On June 1, 2018 Acceleron Pharma Inc. (Nasdaq:XLRN), a leading biopharmaceutical company in the discovery and development of TGF-beta therapeutics to treat serious and rare diseases, reported updated results from the Phase 2 trials of luspatercept in patients with lower-risk myelodysplastic syndromes (MDS) at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2018 Annual Meeting in Chicago (Press release, Acceleron Pharma, JUN 4, 2018, View Source [SID1234527159]). Luspatercept is being developed as part of a global collaboration between Acceleron and Celgene.

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"The ongoing Phase 2 trials continue to provide important insights into luspatercept’s potential to deliver long-term benefit to thousands of patients with lower-risk MDS," said Habib Dable, President and Chief Executive Officer of Acceleron. "With multiple patients on treatment for more than three years, we are increasingly confident in luspatercept’s novel mechanism as an erythroid maturation agent to address a significant unmet medical need in lower-risk MDS. We look forward to sharing top-line results from the MEDALIST Phase 3 trial over the next few months."

Patients with MDS suffer from insufficient production of red blood cells, resulting in chronic anemia that can lead to debilitating fatigue, diminished quality of life and increased mortality. Because MDS-related chronic anemia often fails to respond to unapproved therapies which include erythropoiesis-stimulating agents, many patients require frequent red blood cell transfusions.

Phase 2 Results

A total of 101 patients with lower-risk MDS have been treated with luspatercept (dose levels ≥ 0.75 mg/kg) in the Phase 2 trials.

55% (55 of 101 patients) achieved a clinically meaningful erythroid improvement (IWG HI-E criteria).
44% (30 of 68 patients) with a red blood cell (RBC) transfusion burden at baseline achieved RBC transfusion independence (RBC-TI) for at least 8 weeks.
The mean duration of treatment for RBC-TI responders was 18.3 months (n=30, ongoing).
Multiple patients continue on treatment through 40 months, and continue to sustain a clinically meaningful increase in hemoglobin and reduction in transfusion burden.
Phase 2 Safety Summary

The majority of adverse events (AEs) were Grade 1 or 2. Grade 3 non-serious AEs possibly related to study drug were ascites, blood bilirubin increase, bone pain, hypertension, mucosal inflammation, platelet count increase, and transformation to AML (previously reported as a blast cell count increase). The Grade 3 non-serious AEs occurred in one patient each, with the exception of hypertension in 2 patients.

Serious AEs (SAEs) possibly related to study drug were general physical health deterioration, muscular weakness, musculoskeletal pain, and myalgia. The four SAEs occurred in three individual patients.

The ASCO (Free ASCO Whitepaper) MDS poster presentation is available under the Science page of the Company’s website at www.acceleronpharma.com.

Luspatercept is an investigational product that is not approved for any use in any country.

About the Ongoing MDS Phase 2 Trials

Data from two Phase 2 trials were presented at the 2018 ASCO (Free ASCO Whitepaper) Annual Meeting: the base study in which patients with lower-risk MDS received treatment with luspatercept for three months and the long-term extension study in which patients who completed the base study may receive treatment with luspatercept for up to an additional five years.

About Luspatercept

Luspatercept is a first-in-class erythroid maturation agent (EMA) that regulates late-stage red blood cell maturation. Acceleron and Celgene are jointly developing luspatercept as part of a global collaboration. Phase 3 clinical trials are underway to evaluate the safety and efficacy of luspatercept in patients with MDS (the MEDALIST trial) and in patients with beta-thalassemia (the BELIEVE trial). A Phase 3 trial is being planned in first-line, lower-risk, MDS patients (the COMMANDS trial). The BEYOND Phase 2 trial in non-transfusion-dependent beta-thalassemia and a Phase 2 trial in myelofibrosis are ongoing. For more information, please visit www.clinicaltrials.gov.

On June 4, 2018 HUYA Bioscience International (HUYA), the leader in accelerating global development of China’s pharmaceutical innovations, reported it is at a key stage in the company’s development of HBI-8000, HUYA’s lead novel epigenetic drug with important immunomodulatory properties (Press release, HUYA Bioscience, JUN 4, 2018, View Source [SID1234527194]). HUYA is conducting a Phase 2 trial of HBI-8000 in the US, investigating efficacy and safety in combination with nivolumab for the treatment of solid tumors. The ongoing Phase 2 study is an open label study of patients with advanced renal cell cancer, non-small cell lung cancer and melanoma.

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"We are at an important milestone in the development of HBI-8000 as we test the compound’s ability to improve the clinical benefit of checkpoint inhibitors for the treatment of solid tumors" said Dr Mireille Gillings, HUYA’s CEO and Executive Chair. "The emerging data for the combination are encouraging, leading to our ultimate goal which is to harness the demonstrated immunomodulatory properties of HBI-8000 to improve the outcome for patients treated with immunological therapies."

HBI-8000 is a member of the benzamide class of histone deacetylase (HDAC) inhibitors designed to block the catalytic pocket of Class I HDACs. Recent data show greatly expanded immunomodulatory properties which explain in greater depth the strong results now being seen in the clinic. HBI-8000 is an orally bioavailable, low-nanomolar inhibitor of cancer-associated HDAC enzymes with favorable pharmacology and safety profiles. Studies with human-derived tumor cell lines and animal tumor models have demonstrated that HBI-8000 inhibits the growth of many tumors via multiple mechanisms of action, including epigenetic regulation of tumor cell growth and apoptosis, immunomodulatory effects regulating antitumor activity, as well as repression of genes associated with drug resistance. HBI-8000 is approved in China for the treatment of peripheral T-cell lymphoma.

Dr Bob Goodenow, President, HUYA, said "We’ve targeted a significant improvement for the combination relative to nivolumab’s overall response rate, disease control rate and other clinical parameters to proceed to registration studies. Our results to date exceed expectations and clearly demonstrate the combination should be tested in a pivotal setting for the clinical benefit observed in our Phase 2 trial."

On June 4, 2018 Clovis Oncology, Inc. (NASDAQ: CLVS) reported the submission of a regulatory application to the European Medicines Agency (EMA), as part of a type II variation seeking to expand the marketing authorization for Rubraca (rucaparib) to include maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum based chemotherapy (Press release, Clovis Oncology, JUN 4, 2018, View Source [SID1234527248]).

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On May 29, 2018, Rubraca became the first PARP inhibitor licensed in the EU as a monotherapy treatment for women with recurrent ovarian cancer. It is currently indicated for adult patients with platinum sensitive, relapsed or progressive, BRCA mutated (germline and/or somatic), high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have been treated with two or more prior lines of platinum based chemotherapy, and who are unable to tolerate further platinum based chemotherapy. The Rubraca Summary of Product Characteristics is available on the European Medicines Agency website.

This submission is based on the positive results from the phase 3 ARIEL3 study, which evaluated rucaparib in the ovarian cancer maintenance treatment setting among three populations: 1) BRCA mutant (BRCAmut+) 2) HRD positive inclusive of BRCAmut+ and, 3) all patients treated in ARIEL3. ARIEL3 successfully achieved its primary endpoints, extending investigator assessed progression-free survival (PFS) versus placebo in all patients treated, regardless of BRCA status. Safety findings from the ARIEL3 trial were consistent with previous clinical trials.

Based on the timing of this submission, the company anticipates an opinion from the Committee for Medicinal Products for Human Use (CHMP) by end of 2018.

About the ARIEL3 Clinical Trial
The ARIEL3 pivotal study of rucaparib is a confirmatory randomized, double-blind study comparing the effects of rucaparib against placebo to evaluate whether rucaparib given as a maintenance treatment to platinum-sensitive ovarian cancer patients can extend the period of time for which the disease is controlled after a complete or partial response to platinum-based chemotherapy. The study enrolled 564 patients with high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer. To be eligible for the study, participants had to have received at least two prior platinum-based treatment regimens, been sensitive to the penultimate platinum regimen, and achieved a complete or partial response to their most recent platinum-based regimen. There were no genomic selection criteria for this study. Trial participants were randomized 2:1 to receive 600 milligrams of rucaparib twice daily (BID) or placebo.

About Rubraca (rucaparib)
Rucaparib is an oral, small molecule inhibitor of PARP1, PARP2 and PARP3 being developed in multiple tumor types, including ovarian, metastatic castration-resistant prostate, and bladder cancers, as monotherapy, and in combination with other anti-cancer agents. Exploratory studies in other tumor types are also underway. Clovis holds worldwide rights for rucaparib. Rucaparib is an unlicensed medical product outside of the U.S. and Europe.

Rubraca EU Authorized Use
Rucaparib is licensed for adult patients with platinum sensitive, relapsed or progressive, BRCA mutated (germline and/or somatic), high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have been treated with two or more prior lines of platinum based chemotherapy, and who are unable to tolerate further platinum based chemotherapy.
Click here to access the current Summary of Product Characteristics. Healthcare professionals should report any suspected adverse reactions via their national reporting systems.

Rubraca U.S. FDA Approved Indications and Important Safety Information
Rubraca is indicated as monotherapy for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.
Rubraca is indicated as monotherapy for the treatment of adult patients with deleterious BRCA mutation (germline and/or somatic) associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or more chemotherapies and selected for therapy based on an FDA-approved companion diagnostic for Rubraca.

Select Important Safety Information
Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) occur uncommonly in patients treated with Rubraca, and are potentially fatal adverse reactions. In approximately 1100 treated patients, MDS/AML occurred in 12 patients (1.1%), including those in long term follow-up. Of these, 5 occurred during treatment or during the 28-day safety follow-up (0.5%). The duration of Rubraca treatment prior to the diagnosis of MDS/AML ranged from 1 month to approximately 28 months. The cases were typical of secondary MDS/cancer therapy-related AML; in all cases, patients had received previous platinum-containing regimens and/or other DNA damaging agents.
Do not start Rubraca until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1).

Monitor complete blood counts for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities (> 4 weeks), interrupt Rubraca or reduce dose (see Dosage and Administration (2.2) in full Prescribing Information) and monitor blood counts weekly until recovery. If the levels have not recovered to Grade 1 or less after 4 weeks or if MDS/AML is suspected, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Rubraca.

Based on its mechanism of action and findings from animal studies, Rubraca can cause fetal harm when administered to a pregnant woman. Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Rubraca.

Most common adverse reactions in ARIEL3 (≥ 20%; Grade 1-4) were nausea (76%), fatigue/asthenia (73%), abdominal pain/distention (46%), rash (43%), dysgeusia (40%), anemia (39%), AST/ALT elevation (38%), constipation (37%), vomiting (37%), diarrhea (32%), thrombocytopenia (29%), nasopharyngitis/upper respiratory tract infection (29%), stomatitis (28%), decreased appetite (23%), and neutropenia (20%).

Most common laboratory abnormalities in ARIEL3 (≥ 25%; Grade 1-4) were increase in creatinine (98%), decrease in hemoglobin (88%), increase in cholesterol (84%), increase in alanine aminotransferase (ALT) (73%), increase in aspartate aminotransferase (AST) (61%), decrease in platelets (44%), decrease in leukocytes (44%), decrease in neutrophils (38%), increase in alkaline phosphatase (37%), and decrease in lymphocytes (29%).

Most common adverse reactions in Study 10 and ARIEL2 (≥ 20%; Grade 1-4) were nausea (77%), asthenia/fatigue (77%), vomiting (46%), anemia (44%), constipation (40%), dysgeusia (39%), decreased appetite (39%), diarrhea (34%), abdominal pain (32%), dyspnea (21%), and thrombocytopenia (21%).

Most common laboratory abnormalities in Study 10 and ARIEL2 (≥ 35%; Grade 1-4) were increase in creatinine (92%), increase in alanine aminotransferase (ALT) (74%), increase in aspartate aminotransferase (AST) (73%), decrease in hemoglobin (67%), decrease in lymphocytes (45%), increase in cholesterol (40%), decrease in platelets (39%), and decrease in absolute neutrophil count (35%).

Co-administration of rucaparib can increase the systemic exposure of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, which may increase the risk of toxicities of these drugs. Adjust dosage of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, if clinically indicated. If co-administration with warfarin (a CYP2C9 substrate) cannot be avoided, consider increasing frequency of international normalized ratio (INR) monitoring.
Because of the potential for serious adverse reactions in breast-fed children from Rubraca, advise lactating women not to breastfeed during treatment with Rubraca and for 2 weeks after the last dose.
You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Clovis Oncology, Inc. at 1-844-258-7662.
Click here for full Prescribing Information and additional Important Safety Information.

On June 4, 2018 Transgene (Paris:TNG), a biotech company that designs and develops virus-based immunotherapies against cancers and infectious diseases, and University of Leeds, reported that new clinical data1 obtained with Pexa-Vec further demonstrate anti-tumor activity after intravenous (i. v.) infusion (Press release, Transgene, JUN 4, 2018, View Source [SID1234621826]). These data were presented by Dr. Alan Anthoney (University of Leeds) in a poster presentation at the American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, June 4, in Chicago .

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These first clinical results confirm Pexa-Vec’s activation of anti-tumor immunity and targeted oncolytic activity. The key findings of the trial show:

selective expression and replication of Pexa-Vec in the tumor tissues;
induction of a robust anti-tumor immune response:
with the stimulation of an adaptive response (T cells) targeted to tumor specific antigens,
the activation of innate immune response (NK cells), and
an elevation of cytokines associated with immune stimulation;
one partial and one complete necrosis of tumors among the patients with colorectal cancer and liver metastases (pathological responses);
upregulation of PD-L1 and PD-1 signaling molecules, a finding that strongly supports the rationale for combining Pexa-Vec with anti-PD-1 inhibitors.
Dr Alan Anthoney, Consultant in Medical Oncology at Leeds Teaching Hospitals, Senior Lecturer in the Institute of Cancer & Pathology at the University of Leeds and principal investigator of the trial, said: "We are very encouraged to report that a single IV administration of Pexa-Vec displayed cytolytic activity at tumor sites, where it elicited a robust activation of tumor-antigen specific immune cells. In one patient with colorectal cancer liver metastasis a complete pathological response has been observed. These data clearly support the anti-tumor activity of Pexa-Vec. The final data from this trial will be published in an upcoming paper. Our decision to lead this clinical trial, investigating the potential of new weapons against cancers, testifies to our commitment at Leeds University and Leeds Teaching Hospitals NHS Trust to evaluate new innovative options that might improve the lives of our patients with cancer."

Maud Brandely, Chief Medical Officer of Transgene, added: "These very positive translational data confirm the targeted oncolytic activity and the potential of Pexa-Vec in advanced stages cancers. The observed upregulation of PD-1 and PD-L1 positive pathways strongly supports the rationale for combining Pexa-Vec with anti-PD-1 immunotherapies, which is the focus of an ongoing Phase 1/2 trial in the first-line treatment of liver cancer (HCC). These data are also crucial for our next generation of multifunctional oncolytic viruses based on our Invir.IOTM platform: this trial clearly shows that Vaccinia virus based immunotherapeutics can reach the tumor sites after i. v. administration, and selectively replicate within cancer cells. This neoadjuvant trial is the first clinical trial led by Transgene to readout this year. We look forward to announcing additional clinical results this year, not only with Pexa-Vec, but also on our four other clinical-stage immunotherapeutics."

About the Pexa-Vec "neo-adjuvant" trial:
This clinical study is aimed at evaluating the biological effects of pre-operative intravenous administration of Pexa-Vec prior to planned surgical resection of locally advanced/poor prognosis or metastatic cancers. This single center, open label, non-randomized trial recruited 9 patients including 8 evaluable patients (3 with metastatic melanoma and 5 with colorectal cancer metastases to the liver). They received a single intravenous dose of 1×109 pfu of Pexa-Vec, 14 days prior to planned surgery. Up to 6 blood samples were collected pre- and post- injection for each patient. Imaging was performed prior at baseline and within 7 days prior to surgery. Tumor tissue was collected at surgery for histologic and translational assessments.
University of Leeds is the sponsor of the trial that was supported by Transgene and run through the NIHR Clinical Research Facility at St James’ Hospital, Leeds.

The poster is available on Transgene’s website.

About Pexa-Vec
Pexa-Vec (JX594) is an oncolytic immunotherapeutic based on an oncolytic vaccinia virus armed with a GM-CSF gene that promotes an anti-tumor immune response. Pexa-Vec is designed to selectively target and destroy cancer cells through three different mechanisms of action: selectively destroy cancer cells through the direct lysis (breakdown) of cancer cells through viral replication, reduce the blood supply to tumors through vascular disruption, and stimulate the body’s immune response against cancer cells.
Pexa-Vec is currently being evaluated in a Phase 3 trial in hepatocellular carcinoma (HCC, liver cancer) in combination with sorafenib (current standard of care). Other trials evaluating the oncolytic virus in solid tumors are underway and expected to readout in 2018, including a Phase 2 trial in combination with nivolumab (HCC).
Transgene has exclusive rights to develop and commercialize Pexa-Vec for the treatment of solid tumors in Europe. Its partner SillaJen, Inc. is focused on developing Pexa-Vec for the North American market and has also granted exclusive development and commercial rights to Pexa-Vec in Hong Kong and The People’s Republic of China to Lee’s Pharmaceutical.

On June 4, 2018 MEI Pharma, Inc. (NASDAQ: MEIP) a pharmaceutical company focused on leveraging its extensive development and oncology expertise to identify and advance new therapies for cancer, reported that data presented at ASCO (Free ASCO Whitepaper) 2018 from a Phase 1b study of ME-401 demonstrate a 90% objective response rate in patients with relapsed or refractory follicular lymphoma (FL), chronic lymphocytic lymphoma (CLL) and small lymphocytic lymphoma (SLL) (Press release, MEI Pharma, JUN 4, 2018, View Source [SID1234527128]). Based on the data in this program, MEI anticipates progressing into a single-agent registration study later in 2018 for the treatment of adults with relapsed or refractory follicular lymphoma. ME-401 is a next-generation selective oral inhibitor of PI3K delta.

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"The clinical evidence we are accumulating from the Phase 1b study of ME-401 is very promising; the data demonstrate a 90% response rate across all patients with relapsed or refractory FL, CLL and SL, and an 86% rate in patients with relapsed or refractory follicular lymphoma," said Daniel P. Gold, Ph.D., president and chief executive officer of MEI Pharma. "There continues to be a need for effective treatment options among patients with relapsed or refractory follicular lymphoma. We therefore anticipate moving into a single-agent registration study by the end of the year"

The ME-401 ASCO (Free ASCO Whitepaper) 2018 poster can be accessed on the MEI Pharma website.

ME-401 Phase 1b Data
ME-401 is being evaluated in a Phase 1b dose escalation study in patients with relapsed or refractory FL, CLL and SLL. As of May 14, 2018, 46 patients were enrolled: 31 patients received monotherapy and 30 were evaluable for efficacy (12 patients at 60 mg, 12 patients at 120 mg and six patients at 180 mg). Based on the data, the Company determined that no further dose escalation was required. An expansion cohort of up to 30 patients with FL, CLL and SLL was added to further evaluate the safety and efficacy of ME-401 as a single agent at the 60 mg dose. An additional 15 patients are enrolled in the study arm evaluating ME-401 (60 mg) in combination with rituximab (marketed as Rituxan) in patients with various B cell malignancies.

ME-401 administered as a single-agent achieved a high response rate of 90% in all evaluable patients as well as a high rate of 86% in the group of patients with FL: