FDA Grants Orphan Designation to CYNK-001 for GBM

Robert J. Hariri, MD, PhD

The FDA has granted an orphan drug designation to the placental-derived natural killer (NK) cell therapy CYNK-001 as a potential treatment for adult patients with recurrent glioblastoma multiforme (GBM), according to a statement from Celularity, the developer of the off-the-shelf therapy.

The orphan drug designation is intended for products that treat rare diseases or conditions and was established under the Orphan Drug Act. The designation provides a number of incentives, according to the FDA, including tax credits for qualified clinical testing. Moreover, a company developing an orphan product is not required to pay prescription drug user fees when submitting a marketing application for the designated indication.

In early March, the FDA also granted CYNK-001 a fast track designation for the same indication. This designation is meant to facilitate and expedite the development of treatments for serious conditions that fill an unmet need. With the fast track designation, Celularity will benefit from more frequent interaction with the FDA. Additionally, if clinical studies are successful, the company will be eligible for an accelerated approval, priority review, and the ability to submit a rolling biologic license application.

“We are very pleased the FDA has granted orphan designation in malignant gliomas to continue to develop off-the-shelf therapies for serious unmet clinical needs,” Robert J. Hariri, MD, PhD, founder, chairperson, and CEO of Celularity, said in a statement. “Building on the FDA’s recent decision to grant fast track status to CYNK-001, we view the orphan drug designation as yet another milestone on our journey to deliver patients a potentially novel treatment."

CYNK-001 consists of nongenetically modified, cultured, and cryopreserved allogeneic NK cells that are derived from placental hematopoietic stem cells. The cells express NKG2D and CD94 along with several NK activating receptors.

In preclinical models, CYNK-001 showed signs of activity a number of biomarker indicators. Following administration of the cells, there was expression of perforin and granzyme B, signs of cytolytic activity in cell lines, and the secretion of immunomodulatory cytokines. In addition to GBM, CYNK-001 is also being investigated as an off-the-shelf therapy for the treatment of patients with acute myeloid leukemia, multiple myeloma, and COVID-19.

"To date, we have observed the potential of CYNK-001 in multiple preclinical models as well as early evidence of activity in the clinic and believe this approach may shift the paradigm in augmenting the body’s natural immune response to diseases such as glioblastoma, other cancer indications and infectious diseases," Hariri said. "We are very excited to continue working with the FDA on the development of this exciting therapy.”

A phase 1 study (CYNK001GBM01; NCT04489420) is currently exploring CYNK-001 for adult patients with recurrent GBM. The primary goal of the study is to determine the optimal administration route and maximum tolerated dose. The study will consist of 2 arms: one exploring intravenous (IV) administration and the other looking at intratumoral (IT) treatment, which involves an Ommaya placement surgery.

In the IV group, lymphodepleting chemotherapy will be followed by infusion of CYNK-001. In this arm, cohort 1A will enroll 6 patients with recurrent GBM to receive CYNK-001 at a dose of 1.2 x 109 cells/dose on days 0, 7, and 14. These individuals will be followed for 42 days for dose-limiting toxicity (DLT). If a DLT occurs, a lower dose of 600 x 106 cells will be explored in a separate 6-patient cohort (1C), which will follow the same dosing and monitoring pattern. Cohort 1B will enroll following cohort 1A (and also cohort 1C, if required) to examine the cell therapy in 6 patients with surgically resectable GBM. Patients with receive CYNK-001 at the maximum tolerated dose from the prior cohorts on days 0, 7, and 14. Following this, tumor resection will be performed during the DLT period.

The IT group will follow a similar pattern as the IV arm; however, enrollment into the IT cohorts will not begin until the safe completion of the IV cohorts and there will be no lymphodepletion. In this arm, the Ommaya catheter will be place 1 week prior to treatment with CYNK-001. In cohort 2A, treatment will be given at 200 x 106 (±50 x 106 cells) on days 0, 7, and 14 to 6 patients with recurrent GBM. Cohort 2C will examine a less frequent IT dose of 200 x 106 (±50 x 106 cells) on days 0 and 7 in 6 patients with recurrent GBM. Cohort 2C will treat 6 patients with GBM with the maximum tolerated dose from the prior cohorts followed by surgical resection.

Based on this design, the study plans to enroll 36 patients. All participants are to have a Karnofsky performance status score ≥60, adequate organ function, and measurable disease. Those with HIV/AIDs and Hepatitis are eligible, under certain conditions. The study excludes individuals who have undergone recent radiation therapy, growth factor support, chemotherapy, or any prior cellular or gene therapy. Those with a history of malignancy other than GBM, active autoimmune disease, or immunodeficiency are also excluded.

The primary end points of the trial are dose-limiting toxicities and adverse events, and secondary end points include overall response rate, duration of response, progression-free survival, time to progression, and overall survival.