Summary of Drug Rediscovery and Its Impact
While the history of Bisantrene is long and detailed, its journey from the clinic to commercialization has only just begun. A common theme among those lacking competence in evaluating scientific literature is the erroneous belief that Bisantrene is a failed molecule from the 1980s. The evidence not only refutes this viewpoint but also highlights that rediscovered drugs, including those approved for uses other than their original development, have consistently become first-in-class agents, establishing new fields of therapy. Research from the Boston Consulting Group shows that first-in-class agents capture the largest market share and are highly valued by pharmaceutical companies.
Drug rediscovery has proven to be a valuable process in modern medicine, highlighting that many drugs still in use today were not fully understood at the time of their initial development. The journey of Bisantrene exemplifies this phenomenon. Initially developed as a less cardiotoxic anthracene in the 1970s, Bisantrene has evolved over the past 50 years. Recent preclinical models have uncovered its world-leading FTO inhibitory and cardioprotective mechanisms, thus redefining its original class and expanding its therapeutic potential.
The following table summarizes several drugs that were rediscovered and became first-in-class agents in their respective fields:
Key Findings on Drug Rediscovery
1. Historic Clinical Evidence Accelerating Approval and Commercialization:
Historic clinical evidence has played a crucial role in the re-evaluation and rapid approval of rediscovered drugs. For example, the use of historic data for drugs like Thalidomide and Metformin significantly influenced their re-entry into the market.
Metformin: Discovered in the 1920s and recognized for its anti-diabetic properties in the 1950s, Metformin faced delays in its acceptance in the USA until the 1990s. Historic clinical trials and its use in other countries like France played a vital role in its eventual approval by the FDA, establishing it as a first-in-class oral antidiabetic biguanide.
Thalidomide: Initially developed in the 1950s as a sedative, it was withdrawn due to severe birth defects. Rediscovered in the 1990s for its immunomodulatory properties, Thalidomide became a first-in-class treatment for multiple myeloma. Historic clinical evidence from its initial use expedited its re-approval and commercialization in cancer therapy. The success of Thalidomide in multiple myeloma led to the development of Lenalidomide, which paved the way for multi-billion dollar immunomodulatory drugs.
2. Rediscovered Drugs as First-in-Class Options:
In all documented cases, rediscovered drugs have become first-in-class options in their respective fields, largely influenced by historic knowledge and clinical evidence.
Lenalidomide: Developed due to Thalidomide's rediscovery, Lenalidomide improved safety and efficacy, establishing itself as a first-in-class immunomodulatory derivative for multiple myeloma and other cancers.
Botox: Initially used for treating strabismus, Botox was rediscovered in the 1980s for cosmetic use. It became the first-in-class neurotoxin for cosmetic treatments, revolutionizing both medical and cosmetic fields.
Raloxifene: Originally investigated for breast cancer treatment, Raloxifene's rediscovery in 1997 for osteoporosis and breast cancer prevention established it as a first-in-class SERM, pioneering the management of these conditions.
3. Innovative Mechanisms and Expanded Therapeutic Uses:
Rediscovered drugs often unveil new mechanisms of action and expanded therapeutic uses, demonstrating the importance of continued research and innovation.
Minoxidil: Initially an antihypertensive drug, Minoxidil was repurposed in the 1980s for hair loss treatment due to its side effect of hair growth, creating a new market for topical hair regrowth treatments.
Imatinib: Initially developed for niche CML, Imatinib's targeted action as a tyrosine kinase inhibitor revolutionized cancer therapy, becoming a first-line treatment for multiple cancers and a model for targeted cancer therapies.
4. Potential and Challenges in Rediscovery:
The process of drug rediscovery, while beneficial, also faces challenges such as initial lack of understanding, regulatory hurdles, and commercial viability. However, the successful examples highlight the immense potential and transformative impact of this approach.
Daptomycin: Initially discovered in the 1980s by Eli Lilly, Daptomycin faced significant challenges due to adverse musculoskeletal effects in early clinical trials, which led to its discontinuation. Cubist Pharmaceuticals later revisited Daptomycin, overcoming these challenges by optimizing the dosing regimen. This strategic adjustment minimized adverse effects, leading to the drug's successful approval for complicated skin and skin-structure infections in 2003 and Staphylococcus aureus bacteremia in 2006.
Bisantrene
Initially perceived as a less cardiotoxic anthracene, Bisantrene's rediscovery in 2017 and the discovery of its FTO inhibition and cardioprotective mechanisms illustrate the evolving understanding of drug mechanisms and its therapeutic potential. A thorough review of the in-human clinical data for Bisantrene challenges the less cardiotoxic anthracene narrative and supports FTO inhibition and cardioprotection as the main drug effects. Some of the key findings from historic research include:
Incorrect Dosing Still Drives Significant Effects: Single-agent high-dose Q3W Bisantrene outperformed approved anthracyclines Doxorubicin and Mitoxantrone in a phase III breast cancer trial (Bis-Dox HR 0.92 [95% CI 0.7-1.21]; Mit-Dox 1.48 [95% CI 1.12-1.95]) with no cardiotoxic events. Low-dose 5-day dosing regimen achieved 43% more responses than high-dose Q3W dosing in a separate phase II breast cancer trial, suggesting long-term inhibition of FTO is more effective in solid tumors as a single agent.
Precision Oncology: Patients added into a P1 dose escalation trial because their tumor samples were sensitive to Bisantrene achieved clinically meaningful responses, typical of precision therapies like FTO inhibition.
FTO Inhibition Resensitizes Resistant Cancers + Cardioprotection: Bisantrene resensitized AML, AUL, ALL pediatric patients refractory to Ara-C, achieving a 57% CR rate (subgroup analysis excluding those who died and who did not receive prior Ara-C) in combination with high-dose Ara-C. There were no clinical signs of cardiotoxicity despite extensive prior anthracycline history. In combination with cardiotoxic antimetabolites Clofarabine and Fludarabine in AML patients, Bisantrene achieved a 40% ORR (5CR; 1PR) with no clinically relevant cardiotoxicity. Multiple preclinical models have shown that FTO inhibition resensitizes resistant cancer cells to a wide range of antimetabolites.
Extremely Strong Clinical Efficacy in Resistant Populations: Achieved an average 48% ORR (with the majority representing CRs) using a 4-7 day dosing regimen across 7 phase II trials, supporting the efficacy of consistent daily doses of an FTO inhibitor.
The knowledge of FTO inhibitory and cardioprotective mechanisms enables those with sufficient skill and rigor to understand and address inconsistencies seen in the scientific literature for Bisantrene that challenge the ‘less cardiotoxic anthracene’ narrative. Bisantrene is a unique molecule with many secrets soon to be uncovered, but there is nothing more evident than the extensive clinical support for its use in humans.
Conclusion
The evidence supporting drug rediscovery underscores the importance of revisiting and re-evaluating older drugs. The journey of Bisantrene, along with other notable examples, highlights how historic clinical evidence and innovative research can transform previously misunderstood drugs into first-in-class therapies. This approach not only fast-tracks approval and commercialization but also expands therapeutic options and improves patient outcomes across various medical fields. The continued exploration of drug rediscovery holds significant promise for the future of medicine. Is Bisantrene the next drug rediscovery story that leads to a first-in-class title? Only time will tell.
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