Cardioprotection thread

Given we have an FTO thread I thought we should have a dedicated cardioprotection thread as well for any relevant links/discussion.

For any newcomers I’ve done some copy paste to whet the appetite and give context to further discussions.

Here’s a brief intro from the Race Oncology website on the history of bisantrene (Zantrene) and why it is being investigated as a cardioprotective anticancer agent.

"Bisantrene is a small molecule anthracene-based chemotherapeutic that was originally developed by American Cyanamid (Lederle Laboratories) in the 1970s & 1980s with the goal of creating a less cardiotoxic/toxic anthracycline-like chemotherapeutic."

"Bisantrene has been evaluated in over 46 clinical trials and 70 peer reviewed publications, with around 1.8k patients treated, demonstrating efficacy and a well characterised safety profile.

Anthracyclines have been the most administered category of chemotherapy agents for decades, however they can cause significant toxicity in the body. Lifetime limits of anthracyclines are enforced due to the risk of potentially fatal, congestive heart failure.

Studies have shown bisantrene reduces risk of cardiotoxicity and has higher tolerability than anthracyclines, while also demonstrating cardio-protection when used in conjunction with anthracyclines."

A short summary of Race’s journey with cardioprotection and some highlights.

April 2021- Race Initiates Heart Safety Preclinical Study For Bisantrene
HC Thread - https://hotcopper.com.au/threads/ann-race-initiates-heart-safety-preclinical-study-for-bisantrene.6027908/

"Race Oncology Limited (“Race”) is pleased to announce that it has entered into a collaborative preclinical research program with The University of Newcastle to investigate the heart safety bisantrene offers over current anthracycline therapeutics. Eminent cardiotoxicity researchers, Associate Professors Aaron Sverdlov and Doan Ngo of the University of Newcastle, will lead the project."

As a side note, Doan Ngo was awarded the Australian Cardiovascular Alliance 2022 Game Changer award for research into bisantrene's cardiovascular and anti-cancer properties.

Nov 2021 - Breakthrough Chemotherapy Heart Protection Discovery For Zantrene
HC Thread - https://hotcopper.com.au/threads/ann-breakthrough-zantrene-heart-protection-discovery.6435902/

1. Zantrene protects cardiomyocytes from doxorubicin-induced cell death
2. Zantrene synergises with doxorubicin and epirubicin to better kill breast cancer cells
3. Cardio-protective mechanism of Zantrene is independent of FTO inhibition

Dec 2021 - Expanded Heart Protection Discovery For Zantrene
HC Thread - https://hotcopper.com.au/threads/ann-expanded-heart-protection-discovery-for-zantrene.6473741/

1. Zantrene protects cardiomyocytes from carfilzomib-induced cell death
2. Zantrene is highly active in killing multiple myeloma cancer cells
3. Zantrene synergises with carfilzomib to better kill breast cancer cells

Dec 2021 - Race Extends Heart Protection Collaboration With University Of Newcastle
HC Thread - https://hotcopper.com.au/threads/ann-uni-of-newcastle-heart-protection-collaboration-extended.6479108/

This collaboration builds on the initial heart safety preclinical study (ASX announcement: 28 April 2021) and will explore the cardio-protective attributes of Zantrene in vitro when used in combination with an expanded panel of anti-cancer drugs known to damage the hearts of cancer patients, as well as to undertake animal studies.

June 2022 - Zantrene Protects Mouse Hearts from Chemotherapy Damage
HC Thread - https://hotcopper.com.au/threads/ann-zantrene-protects-mouse-hearts-from-chemotherapy-damage.6818818/

1. Zantrene protects mouse hearts from doxorubicin induced damage
2. Zantrene allows higher chemotherapeutic doses to be used without additional general toxicity or myelosuppression.

March 2023 - Race Initiates New Collaboration to Understand Zantrene Cardioprotection Mechanism
HC Thread - https://hotcopper.com.au/threads/ann-race-initiates-heart-safety-preclinical-study-for-bisantrene.6027908/

• Collaboration will use state-of-the-art biochemical, cellular and mouse models of cardioprotection
• Program led by leading international cardio-oncologist Dr Brian Jensen of the McAllister Heart Institute, University of North Carolina at Chapel Hill, USA

April 2023 - Race releases complete cardio-protection data presentation and video
HC Thread - https://hotcopper.com.au/threads/ann-race-releases-complete-cardio-protection-data-video.7330726/

• Independent analysis suggests use case for Zantrene in nearly the entire identified target patient population as a cardio-protective oncology drug if anticancer benefits are demonstrated
• If anti-cancer efficacy is demonstrated, sales for Zantrene could represent an overall peak commercial value of ~$1.7B USD in breast cancer alone within the US (~$3.4B USD globally)
• Revenue may extend to $5-8B USD annually if expansion is achieved into additional identified cancer indications and further approvals are obtained in exUS markets.

Nov 2023 - Chaim Sheba Phase 2 AML clinical results are released

HC Thread - https://hotcopper.com.au/threads/ann-impressive-bisantrene-phase-2-aml-clinical-results.7684132/
Boffin99 Thread - https://hotcopper.com.au/threads/ash2023-sheba-2-0.7678945/

"Clinical-relevant cardiac toxicity was not observed in any of the pts and no one developed ECG changes"
4292 Bisantrene in Combination with Fludarabine and Clofarabine As Salvage Therapy for Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML)- an Open-Label, Phase II, Study

It is worth noting that this result (outside of the impressive 40% response rate) was in heavily pretreated AML patients. While cardiac dysfunction with fludarabine use is more rare, clofarabine is well known to be cardiotoxic.

“Mitomycin C, ifosfamide, cyclophosphamide, clofarabine, and vincristine are frequently recognized as being highly cardiotoxic, causing CTRCD in ≥10% of patients.”
Cancer Therapy-Related Cardiac Dysfunction of Nonanthracycline Chemotherapeutics: What Is the Evidence?

An historical data bonus:
In a combination trial in 1994, bisantrene was administered with high dose aracytine (cytarabine/ara-C) where "no significant cardiac toxicity was noted".
1994 - Treatment of relapsed or refractory acute leukemia in childhood with bisantrene combined with high dose aracytine

“Antimetabolite agents, such as capecitabine or cytarabine, can induce ischemia, pericarditis, CHF, and cardiogenic shock” - Cardiotoxicity of Anticancer Drugs: The Need for Cardio-Oncology and Cardio-Oncological Prevention

Nov 2023 - Updated Strategy and Investor Presentation
HC Thread - https://hotcopper.com.au/threads/ann-updated-strategy-and-investor-presentation.7713415/

Strategic update is released with a plan for “an ‘all comers’ Bayesian dose escalation Phase 1a trial of RC220 in any solid tumor patient where anthracycline use is indicated."
Phase 1a establishes optimal bisantrene anthracycline dosing and safety
Phase 1b generates proof-of-concept cardioprotection efficacy data in combination with anthracyclines

Data generated will be used to support a Phase 2 efficacy trial.

VO2 Peak

While all cardiac markers will be measured, VO2 peak will also now to be used as a marker which provides a potential pathway to accelerated approval from Phase 2 data.

“Anthracycline exposure was found to reduce average VO2Peak in patients by 8-11% (equivalent of 8 to 11 years of normal ageing) with the rates of functional disability nearly doubled (15% vs. 26%) 43% of the anthracycline exposure patients experienced a 10% or greater reduction in VO2Peak performance levels.

VO2Peak offers a clinically relevant endpoint that can provide clear evidence of cardioprotection and improvement in patient Quality of Life”

CEO Daniel Tillett stated"The significance of the VO2Peak is massive for Race as it provides a possible pathway to both early proof-of-concept and accelerated approval out of Phase 2 data. This discovery has probably added more value to Race than anything since RC220."

Website: https://raceoncology.com/

Thanks to @PatchKolan for the once-over and suggestions.