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 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 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.

On October 27, 2017 Kura Oncology, Inc. (Nasdaq:KURA), a clinical stage biopharmaceutical company focused on the development of precision medicines for oncology, reported presented updated preliminary results from its Phase 2 open-label trial of tipifarnib, a farnesyltransferase inhibitor, in patients with head and neck squamous cell carcinomas (HNSCC) with HRAS mutations (Press release, Kura Oncology, OCT 27, 2017, View Source [SID1234521243]).

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The results were featured in a late-breaking, oral presentation by Dr. Alan Ho of Memorial Sloan Kettering Cancer Center at the Spotlight on Proffered Papers Session 1 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), taking place today in Philadelphia.

Four out of six evaluable HRAS mutant HNSCC patients enrolled in the study achieved a confirmed partial response, as defined by standard RECIST criteria. In addition, as of the data cutoff date of October 4, 2017, four HRAS mutant HNSCC patients remained on study in cycles 21, 7, 5 and 3. The patients in cycles 21, 7 and 5 had all experienced partial responses while the patient in cycle 3 experienced stable disease as of the first response assessment in cycle 2. One HRAS mutant HNSCC patient with a confirmed partial response remained on study through cycle 20 and withdrew in cycle 21 with progressive disease. Another HRAS mutant HNSCC patient experienced a best response assessment of stable disease and withdrew from the study in cycle 8.

Tipifarnib has demonstrated clinical activity in previously treated patients, including those who have progressed on chemotherapy with or without cetuximab or immune therapy. The majority of adverse events reported by the investigators have been mild to moderate and are consistent with the adverse event profile previously reported for tipifarnib.

“The responses, durability and safety data with tipifarnib clearly suggest this is an important drug candidate for patients with HRAS mutant head and neck cancers,” said Alan Ho, M.D., Ph.D., of Memorial Sloan Kettering Cancer Center and presenter of the tipifarnib oral presentation. “We are excited to continue to follow these patients and treat additional HRAS mutant patients in the ongoing Phase 2 trial.”

“The consistent clinical activity of tipifarnib in HNSCC patients with HRAS mutations is very encouraging,” said Antonio Gualberto, M.D., Ph.D., chief medical officer of Kura Oncology. “Based on these positive results, we continue to explore available options to rapidly advance the development of tipifarnib and subject to input from regulatory authorities, we plan to initiate a registration-enabling study in HRAS mutant HNSCC in 2018.”

About HRAS Mutant HNSCC

Head and neck cancer is one of the leading causes of cancer-related deaths worldwide, with squamous cell carcinomas accounting for most head and neck cancers. Response rates for the three agents approved for treatment of HNSCC in the second line, including cetuximab and immune therapy agents, are in the range of 13-16%, and median overall survival is up to 7.5 months. HRAS is a proto-oncogene that has been implicated in the development and progression of HNSCC and has been established to be uniquely farnesylated.

On October 27, 2017 Eagle Pharmaceuticals, Inc. (Nasdaq:EGRX) (“Eagle” or “the Company”) reported that the United States Food and Drug Administration (“FDA”) has granted tentative approval for the Company’s PEMFEXY, a pemetrexed injection ready-to-dilute formulation for locally advanced or metastatic nonsquamous non-small cell lung cancer in combination with cisplatin; locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy, as maintenance treatment; locally advanced or metastatic nonsquamous non-small cell lung cancer after prior chemotherapy as a single agent; and malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery in combination with cisplatin (Press release, Eagle Pharmaceuticals, OCT 27, 2017, View Source [SID1234521256]).

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“We are pleased to have received this tentative approval for PEMFEXY, which we believe offers a material benefit to healthcare providers. PEMFEXY fits well within our growing portfolio of oncology drugs, including BENDEKA, bendamustine hydrochloride ready-to-dilute and rapid infusion, DOCETAXEL INJECTION, and fulvestrant, which is in development. We will work toward bringing this much needed drug to market as soon as the patent issues are resolved,” stated Scott Tarriff, Chief Executive Officer.

“Tentative approval” means that FDA has concluded that a drug product has met all required quality, safety and efficacy standards, but is not eligible for marketing in the U.S. because of existing patent protections. The tentative approval will be eligible for conversion to a final approval subject to the resolution of the current patent litigation between Eagle and Eli Lilly and Co.

“Our formulation does not require reconstitution, reducing the potential for dosing errors during mixing as well as the hazards of inhaling cytotoxic vapors that can occur when handling the powder form of the drug during preparation. We believe there is a need in the market for our improved formulation,” concluded Tarriff.

Eagle submitted, and the FDA accepted for filing, its NDA under Section 505(b)(2) of the Federal Food, Drug and Cosmetic Act (“FDCA”) for PEMFEXY ready-to-dilute in December 2016.

This NDA references ALIMTA, the branded product manufactured by Eli Lilly and Co., which had annual U.S. sales of approximately $1.0 billion over the last twelve months.