On September 6, 2018 Nicox SA (Euronext Paris: FR0013018124, COX), an international ophthalmic company, reported the financial results for the Nicox Group for the six months ending June 30, 2018 and provided an update on its activities (Press release, NicOx, SEP 6, 2018, View Source [SID1234529343]).

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Michele Garufi, Chairman and Chief Executive Officer of Nicox, said: "Nicox is entering a new and exciting phase with the initiation of the Phase 2 study for our lead product candidate NCX 470 for IOP reduction in patients with open-angle glaucoma or ocular hypertension, and by strengthening our U.S. presence in our new site in Research Triangle Park in North Carolina. We have assembled the right team to achieve our important near term clinical and corporate milestones and continue delivering on all objectives in line with our growth strategy."

Key Upcoming Milestones
Q1 2019: Planned Investigational New Drug (IND) submission to the United States (U.S). Food and Drug Administration (FDA) for NCX 4251 to enable a Phase 2 clinical study in patients with acute exacerbations of blepharitis.
Q1 2019: Expected delivery of ZERVIATETM (cetirizine ophthalmic solution), 0.24% commercial product to Eyevance Pharmaceuticals LLC, followed by a launch for the spring 2019 allergy season in the U.S.
H2 2019: Expected top-line data from the NCX 470 Phase 2 study for the reduction of intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension.

Product and Product Candidates Updates
A Phase 2 study was initiated in Q3 2018 for Nicox’s product candidate NCX 470, a novel second generation nitric oxide (NO)-donating prostaglandin analog. This multicenter, double-masked, 28-day, parallel group, dose response study aims to evaluate the efficacy and safety of NCX 470 compared to latanoprost 0.005% in adult patients with elevated IOP due to open-angle glaucoma or ocular hypertension. The study is expected to randomize 420 patients in clinical sites across the U.S. The primary endpoint of the study is the mean reduction in diurnal IOP after 4 weeks of treatment, while the overall objective is to identify the appropriate dose of NCX 470 to be advanced into Phase 3 studies. This Phase 2 study was initiated following the submission of an IND application in June 2018, ahead of the previously disclosed target date of the third quarter of 2018. Nicox expects to report top-line data from this Phase 2 study in the second half of 2019.

Preclinical and formulation development of Nicox’s product candidate NCX 4251, a novel, patented ophthalmic suspension of fluticasone propionate nanocrystals, is continuing on track for the Q1 2019 IND submission to the U.S FDA to enable a Phase 2 study to evaluate the safety and efficacy of NCX 4251 compared to its vehicle in patients with acute exacerbations of blepharitis. An additional and positive pre-IND meeting was held with the U.S. FDA in June 2018, which addressed specific questions on development, including the potential primary endpoints. Based on FDA feedback, we are finalizing the design of the first-in-human Phase 2 study.

Two molecules from our future generation stand-alone NO-donors that target IOP reduction, NCX 667 and NCX 1660, are currently in formulation development and testing with the Re-Vana EyeLiefTM technology under the research collaboration agreement signed in October 2017. Depending on the release profile of these molecules with this technology in preclinical animal models of ocular pharmacokinetics, they may be advanced into further development and/or we may decide to test other molecules in the same technology.
Our research activities continue both in our research collaboration agreement with Ironwood, announced in June 2018, which is focused on combining Ironwood’s expertise in soluble guanylate cyclase with our proprietary NO-donating research platform, and in our internal programs combining NO with other undisclosed pharmacological mechanisms of action. We expect to be able to announce a preclinical candidate from one of these programs in the next 18 months.

VYZULTATM (latanoprostene bunod ophthalmic solution), 0.024% is now a revenue generating asset for Nicox, following the U.S. launch in December 2017 by partner Bausch + Lomb. In March 2018, the Company announced an amendment to the global licensing agreement under which royalties paid to Nicox on worldwide net sales of VYZULTA will increase by 1% over the original royalty on net sales above $300 million per year. In addition, the potential milestone payments payable to Nicox by Bausch + Lomb have been increased by $20 million.
We expect to ship commercial product and trade samples for ZERVIATETM (cetirizine ophthalmic solution), 0.24% to our partner Eyevance by Q1 2019, which will allow Eyevance to launch ZERVIATETM in the United States in time for the 2019 spring allergy season. The shipment of product triggers a $1 million milestone payment to Nicox by Eyevance, with up to $3 million of potential future milestones payments related to certain regulatory acceptance provisions and certain near term manufacturing objectives.
H1 2018 Financial Summary
Net revenue1 for the first half of 2018 was €0.3 million, comprised exclusively of royalties on H1 2018 sales of VYZULTATM by global partner Bausch + Lomb, after deduction of royalty payments due by Nicox. The Nicox Group recorded no revenues for the first half of 2017.

The operating expenses for the first half of 2018 were consistent with the same period last year (€10.0 million for the first six months of 2018 compared to €10.2 million for the first six months of 2017).

The Nicox Group recorded a net loss of €7.6 million for the six months ended June 30, 2018, compared to a net loss of €12.2 million for the same period in 2017.

As of June 30, 2018, the Nicox Group had cash and cash equivalents of €32.7 million as compared with €36.3 million at March 31, 2018 and €41.4 million at December 31, 2017.

Reference
1. Net revenue consists of revenue from collaborations less royalty payments which corresponds to Net profit from collaborations in the condensed consolidated statements of profit or loss for the six-month periods ended June 30, 2018.

The diligences related to the half-year review were performed by the auditors. The review report will be issued once procedures will be finalized over the half-year financial report.

On September 6, 2018 Verastem, Inc. (Nasdaq:VSTM), operating as Verastem Oncology, a biopharmaceutical company focused on developing and commercializing medicines to improve the survival and quality of life of cancer patients, reported dosing of the first patient in a multicenter Phase I/II clinical trial at the Dana-Farber/Harvard Cancer Center of duvelisib in combination with venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) (Press release, Verastem, SEPT 6, 2018, View Source [SID1234529326]).

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"Duvelisib and venetoclax target different pathways fundamental to CLL biology and have distinct mechanisms of action. We have found that CLL cells from duvelisib-treated patients are primed for apoptosis in response to treatment with agents such as venetoclax. We now have the opportunity to explore whether this combination may be an effective therapy for the treatment of patients with CLL," said Matthew Davids, MD, MMSc, Assistant Professor of Medicine, Harvard Medical School, and Associate Director, Center for Chronic Lymphocytic Leukemia, Dana-Farber Cancer Institute and the study’s principal investigator. "We are excited to conduct this trial, as these new, targeted agents in development have the potential to improve patients’ response through combination therapies."

This trial will investigate venetoclax, an oral, potent, selective inhibitor of BCL-2 – a key mediator of the intrinsic pathway of apoptosis, the process of programmed cell death – given in combination with duvelisib. Preclinical data support this combination, as duvelisib has been shown to upregulate BCL-2 transcript and protein expression levels and enhance the ability of venetoclax to induce apoptosis in ex vivo human CLL cells. The trial will use BH3 profiling – a functional assay that determines the apoptotic threshold of a cell – which Davids and colleagues previously used to show that inhibition of phosphoinositide 3-kinase (PI3K) enhances the apoptotic threshold of CLL cells and sensitivity to BCL-2 inhibition.

The phase I primary objectives are to determine the maximum tolerated dose, as well as the recommended phase II dose of venetoclax for this combination regimen with duvelisib in patients with relapsed or refractory CLL/SLL. The phase II primary objective is to determine the rate of complete response (CR) of the combination, as defined by the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria.

"As we continue to explore the potential of duvelisib, we are very encouraged by the strong scientific rationale and the preclinical data supporting the combination of duvelisib and venetoclax. We expect this trial will help enhance our understanding of the effects of this combination in the treatment of patients with CLL/SLL," said Diep Le, MD, PhD, Chief Medical Officer of Verastem Oncology. "Our goal at Verastem Oncology is to bring innovative therapeutic options to patients living with cancers that are in need of additional treatment options. Given the significant unmet need that exists among patients living with CLL and SLL, we look forward to the insight generated from this trial that could inform potential future clinical development for duvelisib."

More information about this trial is available at www.clinicaltrials.gov.

About Duvelisib

Duvelisib is a first-in-class investigational oral, dual inhibitor of phosphoinositide 3-kinase (PI3K)-delta and PI3K-gamma, two enzymes known to help support the growth and survival of malignant B-cells and T-cells. PI3K signaling may lead to the proliferation of malignant B- and T-cells and is thought to play a role in the formation and maintenance of the supportive tumor microenvironment.1,2,3 Duvelisib was evaluated in late- and mid-stage extension trials, including DUO, a randomized, Phase 3 monotherapy study in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL),4 and DYNAMO, a single-arm, Phase 2 monotherapy study in patients with refractory indolent non-Hodgkin lymphoma (iNHL).5 Both DUO and DYNAMO achieved their primary endpoints. Verastem Oncology’s New Drug Application (NDA) requesting the full approval of duvelisib for the treatment of patients with relapsed or refractory CLL/SLL, and accelerated approval for the treatment of patients with relapsed or refractory follicular lymphoma (FL) was accepted for filing by the U.S. Food and Drug Administration (FDA), granted Priority Review and assigned a target action date of October 5, 2018. Duvelisib is also being developed by Verastem Oncology for the treatment of peripheral T-cell lymphoma (PTCL), and is being investigated in combination with other agents through investigator-sponsored studies.6 Information about duvelisib clinical trials can be found on www.clinicaltrials.gov.

On September 5, 2018 Loxo Oncology, Inc. (Nasdaq:LOXO), a biopharmaceutical company developing highly selective medicines for patients with genomically defined cancers, reported that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation to LOXO-292, a selective RET inhibitor, for (Press release, Loxo Oncology, SEPT 5, 2018, View Source [SID1234529287]):

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the treatment of patients with metastatic RET-fusion-positive non-small cell lung cancer who require systemic therapy and have progressed following platinum-based chemotherapy and an anti-PD-1 or anti-PD-L1 therapy; and for
the treatment of patients with RET-mutant medullary thyroid cancer who require systemic therapy, have progressed following prior treatment and have no acceptable alternative treatment options.
"We look forward to working with FDA to streamline the development of LOXO-292 in the two patient populations that have comprised the bulk of our initial clinical trial enrollment," said Josh Bilenker, M.D., chief executive officer at Loxo Oncology. "Given the many available therapies for non-small cell lung cancer and medullary thyroid cancer, we are pleased that LOXO-292 has shown encouraging data in refractory patients, and hope to demonstrate the full potential of this treatment in additional populations over time."

The LOXO-292 Breakthrough Therapy Designation was based on data from the ongoing global Phase 1/2 LIBRETTO-001 clinical trial. In 2019, the company plans to provide an update on the overall long-term LOXO-292 clinical development plan, based on feedback from global regulators.

The FDA’s Breakthrough Therapy Designation is intended to expedite the development and review of a drug candidate that is planned for use to treat a serious or life-threatening disease or condition when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.

About LOXO-292
LOXO-292 is an oral and selective investigational new drug in clinical development for the treatment of patients with cancers that harbor abnormalities in the rearranged during transfection (RET) kinase. RET fusions and mutations occur across multiple tumor types with varying frequency. LOXO-292 was designed to inhibit native RET signaling as well as anticipated acquired resistance mechanisms that could otherwise limit the activity of this therapeutic approach. LOXO-292 has been granted Breakthrough Therapy Designation by the U.S. FDA.

LOXO-292 is currently being studied in the global LIBRETTO-001 Phase 1/2 trial. For additional information about the LOXO-292 clinical trial, please refer to www.clinicaltrials.gov. Interested patients and physicians can contact the Loxo Oncology Physician and Patient RET Clinical Trial Hotline at 1-855-RET-4-292 or email [email protected].

About RET-Altered Cancers
Genomic alterations in the RET kinase, which include fusions and activating point mutations, lead to overactive RET signaling and uncontrolled cell growth. RET fusions have been identified in approximately 2% of non-small cell lung cancer, 10-20% of papillary and other thyroid cancers, and a subset of other cancers. Activating RET point mutations account for approximately 60% of medullary thyroid cancer (MTC). Both RET fusion cancers and RET-mutant MTC are primarily dependent on this single activated kinase for their proliferation and survival. This dependency, often referred to as "oncogene addiction," renders such tumors highly susceptible to small molecule inhibitors targeting RET.

On September 5, 2018 Hutchison China MediTech Limited ("Chi-Med") (AIM/Nasdaq: HCM) reported that fruquintinib capsules have been granted approval for drug registration by the National Medical Products Administration of China ("NMPA", formerly the China Food and Drug Administration) for the treatment of metastatic colorectal cancer ("CRC") patients, who have failed at least two prior systemic antineoplastic therapies including fluoropyrimidine, oxaliplatin and irinotecan, with or without prior use of anti-vascular endothelial growth factor ("VEGF") or anti-epidermal growth factor receptor ("EGFR") therapies (Press release, Hutchison China MediTech, SEP 5, 2018, View Source [SID1234529315]). Fruquintinib is a highly selective and potent small molecule oral inhibitor of vascular endothelial growth factor receptors ("VEGFR") 1, 2 and 3 designed to be a global best-in-class VEGFR inhibitor for many types of solid tumors. Fruquintinib capsules are to be marketed in China under the brand name Elunate. The approval is based on results from the Phase III FRESCO trial, which were presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2017 Meeting and published in the JAMA (Journal of the American Medical Association) in 2018 .

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"Today’s approval is a major achievement for Chi-Med," said Simon To, Chairman of Chi-Med. "Elunate is the first home-grown, China-discovered and developed drug we are aware of in an oncology indication to be unconditionally approved through a randomized clinical trial in China," he added, "This is the result of over a dozen years of steadfast commitment by Chi-Med in research and development in China’s emerging biotech ecosystem."

"We are particularly grateful to the patients, their families, investigators, nurses, caregivers and study team members who participated in the clinical development of Elunate and now look forward to making this world-class new therapy available as quickly as possible to patients with CRC in China."

In the FRESCO trial led by Dr. Jin Li and Dr. Shukui Qin, Elunate was shown to provide a statistically significant and clinically meaningful improvement in overall survival ("OS") versus placebo, with median OS of 9.3 (95% CI 8.2, 10.5) vs. 6.6 (95% CI 5.9, 8.1) months, respectively (HR=0.65, 95% CI 0.51-0.83; p<0.001), and a manageable safety profile. In addition to the significant efficacy, fruquintinib’s good kinase selectivity has been shown to limit off-target toxicity and deliver what Chi-Med assesses to be best-in-class tolerability. This allows it to be evaluated in combination with other agents such as chemotherapies, targeted therapies and immunotherapies, thereby maximizing the number of potential patients who may benefit from this novel cancer treatment.

CRC is the second most common cancer type in China,1 with about 380,000 new cases per year.2 There were approximately 1.5 million new CRC cases globally in 2015 which are expected to increase to approximately 1.7 million new cases per year by 2020, according to Frost & Sullivan.

The market launch of Elunate in China will be through collaboration with our partner Eli Lilly & Company ("Lilly"). Dr. Wang Li, Senior Vice President, Head of Lilly China Drug Development & Medical Affairs Center, said, "The approval is a testament to the overall clinical profile of Elunate and is an important step forward for our collaboration with Chi-Med." This approval also triggers an approximately US$13.6 million milestone payment to Chi-Med from Lilly.

About Elunate

Elunate is the brand name of fruquintinib capsules. Fruquintinib (HMPL-013) is a small molecule, selective and highly potent inhibitor of VEGFR 1, 2 and 3. VEGFR inhibitors play a pivotal role in tumor-related angiogenesis, cutting off the blood supply that a tumor needs to grow rapidly. The global market for anti-angiogenesis therapies was estimated at approximately US$18 billion in 2017, with both monoclonal antibodies and small molecules approved in around 30 tumor types. During the discovery research process, which began at Chi-Med in 2007, fruquintinib was successfully designed to be differentiated by improving kinase selectivity in comparison to other approved small molecule tyrosine kinase inhibitors (TKIs), to minimize off-target toxicities, improve tolerability and provide more consistent target coverage, resulting in better clinical efficacy. The superior tolerability, along with fruquintinib’s low potential for drug-drug interaction based on preclinical assessment, suggests that it may be highly suitable for innovative combinations with other anti-cancer therapies.

In October 2013, Chi-Med entered into a licensing, co-development and commercialization agreement in China with Lilly for fruquintinib. Under the terms of the agreement, the costs of development of fruquintinib, carried out by Chi-Med, are shared; Chi-Med has received upfront payments and development and regulatory approval milestone payments; and upon commercialization in China, Chi-Med would receive royalties. Chi-Med and Lilly agreed to develop fruquintinib in three initial solid tumor indications, CRC, non-small cell lung cancer ("NSCLC") and gastric cancer.

The most common adverse reactions included hypertension, hand-foot syndrome and proteinuria. Clinically effective management of these adverse effects is feasible. For important safety information about Elunate, please see www.chi-med.com.

About Fruquintinib Development in CRC in China

Clinical development of fruquintinib began in 2011 with an initial Phase I trial in 40 solid tumor patients, followed by a Phase Ib study in 62 CRC patients, and a Phase II clinical trial in 71 CRC patients. Chi-Med began enrollment in December 2014 of the FRESCO study, a Phase III pivotal registration trial of fruquintinib in 416 patients in China, and subsequently reported positive top-line results in March 2017.

In October 2016, fruquintinib was the first novel drug to be granted Market Authorization Holder ("MAH") designation under the Shanghai FDA, a new system designed to improve speed and efficiency of novel drug development in China. The New Drug Application ("NDA") for fruquintinib in CRC, that was submitted in June 2017 and awarded priority review status in September 2017, was supported by data from the successful FRESCO study. FRESCO was highlighted in an oral presentation at the ASCO (Free ASCO Whitepaper) Annual Meeting held on June 5, 2017, and then the full results were published in the JAMA on June 26, 2018. Additional details about the FRESCO study can be found at clinicaltrials.gov, using identifier NCT02314819.

Fruquintinib is only approved for use in mainland China with the approved dose in CRC being 5mg orally once per day, on a three-weeks-on / one-week-off cycle and it will be made available in the market in both 1mg and 5mg capsule packages.

About Other Fruquintinib Development Programs

Lung cancer in China: FALUCA is an ongoing randomized, double-blind, placebo-controlled, multi-center, Phase III registration study of fruquintinib treating patients with advanced non-squamous NSCLC, who have progressed after two lines of systemic chemotherapy. The trial completed enrollment of 527 patients in February 2018 (clinicaltrials.gov identifier NCT02691299) and top-line results are expected in late 2018. FALUCA was initiated following a similar Phase II clinical trial in 91 third-line NSCLC patients. Results were highlighted in an oral presentation at the 17th World Conference on Lung Cancer on December 6, 2016 (clinicaltrials.gov identifier NCT02590965).

Along with FALUCA, fruquintinib is concurrently being studied in a Phase II study in combination with Iressa (gefitinib) in patients with untreated advanced or metastatic NSCLC (clinicaltrials.gov identifier NCT02976116). Preliminary results were highlighted in an oral presentation at the 18th World Conference on Lung Cancer on October 16, 2017.

Gastric cancer in China: In October 2017, Chi-Med initiated a pivotal Phase III clinical trial of fruquintinib in combination with Taxol (paclitaxel), known as the FRUTIGA study, in approximately 500 patients with advanced gastric or gastroesophageal junction ("GEJ") adenocarcinoma who have progressed after first-line standard chemotherapy (clinicaltrials.gov identifier NCT03223376). An interim analysis on FRUTIGA, to establish proof-of-concept ("POC"), is anticipated during the first half of 2019 and if successful could trigger a POC milestone from Lilly. The FRUTIGA study followed a Phase I/II clinical trial in 34 patients with gastric cancer that demonstrated that combination therapy of fruquintinib and Taxol was generally well-tolerated with promising tumor response (clinicaltrials.gov identifier NCT02415023).

United States: In December 2017, Chi-Med initiated a multi-center, open-label, Phase I clinical study to evaluate the safety, tolerability and pharmacokinetics of fruquintinib in U.S. patients with advanced solid tumors (clinicaltrials.gov identifier NCT03251378).

On September 5, 2018 Stemline Therapeutics, Inc. (Nasdaq: STML), a clinical-stage biopharmaceutical company developing novel oncology therapeutics, reported that Ivan Bergstein, M.D., Stemline’s CEO, will present at the H.C. Wainwright 20th Annual Global Investment Conference on Wednesday, September 5, 2018 at 9:10 AM ET at the St. Regis New York Hotel (Press release, Stemline Therapeutics, SEPT 5, 2018, View Source [SID1234529288]). A live webcast of the presentation can be viewed on the company’s website at www.stemline.com.

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