Bisantrene in Combination with Decitabine
I’m very excited about the potential developments in combining Bisantrene with Decitabine for solid tumors. Due to IP restrictions influencing the amount of data RAC can report, I speculate that they are much more informed about this synergy and have been for some time. Discoveries like the Bisantrene IV formulation, cardioprotection MoA, and now this take a long time to establish patent coverage, thus it is my assumption that what we are seeing is relatively old news for them. Such is the nature of first-in-class agents and IP protection. With this in mind, the evidence available to me strongly suggests that Otsuka may initiate a strategic partnership with RAC to fund a Phase 1b/2 basket trial, exploring solid tumor types suitable for the Bisantrene and Inqovi combination.
Inqovi
Inqovi, an oral therapy by Astex Pharmaceuticals (Otsuka Pharmaceuticals), combines Decitabine, a DNA methyltransferase inhibitor, with Cedazuridine, a cytidine deaminase inhibitor. This combination enhances Decitabine's bioavailability and efficacy by preventing its degradation in the gastrointestinal tract and liver. Inqovi is FDA-approved for treating myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML).
The innovative oral formulation of Inqovi maintains therapeutic levels of Decitabine, which traditionally requires intravenous administration. This advancement offers a more convenient and effective treatment option for patients, expanding Decitabine’s potential applications in hematologic malignancies.
Decitabine's Limitations for Solid Tumor Use
Decitabine's limited efficacy in solid tumors stems from poor drug penetration, resistance mechanisms, tumor heterogeneity, and pharmacokinetic challenges. The dense extracellular matrix and abnormal vasculature in solid tumors hinder Decitabine's penetration and distribution, reducing its efficacy. Additionally, high levels of drug efflux pumps like P-glycoprotein decrease Decitabine's intracellular concentration. Its short half-life necessitates frequent dosing, complicating treatment and increasing systemic toxicity.
Half-Life of Inqovi Supports Solid Tumor Use
The half-life of Decitabine is crucial for its effectiveness, particularly for solid tumors with slower proliferation rates compared to blood cancers. Intravenous Decitabine has a half-life of approximately 0.62 hours. In contrast, Inqovi extends the bioavailable Decitabine half-life to about 1.5 hours, allowing more time for the cytotoxic agent to penetrate cancer cells and exert therapeutic effects. Both IV Decitabine and Inqovi are typically dosed daily over 5 consecutive days. This regimen, especially with Inqovi, ensures that Decitabine blood concentrations remain at synergistically relevant levels for a longer period, enhancing the potential for effective synergy with Bisantrene in targeting cancer cells.
Decitabine dose for Bisantrene synergy supports solid tumor use
Extremely low concentrations of Decitabine (3.2 nM to 316 nM) synergize effectively with Bisantrene to enhance the killing of certain solid tumors. The typical dosing regimen for Inqovi achieves peak plasma concentrations of approximately 500 nM, though this is individual- and regimen-specific. This improved bioavailability and prolonged maintenance of therapeutic levels make Inqovi well-tolerated and suitable for combination therapies with Bisantrene, enhancing its efficacy in solid tumors.
Bisantrene cell killing enhanced significantly by Decitabine
The key takeaway is that the increase in cell killing is referenced primarily to Bisantrene rather than Decitabine. Using the IC50 values above, Bisantrene demonstrates excellent cytotoxicity at very low nanomolar concentrations in many cell lines. The fact that this efficacy improves more than two-fold 56% of the time highlights the significant potential of the combination therapy. A 200 mg/m2 dose of Bisantrene is expected to reach peak plasma concentration of 3,000 nM, well within the required dose for clinical efficacy.
It is currently unclear whether Bisantrene's mechanism of action (potentially through FTO inhibition or another unknown pathway) sensitizes solid tumors to the effects of Decitabine and DNA methyltransferase inhibition, or vice versa. My suspicion is that Bisantrene’s mechanism plays a crucial role in this sensitization allowing Decitabine to potently synergise. This highlights the importance of further research to fully understand the synergy between these two drugs and optimize their combined use in treating solid tumors.
Bisantrene + Decitabine Synergy in In Vivo EMD AML Model
Penetrating the tumor microenvironment is a challenge for many oncology drugs. However, in vivo studies by RAC in March 2022 showed that the combination of Bisantrene and Decitabine was highly effective in mouse models of extramedullary (EMD) AML, which resembles solid tumors. This indicates the combination's potential to target solid tumors effectively.
Otsuka heavily involved in clinical programs for Inqovi
Astex/Otsuka sponsors 23 active clinical trials, primarily targeting hematologic malignancies, including acute myeloid leukemia and high-risk myelodysplastic syndromes. This active engagement highlights Otsuka's strategic efforts to expand their drugs' therapeutic applications. With 16 (70%) active combination trials, they show a preference for treatment synergies. The total enrollment across these trials is 1,224 patients, with approximately $194 million USD (AUS $292 million) in funding.
A strategic partnership involving a $10 million USD commitment (~5% of current spending) with RAC for a Phase 1b solid tumor basket trial, with Phase 2 expansions for successful applications, aligns with Otsuka’s interest in increasing the TAM for Inqovi. This partnership represents a relatively modest investment with the potential for significant returns.
Potential challenges
Inqovi has a safety profile comparable to intravenous Decitabine, though some studies report higher incidences of grade 3-4 toxicities. Common safety concerns associated with Inqovi include myelosuppression, infections, and sometimes cardioto…nevermind about that. When used in combination with other approved therapies, Inqovi demonstrates improved activity in hematological cancers with an acceptable safety profile. However, since Bisantrene also causes myelosuppression and infections, combining these drugs may result in compounded toxicities, necessitating careful consideration of dosing.
Administering drugs into cells in a lab setting is different from injecting them into a patient's bloodstream, where biology becomes tough. The concentration of Decitabine required for synergistic killing of cancer cells in vitro ranges from 3.2 to 316 nM, which is relatively extremely low to moderate compared to the peak plasma concentrations achieved (50-500 nM) with Inqovi's dosing protocol. There is a concern that the cancer cells might not receive the necessary Decitabine concentrations to synergize effectively with Bisantrene due to Decitabine's short half-life and the upper limit of plasma concentrations.
Fortunately, Bisantrene's effective doses fall within the peak plasma concentrations of Decitabine, and the consecutive five-day dosing regimen of Inqovi may help overcome the half-life and concentration challenges, potentially ensuring adequate drug exposure for effective synergy.
Conclusions
Bisantrene, when combined with clinically relevant doses of Decitabine, effectively synergizes to kill solid tumor cells. Although there are numerous limitations that influence Decitabine’s effectiveness in solid tumors, many of these limitations are common to all chemotherapies. The half-life for Inqovi is 2.5 times longer than IV Decitabine, facilitating the maintenance of synergistically relevant concentrations in plasma for a longer duration. In vivo work completed by RAC suggests that the combination of Bisantrene and Decitabine can penetrate the tumor microenvironment in EMD AML mice and synergize effectively to kill cancer cells. While this mouse model is not a perfect representation of solid tumors, it provides valuable insights into the pharmacodynamics of the combination in an organism. Additionally, Otsuka is heavily invested in expanding their TAM, and a relatively small investment into RAC has the potential to significantly broaden the reach of their drug, Inqovi.
RAC have cracked open the door to a whole world of potential, it’s up to the right suiter to step through. My bet is October.
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