Karyopharm Therapeutics Announces Submission of New Animal Drug Application Effectiveness and Safety Sections for Novel, Oral, Small-Molecule Selective Inhibitor of Nuclear Export (SINE) Verdinexor for Canine Lymphoma to FDA's Center for Veterinary Medicine
NATICK, Mass., Jan. 7, 2014 (GLOBE NEWSWIRE) -- Karyopharm Therapeutics Inc. (KPTI), a clinical-stage pharmaceutical company focused on the discovery and development of novel first-in-class drugs directed against nuclear transport targets for the treatment of cancer and other major diseases, today 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.
"We are very excited about the potential of our SINE compounds to treat lymphomas through a novel mechanism. We are hopeful that Verdinexor could become an option for veterinarians and for dog owners for the treatment of their pets with lymphoma," commented Dr. Dilara McCauley, Vice President of Product Leadership at Karyopharm. "Following several preliminary meetings with the FDA, we look forward to working with them on our final submissions under the NADA and to the potential approval of Verdinexor for the treatment of canine lymphoma."
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.
"There have been no new agents approved for the treatment of canine lymphoma in more than two decades. We are currently restricted to the use of standard chemotherapeutics, most of which require intravenous administration, often on a weekly basis. Many dog owners are not able to make the frequent hospital visits and in some instances, are reluctant to pursue the use of cytotoxic chemotherapy due to potential side effects associated with this type of treatment," commented Cheryl London, D.V.M., Ph.D., Diplomate of the ACVIM (Oncology), Shackelford Professor of Veterinary Medicine at the Ohio State University College of Veterinary Medicine and Lead Investigator on the trial. "Verdinexor is an easily administered, oral therapy with a low side effect profile that provides an alternative approach to treating lymphoma by halting disease progression in many dogs and in some cases, inducing responses. If approved, the availability of Verdinexor could represent a significant advancement in veterinary medicine for the treatment of dogs with lymphoma."
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.
About Canine Lymphoma
Lymphoma is one of the most common cancers in dogs, and is rapidly fatal if untreated. Canine lymphoma is quite similar to human non-Hodgkin Lymphoma (NHL) and includes approximately 75% to 80% of B-cell derived tumors; the remainder are T-cell in origin or of undetermined phenotype. The majority of canine B-cell lymphomas are classified as diffuse large B-cell lymphoma (DLBCL), which is the most common type of human NHL, and like human DLBCL, is considered highly aggressive. Canine T-cell lymphomas are considered to be more challenging to treat than B-cell lymphoma (also similar to human NHLs) and often refractory to standard chemotherapeutics. Current therapeutic options for dogs with lymphoma include multi-agent intravenous chemotherapy protocols with steroids such as CHOP (cyclophosphamide, hydroxydaunorubicin [Adriamycin], Oncovin [vincristine], and prednisone), high dose steroids alone, or palliative care. Chemotherapy combinations generally require administration under the care of specialized veterinary oncologists, frequent blood testing and follow up visits. While these combinations induce high response rates, more than 80% of treated dogs eventually relapse with median survival times ranging from 10 to 14 months. Novel treatments with improved tolerability and ease of administration are needed given the lack of advances in disease management over the last two decades. Canine lymphoma has been designated a "minor use" indication allowing initial FDA/CVM marketing applications to be made under the MUMS designation, similar to orphan drug/accelerated approvals used for submissions of human therapeutics.
About the New Animal Drug Application (NADA)
Marketing authorization for a drug for veterinary use requires approval by the FDA's Center for Veterinary Medicine (CVM). The NADA includes four major technical sections: (i) Effectiveness (RXE), (ii) Target Animal Safety (TAS), (iii) Environmental Impact and (iv) Chemistry, Manufacturing & Controls (CMC). These sections may be submitted as "rolling submissions," meaning that CVM will review each section independently. Approval under the MUMS designation requires [that a separate confirmatory efficacy study be conducted within five years of MUMS authorization, and also narrows the scope of marketing permitted (compared with a full approval not under the MUMS designation).
Karyopharm Therapeutics Inc. is a clinical-stage pharmaceutical company focused on the discovery and development of novel first-in-class drugs directed against nuclear transport targets for the treatment of cancer and other major diseases. Karyopharm's SINE compounds function by blocking XPO1, preventing the export of various proteins out of the nucleus. SINE compounds have shown biological activity in models of cancer, autoimmune disease, certain viruses, and wound-healing. Karyopharm was founded by Dr. Sharon Shacham and is located in Natick, Massachusetts.
This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Such forward-looking statements include those regarding the therapeutic potential of and potential clinical development plans for Verdinexor, including future filings with the FDA/CVM and the timing of such filings. Such statements are subject to numerous important factors, risks and uncertainties that may cause actual events or results to differ materially from the company's current expectations. For example, there can be no guarantee that Verdinexor, the related drug candidate Selinexor (KPT-330), in clinical trials for use in humans, or any other drug candidate Karyopharm is developing will successfully complete necessary preclinical and clinical development phases or that development of any of Karyopharm's drug candidates will continue. Further, there can be no guarantee that any positive developments in Karyopharm's drug candidate portfolio will result in stock price appreciation. Management's expectations and, therefore, any forward-looking statements in this press release could also be affected by risks and uncertainties relating to a number of other factors, including the following: Karyopharm's results of clinical trials and preclinical studies, including subsequent analysis of existing data and new data received from ongoing and future studies; the content and timing of decisions made by the FDA, CVM and other regulatory authorities, investigational review boards at clinical trial sites and publication review bodies; Karyopharm's ability to obtain and maintain requisite regulatory approvals and to enroll patients in its clinical trials; unplanned cash requirements and expenditures; development of drug candidates by Karyopharm's competitors for diseases in which Karyopharm is currently developing its drug candidates; and Karyopharm's ability to obtain, maintain and enforce patent and other intellectual property protection for any drug candidates it is developing. These and other risks are described under the caption "Risk Factors" in Karyopharm's Quarterly Report on Form 10-Q for the quarter ended September 30, 2013, which is on file with the Securities and Exchange Commission (SEC), and in other filings that Karyopharm may make with the SEC (SCUR) in the future. Any forward-looking statements contained in this press release speak only as of the date hereof, and Karyopharm expressly disclaims any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise.
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