Development of CMX001 (Brincidofovir) for the treatment of serious diseases or conditions caused by dsDNA viruses

Abstract

CMX001 (hexadecyloxypropyl-cidofovir, Brincidofovir) is a broad spectrum, lipid conjugate of cidofovir that is converted intracellularly into the active antiviral, cidofovir diphosphate. The lipid conjugation results in oral bioavailability, higher intracellular concentrations of active drug, lower plasma concentrations of cidofovir and increased antiviral potency against dsDNA viruses.

Keywords::

• adenovirus
• BK virus
• Brincidofovir
• CMX001
• cytomegalovirus
• dsDNA virus
• JC virus
• molluscum
• orthopoxvirus
• vaccinia virus

Acknowledgement

The authors thank Litton E for assistance in preparation of this manuscript.

Financial & competing interests disclosure

Florescu DF has received a grant from Chimerix and has received consultancy fees from Chimerix. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• CMX001 has a broad antiviral spectrum.

• It blocks viral DNA replication by acting as a competitive substrate inhibitor of the viral DNA polymerases in dsDNA viruses.

• It has greater in vitro potency compared with cidofovir and potentially higher barrier to mutations.

• The increased antiviral activity of CMX001 has been attributed to its enhanced cellular uptake and the high intracellular concentrations of cidofovir diphosphate.

• The dosing is very convenient (once or twice per week) that would increase patients’ compliance.

• It does not seem to be nephrotoxic and the dose does not need adjustment in patients with renal impairment. CMX001 is not a substrate for human organic anion transporters and as a consequence it does not accumulate in renal tubules like cidofovir.

• It is not myelosuppressive, potentially decreasing administration of granulocyte colony stimulating factor, and can be started in the engraftment phase in hematopoietic-cell transplant recipients.

• CMX001 is only available as an oral formulation and absorption would not be reliable in patients with severe graft versus host disease or uncontrolled diarrhea, leading to suboptimal drug exposure and therapeutic failure.