OBI-999, a Novel First-in-class ADC, Granted FDA Orphan Drug Designation for Pancreatic Cancer

OBI-999, a novel antibody-drug conjugate or ADC being developed by OBI Pharma, a Taiwan based biopharmaceutical company, has been granted orphan drug designation for the treatment of pancreatic cancer. The investigational agent is a first-in-class antibody-drug conjugate with a proprietary linker technology that provides a consistent drug-to-antibody ratio (DAR) for cancer treatment targeting globohexaosylceramide (Globo H), a hexasaccharide glycosphingolipid or glycolipid antigen expressed in up to 15 epithelial cancers.

Globo H is minimally or not expressed on healthy, normal cells; its expression on cancer cells is associated with increased proliferation and poor prognosis.

The drug covalently links a humanized monoclonal antibody (OBI-888) to monomethyl auristatin E (MMAE), an auristatin derivative and a potent microtubule disrupting agent.[1]

After administration of anti-globo H/MMAE antibody-drug conjugate OBI 999, the antibody moiety of OBI 999, targets and binds to Globo H on tumor cells and is rapidly internalized and trafficked to endosome and lysosome (within 2.5 to 5 hours) suggesting that the the synthetic antineoplastic MMAE payload was delivered intracellularly and cleaved in a lysosome dependent manner.[1]

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Following proteolytic cleavage, MMAE targets and binds to tubulin and inhibits its polymerization. This resuls in G2/M checkpoint arrest and apoptosis in Globo H-expressing tumor cells.[1]

Preclinical tissue distribution studies revealed that OBI-999 is accumulated gradually at the tumor site, with levels of OBI-999 decreasing at a time dependent decrease in blood-rich organs. Furthermore, accumulation of OBI-999 at the tumor site, which reached its maximum level at 168 hour post treatment with levels of the payload approximately 25 folds higher than that in other organs and 250 folds higher than that in serum, suggesting that OBI-999 targets and releases its payload at tumor region.[1]

Overall, Iin pre-clinical xenograft animal models in multiple tumor types (pancreatic, lung, gastric, and breast), OBI-999 demonstrated convincing tumor shrinkage at various doses. In pre-clinical single and repeated dose toxicology studies, OBI-999 was well-tolerated, and achieved a favorable safety margin which warrants further clinical development.

The orphan drug designation is designed to support development of novel drugs for the treatment of rare diseases or conditions that affect fewer than 200,000 people.

Limited treatment options
Pancreatic Cancer, a lethal disease affecting nearly 70,000 people in the United States, originates in the exocrine or endocrine pancreatic cells and is thought to be caused by poor diet, smoking, and genetic factors.

Treatment options are generally limited to surgical resection for patients with early stages of the disease and these patients may only have a five-year survival rate of up to 34.3%. Because the disease is asymptomatic in early stages, a majority of patients remain undiagnosed or misdiagnosed until advanced stages of the disease.

In the advanced stages surgery is no longer effective, leaving a large population with limited treatment options.

Clinical trials
A Phase I/II clinical trial of OBI-999 at the University of Texas M.D. Anderson Cancer Center, enrollment 185 patients with locally advanced or metastatic solid tumors, including pancreatic, gastric, colorectal and esophageal cancers. The objective of the trial is to verify the safety and preliminary efficacy profile of OBI-999 in these patient populations.

The purpose of this study is to establish the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of OBI-999 as monotherapy, and to characterize the safety and preliminary clinical activity profile of the RP2D of OBI-999 in patients with advanced solid tumors.

OBI Pharma owns global rights to OBI-999.

First patients
“We are excited to treat the first patients with OBI-999. [This] novel first-in-class antibody-drug conjugate [has a] unique potential and [may] bring [multiple advances] to patients with [a variety of] tumor types.” noted Apostolia Tsimberidou, MD, Ph.D., a tenured professor, at the Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

“The aberrant expression of the glycolipid Globo-H in epithelial tumors makes it an attractive target and this ADC holds the promise to induce clinically meaningful responses,” Tsimberidou added.

“We are very excited about the potential value that OBI-999 may provide to patients with pancreatic cancer given both the high potency we have observed using OBI-999 in pancreatic cancer xenograft models and because many pancreas cancers highly overexpress Globo H, the glycolipid target of OBI-999, using the validated IHC assay that will be available for selecting patients for the Phase 2 portion of this first-in-human clinical trial,” Tillman Pearce, MD, CMO, OBI Pharma noted,

Clinical trials
Phase I/II Study of OBI-999 in Patients With Advanced Solid Tumors – NCT04084366

Reference
[1] Yang MC, Chen YJ, Shia CS, Chang HW, Li WF, Tony Yu CD, Chen IJ. Novel Globo H targeting antibody-drug conjugate with binding specificity and anti-tumor efficacy in multiple cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4815.