By Mark Terry
It’s been a busy week for Nektar Therapeutics. The company announced today that it had submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for NKTR-181, a new molecular entity (NME), a mu-opioid agonist for pain relief. Yesterday it inked a non-exclusive, clinical collaboration deal with Syndax Pharmaceuticals to develop Nektar’s NKTR-214, a CD122-biased agonist in combination with entinostat, Syndax’s HDAC inhibitor in metastatic melanoma.
Under the deal with Syndax, the two companies will evaluate the combination therapy in a Phase Ib trial and into a Phase II trial. Progression-free survival and overall survival will be evaluated, as well as overall efficacy, objective response rate and durability of response.
They will utilize biomarkers to identify patients with enhanced responses to the combination. Syndax will conduct the Phase Ib/II trial. In preclinical testing, the combination of entinostat and NKTR-214 inhibited tumor growth in kidney and colon cancer models. It also showed a dramatic increase in the activation and cytotoxic activity of CD8+ T cells in the tumors, in addition to modulation of immune suppressor cells in the tumor microenvironment.
“We are excited to be working with Nektar as we build upon our strategy of establishing clinical collaborations to test novel combinations of entinostat with leading-edge immune therapies,” said Briggs Morrison, Syndax’s chief executive officer, in a statement. “Previous Phase II data with entinostat and high dose IL-2 in renal cell cancer and our promising preclinical data generated with NKTR-214, laid the scientific and clinical foundation for this collaboration. Working with Nektar allows us to increase the potential impact entinostat may have in the treatment of PD-1 refractory metastatic melanoma patients, and complements the exciting data we have seen when combining entinostat with Keytruda in a similar population.”
And today Nektar submitted the NDA for NKTR-181. The company says this new molecular entity is the first analgesic opioid molecule to show a reduced incidence of specific CNS-mediated side effects like euphoria. Which is to say, it seems to reduce pain without getting the patient high.
The NDA submission was based on 15 clinical trials in 2,234 patients, including a 600-patient efficacy trial in patients with chronic low back pain new to opioids and a 630-patient long-term 52-week safety trial in patients with noncancer pain new to opioids in addition to patients who already had opioid therapy.
The drug is a long-acting, selective full mu-opioid agonist. It is designed to have low permeability across the blood-brain barrier, which slows the rate of entry into the brain, making it less likely to cause the dopamine release related to euphoria.
“The submission of the NDA for NKTR-181 is an important milestone for Nektar, and we would like to thank our employees, investigators, clinical trial sites and most importantly the patients and families of those living with chronic pain for all of their help in the development of this medicine,” stated Steve Doberstein, Nektar’s senior vice president of Research and Development and chief development officer. “This innovative investigational medicine separates analgesic efficacy from the high levels of euphoria that too often lead to the abuse and addiction of traditional opioids.”