NKTR: IR's short rebuttal

I received this from a friend who asked me to post it to this board:

Thank you for your inquiry on the “report” issued by Plainview. Please find below the company’s response. The report was lengthy and filled with what was positioned to be science but were actually inaccurate scientific inaccuracies and mis-calculations. Below, we chose to focus on the major inaccuracies to point out the author’s flaws in the central premise. My team and I are available for a call today if needed – please let me know if you need it.

With our partner Bristol-Myers Squibb, we are developing NKTR-214 with nivolumab in 9 tumor types in over 20 registrational trials. We have a melanoma Phase 3 trial that has already been initiated and several additional registrational trials that are planned to start in renal cell carcinoma and bladder cancer by the end of the year. Clearly, the commitment of our two companies to the long-term development of the combination underscores our conviction in the combination results and our belief in the potential value of NKTR-214 and Opdivo to patients and physicians in the fight against cancer.

As we stated on our last financial results call, we look forward to presenting mature data from the fully enrolled 38-patient Stage IV melanoma cohort from PIVOT at the upcoming SITC conference in November. The data will be presented in an oral presentation on Friday, November 9th in the Cytokines Reinvented session. As data from the PIVOT cohorts mature over the next six to 18 months, Nektar and Bristol are planning to present each of the data sets at various medical meetings, including tumor-specific conferences, in the lung, melanoma, GU and breast cancer specialty areas.

The report written and issued by Plainview has a flawed central premise, contains many scientific inaccuracies, and deliberately omits published data that did not support its premise. The author did not conduct diligence with the company or the authors of peer-reviewed published data on NKTR-214. While the report is long and cites a number of references, many references are omitted and those cited are selective. As a result, we focused on the most egregious inaccuracies and omissions found in the executive summary. Please don’t hesitate to reach out if you have any further questions.

Lymphocyte Effects

The writer uses as his premise in multiple areas that lymphocyte levels following treatment with NKTR-214 did not increase sufficiently. However, the writer ignores a more complete 2018 dataset presented for NKTR-214 to make this argument. Instead, he cites 2017 data from a handful of early patients enrolled in the dose-escalation stage of the PIVOT trial (ASCO 2017) and references only a 30-50% increase in lymphocyte levels. At ASCO 2018, the company presented comprehensive lymphocyte level data for over 200 patients who were treated with the recommended Phase 2 dose of NKTR-214. The data show an increase over baseline after first cycle of >100% (achieving a level of >200% of baseline) and in subsequent cycles with NKTR-214 lymphocyte levels range up to a 200% increase over a baseline (achieving a level of 300% of baseline) which is then sustained over 10 cycles of therapy (over 200 days):
Source: ASCO 2018 — graph notes added: A: ~200% of baseline, B: ~300% of baseline
These ASCO 2018 results are concordant with what is known from the literature about lymphocyte increases following HD-IL-2. Contrary to the author’s conclusion, the pharmacodynamic effect for NKTR-214 is in fact consistent with modeling expectations for HD-IL-2.

However, NKTR-214 maintains an essential difference to HD-IL-2 in that it is very-well tolerated and allows for continuous dosing (note the 10 cycles of therapy shown in the chart above). This provides a longer duration of sustained IL-2 receptor agonism and sustained increased lymphocyte levels, much longer in duration than the short increase provided by one to two cycles of HD-IL-2.

Overall Response Rate for Monotherapy HD-IL-2 vs NKTR-214

The body of selected data listed in report with high-dose IL-2 is in first-line previously untreated patients. ORR reported in the older literature vary but the studies were conducted prior to the availability of TKI therapies, BRAF therapies and checkpoint inhibitors. As is well-known, the IL-2 response rates were achieved at the expense of safety in these relatively healthy first-line patients. As an example, the author omits Phase 1 clinical data in second-line RCC patients where high-dose IL-2 was evaluated and had no responses. An important retrospective analysis by Dr. Daniel Cho (Journal of Immunotherapy 2009), highlights 28 patients who received high-dose IL-2 following treatment with TKI therapy/bevacizumab therapy. Only 3 of 28 or 11% experienced stable disease and there were no PRs or CRs (unconfirmed or otherwise). Only 1 of 23 patients could receive a second cycle of high-dose IL-2 and 26% of patients experienced severe cardiovascular toxicities, including cardiac arrest and acute pulmonary edema.

NKTR-214 was evaluated in a dose-ranging monotherapy trial in 28 patients with advanced, pre-treated cancer with a median number of prior therapies of 2 (and a range of 1-12). The breakout for pre-treatment was as follows: 16 (57.1%) had received targeted therapy; 16 (57.1%) had received an immune checkpoint inhibitor; and 6 (21.4%) had received an immune checkpoint inhibitor in addition to other immunotherapy. Tumor shrinkage was observed in 32% or 9 out of 28 patients (ranging from 2-30% tumor shrinkage), with a best response of stable disease in 50% or 14/28 patients. One patient experienced an unconfirmed partial response (a patient with advanced renal cell carcinoma who was treated with a prior TKI regimen). Another patient with pre-treated renal cell carcinoma had a 40% reduction on the right adrenal gland at the first on-treatment scan (the overall response was stable disease). Durable, stable disease > 1 year was also seen in 2 patients who continued on therapy for over one year. One patient with metastatic melanoma, previously treated with ipilimumab and a BRAF inhibitor, received 25 cycles of NKTR-214 and had durable stable disease (SD) for 15 months. A second patient with metastatic RCC, who had progressed on HD-IL-2 and was refractory to single-agent OX40 and nivolumab, was treated with 19 cycles of NKTR-214 and had durable SD for 13 months. Every patient evaluated showed evidence of immune activation and these effects were reproduced with repeated administration. Only 21% of patients experienced a G3 toxicity but these were reversible and short-lived; there were no G4/5 AEs reported. (SITC 2016, ASCO 2017 and SITC 2017)

Finally, the author quotes a paper from 2005 by Maker et al in order to disparage the combining of an IL-2 mechanism with a checkpoint inhibitor and its clinical benefit. However, the writer omits the conclusions from a later paper published by Prieto et al in 2012 which analyzed the same patients cited in the Maker study in a longer-term follow-up and highlighted the long-term clinical benefit of the combination, namely a high rate of durable complete responses achieved in these patients.

Exposure Comparisons of NKTR-214 Active Drug and HD-IL-2

The author mis-casts the receptor-bias inherent to NKTR-214 by pulling a partial figure from a published peer-reviewed publication (2017 Charych et al PLOS ONE). If the full figure is viewed, it is clear that NKTR-214 exhibits a biased receptor occupancy favoring the IL-2 beta-gamma receptor. As a result of its bias, direct comparison of exposure (AUC) from PK evaluation of NKTR-214 active drug vs HD-IL-2 is not relevant.

Further, HD-IL-2 clears rapidly and requires TID dosing. NKTR-214 has a prodrug design with a long half-life and q3 week dosing. Given the difference in mechanisms, an analysis of PD changes, notably the increases in lymphocyte levels after drug administration (or the desired effects of dosing) is the more important measure of adequate dose administration. Nektar has highlighted achievement of this desired effect in data presented at ASCO 2018 (refer to above section on Lymphocyte Effects).

Modified T Reg Increase in the Peripheral Blood and Not in the Tumor

NKTR-214 was designed to avoid Treg accumulation in the tumor microenvironment. Our earliest preclinical studies demonstrated the ability to promote transient Treg elevations in the peripheral blood, but not the tumor. Inherent to its design, it is necessary to preserve some binding to IL-2R-alpha because that receptor is needed for T-cell priming reactions in the lymph node.

TIL Increases with NKTR-214

The statements made around TIL increases with NKTR-214 are inaccurate; in the monotherapy trial, substantial increases in intratumoral CD8+ T cells were reported with no intratumoral CD4+ T regulatory expansion (SITC 2016, ASCO 2017 and SITC 2017). These data have been published at numerous congresses.

As stated above, NKTR-214 causes elevations in lymphocytes. These elevations are seen in blood and in tumor. The fact is that substantial lymphocyte increases with NKTR-214 were observed in the periphery so this can’t be used to refute the reported TIL increases with NKTR-214 in the published data as the author attempts.

In the tumor, we have observed high concordance of TIL increases with monitoring using multiple methods; immunohistochemistry (IHC), fresh tissue flow cytometry, and T cell DNA analysis (a method that compares T cell-specific DNA vs non T cell-specific DNA to quantify the mass of T cells in tumor tissue) and all three methods have produced concordant results (manuscript in preparation). The use of several methods is critical as it important to observe concordance across these methods to increase confidence in the results.

The author uses older SITC 2016 data rather than referring to more recent publications. At ASCO 2018, Nektar reported IHC data on TIL elevations from 33 tumor biopsies in PIVOT patients at the RP2D. IHC is the most common method used in the historical literature for other agents and allows for comparison to nivolumab. The author uses a Tumeh paper to support an argument that TIL increases are observed with nivolumab. However, the author declines to point out that the Tumeh paper only demonstrates that select patients with elevated baseline TILs were able to experience a small 2-fold or less increase in TILs following nivolumab. The reality is that a 10-fold increase in TILs was observed following treatment with NKTR-214 even in patients with low baseline TILs which has not been shown with nivolumab. This is consistent with the mechanism of action of NKTR-214.

Comparison to epacadostat

Unlike the epacadostat open label single arm trials, the PIVOT trial of NKTR-214 and Opdivo has independent blinded central data review for ORR. Nektar and BMS have stated there is a high concordance between the investigator-assessed and independent review. As the separate tumor cohorts are independently presented, such as at the upcoming SITC meeting, Nektar and BMS plan to present the investigator and independent ORR side-by-side for full transparency. The NKTR-214 and nivolumab PIVOT trial is enrolling Stage IV patients and did not enroll Stage III patients as the epacadostat studies did.

Nektar has demonstrated translational data from NKTR-214 monotherapy and the nivolumab combination studies that clearly differentiates from the mechanism of IDO inhibition. NKTR-214 promotes TIL increases, proliferation of lymphocytes (Ki67+ expressing), increases in PD-1 and ICOS expression, and increases in PD-L1 in the tumor. The MOA of NKTR-214 changes the immune system and the tumor microenvironment in a beneficial way that is non-overlapping and complementary with anti-PD1 checkpoint antibodies. We’ve observed high response rates with NKTR-214 and nivolumab in baseline PD-L1 negative patients, deepening of responses over time, and a low immune-mediated AE profile which is critically important in an I-O combination therapy.

Jennifer Ruddock
SVP, Investor Relations & Corporate Affairs
Nektar Therapeutics | 455 Mission Bay Boulevard South, San Francisco, CA 94158


Thanks Chris,

Nice to have the company’s thoughts and rebuttal to the short article.

After reading that, I’m thinking of upping my exposure from just over 1% to 2% before the 11/9 presentation.

I’ve maintained a small position in Nektar. My position is not even related to their cancer research. I think NKTR-181 (whatever the trade name is) will be a very successful therapy. If I understand it correctly (and I may not as biotech info generally makes my eyes glaze over), 181 should be on the market this coming May.

For those who don’t know, NKTR-181 is an opioid derivative analgesic medication administered in pill form which does not cause the euphoric effect of all other opioids currently available (something about the way it crosses the blood/brain barrier which I don’t understand). As it does not get the subject “high” there is far less likelihood of it leading to abusive behavior resulting in addiction.


I am holding and more interested in 181 as well, at least in the near term. Given the increased focus recently by the FDA on developing non addictive pain medication, 181 could be a pretty big deal. As far as I know it’s basically the first of its kind as well.