Nektar Therapeutics: Crossing the Barriers and Sailing into the Future

Filled with high hopes and great enthusiasm, we are following up on Nektar’s (NKTR) immunotherapy product NKTR-214, which is in trials by Mayo Clinic and MD Anderson cancer center. The product is a CD122-biased agonist designed to stimulate the patient’s own immune system to kill tumor cells. The technology behind the molecule “targeted polymer conjugate technology” has been validated time and time again in clinical trials and in approved drugs marketed by Nektar partners mainly large pharmaceutical firms.  NKTR-214 uses Nektar’s this technology to enable preferential activation of immunostimulatory IL-2 receptors. It is a novel mechanism of action in immunotherapy, which is what is attracting us to the drug, knowing in fact that existing IL-2 therapy activates both immunosuppressive as well as immune-stimulatory receptors, which has limited its utility in clinical settings before the surfacing of NKTR-214.

The product is designed to preferentially stimulate production of CD8-positive T cells. CD122, also known as the Interleukin-2 receptor beta subunit, is a key signaling receptor that is known to increase proliferation of these effector T cells.

In preclinical studies, NKTR-214 demonstrated a mean ratio of 450:1 within the tumor micro-environment of CD8-positive effector T cells, which promote tumor killing, compared with CD4-positive regulatory T-cells, which are a type of cell that can suppress tumor killing.

A single dose of NKTR-214 resulted in a 500-fold area under the curve (AUC) exposure within the tumor compared with an equivalent dose of the existing IL-2 therapy, enabling, for the first time, an antibody-like dosing regimen for a cytokine. In dosing studies in non-human primates, there was no evidence of low blood pressure or vascular leak syndrome with NKTR-214 at predicted clinical therapeutic doses.

Nektar has entered into a Phase 1/2 clinical research collaboration with The University of Texas MD Anderson Cancer Center to evaluate NKTR-214 in a variety of tumor types as a monotherapy and in combination with the checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4.

On June 6, 2016, Nektar announced new preclinical data for NKTR-214, which is currently being evaluated in cancer patients with solid tumors in a Phase 1/2 clinical trial conducted at MD Anderson Cancer Center and Yale Cancer Center.

The new preclinical data demonstrate the following:  

A single-agent NKTR-214 was capable of mobilizing tumor-killing T cells into colon cancer tumors.

Mouse pharmacodynamics data demonstrated that a single dose of NKTR-214 can increase and sustain STAT5 phosphorylation (a marker of IL-2 pathway activation) through one-week post-dose.

These data were presented at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, IL from June 3-7, 2016.

Jonathan Zalevsky, PhD, Vice President, Biology and Preclinical Development at Nektar Therapeutics stated that the studies presented at ASCO show that NKTR-214 promotes tumor-killing immune cell accumulation directly in the tumor, providing a mechanistic basis for its significant anti-tumor activity in multiple preclinical tumor models.

The ability to grow tissue infiltrating lymphocytes (TILs) in vivo and replenish the immune system is exceptionally important.

Dr. Zalevsky added, “We have now learned that many human tumors lack sufficient TIL populations and the addition of the NKTR-214 TIL-enhancing MOA could improve the success of many checkpoint inhibitors and other agents, and allow more patients to benefit from immuno-therapy.”

Impressive were results of studies previously published demonstrating that a large proportion of mice bearing breast cancer tumors became tumor-free after being treated with NKTR-214.  Anti-tumor immune memory was demonstrated when tumor-free mice were re-challenged by implant with a new breast cancer tumor and then found to clear the new tumor, without further therapy.

The new data presented at ASCO demonstrate that upon re-challenge, there is a rapid expansion of newly proliferative CD8 T cells and particularly CD8 effector memory T cells. Both cell populations were readily detectable in multiple tissues (blood, spleen, and lymph nodes) and likely contribute to the anti-tumor effect observed in these animals.

Adoptive transfer studies confirmed the immune-memory effect as transplant of splenocytes from tumor-free mice into naïve recipients provided the ability to resist tumor growth. 

Dr. Steve Doberstein, Senior Vice President and Nektar’s Chief Scientific Officer said, “NKTR-214 provides a highly unique immune activation profile that allows it to access the IL-2 pathway without pushing the immune system into pathological overdrive. NKTR-214’s unique immune-stimulatory profile and antibody-like dosing schedule positions it as a potentially important medicine within the immuno-oncology landscape.”

Phase 1/2 clinical study aims at evaluating NKTR-214 in patients with advanced solid tumors, including melanoma, renal cell carcinoma and non-small cell lung cancer.

The first stage of this study is evaluating escalating doses of single-agent NKTR-214 treatment in approximately 20 patients with solid tumors. The primary objective of the first stage of the study is to evaluate the safety and efficacy of NKTR-214 and to identify a recommended Phase 2 dose.

The study is also to assess the immunologic effect of NKTR-214 on TILs and other immune cells in both blood and tumor tissue, and it will also include TCR repertoire profiling. Dose expansion cohorts are planned to evaluate NKTR-214 in specific tumor types, including melanoma, renal cell carcinoma and non-small cell lung cancer.

The NKTR-214 clinical study is being conducted at MD Anderson Cancer Center under Drs. Patrick Hwu and Adi Diab; In Yale Cancer Center, the trial is conducted under Drs. Mario Sznol and Michael Hurwitz.

Patients and physicians interested in the ongoing NKTR-214 study can visit the “Clinical Trials” section of using identifier 2015-0573 or;


Prohost Observations

Nektar’s robust R&D pipeline and portfolio of approved partnered medicines are impressive. The pipeline comprises oncology drugs, pain products, immunology therapeutics and others.

In the area of oncology, we have already described Nektar’s product NKTR-214. Another oncology product ONZEALD™ (etirinotecan pegol) is a long-acting topoisomerase I inhibitorfor breast cancer and brain metastases and is partnered with Daiichi Sankyo in Europe.

With regard to pain treatment, AstraZeneca has an exclusive worldwide license agreement with Nektar for MOVANTIK™ (naloxegol), the first FDA-approved once-daily oral peripherally-acting mu-opioid receptor antagonist (PAMORA) medication for the treatment of opioid-induced constipation (OIC), in adult patients with chronic, non-cancer pain.

Movantik is also approved in the European by the name MOVENTIG® and is indicated for adult patients with OIC who have had an inadequate response to laxatives.

AstraZeneca agreement includes NKTR-119, an earlier stage development program that is a co-formulation of MOVANTIK

NKTR-181, a wholly owned analgesic molecule for chronic pain conditions, is in Phase 3 development.

In hemophilia, Nektar has a collaboration agreement with Baxalta for ADYNOVATE™ – a longer-acting PEGylated Factor VIII therapeutic approved in the U.S. and Japan for patients over 12 with hemophilia A.

In anti-infectives, the company has two collaborations with Bayer Healthcare, Cipro Inhale in Phase 3 for non-cystic fibrosis bronchiectasis and Amikacin Inhale in Phase 3 for patients with Gram-negative pneumonia.

As we mentioned above, Nektar’s technology is behind the production of nine approved products in the U.S. or Europe through partnerships with leading biopharmaceutical companies, including AstraZeneca’s, Baxalta, UCB, Roche and Amgen.

We believe Nektar is walking towards becoming a second Regeneron (REGN). The firm has a strong management, great technological capability and robust pipeline of products some might become blockbuster best selling drugs.

Although the stock has had a positive performance, NKTR, we believe, is tremendously undervalued.

We have a lot to tell you. We will post Prohost Letter #399 soon to give it all to you. It is fascinating what’s going on in the biotech scientific world.

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