The C-natriuretic peptide (CNP) analog vosoritide recently became the first drug approved for the treatment of achondroplasia in children, clearly a significant milestone in the history of this rare disease. However, the dosing regimen is very burdensome for the young patients, requiring daily subcutaneous injections for potentially more than a decade. At ProLynx, using our half-life extension technology we have developed a long-acting CNP analog conjugate that demonstrates equal or greater efficacy to vosoritide while at the same time requiring less frequent, more convenient dosing. Our half-life extension technology utilizes β-eliminative linkers to attach a drug to pre-fabricated tetra-polyethylene glycol hydrogel microspheres (tetra-PEG microspheres). When injected subcutaneously, these microspheres act as a stationary depot where the chemistry of the β-eliminative linkers allows for controlled release of the attached drug, which translates directly to control of the plasma half-life. Two microsphere conjugates were prepared with release rates designed to allow once-weekly and once-monthly administration using a highly active, deamidation resistant CNP analog, [Gln 6,14]CNP-38. In vitro studies in mice demonstrated that [Gln 6,14]CNP-38 was slowly released from the conjugates into the systemic circulation with biphasic elimination pharmacokinetics and terminal half-lives of ∼200 h and ∼600 h. In addition, studies in mice using weekly to monthly dosing regimens demonstrated growth comparable to or exceeding daily injections of vosoritide. Further studies in cynomolgus monkeys showed a similarly extended terminal half-live of ~600 h. Simulations of the human pharmacokinetics indicate that plasma levels of [Gln 6,14]CNP-38 could be maintained within the required therapeutic window for monthly dosing intervals, significantly reducing the patient burden from ~30 injections per month to one.
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