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Manufacture Small Molecules

Another Chance for Arsenic

Credit: Author supplied

Effective formulation requires a good knowledge of the ingredients, their roles, their mechanisms of action, and their interactions. Indeed, mastering the compatibility of the compounds is essential for success. Even when a formulation proves sufficient for a drug to reach regulatory approval, developers may still work to improve it. Optimizing formulations after commercialization may have benefits for patients by making the API easier to take, reducing adverse events, expanding labels, or improving efficacy. For the drug manufacturer, there can also be intellectual property and other commercial benefits. In some cases, new excipient science can breathe a second life into old drugs. 

Optimization requires thorough characterization of API performance. But it is important to recognize that the full and precise mechanisms of action of many, if not all, medicines are not yet fully understood. Chemical interactions in a living organism can occur at many different molecular levels in different compartments of the cells and tissues. Even a well-chosen excipient could trigger an unprecedented cascade of events, impacting the mechanism of action of even extensively studied drugs.

Reformulation for drug repurposing is an attractive alternative to the traditional development process, skipping past the laborious steps of identifying a drug target and developing a way to exploit it. Recent estimates suggest the development time of a new molecular entity (NME) can be 15 years, whereas a repurposed drug is estimated to take only 6.5 years. An NME can cost as much as $2.9 billion to develop, but repurposing may cost $300 million – or even as little as $8.4 million if late-stage clinical trials are not required (1).

Drugs that are repurposed through new formulations are also valuable because they use a well-validated drug as the starting point. And the final product is likely to offer advantages over existing drugs in terms of efficacy, safety, tolerability, or convenience, without involving the manipulation of less-studied biological targets.

An extraordinary example of the opportunities created by reformulation is the story of therapeutic arsenic. In the early 20th century, the arsenic compound salvarsan (later neosalvarsan or neoarsphenamine) was synthesized by Paul Ehrlich to treat syphilis and trypanosomiasis. This arsenic compound is often considered the first modern chemotherapeutic agent. In 1949, Ernest Friedheim synthesized arsenic-based melarsoprol, marketed by Sanofi under the name Arsobal, which was widely used by colonial doctors to treat trypanosomiasis – despite painful intravenous injections and its numerous side effects. Arsenic trioxide (ATO), authorized in an injectable form (Trisenox) since 2002, has been designated a first-line treatment since 2013 (2) and has made the most dangerous form of acute myeloid leukemia (acute promyelocytic leukemia) the most curable (3). 

Arsenic may not seem like a natural candidate for repurposing given its toxicity at higher levels, but it is frequently discussed in a public health context because of its potent immunomodulatory, antifibrotic, and vascular remodeling properties with fundamental effects on activated cells in the immune system. Indeed, in its extensively studied injectable form, ATO is being evaluated in phase II clinical trials for the autoimmune diseases systemic lupus erythematosus (SLE) (4) and chronic graft-versus-host disease (cGvHD) (5). 

For many years, dosage concerns hampered promising potential uses of ATO in multiple disease areas. At BioSenic, we have participated in efforts to develop an oral formulation, using sodium salts to improve stomach absorption. Leveraging previous studies that used ATO through intravenous administration, oral ATO will move directly to a confirmatory international phase III study in patients with cGvHD between Q4 2024 and Q1 2025. An oral formulation is also being prepared for future clinical trials in SLE and systemic sclerosis (with first patient dosing possible as early as 2027). Pharmacokinetic studies (6,7) and a post-hoc analysis of phase II clinical trials (8) of ATO have already helped identify the best dosing regimen for an effective treatment of cGvHD. However, the development of an oral option would allow patients to be treated at home.

Extensive studies have also shown that combining ATO with metal ions reduces the required ATO dosage and the reversible side effect profile, while maintaining efficacy. Recent preclinical evidence confirms the promise of these combinations for the treatment of autoimmune diseases, including cGvHD (9) and systemic sclerosis (10). 

These studies have revealed that ATO’s mechanisms of action are partly caused by the production of reactive oxygen species, a regulator of cellular processes linked to the pathogenesis of multiple diseases, and other specific intracellular pathways activated in pro-inflammatory and pro-fibrotic cells. This should – and has – encouraged us to consider even more diseases that could be targeted by ATO. With additional formulation innovations, ATO-copper could be used for the development of combination therapies alongside a viscosupplement or a cell therapy. The prospect of improving the efficacy of cutting-edge autoimmune disease therapies via a repurposed ancient molecule is truly exciting.

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  1. A Gonzalez-Fierro et al, “Does Therapeutic Repurposing in Cancer Meet the Expectations of Having Drugs at a Lower Price?”, Clin Drug Investig. 43(4) (2023). DOI: 10.1007/s40261-023-01251-0  
  2. J Lachaine et al, “Cost-Effectiveness Of Arsenic Trioxide + All-Trans Retinoic Acid Compared With All-Trans Retinoic Acid + Idarubicin In The Treatment Of Newly Diagnosed Acute Promyelocytic Leukemia In Canada”, Blood. 122(21) (2013). DOI: 10.1182/blood.V122.21.1677.1677 
  3. X Thomas, “Acute Promyelocytic Leukemia: A History over 60 Years-From the Most Malignant to the most Curable Form of Acute Leukemia”, Oncol Ther. 7(1) (2019) DOI: 10.1007/s40487-018-0091-5
  4. M Hamidou et al, “Safety and efficacy of low-dose intravenous arsenic trioxide in systemic lupus erythematosus: an open-label phase IIa trial (Lupsenic)”, Arthritis Res Ther. 3;23 (2021) DOI: 10.1186/s13075-021-02454-6.
  5. D Rongvaux-Gaïda et al, “High Response Rate and Corticosteroid Sparing with Arsenic Trioxide-Based First-Line Therapy in Chronic Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation”, Transplant Cell Ther. 28;10 (2022). DOI:
  6. F Ravandi et al, “Oral arsenic trioxide ORH-2014 pharmacokinetic and safety profile in patients with advanced hematologic disorders”, Haematologica. 105:6 (2020). DOI: 10.3324/haematol.2019.229583
  7. Australian New Zealand Clinical Trial Registry, “A phase I pharmacokinetic evaluation of oral arsenic trioxide in previously untreated patients with acute promyelocytic leukaemia” (2016). Available at: 
  8. C Chêne et al, “A Fenton-like cation can improve arsenic trioxide treatment of sclerodermatous chronic Graft-versus-Host Disease in mice”, Front Immunol. 9:13 (2022). DOI: 10.3389/fimmu.2022.917739 
  9. C Chêne et al, “Optimal combination of arsenic trioxide and copper ions to prevent autoimmunity in a murine HOCl-induced model of systemic sclerosis”, Front Immunol. 30:14 (2023) Mar:1149869. doi: 10.3389/fimmu.2023.1149869
About the Author
Carole Nicco

Chief Scientific Officer and Chief Operating Officer, Biosenic

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