On April 20, 2016 Medivation, Inc. (NASDAQ: MDVN) reported that data from an investigator-sponsored Phase II study of enzalutamide, an androgen receptor inhibitor, was presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans (Press release, Medivation, APR 20, 2016, View Source [SID:1234511146]). Preliminary data from a 12-patient subset demonstrated that treatment with enzalutamide alone resulted in potential immune-activating properties in patients with non-metastatic castration sensitive prostate cancer. The primary objective of the study was to evaluate the effect of a short-course of enzalutamide (three months) alone or in combination with a therapeutic cancer vaccine (PROSTVAC) on prostate specific antigen kinetics four months after completing enzalutamide. Data from 12 patients treated with enzalutamide alone was presented by the study’s lead investigator Ravi Madan, M.D., Principal Investigator of the Study and Clinical Director, Genitourinary Malignancies Branch at the National Cancer Institute.

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"Existing literature already suggests that inhibition of androgen receptor signaling can potentiate the function of the thymus and improve the profile of the immune system. These new data suggest that in prostate cancer patients, enzalutamide may also enhance immune cell killing of prostate cancer cells throughout the body," said David Hung M.D., Founder, President and Chief Executive Officer of Medivation. "We are very encouraged by these new data and believe that the potential immune-activating properties of enzalutamide warrant further investigation, particularly in combination with other immunotherapy agents."

The effect of enzalutamide on peripheral immune cells was measured in 12 patients who were receiving enzalutamide alone (160 mg daily for 84 days, without androgen deprivation therapy). Measurements of CD4+ and CD8+ T cells, T-regulatory cells (Treg), B cells, conventional and plasmacytoid dendritic cells (cDC, pDC), natural killer cells (NK), natural killer T cells (NKT), and myeloid derived suppressor cells (MDSC), as well as 114 subsets related to immune cell maturation and function, were evaluated. Peripheral blood mononuclear cells were also assessed for T cell receptor excision circles (TREC) to identity recent thymic emigrants and to determine changes in global gene expression.

Results showed that treatment with enzalutamide induced several notable alterations in immune cells consistent with general immune activation. These changes occurred early following treatment, and included an increase in NK cells, decreased frequencies of MDSCs with a suppressive phenotype and decreased frequencies of both CD4+ and CD8+ T-lymphocytes expressing the immune inhibitory checkpoint molecule CTLA4. Additionally, treatment with enzalutamide increased TREC levels by more than 75% in 7 of 12 patients compared with pre-therapy levels (p=0.012). Gene expression analysis of PBMCs corroborated these findings, showing that enzalutamide increased activation of interferon-gamma signaling and related immune-activating pathways. These immune-activating activities for enzalutamide support evaluating the drug in combination with a number of immune-stimulating treatments including checkpoint inhibitors and vaccines.

Enzalutamide is being developed through a collaboration between Medivation and Astellas. Enzalutamide, which is known by the brand name XTANDI, is currently approved by the U.S. Food and Drug Administration for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

About XTANDI
XTANDI (enzalutamide) capsules is an androgen receptor inhibitor that blocks multiple steps in the androgen receptor signaling pathway within the tumor cell. In preclinical studies, enzalutamide has been shown to competitively inhibit androgen binding to androgen receptors, and inhibit androgen receptor nuclear translocation and interaction with DNA. The clinical significance of this MOA is unknown.

XTANDI is approved by the U.S. Food and Drug Administration for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

Important Safety Information
Contraindications XTANDI is not indicated for women and is contraindicated in women who are or may become pregnant. XTANDI can cause fetal harm when administered to a pregnant woman.

Warnings and Precautions
Seizure In Study 1, conducted in patients with metastatic castration-resistant prostate cancer (CRPC) who previously received docetaxel, seizure occurred in 0.9% of XTANDI patients and 0% of placebo patients. In Study 2, conducted in patients with chemotherapy-naive metastatic CRPC, seizure occurred in 0.1% of XTANDI patients and 0.1% of placebo patients. There is no clinical trial experience re-administering XTANDI to patients who experienced a seizure, and limited safety data are available in patients with predisposing factors for seizure. Study 1 excluded the use of concomitant medications that may lower threshold; Study 2 permitted the use of these medications. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity during which sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Posterior Reversible Encephalopathy Syndrome (PRES) In post approval use, there have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES.

Adverse Reactions
The most common adverse reactions ( ≥ 10%) reported from two combined clinical studies that occurred more commonly ( ≥ 2% over placebo) in XTANDI patients were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo.

In Study 1, Grade 3 and higher adverse reactions were reported among 47% of XTANDI patients and 53% of placebo patients. Discontinuations due to adverse events were reported for 16% of XTANDI patients and 18% of placebo patients. In Study 2, Grade 3-4 adverse reactions were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to adverse events were reported for 6% of both study groups.

Lab Abnormalities: Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% Grade 3-4) and 6% of placebo patients (0.5% Grade 3-4). Grade 1-4 thrombocytopenia occurred in 6% of XTANDI patients (0.3% Grade 3-4) and 5% of placebo patients (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of XTANDI patients (0.2% Grade 3-4) and 16% of placebo patients (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI patients (0.1% Grade 3-4) and 2% of placebo patients (no Grade 3-4).
Infections: In Study 1, 1% of XTANDI patients compared to 0.3% of placebo patients died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death.

Falls (including fall-related injuries), occurred in 9% of XTANDI patients and 4% of placebo patients. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients, and included non-pathologic fractures, joint injuries, and hematomas.

Hypertension occurred in 11% of XTANDI patients and 4% of placebo patients. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of all patients.
Drug Interactions

Effect of Other Drugs on XTANDI Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI. If co-administration is necessary, reduce the dose of XTANDI.

Avoid strong CYP3A4 inducers as they can decrease the plasma exposure to XTANDI. If co-administration is necessary, increase the dose of XTANDI.

Effect of XTANDI on Other Drugs Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

For Full Prescribing Information for XTANDI (enzalutamide) capsules, please visit View Source

You are encouraged to report negative side effects of prescription drugs to the FDA.
Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

On April 20, 2016 Mirna Therapeutics, Inc. (Nasdaq:MIRN), a clinical stage biopharmaceutical company developing a broad pipeline of microRNA-based oncology therapeutics, reported the presentation of new preclinical data at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans (Press release, Mirna Therapeutics, APR 20, 2016, View Source [SID:1234511166]). Researchers reported results in two poster presentations from experiments demonstrating that the Company’s lead microRNA therapeutic, MRX34 (miR-34), is synergistic with widely used cancer chemotherapies and next-generation tyrosine kinase inhibitors (TKIs).

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"These in vitro data suggest that MRX34 has strong potential in combination with other cancer drugs," commented Miguel Barbosa, Ph.D., Mirna’s Chief Scientific Officer. "The ability of miR-34 to control multiple oncogenic pathways may overcome both primary and acquired resistance when used in combination with chemotherapy or TKIs."

In a poster (#4829) entitled, "miRNA Combination Therapy: in vitro Anticancer Synergy Between miR-34a Mimic and Cytotoxic Chemotherapy (CT) in NSCLC," researchers from Mirna and the University of Texas Health Science Center at San Antonio reported:

Synergistic anticancer effects were observed between miR-34a and platinum and other commonly used cytotoxic chemotherapy drugs, across a range of non-small cell lung cancer (NSCLC) cell lines with varying degrees of resistance.
The synergy observed suggests the potential for lower, less toxic doses of chemotherapy than currently used in the clinic when in combination with miR-34a.
In a second poster (#4814) entitled, "MicroRNA (miRNA) Combination Therapy: in vitro Anticancer Synergy Between miR-34a Mimic and Next Generation EGFR Tyrosine Kinase Inhibitors (TKIs) in NSCLC," researchers from Mirna reported:

Synergistic anticancer effects were shown between miR-34a and next-generation EGFR TKIs afatinib and rociletinib against a range of wild-type and mutant NSCLC cell lines. These results extend similar findings with the first-generation EGFR TKI erlotinib (Zhao et al, PLoS ONE 9(2):e89105).
Results support the potential of MRX34 and EGFR TKI combinations to overcome both primary and acquired resistance to EGFR TKIs in patients with NSCLC.
Mirna is a grant recipient of the Cancer Prevention Research Institute of Texas (CPRIT) for preclinical and clinical testing of microRNA and targeted drug combination therapies, and also of the National Institutes of Health (NIH) for the study of combination molecular therapies for lung cancer, as well as miRNAs in combination with standard of care chemotherapy.

The posters may be accessed from the Events & Presentations section of the Company’s website.

The accumulation of unfolded protein in the endoplasmic reticulum (ER) initiates an unfolded protein response (UPR) via three signal transduction cascades, which involve protein kinase RNA-like ER kinase (PERK), inositol requiring enzyme-1α (IRE1α) and activating transcription factor-6α (ATF6α). An ER stress response is observed in nearly all physiologies related to acute and chronic liver disease and therapeutic targeting of the mechanisms implicated in UPR signaling have attracted considerable attention. This review focuses on the correlation between ER stress and liver disease and the possible targets which may drive the potential for novel therapeutic intervention. We describe pathways which are involved in UPR signaling and their potential correlation with various liver diseases and underlying mechanisms which may present opportunities for novel therapeutic strategies are discussed.

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On April 20, 2016 RedHill Biopharma Ltd. (NASDAQ:RDHL) (TASE:RDHL) ("RedHill" or the "Company"), a biopharmaceutical company primarily focused on development and commercialization of late clinical-stage, proprietary, orally-administered, small molecule drugs for inflammatory and gastrointestinal diseases, including cancer, reported its financial results for the quarter ended March 31, 2016 (Press release, RedHill Biopharma, APR 20, 2016, View Source [SID:1234511125]).

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Financial highlights for the quarter ended March 31, 2016:

Research and Development Expenses in the first quarter of 2016 were approximately $4.7 million, an increase of approximately $0.9 million, compared to approximately $3.8 million in the first quarter of 2015. The increase resulted primarily from clinical trial costs related to the ongoing Phase III MAP US clinical study with RHB-104 (Crohn’s disease) and the preparations for several Phase II studies with YELIVA for multiple oncology, inflammatory and gastrointestinal indications.

General and Administrative Expenses in the first quarter of 2016 were approximately $1.2 million, an increase of approximately $0.3 million, compared to approximately $0.9 million in the first quarter of 2015. The increase was mainly due to professional fees associated with business development activities, intellectual property costs and share-based compensation costs.

Operating Loss in the first quarter of 2016 was approximately $5.9 million, an increase of approximately $1.1 million, compared to approximately $4.8 million in the first quarter of 2015. The increase was mainly in Research and Development Expenses and General and Administrative Expenses.

Net Cash Used in Operating Activities in the first quarter of 2016 was approximately $5.0 million, an increase of approximately $1.6 million, compared to approximately $3.4 million in the first quarter of 2015. The increase was mainly a result of an increase in research and development activities.

Net Cash Used in Investment Activities in the first quarter of 2016 was approximately $4.6 million, a decrease of approximately $2.5 million, compared to approximately $7.1 million in the first quarter of 2015. The decrease was mainly in bank deposit investments.

Cash Provided by Financing Activities in the first quarter of 2016 was immaterial, compared to approximately $13.2 million in the first quarter of 2015, resulting from a public offering in February 2015 in the U.S.

Cash Balance1 as of March 31, 2016 was approximately $53.4 million, a decrease of approximately $5 million, compared to approximately $58.4 million as of December 31, 2015. The decrease was a result of the ongoing operations, mainly related to research and development activities.

Micha Ben Chorin, RedHill’s CFO, said: "We made significant progress with our advanced clinical programs during the first quarter of 2016 and are excited about the potential milestones expected during the second half of 2016, including the interim DSMB analysis of the RHB-104 Phase III MAP US study for Crohn’s disease, top-line results from the BEKINDA Phase III GUARD study for gastroenteritis and the initiation of a confirmatory Phase III study with RHB-105 for the treatment of H. pylori infection. With a strong cash position of approximately $53 million at the end of the first quarter, we are well-positioned to execute our strategic and operational plans for 2016."

Recent operational highlights:

On February 8, 2016, RedHill announced a research collaboration with Leipzig-based Fraunhofer Institute for Cell Therapy and Immunology (IZI), a research unit of the Fraunhofer Society, one of the largest and most prominent applied research organizations in the world, for the evaluation of RedHill’s Phase II-stage oncology drug candidate, RP101. The research collaboration tests RP101 in pre-clinical oncology models, including pancreatic cancer, in combination with standard-of-care chemotherapies to support existing Phase I and Phase II clinical data. Results from the studies are expected during the second quarter of 2016.

On February 10, 2016, RedHill announced that it had received a Notice of Allowance from the United States Patent and Trademark Office (USPTO) for a new patent covering RHB-104. The patent, entitled "Compositions Comprising Rifabutin, Clarithromycin, and Clofazamine and Uses Therof" has since been issued and is valid through 2029. RedHill currently holds five U.S. patents and multiple international patents for RHB-104.

On March 1, 2016, RedHill announced that it had completed enrollment of over half of the planned 270 patients in the Phase III MAP US study for Crohn’s disease in the U.S. and additional countries. Interim DSMB analysis of the study is expected in the second half of 2016.

On March 10, 2016, RedHill announced the publication of an article evaluating the therapeutic potential of YELIVA (ABC294640), the Company’s orally-administered first-in-class Sphingosine kinase-2 (SK2) selective inhibitor, for the treatment of cholangiocarcinoma (bile duct cancer). The article, describing non-clinical studies conducted with YELIVA, was authored by scientists from the Mayo Clinic Cancer Center, the Hollings Cancer Center at the Medical University of South Carolina and Apogee Biotechnology Corporation. The authors concluded that these findings provide preliminary insight into the possible use of YELIVA as an anticancer drug for cholangiocarcinoma treatment, as well as novel evidence that SK2 may be a rational therapeutic target in the treatment of this cancer.

On March 29, 2016, RedHill and its co-development partner for RIZAPORT, IntelGenx Corp., announced that they had entered into a binding term sheet with Grupo JUSTE S.A.Q.F ("Grupo JUSTE") granting Grupo JUSTE the exclusive license to commercialize RIZAPORT in Spain and a right of first refusal for additional territories. Under the term sheet, subject to remaining conditions, a definitive agreement is planned to be entered into within 60 days of the execution of the term sheet. Under the term sheet, RedHill and IntelGenx Corp. will receive an upfront payment and will be eligible to receive additional milestone payments upon achievement of certain predefined regulatory and commercial targets, as well as tiered royalties. Commercial launch in Spain is estimated to take place in the second half of 2017. RedHill also reported that a new U.S. formulation patent covering RIZAPORT was issued by the USPTO on April 5, 2016. The patent is valid until 2034.

On March 31, 2016, RedHill announced encouraging top-line interim results from its ongoing CEASE-MS Phase IIa proof-of-concept (PoC) clinical study evaluating fixed oral dose RHB-104 in patients treated for relapsing-remitting multiple sclerosis (RRMS). The ongoing CEASE-MS, single-arm, open-label study was designed with a series of exploratory endpoints to evaluate the safety and potential efficacy of fixed oral dose RHB-104 as an add-on therapy to interferon beta-1a in 18 patients treated for RRMS. Interim results after completion of the 24-week treatment period of the study demonstrated positive safety and clinical signals and support further clinical development based on encouraging preliminary data. Additional data reads are due at week 48 following a 24-week follow-up treatment period with interferon beta-1a, without RHB-104 add-on. The top-line interim results demonstrated an annualized relapse rate (ARR) at 24 weeks of 0.288 in the modified intent-to-treat (mITT) population and 0.0 in the per-protocol (PP) population, comparing favorably with previously reported pivotal studies of interferon beta-1a therapies Avonex (0.67)[2] and Rebif (0.87-0.91)[3]. 88% of the mITT patient population and 100% of the PP patient population were relapse free at 24 weeks, comparing favorably with previously reported pivotal data on the use of Rebif (75%) in comparison with Avonex (63%) as standalone first line therapies[4]; No patients in the CEASE-MS study relapsed after week 8 of treatment. With only a single active T1 post gadolinium lesion noted among all patients followed, combined unique active lesions (CUAs) – the primary outcome measure in the study – were almost entirely MRI T2 lesions; Although not powered for efficacy, a reduction in total MRI T2 lesion volume was observed at 24 weeks as compared to baseline, suggesting a decreased burden of disease and comparing favorably with previously reported Avonex[5] and Rebif[6] data.

On April 11, 2016, RedHill announced that it had initiated a randomized, double-blind, placebo-controlled, 2-arm parallel group Phase II clinical study in the U.S. evaluating the safety and efficacy of BEKINDA 12 mg in patients with diarrhea-predominant irritable bowel syndrome (IBS-D). The study is expected to be conducted in 12 clinical sites in the U.S. and to enroll 120 patients who will be randomized 60:40 to receive either BEKINDA 12 mg or a placebo, once daily, for a period of eight weeks. The primary endpoint for the study is the proportion of patients in each treatment group with response in stool consistency as compared to baseline, per FDA guidance definition. Secondary endpoints include the proportion of patients in each treatment group who are pain responders and the proportion of patients in each treatment group who are responders to the combined endpoints of stool consistency and pain, per FDA guidance definition.

On April 18, 2016, RedHill announced that it had concluded a positive Type B Meeting with the U.S. Food and Drug Administration (FDA) regarding the path to marketing approval of RHB-105 and the planned confirmatory Phase III study for the treatment of H. pylori infection. The FDA confirmed, subject to final minutes of the meeting, the planned two-arm, randomized, double-blind, active comparator design of the confirmatory Phase III study with RHB-105 for the treatment of H. pylori infection, expected to be initiated in the second half of 2016. Based on FDA feedback, and subject to successful completion, the planned confirmatory Phase III study, along with the successfully completed first Phase III study and data from a supportive PK program, are expected to support a U.S. New Drug Application (NDA) for RHB-105. The announcement followed the successful final results from the first Phase III clinical study with RHB-105 for the eradication of H. pylori (the ERADICATE Hp study) reported on March 8, 2016. The Phase III Clinical Study Report (CSR) confirmed the positive top-line results. The study successfully met its primary endpoint of superiority over historical standard-of-care (SoC) eradication rate levels of 70%, with high statistical significance (p < 0.001). The final results demonstrated 89.4% efficacy in eradicating H. pylori infection with RHB-105. RHB-105 has been granted Qualifying Infectious Disease Product (QIDP) designation by the FDA, providing a Fast-Track development pathway, as well as Priority Review status, potentially leading to a shorter review time by the FDA of a NDA, if filed. If approved, RHB-105 will also receive an additional five years of U.S. market exclusivity, in addition to the standard exclusivity period, for a total of 8 years of market exclusivity.

On April 20, 2016 MEI Pharma, Inc. (Nasdaq: MEIP), an oncology company focused on the clinical development of novel therapies for cancer, announced new clinical data from a first-in-human study of MEI Pharma’s investigational drug candidate, ME-401, a next generation oral PI3K delta inhibitor (Press release, MEI Pharma, APR 20, 2016, View Source [SID:1234511147]). The data, presented today at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, suggest that ME-401 has an excellent pharmacokinetic (PK) and pharmacodynamic (PD) profile and the potential for an improved therapeutic window compared to other PI3K delta inhibitors, including the approved drug idelalisib (marketed as Zydelig), with a half-life that supports once-daily dosing.

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A copy of the poster presentation, entitled, "Clinical Pharmacokinetics and Pharmacodynamics of ME-401, an Oral, Potent, and Selective Inhibitor of Phosphatidylinositol 3-Kinase P110δ, Following Single Ascending Administration to Healthy Volunteers," is now available at www.meipharma.com.

"PI3K delta is a class of drugs that has shown great promise in the treatment of B-cell malignancies, but with certain toxicities," said Daniel P. Gold, Ph.D., President and Chief Executive Officer of MEI Pharma. "We believe this provides an opportunity for a next-generation drug that can produce therapeutic responses at a safe, effective dose. Thus far, ME-401 has demonstrated all of the attributes we had hoped to see, including linear PK and on-target activity at very low concentrations. Now the goal of our upcoming Phase Ib study will be to show a large therapeutic window in cancer patients. We expect to dose the first patient in this study by the end of June and look forward to providing an update later this year."

The Phase I study was designed to assess the safety and tolerability of ME-401 after single ascending oral doses in healthy volunteers to select the most appropriate dose for further clinical evaluation. The open label study enrolled a total of 15 healthy volunteers in 10, 30, 60, 90 and 150 mg dose levels. ME-401 was well tolerated at all dose levels. One subject experienced two treatment-emergent adverse events that were considered drug-related: pain and headache, graded as mild, after a 60 mg dose.

The first-in-human study of ME-401 was conducted using Quotient Clinical’s Translational Pharmaceutics platform, which collected PK PD data immediately after each dose and allowed for real-time decision making and manufacturing between dose groups.

About ME-401

ME-401 (formerly PWT143) is an orally bioavailable, potent and selective inhibitor of phosphatidylinositol 3 kinase (PI3K) delta, a molecular target that has been shown to play a critical role in the proliferation and survival of certain hematologic cancer cells. ME-401 has a distinct chemical structure from other PI3K delta inhibitors, including idelalisib. Data presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December 2012 demonstrated that ME-401 has superior pre-clinical activity compared to idelalisib. In March 2015, the U.S. Food and Drug Administration approved an Investigational New Drug application for ME-401 in B-cell malignancies. MEI Pharma expects to initiate a Phase Ib dose-escalation study of ME-401 in patients with relapsed refractory chronic lymphocytic leukemia (CLL) or follicular non-Hodgkin’s lymphoma (fNHL) in June 2016. The study is expected to enroll 42-84 patients at approximately 10 sites, with a starting dose of 60 mg.