On October 30, 2017 Sierra Oncology, Inc. (NASDAQ: SRRA), a clinical stage drug development company focused on advancing next generation DNA Damage Response (DDR) therapeutics for the treatment of patients with cancer, reported preclinical data supporting the ongoing clinical development strategy for its Chk1 inhibitor, SRA737 (Press release, Sierra Oncology, OCT 30, 2017, View Source [SID1234521304]). The results were presented in a poster on October 29th at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) held in Philadelphia, Pennsylvania.

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“The data generated from these experiments are consistent with recent findings from our research and demonstrate that a potent and selective Chk1 inhibitor such as SRA737 can effectively synergize with sub-therapeutic doses of gemcitabine to induce replication catastrophe and tumor cell death,” said Dr. Alan R. Eastman, Professor at the Geisel School of Medicine at Dartmouth and the founding Director of the Molecular Therapeutics Research Program of the Norris Cotton Cancer Center at Dartmouth-Hitchcock. “I look forward to results from the clinical study Sierra is conducting which translates this novel strategy for the treatment of patients with advanced cancers.”

“Chk1 is essential for managing replication stress (RS), which is intrinsically elevated in certain oncogene-transformed tumors, and can also be further enhanced by chemotherapeutic drugs like gemcitabine. While gemcitabine likely causes RS by depleting deoxynucleotide (dNTP) and damaging DNA, Chk1 protects against RS through a variety of molecular mechanisms. Consequently, tumor cells become highly reliant on Chk1 to manage replication stress and its downstream consequences in order to survive and continue to proliferate,” added Dr. Christian Hassig, Senior Vice President of Research at Sierra Oncology. “Through our research, we have demonstrated that SRA737 has the potential to synergize with several clinically important chemotherapeutic inducers of RS to kill tumor cells in vitro at low concentrations. We also demonstrated that the combination of SRA737 and gemcitabine may prove efficacious in gemcitabine-resistant clinical settings and that SRA737 can be potentiated by sub-therapeutic doses of gemcitabine in animal models of cancer.”

“Replication stress has been recognized as a potent driver of genomic instability, a fundamental hallmark of cancer, and is rapidly emerging as an area of dynamic scientific research,” stated Dr. Nick Glover, President and CEO of Sierra Oncology. “Tumors harboring high levels of intrinsic or exogenous forms of replication stress are potential candidates for therapeutic intervention using SRA737. We are actively leveraging these concepts in our ongoing monotherapy and low-dose gemcitabine combination clinical trials.”

About the Poster
Title: The Chk1 inhibitor, SRA737, demonstrates chemical synthetic lethality with replication stress-inducing agents, including novel low-dose gemcitabine, in preclinical models of cancer.
Poster #181; Abstract #B181:
The Poster is available on the company’s website at www.sierraoncology.com.

Data reported in the Poster demonstrated that:

The combination of SRA737 with a range of RS-inducing agents was highly synergistic in a panel of 15 cell lines of diverse tissue lineages, with the strongest synergy observed with gemcitabine.
Profound synergy between SRA737 and gemcitabine was observed in several bladder cancer cell lines as well as in human patient-derived bladder cancer 3D cultures, further supporting the clinical development of this RS-inducing combination.

Significant anti-tumor activity and increased survival (vs. control) were observed when SRA737 and gemcitabine were dosed in combination in a highly aggressive gemcitabine resistant bladder carcinoma PDX model. These findings suggest that the combination of SRA737 and gemcitabine may be efficacious in gemcitabine-resistant clinical settings.
Strikingly, anti-tumor activity was observed when SRA737 was combined with a sub-therapeutic dose of gemcitabine in xenograft models of colorectal adenocarcinoma and osteosarcoma. This combination was shown to increase RS markers by three to five-fold over the change noted with gemcitabine alone. These findings support i) the development of SRA737 in combination with low, sub-therapeutic doses of gemcitabine and, ii) the broader application of this unique combination in tumor indications where gemcitabine is not standard of care.

On October 30, 2017 X4 Pharmaceuticals, a clinical stage biotechnology company developing a novel CXCR4 inhibitor to improve immune cell trafficking to treat cancer and rare diseases, reported updated results from the Phase 1 part of an ongoing Phase 1/2 study of X4P-001-IO in combination with Inlyta (axitinib) in patients with clear cell renal cell carcinoma (ccRCC) (Press release, X4 Pharmaceuticals, OCT 30, 2017, View Source [SID1234521340]).

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The results in patients with ccRCC who received the combination treatment of X4P-001-IO, a CXCR4 inhibitor, and Inlyta, Pfizer’s VEGFR kinase inhibitor, showed an objective response rate (ORR) of 29%, including 1 patient achieving a confirmed complete response (CR), with an encouraging disease control rate (DCR) of 93%. 31% of patients entering the study had received one prior line of therapy while the majority of patients (69%) had received at least two prior lines of therapy. The data were presented at the 2017 AACR (Free AACR Whitepaper)-NCI-EORTC Molecular Targets and Cancer Therapeutics Conference on October 29 in Philadelphia.

"The combination of CXCR4 inhibition and VEGFR inhibition shows promising clinical results in this very difficult to treat population of patients with ccRCC. These results suggest that X4P-001-IO may address some of the limitations and augment the clinical utility of axitinib, which is a clinically meaningful drug in the treatment of patients with advanced metastatic ccRCC," said Michael Atkins, MD, Deputy Director, Georgetown Lombardi Comprehensive Cancer Center, William M. Scholl Professor of Oncology at Georgetown University School of Medicine, and lead investigator of the study. "These results, while early, are very promising with a strong disease control rate and a manageable safety profile."

Results from the 16 patients with advanced ccRCC enrolled in the dose escalation part of the ongoing Phase 1/2 study as of the data cutoff date of October 2, 2017 were presented and highlights of the poster presentation include:

The combination of X4P-001-IO and Inlyta showed one confirmed complete response (CR) and produced a DCR and ORR of 93 percent (13/14) and 29 percent (4/14), respectively, in the evaluable patient population.
The median duration on treatment at the data cutoff was 22.1 weeks and 44 percent of patients had been exposed to study treatment for at least 24 weeks.
X4P-001-IO in combination with Inlyta was considered to be safe and generally well tolerated. The most frequent treatment-related adverse events (AEs) were hypertension, diarrhea, fatigue, nausea, decreased appetite, headache and dry eye. No grade 4 or 5 AEs were observed.
Pharmacodynamic (PD) measurements demonstrated that the 400 mg dose inhibited the intended target chemokine receptor CXCR4.
Based on the study results, a dose of 400 mg X4P-001-IO once daily with 5 mg Inlyta twice daily has been selected for the Phase 2 portion of the ongoing Phase 1/2 study.
"We are encouraged by the results to date in this first cohort of patients, many of whom have been on study for over six months and have seen early signs of clinical efficacy with manageable side effects," said Sudha Parasuraman, MD, Chief Medical Officer of X4. "We look forward to sharing a comprehensive update on the ongoing Phase 2a clinical trial, as well as the path forward for further development, in 2018."

The Phase 2 portion of the study continues to enroll patients to evaluate the clinical efficacy of X4P-001-IO as measured by objective response rate (ORR), duration of response (DOR), and progression free survival (PFS), as well as explore the correlation of biomarkers with efficacy. (View Source)

About X4P-001-IO in Cancer

X4P-001-IO is an investigational selective, oral, small molecule inhibitor of CXCR4 (C-X-C receptor type 4) that regulates the tumor microenvironment thereby enhancing endogenous anti-tumor responses. CXCR4 is a chemokine receptor that modulates immune function and angiogenesis through the trafficking of key immune cells such as T- cells, dendritic cells, and myeloid derived suppressor cells. CXCR4 signaling is disrupted in a broad range of cancers, facilitating tumor growth by allowing cancer cells to evade immune detection and creating a pro-tumor microenvironment.

About Renal Cell Carcinoma

Kidney cancer is among the ten most common cancers in both men and women with more than 60,000 new diagnoses each year in the United States.1 Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer, and advanced ccRCC accounts for approximately 20% of the patient population. Therapies for advanced ccRCC include immunotherapies, mammalian target of rapamycin (mTOR) kinase inhibitors, and angiogenesis inhibitors, such as vascular endothelial growth factor (VEGF) inhibitors.2 There continue to be unmet medical needs with advanced ccRCC because durable responses remain a serious clinical challenge for patients with advanced disease.

On October 29, 2017 Esanex, Inc., a clinical stage company developing Heat Shock Protein inhibitors for the treatment of cancer, reported that it is presenting preclinical data from its Heat Shock Protein 90 (Hsp90) inhibitor SNX-5422 program, showing promising anti-tumor effects both alone and in combination with checkpoint inhibitors, at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) (Press release, Esanex, OCT 29, 2017, View Source [SID1234521339]).

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"Results from these two studies reaffirm our belief in the potential of SNX-5422 both as a monotherapy and in combination with immuno-oncology drugs," said Everardus (Eric) Orlemans, Ph.D, Chief Scientific Officer and Senior Vice President, Development, Esanex. "We are conducting further research to explore the potential of SNX-5422 in other indications as well as through our ongoing Phase 1b trial in chronic lymphocytic leukemia. The results from the combination research support further development of SNX-5422 in combination with checkpoint inhibitors for the potential treatment of a number of cancer types."

The two posters will be presented October 29th at 12:30 – 4:00 pm EST, in Hall E, Pennsylvania Convention Center.

Poster B139: "Promising antitumor effects of SNX-5422 in combination with checkpoint inhibitors in an MC38 murine model", presented at the session PO.B20 – Therapeutic Agents: Other Topics.
SNX-5422 is an orally active prodrug of SNX-2112, a potent, highly selective inhibitor of Hsp90. The results described in the poster show that SNX-5422 at either 25 mg/kg or 40 mg/kg, in combination with the immune checkpoint inhibitors anti-PD1, PD-L1 or CTLA4, demonstrated significant antitumor activity in the MC38 murine colon cancer model.

Poster B026: "SNX-2112 interferes with mitochondrial metabolism in TP53 mutant tumors", presented at the session PO.B05 – Metabolism.
In vitro work with SNX-2112, the active derivative of SNX-5422, demonstrated significant antitumor activity in TP53 null tumors and in rearranged MYC hematologic and selected solid tumors (e.g., hepatocellular carcinoma, mesothelioma). This activity appears to be, in part, the result of interference with cancer related metabolic pathways.

About SNX-5422
SNX-5422 is a chemically unique, orally active Hsp90 inhibitor that has provided durable clinical responses in open label trials in non-small cell lung cancer (NSCLC) and neuroendocrine tumors (NET). The potential of SNX-5422 in hematologic cancers is currently being explored in a chronic lymphocytic leukemia (CLL) open label clinical trial (clinicaltrials.gov ID#NCT02973399). With approximately 200 patients treated to date, SNX-5422 has a well-established safety profile that supports studying it in combination with existing approved drugs in a variety of clinical settings.

On October 29, 2017 Rgenix, Inc., a clinical stage biopharmaceutical company developing first-in-class small molecule and antibody can, cer therapeutics, reported preliminary data from an ongoing Phase 1a/b clinical trial with its lead oral investigational agent, RGX-104 (Press release, Rgenix, OCT 29, 2017, View Source [SID1234521283]). These data demonstrate immune-stimulatory activity in solid tumor patients with highly-refractory malignancies, including patients who have failed prior checkpoint inhibitors. Also presented were pre-clinical data establishing the immune-modulatory and anti-tumor effects of RGX-104. The company presented the data at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) in Philadelphia.

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RGX-104 is a liver X receptor (LXR) agonist that upregulates the expression of the target gene, Apolipoprotein E (ApoE), triggering several downstream effects via ApoE receptors. In pre-clinical data presented today, treatment with RGX-104 in mouse models resulted in dual effects on myeloid-derived suppressor cells (MDSCs) and dendritic cells (DCs), both innate immune cells that play a central role in regulating anti-tumor immunity and response to checkpoint inhibitors. Innate immune activation with RGX-104, coupled with a reduction in tumor blood vessels, resulted in anti-tumor activity as a monotherapy as well as synergy with checkpoint inhibitors (CPI) in several drug-resistant mouse models. These data provide rationale for Rgenix’s ongoing Phase 1a/b trial of RGX-104 in advanced cancer patients and support evaluation of RGX-104 as both a monotherapy as well as in combination with CPIs.

As part of the ongoing Phase 1a/b clinical trial, 15 patients with a variety of solid tumors have been treated with escalating doses of RGX-104 monotherapy. Patients treated with RGX-104 had a median of six prior therapies with a range of 1-12, highlighting a population of patients with profoundly resistant disease.

Activation of the LXR-ApoE pathway with oral administration of RGX-104 was associated with immune-stimulatory activity in 9 of 10 evaluable patients. This was demonstrated by an increase (up to 11-fold) in activated circulating PD-1+CD8+ T cells during treatment. T cell activation was observed in patients who experienced modulation of the innate immune system during treatment. The effect of RGX-104 on the innate immune system consisted of both MDSC depletion (up to 95% decrease) as well as DC activation as indicated by induction of PD-L1 expression (up to 100% increase). In most cases these effects were observed within two weeks of treatment initiation and generally preceded the onset of T cell activation.

Safety data demonstrate good tolerability with on-target safety findings in the first three dosing cohorts. One patient experienced a DLT of grade 4 reversible neutropenia – a known potential effect of LXR agonism – that reversed within one week, allowing the patient to subsequently tolerate a 50% dose reduction. No MTD has been reached to date. Stable disease has been observed in 4 of 12 evaluable patients, including three who have failed prior checkpoint inhibitor therapy, for periods of at least 8 weeks.

“We are very pleased to see robust evidence of immune stimulation in such highly-pretreated patients,” said Roger Waltzman, MD, MBA, and Chief Medical Officer of Rgenix. “CPI therapy is now commonplace but only a minority of patients derive clinical benefit. We hope the effects of RGX-104 on modulating barriers to innate and adaptive immune function will enable a larger number of patients to benefit from this therapy. These preliminary results also highlight the potential for development of RGX-104 as a monotherapy.”

Rgenix plans to enroll subsequent dose-escalation cohorts of the RGX-104 monotherapy trial in Q4 2017. Additionally, Rgenix is planning to initiate the Phase 1b expansion component of the study, comprised of disease directed cohorts receiving RGX-104 monotherapy as well as cohorts receiving RGX-104 combined with a CPI, projected to begin in 1H 2018.

“These preliminary data establish RGX-104 as a potential first-in-class oral immunotherapy agent with broad immune-stimulatory activity and a unique dual mechanism targeting innate immunity,” said Masoud Tavazoie, MD, PhD, and Chief Executive Officer of Rgenix. “These results also further validate our discovery platform at Rgenix, as well as our pipeline of other drug candidates slated to begin entering clinical-stage development in 2018.”

The LXR-ApoE pathway was discovered as a cancer target using a microRNA (miRNA) based target discovery approach originally developed at The Rockefeller University and now exclusively licensed to Rgenix.

On October 28, 2017 Kura Oncology, Inc. (Nasdaq:KURA), a clinical stage biopharmaceutical company focused on the development of precision medicines for oncology, reported new results for KO-539, the company’s potent and selective inhibitor of the menin-MLL protein-protein interaction, which is currently in preclinical development as a potential treatment for patients with genetically-defined subsets of acute leukemias (Press release, Kura Oncology, OCT 28, 2017, View Source [SID1234521274]). The results were featured in a late-breaking presentation today at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) in Philadelphia.

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Although KO-539 was originally designed as a potential therapy for the MLL-rearranged leukemias, the new results demonstrate significant activity in preclinical models of additional genetically-defined subsets of AML, including those with oncogenic driver mutations in NPM1, IDH1, IDH2 and DNMT3A. Preliminary pharmacodynamic data suggests that KO-539 exerts anti-leukemic activity by induction of myeloid differentiation in AML blasts, a mechanism that is distinct from and potentially complementary to existing cytotoxic and antiproliferative therapies. The menin-MLL complex appears to be a central node in epigenetic dysregulation driven by several distinct oncogenic driver mutations known to be important in diverse leukemias and myeloproliferative disorders.

“Although AML is a relatively common hematologic malignancy with a generally poor prognosis, the development of novel therapeutic approaches has been hampered by the many different genetic and clinical subgroups found in the disease and the relatively short durations of response,” said Yi Liu, Ph.D., Chief Scientific Officer, Kura Oncology. “We’re encouraged by the results presented today because they demonstrate that menin-MLL inhibitors have the potential to be active in subtypes representing approximately half of the patients with AML and drive robust and persistent responses in preclinical models.”

A copy of the poster, entitled “A novel small molecule menin-MLL inhibitor for potential treatment of MLL-rearranged leukemias and NPM1/DNMT3A-mutant AML,” is now available on the company’s website at www.kuraoncology.com.