Karyopharm Therapeutics Inc. announced that it has submitted to the U.S. Food and Drug Administration (FDA) Center for Veterinary Medicine (CVM), the effectiveness and safety technical sections under a New Animal Drug Application (NADA) for Verdinexor (KPT-335) for the treatment of dogs with newly diagnosed or first relapsed non-Hodgkin lymphoma (NHL). Verdinexor has received a designation from the CVM's Office of Minor Use and Minor Species (MUMS) for the treatment of companion dogs with lymphoma, and the required portions of the NADA are being submitted initially under the CVM's MUMS guidelines. Verdinexor is a novel, oral, small-molecule SINE compound being developed for canine cancers including lymphoma.

SINE compounds inhibit the nuclear export function of Exportin-1 (XPO1 or CRM1), which prevents the export of tumor suppressor proteins and leads to their accumulation in the nucleus, subsequently reinitiating and amplifying their natural apoptotic function. Activated tumor suppressor proteins detect cancer-associated DNA damage leading to the selective apoptosis of cancer cells; normal cells, which do not have significant DNA damage, are spared. Following a Phase 1 dose escalation study, Verdinexor was tested in a single-arm study designed to meet requirements for conditional approval in companion dogs with B-cell or T-cell NHL.

The study was managed by Animal Clinical Investigation (ACI) and conducted at ten institutions and overseen by board certified veterinary medical oncologists at each site. Fifty-eight pet dogs were enrolled in the study: 35 with newly diagnosed lymphoma and 23 with lymphoma at first relapse following standard chemotherapy treatment. Of the 58 dogs, 42 had B-cell lymphoma, 14 had T-cell lymphoma and two had lymphoma of undetermined phenotype.

Owners administered Verdinexor to their dogs two to three times per week at doses of 1.25-1.5 mg/kg, orally after a meal. Response evaluation was based on objective measures per the Veterinary Cooperative Oncology Group (VCOG) standardized response criteria for peripheral lymphoma. Oral Verdinexor was generally well tolerated with rare serious adverse events.

The most common side effect was reduced food intake, which was usually reversible with altered diet, the addition of low dose prednisone, and/or by alteration of Verdinexor dose or schedule. Single agent Verdinexor induced an overall response rate of 34% (20/58 dogs) including 19 partial responses and one complete response (in a dog with T-cell lymphoma). There was little evidence of cumulative toxicity and approximately 20% of the dogs continued therapy for more than three months and approximately 15% of the dogs continued therapy for more than four months.

Questionnaires commonly used to assess quality of life in dogs undergoing cancer therapy were completed by the owners of the dogs on study and indicated that Verdinexor treatment was generally well tolerated and did not negatively impact the quality of life of the enrolled dogs. The FDA has confirmed that Verdinexor for the treatment of canine lymphoma will pose no significant environmental impact, and they have further confirmed receipt of the effectiveness and safety technical sections of the NADA. Karyopharm anticipates working with a marketing partner to complete the final technical section of the NADA, which covers the commercial-scale manufacturing (CMC) of Verdinexor.