The valuation of Bristol-Myers Squibb ($BMY) remains closely trimmed; it’s lost about one-quarter of its valuation, or around $30 billion, since early August. That’s when its PD-1 checkpoint inhibitor Opdivo (nivolumab) failed in a Phase III first-line advanced non-small cell lung cancer (NSCLC) trial.
The biopharma emphasized then that a combination strategy is key to further development of Opdivo; it’s particularly under pressure given that the pharma with the only other approved PD-1 immune checkpoint inhibitor, Merck ($MRK), reported positive Phase III data in the same indication in June for its Keytruda (pembrolizumab).
Now, BMS has partnered with Nektar Therapeutics ($NKTR) in a clinical collaboration that aims to boost the efficacy of Opdivo with Nektar candidate NKTR-214. The latter is designed to stimulate the immune system by expanding specific cancer-fighting T cells and natural killer (NK) cells directly in the tumor microenvironment and increase expression of PD-1 on these immune cells.
The collaboration is structured to get a broad snapshot of the combo’s activity across 5 tumor types--melanoma, kidney, colorectal, bladder and NSCLC--and 7 potential indications. It’s slated to evaluate a total of 240 or 250 patients.
“NKTR-214 is an engineered cytokine that we invented here at Nektar. It’s a biased agonist of CD122, a receptor in the immune system,” Nektar SVP and CSO Steve Doberstein told FierceBiotech. “It’s a central growth factor for T cells, in particular the effect on effector T cells that enter and kill tumor cells. It’s engineered so it has the ability to selectively increase effector T cells without boosting regulatory T cells--those are the ones you don’t want. The rationale is clear to us from a scientific standpoint, use the foot on the gas of immune response with 214 and take the foot off the immune brake with Opdivo.”
He noted that PD-1 inhibition works particularly well in the presence of an existing robust immune response, which could make ‘214 a useful precursor as it turns a "cold" immune response to a "hot" one.
BMS and Nektar are splitting the costs of the clinical trials evenly under the collaboration, with oversight by a joint steering committee and Nektar managing the trials. BMS has the right of first refusal to commercialize NKTR-214; the clinical partners would require a subsequent deal to continue into Phase III development.
Up first is a dose-escalation trial with two- and three-week dosing regimens of ‘214. That’s expected to be complete during the first half of next year. Starting in about the second quarter of 2017, the pair will start the Phase I/II, open-label testing. BMS and Nektar expect to do some decision-making in 2018 as data starts to roll in.
Data from the dose-escalation trial will be presented at the Society for Immunotherapy of Cancer (SITC) meeting in National Harbor, MD, in November.
“We are measuring how patients are responding," summed up Doberstein on the early dose-escalation data. "What we’ve seen so far is that when you look at biopsies of patient tumors before and after dosing with ‘214, it increases the number of effector T cells and does not increase, or sometimes decreases, regulatory T cells. It also increases expression of PD-1, which means, in theory, the two molecules go together extremely well. It appears to be acting as we had hoped and as we had designed."