistance: ATR inhibitors can re-sensitize chemotherapy-resistant cancer cells to anthracyclines.

• Mechanism of Action: Anthracyclines cause DNA damage, and when ATR is inhibited, cells cannot stop the cell cycle to repair this damage. This leads to an accumulation of DNA damage and mitotic failure.

• Specific Evidence: Preclinical studies, including in liposarcoma and leukemia models, have confirmed that the addition of ATR inhibitors to doxorubicin significantly enhances anticancer activity.

Potential Clinical Applications

• Solid Tumors and Sarcomas: ATR inhibitors have shown promise in enhancing the sensitivity of various tumors to anthracyclines.

• Combination Therapies: ATR inhibitors (e.g., ceralasertib, berzosertib) are currently being evaluated in clinical trials, often in combination with other DNA-damaging agents.

While promising, these combinations are mainly established in preclinical models, and further clinical trials are necessary to fully determine their efficacy and safety in patients.

Gemini: BAY1895344 Banerji

BAY1895344 (also known as elimusertib) is a highly potent, selective, and orally available inhibitor of the ataxia telangiectasia and Rad3-related (ATR) kinase, a key regulator of the DNA damage response (DDR). U. Banerji is a primary investigator/author associated with the clinical development of this compound.

Clinical Development and Trials (Banerji et al.)

• First-in-Human Study ( https://clinicaltrials.gov/study/NCT03188965 - lasted over six years!): Led by U. Banerji and colleagues, this trial investigated the safety, tolerability, and efficacy of BAY1895344 in patients with advanced solid tumors and lymphomas.

• Safety & Dosage: The maximum tolerated dose (MTD) was identified as 40 mg twice daily, using an intermittent schedule (3 days on/4 days off). The most common adverse events were reversible hematologic toxicities.

• Efficacy: The study found that BAY1895344 had single-agent antitumor activity, particularly in patients with ATM (ataxia-telangiectasia mutated) deleterious mutations or ATM protein loss.

• Results: Partial responses were achieved in 4 patients and stable disease in 8 patients, with a median duration of response of 315.5 days.

Mechanism of Action

• Synthetic Lethality: BAY1895344 blocks ATR, which is essential for repairing DNA replication stress. In cancer cells with pre-existing DDR defects (like ATM loss), ATR inhibition causes overwhelming DNA damage, leading to cell death (synthetic lethality).

• Synergy: Preclinical studies showed that BAY1895344 acts synergistically with DNA-damaging agents, including PARP inhibitors, radiotherapy, and chemotherapy.

Preclinical and Other Studies

• Uterine Leiomyosarcoma (uLMS): Studies showed that BAY1895344 (20 mg/kg) could induce significant growth inhibition in ATRX-mutated uLMS patient-derived xenografts.

• Pharmacokinetics: The drug showed linear, dose-dependent bioavailability at lower doses, with saturation of first-pass metabolism at higher doses.

The results indicate that elimusertib (BAY1895344) is a promising agent for targeting tumors with specific DNA repair deficiencies, with the first-in-human trial led by Banerji establishing its potential as a targeted therapy.

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All BAY1895344 trials: https://clinicaltrials.gov/search?term=BAY1895344

Interesting... A phase I study of ATR inhibitor BAY1895344 (elimusertib) plus topotecan (ETCTN 10402): Results of dose escalation

https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.3076 ( https://clinicaltrials.gov/study/NCT04514497 )

BAY 1895344 (elimusertib) is a potent, highly selective, and orally bioavailable inhibitor of the Ataxia telangiectasia and Rad3-related (ATR) kinase. It is not a topoisomerase-I inhibitor itself; rather, it is designed to be used in combination with topoisomerase-I (Top1) inhibitors (such as topotecan or irinotecan) or as a single agent to enhance cancer cell death.

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My money's on Baye

Always best to ignore - or ridicule - narcissists when they bleat on and on about the same thing just for attention.