Clinical Translation of Interstitial Chemophototherapy with Light-Activated Nanoparticulate Doxorubicin

Summary POP BIO’s goal is to commercialize interstitial chemo-phototherapy (I-CPT) as a new therapeutic option for locally advanced liver cancers. Doxorubicin (Dox) can be actively loaded into long circulating, serum-stable, porphyrin- phospholipid (PoP) liposomes and be released with 665-nm laser light (PhotoDox). This approach leads to vastly enhanced drug accumulation in irradiated tissues, resulting in ultrapotent tumor ablation. In the phase I STTR, we employed this dosimetry-treatment planning platform to guide light administration of I-CPT with PhotoDox. We demonstrated that this treatment planning with light dosimetry is effective in ablating large orthotopic hepatocellular carcinoma tumors in rats. The phase II STTR focuses on optimizing treatment planning with light dosimetry using larger (~50cm3) tumors in woodchucks as well as developing a GLP toxicology package as part of an FDA IND submission based on our pre-IND meeting. POP BIO has previously generated non-GLP toxicity data of PhotoDox in rats including cursory establishment of the maximum tolerated dose. In 2019, POP BIO held a pre-IND meeting with the FDA, who confirmed the suitability of the 505(b)(2) route for components of PhotoDox and provided guidance about the required toxicological studies required prior to first-in-human studies. The toxicology program will also generate sera samples in two animal models that need to be analyzed by LC/MS (the request of this application). In this Commercial Readiness Program application we propose to further advance I-CPT with PhotoDox towards an IND for enabling future clinical studies by assessing the pharmacokinetics of Dox, doxorubicinol (Dox-ol), the major metabolite of Dox, and PPa-lipid, the photoactive excipient of PhotoDox, as well as the stability of PhotoDox under accelerated storage conditions. These tasks are required by the FDA as part of our IND package. The sera samples to assess pharmacokinetics have been generated as part of the parent Phase II STTR award’s GLP toxicology program. Under GLP conditions using LC/MS, the sera concentration of free Dox, liposome entrapped Dox, Dox-ol, and PPa-lipid will be measured. Subsequent pharmacokinetic analysis, as part of this application, will be performed by Roswell Park’s Bioanalytics, Metabolomics & Pharmacokinetics (BMPK) Shared Resource. The result of this application will be the generation of data directly used in POP BIO’s IND package generation. If successful, I-CPT with PhotoDox stands to benefit the majority of new liver cancer patients, who have inoperable and problematic primary tumors.