December 2017 – Page 52 – 1stOncology™: Cancer Intelligence Service

Intellia Therapeutics Announces New, Robust Genome Editing Data for Sickle Cell Disease at the American Society of Hematology Meeting

On December 11, 2017 Intellia Therapeutics, Inc. (NASDAQ:NTLA), a leading genome editing company focused on the development of potentially curative therapeutics using the CRISPR technology, and its collaborator, Novartis, reported initial data from their research collaboration on genome-edited human hematopoietic stem cells (Press release, Intellia Therapeutics, DEC 11, 2017, View Source [SID1234522514]). These data showed successful ex vivo editing of the erythroid specific enhancer of BCL11A, a gene associated with prevention of sickle cell disease, and the ability of these cells to stably engraft in mice while maintaining their desired properties.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

Schedule Your 30 min Free Demo!

These data were presented today at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in the platform presentation session: Hemoglobinopathies, Excluding Thalassemia – Basic and Translational Science: Sickle Cell Disease – Hematopoiesis and Fetal Hemoglobin Augmentation. In the presented studies, the companies:

Achieved approximately 80-95 percent target site modification in human hematopoietic stem and progenitor CD34+ cells following electroporation of ribonucleoprotein (RNP) composed of Cas9 and a guide RNA (gRNA), selected for efficacy and potency;

Demonstrated an approximately 40 percent reduction in BCL11A mRNA with a corresponding two-fold increase in γ-globin transcript and 30-40 percent more fetal hemoglobin-positive cells above background. Similar decreases in BCL11A mRNA and increases in γ-globin transcipt were observed when sickle cell disease-derived cells from patient donors were edited;

Achieved engraftment over 16 weeks following transplantation of edited human bone marrow CD34+ cells into immune compromised mice, while maintaining editing levels in engrafted cells; and

Observed no off-target events in CD34+ cells edited with the selected gRNA, as measured by targeted next generation sequencing of sites identified through in silico prediction and based on an unbiased, genome-wide, oligo-insertion detection method.
"We are pleased to be reporting data from studies generated through Intellia’s collaboration with Novartis, demonstrating successful ex vivo CRISPR/Cas9 editing in hematopoietic stem cells," said John Leonard, M.D., executive vice president, Research & Development, Intellia Therapeutics. "These results are significant as we have shown high levels of editing as well as increased production of fetal hemoglobin to clinically relevant levels, which could potentially ameliorate sickle cell disease in affected patients. We are very encouraged to present this progress given that sickle cell disease is a serious condition that currently has limited treatment options."

About Sickle Cell Disease

Sickle cell disease is a life-threatening, hereditary disorder that impacts approximately 30 million people worldwide. The disease results from a single amino acid change in the β-globin gene, which causes polymerization of hemoglobin and the deformation of red blood cells, leading to vaso-occlusion, severe pain crisis and multi-organ dysfunction. The average life expectancy in the developed world is 40 to 60 years. About 80 percent of sickle cell disease cases are believed to occur in sub-Saharan Africa.

Integra LifeSciences Hosts Investor Day 2017 New York City

On December 11, 2017 Integra LifeSciences Holdings Corporation (NASDAQ:IART), a leading global medical technology company, reported it will host an Investor Day meeting with analysts and institutional investors in New York City, beginning at 8:00 a.m. EST. Members of Integra’s executive leadership team will discuss the company’s financial performance and outlook (Press release, Integra LifeSciences, DEC 11, 2017, View Source [SID1234522512]).

Highlights of today’s conference include:

• Reaffirming 2017 financial guidance as provided on October 26, 2017, including:

Full-year 2017 revenue in the range of $1.165 billion to $1.175 billion, which includes about 4% organic growth

Full-year 2017 adjusted earnings per share in the range of $1.83 to $1.87
• Providing 2018 preliminary revenue estimate in the range of $1.46 billion to $1.48 billion, which includes about 5% organic growth

• Reaffirming 2018 adjusted earnings per share in the range of $2.25 to $2.35, consistent with preliminary estimates provided on October 26, 2017

• Establishing five-year financial targets of approximately $2 billion in revenue and an adjusted EBITDA margin range of 28% to 30%

The company will host a livestream of the presentation and conference materials are available through the Investors section of Integra’s website at www.integralife.com. A replay of the conference will be archived on the company website.

Hookipa Biotech Raises $60 million (€50 million) in an Oversubscribed Round C Financing

On December 11, 2017 Hookipa Biotech AG ("Hookipa"), a clinical stage biotech company pioneering an innovative class of immune activation therapies for oncology and infectious diseases, reported that it has raised $59.6 million (€50.0 million) in an oversubscribed Series C financing (Press release, Hookipa Biotech, DEC 11, 2017, View Source [SID1234522515])

The round was led by an undisclosed blue chip U.S. public investment fund specializing in life sciences, alongside other new investors HBM Partners, Hillhouse Capital, Sirona Capital and strategic investor Gilead. All current Hookipa investors, Sofinnova Partners, Forbion Capital Partners, Boehringer Ingelheim Venture Fund, Takeda Ventures and BioMedPartners participated in the round.

The proceeds of the fundraising will be primarily used to progress two proof-of concept clinical trials of Hookipa’s lead development programs, a phase 2 study of the Company’s prophylactic Cytomegalovirus ("CMV") vaccine in solid organ transplant patients, and a phase 1 study of its TheraT based active immunization therapy in patients with head & neck squamous cell carcinoma. In addition, Hookipa plans to expand its technology platform into other disease areas, such as prostate cancer.

Hookipa’s arenavirus-based vector technologies TheraT and Vaxwave have been designed to infect dendritic cells and stimulate potent and long-lasting immune responses. HB-101, the Company’s Vaxwave-based CMV vaccine successfully completed a phase 1 trial earlier this year, demonstrating safety and immunogenicity. TheraT has been shown to elicit uniquely potent antigen-specific CD8+ cytotoxic T cell responses and strong tumor control in mice. TheraT works by delivering tumor-associated antigen-specific immunization alongside the release of the alarmin interleukin-33 (IL-33), which is key in stimulating potent and protective CD8+ cytotoxic effector T lymphocytes.

Joern Aldag, Chief Executive Officer of Hookipa said: "Our vision is of a world in which the immune system actively controls infectious diseases and cancer, using monotherapy or combinations of medications. We welcome the funding and support from this group of leading current and new investors, who have recognized the potential, versatility, and uniqueness of our novel viral vector platform in this context. This financing allows us to progress two lead development programs through the major inflection points of clinical proof of concept, and to expand our clinical work to additional virology and oncology indications."

ADC Therapeutics Announces Interim Phase I Data from its Novel Antibody-Drug Conjugate ADCT-301

On December 11, 2017 ADC Therapeutics (ADCT), an oncology drug discovery and development company that specializes in the development of proprietary Antibody Drug Conjugates (ADCs) targeting major cancers, reported clinical data from two ongoing Phase I clinical trials evaluating ADCT-301 (camidanlumab tesirine or "Cami-T") in important subtypes of lymphoma and leukemia (Press release, ADC Therapeutics, DEC 11, 2017, View Source [SID1234522513]). The data were presented at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Atlanta, USA.

1. Interim results of a Phase I open label, single agent, dose-escalating study of ADCT-301 evaluating tolerability, safety, pharmacokinetics and efficacy in patients with relapsed or refractory B-cell Hodgkin’s or non-Hodgkin’s lymphoma

Dr. Steven M. Horwitz, Medical Oncologist at Memorial Sloan Kettering Cancer Center in New York City, and Principal Investigator, said: "Despite considerable advances in the treatment of lymphoma, a significant number of patients still relapse or become refractory to existing therapies and need new treatment options. We are excited by the 77 percent overall response rate (ORR) in Hodgkin Lymphoma (HL), including a 44 percent complete response rate. We are also seeing emerging efficacy signals in T-cell lymphomas (ORR: 33 percent) and B-cell lymphomas (ORR: 19 percent). Although still early, we are very encouraged by a median duration of response for HL patients of over 5 months to-date. The safety profile appears consistent with what we expect with this target and warhead. We are now working to determine the best dosing regimen for Phase II."

Data were presented from 86 evaluable, heavily pre-treated patients who had failed, or were intolerant to, any established therapy known to provide clinical benefit. The median age of patients was 53 years and they had a median of 4 prior therapies. Data were reported from Part 1 and Part 2 of the Phase I study as of November 1, 2017. In Part 1 (dose escalation), 71 patients were treated at dose ranges from 3-150 µg/kg every three weeks. In Part 2 (dose expansion), 15 Hodgkin Lymphoma patients were treated at 45 µg/kg every 3 weeks.

Key findings presented at the poster presentation included:

For the 27 response-evaluable patients with HL in Part 1, treated at doses greater than or equal to 45 µg/kg, the ORR was 77 percent (21/27 patients) with 12 patients achieving a complete response (44 percent) and 9 patients achieving a partial response (33 percent).
For the 12 response-evaluable patients with HL in Part 1 and Part 2, treated at the 45 µg/kg dose, the ORR was 100 percent (12/12) with 6 patients achieving a complete response (50 percent) and 6 patients achieving a partial response (50 percent).
For HL patients in Part 1 and Part 2, treated at doses greater than or equal to 45 µg/kg, a complete or partial response was achieved in 21 of 27 patients previously treated with brentuximab vedotin (77 percent), 13 of 18 patients previously treated with a checkpoint inhibitor (72 percent), 9 of 14 patients who had previously undergone a stem cell transplantation (64 percent), and 4 of 8 patients who had previously received all three of these treatments (50 percent).
ADCT-301 has been reasonably well tolerated.
The most common treatment-emergent adverse events of any grade occurring in at least 20 percent of patients in Part 1 and Part 2 were fatigue (30 percent), rash (26 percent), elevated gamma-glutamyltransferase (22 percent), and pyrexia (21 percent). The most common Grade 3 or 4 adverse events occurring in at least 5 percent of patients, regardless of attribution, were elevated gamma-glutamyltransferase (13 percent), reduced platelet count (9 percent), elevated alanine aminotransferase (6 percent), anemia (6 percent), and rash (6 percent). There were three heavily pre-treated patients diagnosed with auto-immune neurotoxicity, including two patients who developed Guillain-Barré syndrome.
These encouraging preliminary safety and efficacy results support further characterization of the dosing regime to optimize the therapeutic window in Hodgkin Lymphoma for a Phase II study.
2. Interim results of a Phase I open label, single agent, dose-escalating study of ADCT-301 evaluating tolerability, safety, pharmacokinetics and efficacy in patients with relapsed or refractory B-cell acute myeloid leukemia or acute lymphoblastic leukemia

Data were presented from 33 evaluable, heavily pre-treated, patients who had failed, or were intolerant to, any established therapy known to provide clinical benefit. The median age of patients was 67 years and they had a median of 3 prior therapies. In Part 1 (dose escalation), 33 patients were treated at dose ranges from 3-92 µg/kg every three weeks, or 30-37.5 µg/kg once weekly.

Key findings presented at the poster presentation included:

One patient achieved a complete response with incomplete blood count recovery.
ADCT-301 has shown an acceptable safety profile.
The most common treatment-emergent adverse events of any grade occurring in at least 20 percent of patients were fatigue (30 percent), nausea (24 percent), febrile neutropenia (21 percent), and pneumonia (21 percent). The most common Grade 3 or 4 adverse events occurring in at least 10 percent of patients, regardless of attribution, were febrile neutropenia (21 percent), thrombocytopenia (15 percent), fatigue (12 percent), reduced neutrophil count (12 percent), and pneumonia (12 percent).
Dose escalation will continue to investigate weekly dosing.
About ADCT-301

ADCT-301 is an antibody-drug conjugate (ADC) composed of a monoclonal antibody that binds to CD25 (HuMax-TAC, licensed from Genmab A/S), conjugated to a pyrrolobenzodiazepine (PBD) dimer toxin. Once bound to a CD25-expresing cell, ADCT-301 is internalized into the cell where enzymes release the PBD-based warhead. CD25 is an attractive target for an ADC approach as it is expressed in a wide range of hematological malignancies, including certain forms of lymphomas and leukemias, while its expression in healthy organs is restricted. ADCT-301 is being evaluated in two ongoing phase Ia/Ib clinical trials in patients with relapsed or refractory Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), and in patients with relapsed or refractory CD25-positive acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). (www.adct-301.com)

Italfarmaco Presents Positive Phase II Study Results for Givinostat in Polycythemia Vera Patients at the ASH Annual Meeting

On December 11, 2017 Italfarmaco Group, a specialty pharmaceutical company, reported the positive results from two clinical trials evaluating its proprietary histone deacetylase (HDAC) inhibitor givinostat in Polycythemia Vera patients -Italfarmaco Group, a specialty pharmaceutical company, reported the positive results from two clinical trials evaluating its proprietary histone deacetylase (HDAC) inhibitor givinostat in Polycythemia Vera patients. The data were presented in an oral and a poster presentation on Saturday December 9th, 2017 at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Meeting & Exposition held in Atlanta, Georgia. In the oral presentation, the company discussed positive safety and efficacy data from a two-part study of givinostat in which over 80% of patients responded to the treatment. These results were further supported by a poster presentation of a long-term evaluation of givinostat’s effect in patients over four years. Combined, the data provide a basis for the company’s decision to proceed with a pivotal Phase III trial in this indication. Polycythemia Vera is a rare blood disease characterized by an increased number of red blood cells, white blood cells and platelets, which significantly raises the risk for thromboembolic and hemorrhagic complications.

"Polycythemia Vera patients have limited treatment options that currently only ameliorate the symptoms of the disease. We look forward to initiating the planned pivotal study in this indication."
Tweet this
In the oral presentation at ASH (Free ASH Whitepaper), the principal investigator described the multi-center, open label Phase Ib/II givinostat study, which included a dose-escalation and an evaluation of preliminary efficacy and tolerability. The data demonstrated that givinostat was well tolerated overall at the defined dose of 100 mg twice daily and the majority of adverse events were mild to moderate in severity. The overall response rate was more than 80% according to European Leukemia Net standard response criteria, which measure a range of parameters including reduction of the size of spleen and liver, peripheral blood count, absence of hemorrhagic and thrombotic events and bone marrow analysis.

In the larger study investigating long-term safety and efficacy, Italfarmaco researchers and collaborators presented data supporting the potential of givinostat as a durable treatment option that reduces the symptoms and underlying risks of the disease while remaining well-tolerated. Overall, 80% of patients maintained at least a partial response for more than four years. After four years of treatment no patient reported microvascular symptoms or headaches. Pruritus (itchiness), one of the typical symptoms of Polycythemia Vera, was absent in 67% of the patients. Furthermore, the overall incidence of thrombosis (1.13% patients per year) was reduced in comparison to the expected incidence rate in this patient population (3% patients/year). Givinostat treatment additionally reduced the levels of mutated Janus Kinase 2 (JAK2), a key underlying cause of the disease, by 25% in over 40% of the patients.

"The givinostat Phase II proof-of-concept and long-term data are very encouraging and demonstrate the potential of this compound to address the underlying mechanism of the disease while remaining well-tolerated," said Dr. Paolo Bettica, Vice President Research and Development. "Polycythemia Vera patients have limited treatment options that currently only ameliorate the symptoms of the disease. We look forward to initiating the planned pivotal study in this indication."

"Italfarmaco is particularly gratified that these results were selected for presentation at ASH (Free ASH Whitepaper) because they underscore the value of our internal research and development efforts," added Dr. Francesco De Santis, President of Italfarmaco.

About Polycythemia Vera

Polycythemia Vera is a rare blood disease characterized by an overproduction of red blood cells, white blood cells and platelets, which thickens the blood and increases the risk of blood clots, a major underlying cause of life-threatening conditions such as thrombosis, embolisms, heart attack or stroke. The disease is associated with mutations in the Janus Kinase 2 (JAK2) gene and disease-related symptoms include headaches, itching and microvascular symptoms. The current standard of care ranges from phlebotomy alone or in combination with low-dose aspirin, to drugs such as the cytoreductive hydroxycarbamide or the JAK inhibitor ruxolitinib. These reduce symptoms, but no treatments targeting the underlying disease mechanism are available.

About Givinostat

Givinostat is a potent, orally-available, class I and II histone deacetylase (HDAC) inhibitor and an investigational product discovered through Italfarmaco’s internal research and development efforts. Through the pharmacological modulation of cell growth, differentiation and apoptosis and the additional specific inhibition of the proliferation of cells bearing the JAK2V617F mutation, givinostat may represent a novel disease modifier in Polycythemia Vera. Besides these properties, givinostat has shown immuno-modulatory activity that may specifically target other diseases, making it a very promising candidate for Duchenne Muscular Dystrophy (Phase III) and Becker Muscular Dystrophy (Phase II). The data were presented in an oral and a poster presentation on Saturday December 9th, 2017 at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Meeting & Exposition held in Atlanta, Georgia. In the oral presentation, the company discussed positive safety and efficacy data from a two-part study of givinostat in which over 80% of patients responded to the treatment. These results were further supported by a poster presentation of a long-term evaluation of givinostat’s effect in patients over four years. Combined, the data provide a basis for the company’s decision to proceed with a pivotal Phase III trial in this indication. Polycythemia Vera is a rare blood disease characterized by an increased number of red blood cells, white blood cells and platelets, which significantly raises the risk for thromboembolic and hemorrhagic complications.