Halozyme Therapeutics, Inc. (Nasdaq: HALO), a biopharmaceutical company developing and commercializing products targeting the extracellular matrix (“Matrix”), announced the presentation of new pre-clinical findings on the controlled modification of the Matrix with HTI-501 at the European Society for Dermatological Research (ESDR) and Japanese Society for Investigative Dermatology (JSID).
HTI-501 is a new recombinant human lysosomal proteinase under development at Halozyme that could provide an effective dermatologic treatment by targeting and degrading the fibrous components of the Matrix in a highly controlled fashion. This Matrix targeting new molecular entity is being explored as a potential solution for therapeutic, as well as aesthetic, dermatology indications for which surgery may be impractical, such as cellulite and certain forms of scarring.
HTI-501 works by a process called enzymatic subscision, which involves degradation of fibrous septae (or cords) in a controllable and predictable manner to release skin tissue from the fibrous cords and smooth out the surface contour, which could be especially beneficial in aesthetic dermatology indications. Other proteinases such as collagenases are not generally feasible therapies for aesthetic dermatology, due to their persistent degradation of surrounding tissue that may create safety concerns or require use of sub-potent dosing regimens. As a strictly pH-dependent enzyme, HTI-501 may be capable of exerting its activity in a tightly regulated fashion.
Key findings were as follows:
– HTI-501 was identified as a member of the lysosomal proteinase family capable of degrading insoluble collagen in vitro at pH 5-6, but catalytically inactive at physiologic pH of 7.4.
– By injection of pH indicators of increasing buffer strength, the study established that temporal-spatial pH control of the extracellular environment from 1-20 minutes post injection could be achieved.
– The efficacy of HTI-501 on fibrous septae in rodent and porcine models was established by release of hydroxyl-proline and histologic evaluation in comparison with bacterial collagenase.
– HTI-501 administration resulted in significant hydroxyproline release at pH 5 compared to bacterial collagenase, but not at pH 7.4. Importantly, skin interstitial pH returned to neutrality within 20 minutes of the administration of HTI-501.
“Due to strict pH dependence for enzyme activity, lysosomal proteinases have been largely neglected as potential therapeutic proteins due to their inability to digest proteins outside the lysosomal compartment in the cell,” said Gilbert Keller, PhD, Halozyme’s Technical Leader in Dermatology. “By bringing this intracellular environment to the extracellular matrix in a temporal fashion, our platform for controlled modulation of the dermal matrix may provide a novel mechanism for tightly controlled pharmacologic subscision of collagenous interstitial matrix. Additional pre-clinical studies are continuing on our lead candidate, HTI-501.”