On June 6, 2016 Peloton Therapeutics, Inc., a drug discovery and development company focused on advancing first-in-class, small molecule cancer therapies targeting unexploited molecular vulnerabilities, reported first-in-human Phase 1 clinical data on its lead investigational candidate, PT2385, at the annual meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago, IL (Press release, Peloton Therapeutics, JUN 6, 2016, View Source [SID:1234513120]). PT2385 is the first clinical stage antagonist of hypoxia inducible factor-2α (HIF-2α), a transcription factor implicated in the development and progression of kidney and other cancers.

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In an oral presentation titled "A Phase 1 Dose-Escalation Trial of PT2385, a first-in-class oral HIF-2α Inhibitor, in Patients with Advanced Clear Cell Renal Cell Carcinoma," it was shown that PT2385 was well tolerated with no dose-limiting toxicities and had pharmacologic activity with encouraging clinical efficacy.

Patients with advanced clear cell renal cell carcinoma (ccRCC) and at least one prior therapy with a VEGF inhibitor were treated with PT2385 to determine the recommended Phase 2 dose and evaluate safety, pharmacokinetics and pharmacodynamics.
Twenty-six patients were enrolled in dose escalation and received PT2385 from 100 to 1800 mg twice per day. Patients were heavily pretreated prior to study entry, with greater than 50 percent having four or more prior therapies. Exposure increased with doses up to the 800 mg cohort without a further increase from 800 to 1800 mg. No dose limiting toxicities were observed at any dose level. Circulating plasma levels of the HIF-2α transcriptional target erythropoietin (EPO) rapidly decreased with treatment with PT2385 and remained suppressed. Based on safety, pharmacokinetic and EPO pharmacodynamic data, 800 mg twice per day was selected as the recommended Phase 2 dose. An additional 25 patients were enrolled in an expansion cohort at the recommended Phase 2 dose.

Among the 51 patients in total, the most common all-grade adverse events (AEs) were anemia, peripheral edema and fatigue. No cardiovascular AEs were noted. To date, one patient had a complete response, three patients had a partial response, and 16 patients had stable disease for 16 or more weeks. Ten percent of patients remain in this ongoing clinical trial for at least one year.
"Research at our institution has shown than HIF-2α is strongly implicated in renal cell carcinoma. PT2385 is the first agent to target this transcription factor and is very well tolerated. Its efficacy in patients with advanced clear cell renal cell carcinoma is promising," said Toni Choueiri, M.D., from the Dana-Farber Cancer Institute and Harvard Medical School, the senior author of the study.
"We are encouraged by the initial efficacy results in this heavily pretreated population and the fact that PT2385 does not have the cardiovascular toxicities of most other kidney cancer treatments, most notably VEGFR tyrosine kinase inhibitors. In light of this favorable safety profile and preclinical evidence of synergistic activity of our HIF-2α antagonists in combination with immune checkpoint inhibitors shown at the recent AACR (Free AACR Whitepaper) conference, we have opened a clinical trial of PT2385 in combination with nivolumab (Opdivo). Additionally, we are planning clinical studies of PT2385 as monotherapy and with other combination regimens," said John Josey, Ph.D., Peloton’s Chief Executive Officer.

About PT2385
PT2385 is a first-in-class small molecule inhibitor of hypoxia-inducible factor-2α (HIF-2α), a transcription factor implicated in the development and progression of kidney cancer. It is currently being investigated in a Phase 1 clinical trial for the treatment of advanced or metastatic clear cell renal cell carcinoma (ccRCC). Loss of the von Hippel-Lindau tumor suppressor (VHL) is the key oncogenic event in up to 95% of patients with ccRCC. With the loss of the VHL protein (pVHL), the transcription factor HIF-2α accumulates and drives the unbalanced expression of numerous gene products. Preclinical data indicate that orally bioavailable PT2385 disrupts HIF-2α activity in ccRCC and thereby blocks the expression of multiple tumorigenic factors responsible for unrestrained cancer cell growth and proliferation, tumor angiogenesis, and suppression of anti-tumor immune responses characteristic of ccRCC.

About Renal Cell Cancer
The American Cancer Society estimates that more than 62,000 new cases of kidney cancer will be diagnosed and more than 14,000 people will die from this disease this year. The National Cancer Institute reports that the prognosis for any treated renal cell cancer patient with progressing, recurring, or relapsing disease is poor, regardless of cell type or stage.
About Peloton Therapeutics

On June 6, 2016 MorphoSys AG (FSE: MOR; Prime Standard Segment, TecDAX; OTC: MPSYY) reported updated safety and efficacy data from an ongoing clinical phase 1/2a study evaluating the anti-CD38 antibody MOR202 alone and in combination with immunomodulatory drugs (IMiDs) lenalidomide (Len) and pomalidomide (Pom) plus dexamethasone (Dex) in 63 heavily pre-treated patients with relapsed/refractory multiple myeloma (MM) (Press release, MorphoSys, JUN 6, 2016, View Source [SID:1234513073]). Data were reported during a poster presentation at the 2016 ASCO (Free ASCO Whitepaper) Annual Meeting. The updates compared to the last presentation of data from this ongoing trial in December 2015 refer in particular to the combination cohorts of MOR202 (8 mg/kg) plus IMiDs.

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In the five-patient cohort receiving 8 mg/kg MOR202 in combination with Pom/Dex, two patients reached a complete response (CR) and two patients a minor response (MR) (one of which is unconfirmed). Among the four patients treated with 8 mg/kg MOR202 in combination with Len/Dex and with a scheduled response assessment after one treatment cycle, two reached a partial response (PR) and one a very good partial response (VGPR).

MOR202 could be given in doses of up to 16 mg/kg as a 2-hour infusion to all patients. Infusion-related reactions (IRRs) were observed in 14% of evaluated patients (10% grade 1, 4% grade 2) and were mainly limited to the first infusion.

Moreover, first biomarker data on CD38 expression on plasma cells derived from bone marrow of all five MM patients with available second biopsies, suggested that the CD38 target molecule was preserved during MOR202 therapy comparing values at baseline and at cycle 2 day1.

"We are very pleased with the updated clinical results for MOR202 in multiple myeloma, in particular with two complete responses out of five patients treated with MOR202 plus Pom/Dex. Since we last reported data in December 2015, new and deep responses have been reported with MOR202 in combination with IMiDs. On the safety side, we were pleased to observe that MOR202 could be given to all patients in a 2-hour infusion time, with infusion-related reactions of grade 1 and 2 in only 14% of patients," commented Dr. Arndt Schottelius, Chief Development Officer of MorphoSys AG. "The dose escalation study will continue as planned, focusing on the combination treatment, in particular the upcoming cohorts of 16mg/kg MOR202 plus Pom/Dex and Len/Dex."

MOR202 is a fully human HuCAL antibody targeting CD38, a highly expressed and validated target in multiple myeloma. Data are from an ongoing clinical phase 1/2a, open-label, multi-center, dose-escalation study conducted in several sites in Germany and Austria. The study is evaluating the safety and preliminary efficacy of MOR202 alone and in combination with the immunomodulatory drugs pomalidomide (Pom) and lenalidomide (Len) plus dexamethasone (Dex) in patients with relapsed/refractory multiple myeloma. The primary endpoints of the trial are the safety, tolerability and recommended dose of MOR202 alone and in combination with the IMiDs. Secondary outcome measures are pharmacokinetics and preliminary efficacy based on overall response rate, duration of response, time-to-progression, and progression-free survival.

MOR208: Updated results confirm responses. Subgroup analysis shows target lesion shrinkage in patients with stable disease and activity of MOR208 independent of the response to a prior rituximab treatment

In addition, MorphoSys today presented updated clinical data including a subgroup analysis of a phase 2a study with the anti-CD19 antibody MOR208 in relapsed/refractory patients with various subtypes of non-Hodgkin’s lymphoma (NHL) including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and other indolent NHL (iNHL). All patients had received at least one prior rituximab-containing therapy.

According to the subgroup analysis data presented today, in addition to patients achieving a partial or complete response (PR, CR), a clinical benefit was also observed in other patients treated with MOR208. The majority of patients (5/6 DLBCL and 12/16 iNHL) with stable disease (SD) also had a reduction in the size of the target lesions – despite the short treatment period of 3 cycles according to protocol. This resulted in a disease control rate of 40% in DLBCL and 73% in iNHL patients. Moreover, progression-free survival (PFS) with MOR208 therapy was observed to be comparable in rituximab refractory and non-refractory NHL patients (median PFS 5.3 versus 6.6 months, HR 0.85, 95% CI 0.45-1.6, p=0.59). Thus, MOR208 has demonstrated in this trial activity independent of the response to a prior anti-CD20 therapy. Updated data for the overall trial population furthermore revealed that after 12 months the PFS rate was 40% in both DLBCL and iNHL patients. Nine patients treated with MOR208 are still in remission (7 CRs, 2 PRs), the longest responses currently ongoing for 26 months.

"We are very happy with the updated clinical trial results with MOR208," commented Dr. Arndt Schottelius, Chief Development Officer of MorphoSys AG. "We are impressed by the duration of responses of up to 26 months with MOR208 as a single-agent in heavily pre-treated patients with relapsed/refractory NHL. We were further pleased to observe a decline in the size of the tumor lesions in many in the subgroup of patients with stable disease even when treated for a short period of 3 cycles only. Overall, the updated clinical data presented at ASCO (Free ASCO Whitepaper) strongly support our strategy to develop MOR208 in B cell malignancies, in particular our planned combination trials in DLBCL and CLL."

MOR208 is an anti-CD19 antibody with a proprietary modification to the Fc portion in clinical development to treat B cell malignancies. The open-label, phase 2a, multicenter study was designed to assess the activity and safety of weekly doses of 12 mg/kg MOR208 as a single agent in 92 pre-treated patients with various subtypes of relapsed/refractory NHL patients. According to the data observed, MOR208 showed a low level of infusion reactions. The overall response rate (ORR) of MOR208 reached 36% in the DLBCL subgroup and 33% in iNHL patients (both based on evaluable patients). Based on all patients with DLBCL and iNHL in the study, the ORR was 26% and 29%, respectively.

In addition, the trial design of a phase 2 study of MOR208 (COSMOS trial) was presented at the ASCO (Free ASCO Whitepaper) 2016 Annual Meeting. The trial is planned to evaluate MOR208 in combination with idelalisib in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), in patients no longer responding to or no longer tolerating Bruton’s tyrosine kinase (BTK) inhibitor therapy (e.g. ibrutinib). After the discontinuation of several combination trials of idelalisib with other compounds, this planned trial is currently under review and discussions with regulatory authorities are ongoing. MorphoSys is currently exploring alternative study designs to evaluate MOR208 in a combination trial in CLL/SLL patients previously treated with a BTK inhibitor.

The posters presented at the Annual ASCO (Free ASCO Whitepaper) Meeting, June 6, 2016, 8:30 am CDT (2:30 pm BST, 3:30 pm CEST), can be downloaded from the Company’s website.

Abstract #8012
M. Raab et al: MOR202 alone and in combination with pomalidomide or lenalidomide in relapsed or refractory multiple myeloma: Data from clinically relevant cohorts from a phase 1/2a study.

Abstract #7545
W. Jurczak et al: Subgroup analyses of diffuse large B-cell lymphoma (DLBCL) and indolent lymphoma cohorts from a phase 2a study of single-agent MOR208 in patients with relapsed or refractory non-Hodgkin’s lymphoma (R-R NHL).

Abstract #TPS7572
C.-M. Wendtner et al: A phase 2 study of MOR208 plus idelalisib in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) previously treated with a Bruton’s tyrosine kinase inhibitor.

MorphoSys will hold on June 6, 2016 at 6:30 p.m. CDT (June 7, 2016 0:30 a.m. BST, 1:30 a.m. CEST) an Investor & Analyst Event at the 2016 ASCO (Free ASCO Whitepaper) Annual Meeting. KOLs will present the new clinical data for MOR208 and MOR202. A replay and the presentation will be made available at View Source Live-Webcast: http://morphosys.equisolvewebcast.com/investor-event-6-6-16

On June 6, 2016 IntegraGen, a leading provider of genomic solutions which transform molecular information into clinical action, reported the presentation of positive clinical results on its miR-31-3p biomarker during the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting being held in Chicago (Press release, Integragen, JUN 6, 2016, View Source [SID:1234513098]). The data presented demonstrates that IntegraGen’s proprietary miR-31-3p biomarker is predictive for both survival and treatment response in patients receiving anti-EGFR therapy. These results are based on an analysis of the expression of miR-31-3p in tumors from 370 RAS wild-type (WT) metastatic colorectal cancer (mCRC) patients enrolled in the FIRE-3 clinical trial (AIO KRK-0306). The data presented represents the first study comparing miR-31-3p expression in mCRC patients treated in first line with anti-EGFR vs. anti-VEGF therapy.

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In addition to confirming miR-31-3p is predictive of improved outcomes for mCRC patients treated with anti-EGFR therapy, the study also demonstrated that patients with a miR-31-3p expression below a pre-defined threshold treated with FOLFIRI plus cetuximab have a one year longer median overall survival, a 40% reduction in mortality risk, and a better treatment response compared to patients treated with FOLFIRI plus bevacizumab. No difference in outcomes were seen between the two groups in patients with miR-31-3p expression above the pre-defined threshold. These results suggest that testing miR-31-3p expression in RAS WT mCRC patients can help identify which 1st line biologic therapy may be most beneficial.

"Our results show that miR-31-3p can predict which mCRC patients will have improved outcomes when treated in first line with cetuximab compared to bevacizumab when combined with FOLFIRI therapy," said Professor Volker Heinemann, from the Department of Medical Oncology and Comprehensive Cancer Center at University Hospital Grosshadern in Munich, Germany and lead investigator for the FIRE-3 study. "These findings are extremely significant clinically since nearly two-thirds of the patients with RAS wild-type tumors in our study had low miR-31-3p expression levels and would therefore benefit from being treated with cetuximab versus bevacizumab as first line therapy for mCRC."

"The results from this study provide strong clinical evidence that IntegraGen’s miR-31-3p biomarker can predict the benefit of anti-EGFR therapy in mCRC patients," stated Dr. Bernard Courtieu, IntegraGen’s CEO. "The data presented at this year’s ASCO (Free ASCO Whitepaper) meeting in patients enrolled in the landmark FIRE-3 study demonstrates that RAS wild-type mCRC patients would benefit from the analysis of miR-31-3p expression prior to the determination of which biologic agent to utilize as first line therapy. This aligns with a more personalized approach to cancer care and contributes to the ability to tailor therapies to patients who are more likely to have clinical benefit of these therapies."

Dr. Courtieu also added that "IntegraGen is currently pursuing options for offering a commercial test based on the miR-31-3p biomarker to physicians and their patients, which we estimate represents a $100 million market opportunity worldwide."

ABOUT THE FIRE-3 CLINICAL TRIAL

The FIRE-3 clinical trial is an independent, randomized, controlled Phase III trial conducted in Europe and led by Ludwig-Maximilians University in Munich, Germany. The study compares outcomes of KRAS Exon 2 wild-type (WT) stage IV colorectal cancer patients randomized to receive FOLFIRI therapy (5-FU, folinic acid and irinotecan) in combination with either cetuximab or bevacizumab.

On June 6, 2016 ProNAi Therapeutics, Inc. (NASDAQ: DNAI), a drug development company advancing targeted therapeutics for patients with cancer, reported interim results from the Wolverine Phase 2 trial of PNT2258 for the treatment of relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) (Press release, ProNAi Therapeutics, JUN 6, 2016, View Source [SID:1234513054]). ProNAi will host an Analyst and Investor Event today from 7:00-8:00am CT at the Hyatt Regency McCormick Place in Chicago where management will discuss these results and provide an update on the PNT2258 development program.

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"Although we observed modest efficacy from PNT2258 in this interim analysis of Wolverine, we do not view these results as robust enough to justify continued development of the drug in DLBCL. We have decided to suspend development of PNT2258 pending further review of these data in order to determine next steps for both this asset and the DNAi platform," said Dr. Nick Glover, President and CEO of ProNAi. "We continue to maintain a strong balance sheet and will focus our resources and activities on advancing our newly licensed Cdc7 inhibitor, PNT141, as well as on securing additional assets to build a broad and diverse pipeline of oncology drugs under our development."

Wolverine is a multicenter Phase 2 study designed to evaluate the safety and efficacy of PNT2258 monotherapy in 61 response evaluable r/r DLBCL subjects and to explore the correlation between various baseline patient characteristics, including biomarkers, and response rate.

Interim safety and efficacy data as of April 25, 2016 are reported for the first 37 subjects enrolled. PNT2258 showed single-agent activity in r/r DLBCL subjects with a response rate of 8.1% overall (n = 37) and 15.8% in the response evaluable subgroup (n = 19), defined as subjects meeting the amended eligibility criteria of a performance status (PS) of 0-1, exposure to 1-3 prior systemic regimens and having received at least eight doses of PNT2258 within 35 days of starting therapy. No responses were observed in the 10 subjects with a PS of 2 and/or > 4 prior lines of therapy enrolled prior to the amendment, nor to date in the eight additional subjects enrolled subsequent to the data cutoff date for this interim analysis.

PNT2258 is also being evaluated in patients with Richter’s Transformation in the Brighton study, a multi-center, single-arm Phase 2 trial. To date, five subjects have been enrolled in this study, of which four have discontinued. The other subject has completed two cycles of treatment. No responses have been observed to date.

"We designed and conducted a robust, well-executed set of experiments, both clinical and preclinical, in order to further our understanding of the PNT2258 asset and the underlying DNAi technology. Unfortunately, advanced DLBCL and Richter’s Transformation are challenging diseases to treat, and PNT2258 did not markedly improve outcomes in these indications," said Dr. Barbara Klencke, Chief Development Officer of ProNAi. "On the basis of these interim assessments, we have decided to close the Wolverine and Brighton studies to further enrollment of new subjects. On behalf of ProNAi, we would like to thank the patients and their families, investigators and staff involved in these studies for their participation and support."

PNT2258 Development
PNT2258 is a clinical-stage drug candidate based on a new therapeutic approach known as DNA interference (DNAi). The DNAi oligonucleotides contained within PNT2258 are designed to target and hybridize with a complementary strand of genomic DNA associated with the BCL2 oncogene.

PNT2258 was evaluated in two studies prior to the Wolverine Phase 2 trial:

In a Phase 1 study (PNT2258-01 study [NCT01191775]) in 22 subjects with advanced solid tumors, PNT2258 was well tolerated at doses from 1 through 150 mg/m2. A Phase 2 dose and schedule was identified from this study.

A pilot, signal seeking study (PNT2258-02 study [NCT01733238]) conducted at three sites enrolled 13 subjects with r/r B-cell non-Hodgkin’s lymphoma (NHL). Significant, durable responses were observed in the four subjects with DLBCL, along with other noteworthy complete responses (CR) or partial responses (PR) and durable stable disease (SD) in follicular lymphoma subjects. Six subjects were progression free at 12 months and progression free survival extended to two years and beyond in four of these six subjects. The majority of the AEs were Grade 1 or 2 in severity and no Grade 5 AEs were observed. Five of the six subjects who were progression free at 12 months with PNT2258 were relapsed (not refractory) at study entry and had responded with their last prior therapy with a median time-to-treatment failure of 48 months, range 23.7-87.6 months. All four responding DLBCL subjects had received 1 or 2 prior therapies.

Wolverine Phase 2 DLBCL Study Interim Results
The Wolverine Phase 2 trial (PNT2258-03-DLBCL [NCT02226965]) is a multicenter, single-arm, open-label study of PNT2258 at a dose of 120 mg/m2 administered as a 4-hour IV infusion on days 1-5 of a 21-day cycle in adults with r/r FDG-PET positive, measureable DLBCL. Other inclusion criteria included: ECOG PS ≤ 2, adequate bone marrow, renal and hepatic function, and exposure to CD20-targeted therapy, an alkylating agent, and a steroid. Following a protocol amendment, enrollment was limited to patients with PS of 0-1 who had been exposed to 1-3 prior systemic regimens.

The primary objective of the study is to assess overall response rate defined as the proportion of subjects with CR/complete metabolic response (CMR) or PR/partial metabolic response (PMR) according to the revised 2014 International Working Group criteria for lymphoma (Lugano Classification) in approximately 61 response evaluable subjects. Subjects are imaged with FDG-PET/CT at Baseline and after 3, 5, and 8 cycles.

A key study objective is to evaluate biomarker data, including BCL2, MYC, and cell of origin (COO), in order to identify correlations and possible predictors of outcome to treatment with PNT2258. Tumor samples are centrally assessed by IHC for protein expression, FISH for chromosomal rearrangement, and by Lymph2Cx gene expression array for COO.

PNT2258 demonstrated single agent activity in Wolverine, with a response rate of 8.1% overall (n = 37) and 15.8% in the response evaluable subgroup (n = 19); all responses were evaluated as PMR. The disease control rate (disease control rate defined as CMR plus PMR plus no metabolic response) was 18.9% overall and 36.8% in the response evaluable subgroup. Of the 37 subjects, the median progression free survival was 1.9 months.

Overall, the safety profile of PNT2258 appears acceptable in subjects with PS 0-1 and ≤ 3 prior lines of therapy. The median treatment duration was 47 days in these subjects compared with 15.5 days in those with PS of 2 and/or ≥ 4 prior lines of therapy. Serious adverse events (SAE) and Grade 5 adverse events (AE) rates, respectively, were 37% and 11% in the 27 subjects with PS 0-1 and ≤ 3 prior lines of therapy, and 60% and 50% in the 10 subjects with PS 2 and/or ≥ 4 prior lines of therapy.

A full report of this interim analysis, including biomarker data, will be presented at an upcoming medical conference

Brighton Phase 2 Richter’s Transformation Study Update

The Brighton Phase 2 trial (PNT2258-04 Richter’s Transformation [NCT02378038]) is a multicenter, single-arm, open-label study of PNT2258 at a dose of 120 mg/m2 administered as a 4-hour IV infusion on days 1-5 of a 21-day cycle in adults with Richter’s Transformation. To date, five subjects have been enrolled of which four have discontinued. One other subject remains on therapy and has completed two cycles of treatment. No responses have been observed to date.

DNAi Platform Development
ProNAi will also be halting all further investment in the DNAi platform.

Analyst & Investor Event
ProNAi will host an Analyst and Investor Event today, Monday, June 6, 2016 from 7:00 – 8:00am CT where the company will present an update on the PNT2258 development program, including interim results from the Wolverine Phase 2 trial. Presenters will include: Dr. Nick Glover, President and Chief Executive Officer, Dr. Barbara Klencke, Chief Development Officer, Dr. Angie You, Chief Business & Strategy Officer and Head of Commercial, and Dr. Christian Hassig, Senior Vice President, Research. The event will take place in the Hyde Park A/CC11A event room at the Hyatt Regency McCormick Place located at 2233 S. Dr. Martin Luther King Jr. Dr., Chicago, Illinois. This event will be webcast live and will be accessible through the company’s website at www.pronai.com. An archived replay of the webcast will also be available.

ASCO 2016 Poster Presentation
Title: A phase 2 study of PNT2258 in patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL): An initial report from the Wolverine study
Trials in Progress Abstract: #TPS7577
Poster: #130b
Poster Session: Hematologic Malignancies – Lymphoma and Chronic Lymphocytic Leukemia
Date and Time: Monday, June 6, 2016, 8:00 – 11:30am CT
Location: McCormick Place, Event room: Hall A, 2301 S King Dr, Chicago, Illinois
Track: Hematologic Malignancies – Lymphoma and Chronic Lymphocytic Leukemia
Presenter: Jason R. Westin, MD, MS, Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center
The poster will be available on June 6, 2016 on the company’s website at www.pronai.com

On June 6, 2016 Nektar Therapeutics (NASDAQ: NKTR) reported new preclinical data for NKTR-214, an immuno-stimulatory CD-122 biased cytokine currently being evaluated in cancer patients with solid tumors in a Phase 1/2 clinical trial being conducted at MD Anderson Cancer Center and Yale Cancer Center (Press release, Nektar Therapeutics, JUN 6, 2016, View Source [SID:1234513074]). The new preclinical data presented demonstrate that treatment with single-agent NKTR-214 mobilizes tumor-killing T cells into colon cancer tumors. In addition, 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) (Free ASCO Whitepaper) Annual Meeting in Chicago, IL from June 3-7, 2016.

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"These latest data build upon our growing body of preclinical evidence demonstrating the unique mechanism of NKTR-214," added Jonathan Zalevsky, PhD, Vice President, Biology and Preclinical Development at Nektar Therapeutics. "The studies presented at ASCO (Free ASCO Whitepaper) 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 TILs1 in vivo and replenish the immune system is exceptionally important. We’ve 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."

In studies previously published for NKTR-214, when mice bearing established breast cancer tumors are treated with NKTR-214 and anti-CTLA4 (a checkpoint inhibitor therapy known as ipilimumab for human treatment), a large proportion of mice become tumor-free. 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 (Free ASCO Whitepaper) 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.

"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," said Dr. Steve Doberstein, Senior Vice President and Chief Scientific Officer. "NKTR-214’s unique immune-stimulatory profile and antibody-like dosing schedule positions it as a potentially important medicine within the immuno-oncology landscape."

The data presentation at ASCO (Free ASCO Whitepaper) entitled, "Immune memory in nonclinical models after treatment with NKTR-214, an engineered cytokine biased towards expansion of CD8+ T cells in tumor," can be accessed at View Source

NKTR-214 is a CD122-biased agonist designed to stimulate the patient’s own immune system to kill tumor cells by preferentially activating production of specific immune cells which promote tumor killing, including CD8-positive T cells and Natural Killer (NK) cells, within the tumor micro-environment. CD122, which is also known as the Interleukin-2 receptor beta subunit, is a key signaling receptor that is known to increase proliferation of these types of T cells.2

In preclinical studies, NKTR-214 demonstrated a highly favorable mean ratio of 450:1 within the tumor micro-environment of CD8-positive effector T cells relative to regulatory T cells.3 Furthermore, the pro-drug design of NKTR-214 enables an antibody-like dosing regimen for an immuno-stimulatory cytokine.4

About the NKTR-214 Phase 1/2 Clinical Study
A Phase 1/2 clinical study is underway to evaluate 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, which is expected to be complete in the second half of 2016, 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. In addition, the study will also 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 initially at two primary investigator sites: MD Anderson Cancer Center under Drs. Patrick Hwu and Adi Diab; and Yale Cancer Center, under Drs. Mario Sznol and Michael Hurwitz. Patients and physicians interested in the ongoing NKTR-214 study can visit the "Clinical Trials" section of www.mdanderson.org using identifier 2015-0573 or visit View Source