During its Feb. 27, 2020, conference call on the previous year’s fourth-quarter results – though not in a related press release – Nektar Therapeutics Inc. let news drop that the prospective breast cancer (BC) therapy Onzeald (etirinotecan pegol) for patients with brain metastases had failed in top-line phase III outcomes.
Called Attain, the study compared Onzeald against physician’s chemotherapy of choice. Researchers designed the experiment based on the doubling of survival seen in a subset of patients from an earlier 852-patient phase III trial called Beacon that pitted Onzeald against physicians’ choice in advanced BC previously treated with an anthracycline, a taxane and capecitabine. Patients in Beacon lived only 2.1 months longer than those treated with a chemo picked by their doctors, missing the phase III study's primary endpoint. While subsets of BC patients fared better, the study missed statistical significance on primary and secondary endpoints.
In the 178-patient Attain effort, Onzeald fell short of the overall survival endpoint. CEO Howard Robin said Nektar will do no more clinical work with the candidate, an extended-release formulation composed of irinotecan, which is a semisynthetic derivative of camptothecin and a topoisomerase I-inhibitor prodrug, that is conjugated by way of a biodegradable ester-based linker, to polyethylene glycol, with antineoplastic activity. Research was partially funded through a partnership with Daiichi Sankyo Co. Ltd., of Tokyo.
Setting Onzeald aside amounted to “the end of an era,” in the words of SVB Leerink analyst Daina Graybosch, and made Nektar purely an immunology and immuno-oncology (I-O) company. Talk on the earnings call dealt mainly with the first randomized, registration-enabling trial with bempegaldesleukin (bempeg, a CD122-preferential interleukin-2 therapy) paired with New York-based Bristol-Myers Squibb Co.’s (BMS) PD-1 targeter, Opdivo (nivolumab), in first-line melanoma. Wall Street expects an interim look at objective response rate (ORR) in early 2021. Meanwhile, Nektar and partner BMS are talking with the FDA about amending the ORR primary endpoint to complete response (CR), since the data were strong on that endpoint in phase I.
Wei Lin, head of development for Nektar, said that “to a large extent, the breakthrough designation we obtained in first-line melanoma was based on the CR” gained earlier. “I think it was very encouraging [to use] that endpoint in assessing the quality and totality of our data. We have ongoing discussions with agencies, multiple agencies worldwide, regarding that endpoint as the first endpoint to take a look at. That's something that we'll provide further update [about] as we complete the regulatory discussions. Right now, the formal first primary readout is still based on ORR.”
The median time to CR is about seven months. “Because of that, if we were to do a CR analysis, we would like to follow the patient for probably a 10-month duration, so there's going to be ongoing discussion with the health authorities regarding the sample size number that will be required for registration based on the CR endpoint,” Lin said. “By our current estimate, [results are] probably going to be roughly around the same time as the current projected ORR. Those things will be made clear in the coming months.”
Earlier in 2020, Nektar amended the BMS pact for an expanded push with bempeg and Opdivo, upping the three studies that were underway to seven trials in first-line and adjuvant settings across four tumor types with more than 3,000 patients. The new registrational program builds upon the opportunity in melanoma, bladder cancer and renal cell carcinoma, and adds plans for a phase II study in first line non-small-cell lung cancer. Along with three registrational bids in first-line metastatic melanoma, first-line cisplatin-ineligible metastatic bladder cancer and first-line metastatic renal cell carcinoma, the pair launched a new phase III study in muscle-invasive bladder cancer and a phase III bid in adjuvant melanoma. Opdivo scored its first approval in advanced melanoma in December 2014.
In analyst Graybosch’s view, the most important near-term catalyst for Nektar is the outcome of an ascending, multiple-dose phase I study with regulatory T-cell stimulator NKTR-358 in systemic lupus erythematosus, partnered with Indianapolis-based Eli Lilly and Co. Data are expected in June at the European Congress of Rheumatology. In the deal, Nektar collected $150 million up front with the potential for up to $250 million in additional development and regulatory milestones.
The lupus effort is moving into phase II, and BMO Capital analyst George Farmer asked on the conference call about the implications for the as-yet-unseen phase I results, which must have seemed worthy. Jonathan Zalevsky, chief R&D officer, pointed out that under the terms of the arrangement Lilly will run at least four phase II studies across multiple autoimmune indications. “This phase II study, obviously, is now diving deeper into the lupus population,” he said. “Obviously, they'll be treating [patients] for much, much longer duration than the multiple ascending-dose study does, and moving into more moderate to severe disease for therapeutic benefit.”
Lupus is an ideal target for the compound, Zalevsky said, since it bears “a very deep biomarker that's driven by regulatory T cells,” and patients “have a well-known and well-characterized dysfunction” in regulatory T cells. “We see this manifested in two ways in patients with disease, especially progressive disease. We see both a lowering of the number of T regs in circulation relative to healthy patients, patients that don't have lupus, and a decreased suppressive capacity.”
Cowen analyst Chris Shibutani likes the Nektar story. “Prospects for the company’s I-O franchise, led by bempeg, continue to underpin the majority of the company’s value proposition,” he wrote in a report. “During 2020, we expect the narrative to broaden as additional clinical-stage assets both in the I-O and inflammatory domains continue to progress.”