The U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to OBI Pharma’s OBI-999 for the treatment of Gastric Cancer.

Gastric or stomach cancer is a disease in which malignant cancer cells form in the lining of the stomach. The majority of gastric cancers, between 90%-95%, presents as adenocarcinomas arising from the mucosa layer. Some of the potential risk factors include Helicobacter pylori infection, high intake of salt, low consumption of fruits and vegetables, obesity, heavy alcohol consumption, chronic atrophic gastritis, and cigarette smoking.[1]

A deadly disease
Gastric cancer is recognized as a deadly disease, with a 5-year survivability of 31.0%. According to the American Cancer Society, an estimated 100,189 individuals were diagnosed with Gastric Cancer in the United States in 2019. Stomach cancers tend to develop slowly, and over many years. Before gastric cancer develops, pre-cancerous changes develop in the inner lining or mucosa of the stomach. These early changes may not cause symptoms and, as a result, often go undetected.[1]

The current standard treatment options for patients with advanced or recurrent gastric cancer are associated with limited efficacy and unfavorable toxicity profile, especially for extended use or maintenance treatment in a patient population which is often already frail and cachectic.

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Targeting agent
OBI-999 is a first-in-class antibody-drug conjugate or ADC targeting Globo H, a tumor-associated carbohydrate antigen exclusively expressed in cancer cells rather than normal or healthy tissue. Globo H has been found on many cancers of epithelial origins, and become an attractive target for the treatment of these cancers.

The novel first-in-class antibody-drug conjugate includes a proprietary linker technology that provides a consistent Drug-to-Antibody ratio or DAR for cancer treatment that is based on Globo H.

OBI-999 uses a Globo H antibody to target cancer cells of high Globo H expression. The drug covalently links a humanized monoclonal antibody (OBI-888) to monomethyl auristatin E (MMAE), an auristatin derivative and a potent microtubule disrupting agent.[2]

After administration of the 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 synthetic anti-neoplastic MMAE payload was delivered intracellularly and cleaved in a lysosome dependent manner.[2]

Following proteolytic cleavage, MMAE targets and binds to tubulin and inhibits its polymerization. This results in G2/M checkpoint arrest and apoptosis in Globo H-expressing tumor cells.[2]

In pre-clinical xenograft animal models in multiple tumor types (gastric, pancreatic, lung and breast), OBI-999 has demonstrated profound 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.

Orphan Drug Designation
Earlier in the development of the investigational agent, OBI-999 was, on December 26, 2019, also granted Orphan Drug Designation for Pancreatic Cancer.

The designation for both gastric and pancreatic cancer, granted to investigational agents to support the development of medicines for rare diseases or conditions that affect fewer than 200,000 people in the U.S., gives OBI Pharma several potential benefits, including market exclusivity upon regulatory approval, exemption of FDA application fees, and tax credits for qualified clinical trials.

A Phase I/II clinical trial of OBI-999 has commenced enrollment at the University of Texas M.D. Anderson Cancer Center, with Dr. Apostolia M Tsimberidou as the Principal Investigator, in patients with locally advanced or metastatic solid tumors, including Gastric, Pancreatic, Colorectal and Esophageal Cancers (NCT04084366). The objective of the trial is to verify the safety and preliminary clinical activity and efficacy profile of OBI-999 in these patient populations, to establish the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of OBI-999 as monotherapy.

“Advanced gastric cancer is an orphan disease where targeted therapies are lacking for the majority of patients. OBI-999 is an antibody-drug conjugate therapeutic targeting the cancer-associated glycolipid antigen, Globo H. OBI-999 incorporates a validated payload, MMAE, with a proprietary linker technology,”  noted Tillman Pearce, MD, the Chief Medical Officer of OBI Pharma.

“It has demonstrated high effectiveness in xenograft models of metastatic gastric cancer that overexpress Globo H. Clinical development of this agent will be guided by evaluation of patients based on a validated Globo H immunohistochemistry assay, which will allow selection of patients whose tumors overexpress this tumor antigen for clinical investigation,” Pearce added.

Clinical trial
Phase 1/2 Study of OBI-999 in Patients With Advanced Solid Tumors – NCT04084366

[1] Gunderson LL, Donohue JH, Alberts SR, Ashman JB, Jaroszewski DE. Cancer of the Stomach and Gastroesophageal Junction. In: Niederhuber, JE, Armitage, JO, Doroshow, JH, Kastan, MB, Tepper, JE, eds. In Abeloff’s Clinical Oncology. 5th ed.Philadelphia, Pa: Elsevier; 2014:1240-1270
[2] 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.

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