On October 31, 2017 AstraZeneca and its haematology research and development centre of excellence, Acerta Pharma, reported that the US Food and Drug Administration (FDA) has granted accelerated approval to Calquence (acalabrutinib) (Press release, AstraZeneca, OCT 31, 2017, View Source [SID1234521359]). Calquence is a kinase inhibitor indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.1

Calquence is approved under the FDA’s accelerated approval pathway, based on overall response rate, which allows for earlier approval of medicines that treat serious conditions and that fill an unmet medical need based on a surrogate endpoint.2 Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.1

Pascal Soriot, Chief Executive Officer of AstraZeneca, said: “The accelerated approval of Calquence is a landmark moment for our company. It provides an exciting new treatment option for patients with mantle cell lymphoma and marks the first approval of a medicine that will be the cornerstone of our presence in haematology. Furthermore, today’s approval demonstrates our commitment to scientific leadership in Oncology and reinforces our progress towards returning to growth.”

Michael L. Wang, MD, Professor, Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, and Principal Investigator of the ACE-LY-004 MCL clinical trial, said: “The acalabrutinib approval represents an important development for patients currently battling mantle cell lymphoma, an aggressive type of blood cancer that is typically diagnosed at an advanced stage and associated with a high relapse rate. In addition to the overall response rate, the high complete response rate of 40% seen in this trial illustrates the potential of acalabrutinib to help patients achieve a deep response.”

Summary of key efficacy results as assessed by Independent Review Committee (IRC) from the ACE-LY-004 trial,1 a Phase II open-label, single-arm clinical trial in 124 adult patients with relapsed or refractory MCL:

Efficacy Measure
Result
Overall Response Rate
80%
(95% CI: 72, 87)
Complete Response
40%
(95% CI: 31, 49)
Partial Response
40%
(95% CI: 32, 50)
Per Lugano classification, CI = Confidence interval

In the ACE-LY-004 trial, the most common adverse reactions (≥20%) of any grade were anaemia (46%), thrombocytopoenia (44%), headache (39%), neutropoenia (36%), diarrhoea (31%), fatigue (28%), myalgia (21%) and bruising (21%). Haematological events were based on laboratory measurements and adverse reactions.1

Dosage reductions or discontinuation due to any adverse reaction were reported in 1.6% and 6.5% of patients, respectively.1 Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 4.8% of patients.1

These data demonstrate the potential impact that Calquence could have on the management of previously-treated MCL. Calquence is not approved for use outside this labelled indication in the US.

Meghan Gutierrez, Chief Executive Officer, Lymphoma Research Foundation, said: “Relapse is common in mantle cell lymphoma patients and represents disease progression.3 When patients learn there is a new treatment option available for their disease, it brings great hope and an opportunity to participate in shared decision making with their healthcare team.”

Full results from the ACE-LY-004 clinical trial have been submitted for presentation at a forthcoming medical meeting. This will be the first MCL trial data to be presented from the Calquence development programme, which includes both monotherapy and combination therapies in a broad range of blood cancers and solid tumours. Calquence is also being evaluated in combination with bendamustine and rituximab as a potential 1st-line treatment for patients with MCL in the Phase III ACE-LY-308 clinical trial.4

NOTES TO EDITORS

About Calquence

Calquence (acalabrutinib; previously known as ACP-196) is a selective inhibitor of BTK. Calquence binds covalently to BTK, thereby inhibiting its activity, and has demonstrated this with minimal interactions with other immune cells in pre-clinical studies.1,5,6 In B cells, BTK signalling results in activation of pathways necessary for B cell proliferation, trafficking, chemotaxis and adhesion.1

The recommended dose of Calquence is one 100mg capsule taken orally approximately every twelve hours until disease progression or unacceptable toxicity.1 Calquence may be taken with or without food.1

Calquence is also in development for the treatment of multiple B-cell malignancies and other cancers including chronic lymphocytic leukaemia (CLL), MCL, Waldenström macroglobulinaemia (WM), follicular lymphoma, diffuse large B-cell lymphoma, and multiple myeloma. It is also being studied as a monotherapy and in combination trials for solid tumours. More than 35 clinical trials across 40 countries with more than 2,500 patients are underway or have been completed.7

Calquence was granted Orphan Drug Designation by the US FDA for the treatment of adult patients with MCL in September 2015 and by the European Commission in March 2016 for the treatment of adult patients with CLL, MCL and WM. Calquence was granted Breakthrough Therapy Designation by the FDA in August 2017 for the treatment of adult patients with MCL who have received at least one prior therapy.

About Mantle Cell Lymphoma (MCL)

MCL is an aggressive B-cell non-Hodgkin lymphoma (NHL) with poor prognosis.8,9,10,11 MCL accounts for approximately 3% to 6% of new NHL cases in Western countries each year; in the US, approximately 3,300 new cases of MCL are diagnosed each year.9,13 The median age at diagnosis is 68 years, with a 3:1 male predominance.10 While MCL patients initially respond to treatment, there is a high relapse rate.9

About the ACE-LY-004 trial

ACE-LY-004 is a Phase II open-label, single-arm clinical trial in 124 adult patients with relapsed or refractory MCL. The trial showed that 80% (95% CI: 72, 87) of patients treated with Calquence achieved an overall response; 40% (95% CI: 31, 49) achieved a complete response and 40% (95% CI: 32, 50) achieved a partial response per 2014 Lugano classification as assessed by Independent Review Committee.1

About Acerta Pharma

Acerta Pharma, a member of the AstraZeneca Group, is creating novel therapies intended for the treatment of cancer and autoimmune diseases. AstraZeneca acquired a majority stake interest in Acerta Pharma, which serves as AstraZeneca’s haematology research and development centre of excellence. For more information, please visit www.acerta-pharma.com.

About AstraZeneca in Oncology

AstraZeneca has a deep-rooted heritage in Oncology and offers a quickly-growing portfolio of new medicines that have the potential to transform patients’ lives and the Company’s future. With at least six new medicines to be launched between 2014 and 2020 and a broad pipeline of small molecules and biologics in development, we are committed to advance New Oncology as one of AstraZeneca’s five Growth Platforms focused on lung, ovarian, breast and blood cancers. In addition to our core capabilities, we actively pursue innovative partnerships and investments that accelerate the delivery of our strategy as illustrated by our investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.

On October 31, 2017 Siamab Therapeutics, Inc., a biopharmaceutical company developing novel cancer immunotherapies, reported the presentation of new preclinical data demonstrating the safety of its novel anti-Sialyl-Tn (STn) antibody drug conjugates (ADCs) in multiple animal models, including non-human primates (NHPs) (Press release, Siamab Therapeutics, OCT 31, 2017, View Source [SID1234521355]). These results add to the company’s efficacy data findings showing that its anti-STn antibody therapeutics inhibit tumor progression in cell-line-derived and patient-derived xenograft (PDX) ovarian cancer and pancreatic cancer mouse models, with complete regression observed in some treatment arms. The preclinical efficacy and safety data were presented in a poster presentation at the 2017 AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper), held October 26-30, 2017, in Philadelphia.

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Siamab’s platform enables the development of highly specific monoclonal antibody (mAb) therapeutics that target cancer cell surface glycans called tumor-associated carbohydrate antigens (TACAs), a novel class of cancer-specific antigens. TACAs are implicated in immune suppression, chemoresistance, and a cancer stem cell (CSC) phenotype.

“Our lead ST1 program shows compelling efficacy and safety across a range of PDX and xenograft studies, underscoring the promise of our anti-STn antibody approach to treat chemoresistant solid tumors,” said Jeff Behrens, president and chief executive officer of Siamab. “The new data from a pilot pharmacokinetic/toxicity study in primates demonstrate the favorable safety and tolerability of ST1 in large animals. The NHP results are extremely encouraging and provide an important step to de-risk IND-enabling GLP toxicity studies, which we plan to initiate in 2018.”

The poster presentation, titled “Humanized anti-Sialyl-Tn monoclonal antibody-drug conjugates (ADCs) inhibit tumor growth in vitro and in vivo,” was presented during the Therapeutic Agents: Biological poster session. In the poster, Siamab scientists and collaborators reported data demonstrating anti-tumor effect in vitro utilizing humanized anti-STn ADCs as well as inhibition of tumor progression in vivo in both cell line and PDX ovarian cancer models with complete regressions observed in some treatment groups. No significant weight loss was observed for any of the treatment groups in these models indicating the therapy was well tolerated by all the groups. In addition, the poster featured new safety data demonstrating Siamab’s anti-STn ADC has an excellent safety profile through the completion of a non-GLP pilot pharmacokinetic/toxicity study in non-human primates. Two doses were administered at days 1 and 22. Dose levels were 1mg/kg, 3mg/kg, and 6mg/kg. No weight loss or deaths occurred in the study and no gross pathology changes were observed in all organs examined. All clinical chemistry results (liver, kidney function, etc.) were normal throughout the study.

ST1, Siamab’s lead antibody program targeting STn, is in late stage preclinical development for the treatment of solid tumors. The elevated presence of STn—a key TACA observed in a number of solid tumors, including ovarian, prostate, pancreatic, gastric, and colon—is associated with metastatic disease, poor prognosis, and reduced overall survival. Elevation of STn expression is linked to chemotherapy resistance and enables tumors to evade the host immune system. Siamab has also identified the presence of STn on myeloid-derived suppressor cells (MDSCs), which are major regulators of immune response in cancer and influence the tumor microenvironment by suppressing T cells. STn is a major reported constituent of two established CSC biomarkers, CD44 and MUC1, which reside on both CSCs and mature malignant cells in some cancer types.

Siamab is utilizing STn-selective antibodies to develop both tissue- and serum-based biomarker assays with the potential to become companion diagnostics for both the stratification of patients as well as tools for assessing the pharmacodynamic action of the anti-STn therapeutic in the clinic.

Siamab recently announced it has entered into a strategic discovery collaboration with Boehringer Ingelheim with the goal of developing anti-cancer therapeutics targeting TACAs. Siamab will apply its proprietary technology platform to generate TACA-specific antibodies for use in multiple solid tumor applications. Financial terms of the agreement were not disclosed.

On October 31, 2017 Halozyme Therapeutics, Inc. (NASDAQ: HALO), a biotechnology company developing novel oncology and drug-delivery therapies, reported that Janssen Biotech, Inc. has initiated the first of three planned Phase 3 clinical trials evaluating a subcutaneous (SC) delivery of Darzalex (daratumumab) with Halozyme’s proprietary ENHANZE technology (Press release, Halozyme, OCT 31, 2017, View Source [SID1234521351]).

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The initial Phase 3 study is in amyloidosis patients, with additional Phase 3 studies in multiple myeloma and smoldering myeloma patients planned for near-term initiation.

The subcutaneous formulation of daratumumab has an estimated administration time of approximately 5 minutes compared to the multi-hour intravenous infusion, potentially offering new benefits to patients, caregivers and health systems. Halozyme’s ENHANZE technology enables the administration of medications with an injection under the skin rather than an infusion into a vein.

“Our goal has been to make the injection of life saving medicines less disruptive to patients using Halozyme’s ENHANZE technology,” said Dr. Helen Torley, president and CEO of Halozyme. “These studies aim to demonstrate the transformative potential of ENHANZE when combined with Darzalex.”

The Phase 3 study follows a Phase 1b clinical trial that demonstrated the safety, pharmacokinetics and anti-tumor activity of the subcutaneous formulation in relapsed or refractory multiple myeloma patients.

Halozyme will receive a $15 million milestone payment from Janssen following dosing of the third patient in a Phase 3 trial.

Darzalex is a human monoclonal antibody that targets CD38 on the surface of cells and is in clinical development by Janssen in a range of cancers and immune diseases.

Halozyme Collaboration with Janssen Biotech, Inc.
In December 2014, Halozyme and Janssen entered into a collaboration and license agreement. Under the terms of the agreement, Halozyme has granted Janssen a worldwide license to develop and commercialize products for up to five targets, combining rHuPH20 with Janssen’s proprietary compounds. CD38, which is targeted by daratumumab, is the first of these five targets. Halozyme is eligible to receive payments upon Janssen’s achievement of specified development, regulatory and sales-based milestones, totaling up to $113 million per target. Halozyme is also entitled to royalty payments based on net sales of products using the ENHANZE technology.

About ENHANZE Technology
Halozyme’s proprietary ENHANZE drug-delivery technology is based on its patented recombinant human hyaluronidase enzyme (rHuPH20). rHuPH20 has been shown to remove traditional limitations on the volume of biologics that can be delivered subcutaneously (just under the skin). By using rHuPH20, some biologics and compounds that are administered intravenously may instead be delivered subcutaneously. ENHANZE may also benefit subcutaneous biologics by reducing the need for multiple injections. This delivery has been shown in studies to reduce health care practitioner time required for administration and shorten time for drug administration.

On October 31, 2017 Geron Corporation (Nasdaq:GERN) reported that the United States Food and Drug Administration (FDA) has granted Fast Track designation to imetelstat for the potential treatment of adult patients with transfusion-dependent anemia due to Low or Intermediate-1 risk myelodysplastic syndromes (MDS) who are non-del(5q) and who are refractory or resistant to treatment with an erythropoiesis stimulating agent (ESA) (Press release, Geron, OCT 31, 2017, View Source [SID1234521343]). Imetelstat is a telomerase inhibitor initially developed by Geron and exclusively licensed to Janssen Biotech, Inc. (Janssen) on a worldwide basis. Janssen sponsored the application for Fast Track designation utilizing preliminary data from IMerge, the ongoing clinical trial being conducted by Janssen in lower risk MDS.

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The FDA’s Fast Track Program is designed to facilitate the development and expedite the review of new drugs that are intended to treat serious conditions and supported by data that demonstrate the potential to address an unmet medical need. Fast Track designation provides opportunities for frequent interactions with FDA review staff, including meetings to discuss the drug’s development plan and to ensure the collection of appropriate data needed to support approval. Through the Fast Track Program, a product candidate may be eligible for priority review, if supported by the clinical data, and for the ability to submit completed sections of a New Drug Application (NDA) on a rolling basis as data become available prior to completion of the full application.

Imetelstat Clinical Development in MDS

Imetelstat is being evaluated in an ongoing Phase 2/3 clinical trial (IMerge) in transfusion dependent patients with Low or Intermediate-1 risk MDS who have relapsed after or are refractory to prior treatment with an ESA. IMerge is designed in two parts: Part 1 is a Phase 2, open-label, single-arm design and Part 2 is designed to be a Phase 3, randomized, controlled trial.

As previously announced, 32 patients were enrolled in Part 1 of IMerge, of which a subset of 13 patients had not received prior treatment with either a hypomethylating agent (HMA) or lenalidomide and did not have a del(5q) chromosomal abnormality. As of May 2017, the 13-patient subset showed an increased durability and rate of red blood cell (RBC) transfusion independence (TI) compared to the overall trial population (≥8-week RBC-TI: 53.8% vs 34.4%). Based on these data, Part 1 is being expanded to enroll approximately 20 additional patients who are non-del(5q) and naïve to HMA and lenalidomide treatment to increase the experience and confirm the benefit-risk profile of imetelstat in this refined target patient population. Janssen has opened the expanded Part 1 for patient enrollment. For more information about IMerge, please visit View Source

Results for the original 32 patients in Part 1 of IMerge, including hematologic improvement and rate of RBC-TI lasting at least 24 weeks, as well as duration of response and safety information, are expected to be presented at an upcoming major medical conference.

About Imetelstat

Imetelstat (GRN163L; JNJ-63935937) is a potent and specific inhibitor of telomerase that is administered by intravenous infusion. This first-in-class compound, discovered by Geron, is a specially designed and modified short oligonucleotide, which targets and binds directly with high affinity to the active site of telomerase. Preliminary clinical data suggest imetelstat might have disease-modifying activity by inhibiting the progenitor cells of the malignant clones associated with hematologic malignancies in a relatively select manner. Most commonly reported adverse events in imetelstat clinical studies include fatigue, gastrointestinal symptoms and cytopenias. Imetelstat has not been approved for marketing by any regulatory authority.

About the Collaboration with Janssen

On November 13, 2014, Geron entered into an exclusive worldwide license and collaboration agreement with Janssen Biotech, Inc., to develop and commercialize imetelstat for oncology, including hematologic myeloid malignancies, and all other human therapeutics uses. Under the terms of the agreement, Geron received an upfront payment of $35 million and is eligible to receive additional payments up to a potential total of $900 million for the achievement of development, regulatory and commercial milestones, as well as royalties on worldwide net sales. All regulatory, development, manufacturing and promotional activities related to imetelstat are being managed through a joint governance structure, with Janssen responsible for these activities.

On October 31, 2017 Minneapolis-based Humanetics Corporation (Humanetics) reported data at the annual meetings of the American Society for Radiation Oncology (ASTRO) and the Radiation Research Society (RRS) (Press release, Humanetics, OCT 31, 2017, View Source [SID1234521342]). The annual ASTRO meeting was held September 24th through the 27th in San Diego, California and the annual RRS meeting was held October 15th through the 18th in Cancun, Mexico. Dr. Zeljko Vujaskovic, M.D., Ph.D., a professor of radiation oncology at the University of Maryland School of Medicine (UMSOM) and director of the school’s Division of Translational Radiation Sciences, and Michael Kaytor, Ph.D., vice president of research and development at Humanetics, respectively, presented data related to Humanetics’s new drug candidate, BIO 300, which is being evaluated as a potential treatment to prevent erectile dysfunction in patients undergoing radiotherapy for prostate cancer.

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Prostate cancer is the most common non-skin cancer affecting men in the U.S. According to the National Cancer Institute (NCI), nearly 162,000 men will be diagnosed with prostate cancer in the U.S. in 2017, representing approximately 20% of all new cancers in men. While survival rates are high, radiation-induced erectile dysfunction (ED) is a common and lingering side effect associated with prostate radiotherapy. Nearly half of all men undergoing radiation treatment for prostate cancer will experience some level of ED.

Data presented included the results of nonclinical studies that were conducted at UMSOM. These studies demonstrated the potential of BIO 300 to both mitigate radiation-induced ED and also to improve the effectiveness of radiation therapy to kill tumors. “These compelling results show the promise of BIO 300 to enhance a prostate cancer patient’s quality of life, while also directly impacting the ability of radiation therapy to kill the tumor,” said Dr. Vujaskovic. “If this result can be translated to the clinical treatment of prostate cancer, it would represent a breakthrough in prostate cancer treatment outcomes.”

At present, there are no FDA-approved drugs to mitigate radiation-induced ED. “BIO 300’s potential to enhance radiation’s killing effect on the tumor while reducing treatment-related side effects is unparalleled,” said Dr. Kaytor. “These findings support the advancement of BIO 300 into a human efficacy study, which is anticipated to begin in 2018.”

BIO 300 is in development for prevention and mitigation of toxicities associated with radiation exposure for the treatment of multiple cancers and is currently in a Phase Ib/IIa clinical trial in patients with non-small cell lung cancer who are receiving chemoradiotherapy.