On December 9, 2017 Seattle Genetics, Inc. (Nasdaq: SGEN) reported updated results from the phase 3 ALCANZA clinical trial evaluating ADCETRIS (brentuximab vedotin) in CD30-expressing cutaneous T-cell lymphoma (CTCL) at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition taking place in Atlanta, Georgia, December 9-12, 2017 (Press release, Seattle Genetics, DEC 9, 2017, View Source;p=RssLanding&cat=news&id=2321936 [SID1234522472]). The presentation highlighted longer-term durability data from the phase 3 ALCANZA clinical trial of single-agent ADCETRIS for the treatment of patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF). Together, these comprise approximately 70 percent of CTCL diagnoses and the majority of patients who require systemic therapy.

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"The updated analyses from the phase 3 ALCANZA clinical trial presented at this year’s ASH (Free ASH Whitepaper) annual meeting are based on longer-term follow-up by investigators. Since the initial presentation at the ASH (Free ASH Whitepaper) Annual Meeting in 2016, the ALCANZA results continue to show superior clinical efficacy of ADCETRIS over standard-of-care therapies in patients with CD30-expressing CTCL," said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. "The updated analyses demonstrate that the primary and secondary endpoints per investigator are better than previously reported by independent review facility assessment. CTCL is a debilitating and disfiguring disease. With the recent FDA approval of ADCETRIS for use in two common subtypes based on the ALCANZA results, we are now able to provide patients with a clinically meaningful therapeutic option in the approved settings. This is a significant milestone for the lymphoma community and for our goal to make ADCETRIS available to as many patients as possible with CD30-expressing lymphomas."

Updated Analyses of the International, Open-Label, Randomized, Phase 3 ALCANZA Study: Longer-term Evidence for Superiority of Brentuximab Vedotin Versus Methotrexate or Bexarotene for CD30-Positive Cutaneous T-Cell Lymphoma (Abstract #1509, poster presentation on Saturday, December 9, 2017)

ALCANZA was a randomized, open-label phase 3 study designed to evaluate single-agent ADCETRIS versus a control arm of investigator’s choice of standard of care therapies, methotrexate or bexarotene, in patients with CD30-expressing pcALCL or MF. Patients with pcALCL must have received at least one prior systemic or radiation therapy and patients with MF must have received at least one prior systemic therapy. A total of 131 patients were randomized with 128 patients in the intent-to-treat population. Sixty-four patients were assigned to the ADCETRIS arm and 64 patients were assigned to the control arm. Patients received ADCETRIS or investigator’s choice of methotrexate or bexarotene for up to approximately one year.

Data from longer-term patient follow-up per investigator assessment in the phase 3 ALCANZA trial after a median observation time of 33.9 months from the first dose of ADCETRIS versus physician’s choice include:

The trial achieved its primary endpoint of demonstrating a highly statistically significant improvement in the rate of objective response lasting at least four months (ORR4) in the ADCETRIS arm versus the control arm. The ORR4 per investigator assessment was 60.9 percent in the ADCETRIS arm compared to 7.8 percent in the control arm (p-value <0.001).
The key secondary endpoints per investigator, including complete response (CR) rate, progression-free survival (PFS) and reduction in the burden of symptoms during treatment (per Skindex-29 questionnaire), continued to be all highly statistically significant in favor of the ADCETRIS arm.
The median PFS per investigator in the ADCETRIS arm was 15.8 months compared to 3.6 months in the control arm (HR 0.373; 95% CI, 0.245-0.569; p-value <0.001).
The CR rate in the ADCETRIS arm was 18.8 percent compared to zero percent in the control arm (p-value <0.001).
Patient-reported quality of life assessed by the Skindex-29 questionnaire showed significantly greater symptom reduction for patients in the ADCETRIS arm versus the control arm (mean maximum change of -28.08 vs -8.62; p-value <0.001).
At time of the analyses, 47 patients (73 percent) in the ADCETRIS arm and 48 patients (75 percent) in the physician’s choice arm had received one or more subsequent skin-directed or systemic therapy. The median time to next treatment in the ADCETRIS arm was significantly longer at 14.2 months compared with the physician’s choice arm at 6.1 months (p-value <0.001). In the ADCETRIS versus physician’s choice arms, the probability of patients not requiring subsequent skin-directed or systemic therapy was greater at one year (65.5 percent vs. 15.3 percent) and two years (24.6 percent vs. 4.4 percent).
Peripheral neuropathy events were observed in 44 of 66 patients (67 percent) in the ADCETRIS arm and four of 62 patients (six percent) in the physician’s choice arm. In the ADCETRIS arm, 86 percent of patients reported resolution or improvement in peripheral neuropathy events, with 59 percent reporting resolution of all events after a median of 30 weeks and 27 percent reporting some improvement after a median of 13 weeks. Eighteen patients had ongoing peripheral neuropathy events, including 15 patients with Grade 1 and three patients with Grade 2.
In November 2017, the U.S. Food and Drug Administration (FDA) approved ADCETRIS for the treatment of adult patients with pcALCL or CD30-expressing MF who have received prior systemic therapy based on the results of the phase 3 ALCANZA clinical trial.

About CTCL

Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Cutaneous lymphomas are a category of non-Hodgkin lymphoma that primarily involve the skin. According to the Cutaneous Lymphoma Foundation, CTCL is the most common type of cutaneous lymphoma and typically presents with red, scaly patches or thickened plaques of skin that often mimic eczema or chronic dermatitis. The most common subtypes of CTCL include mycosis fungoides and primary cutaneous anaplastic large cell lymphoma. Progression from limited skin involvement may be accompanied by skin tumor formation, ulceration and exfoliation, complicated by itching and infections. Advanced stages are defined by involvement of lymph nodes, peripheral blood and internal organs.

According to the American Cancer Society and the Leukemia and Lymphoma Society, CTCL represents approximately four percent of non-Hodgkin lymphoma, which is about 2,800 patients. Not all newly diagnosed patients require systemic therapy. The standard treatment for CTCL patients includes skin-directed therapies, radiation and systemic therapies. Prior to the FDA approval of ADCETRIS, systemic therapies approved for treatment demonstrated 30 to 45 percent objective response rates, with low complete response rates and low durability as demonstrated by a median time to next systemic treatment of 3.9 months for chemotherapy and 4.5 months for histone deacetylase inhibitors.

About ADCETRIS

ADCETRIS is being evaluated broadly in more than 70 clinical trials, including three phase 3 studies: the completed ECHELON-1 trial in frontline classical Hodgkin lymphoma that supported the recent FDA Breakthrough Therapy Designation and submission of the supplemental Biologics License Application (BLA) for use in this setting, the ongoing ECHELON-2 trial in frontline mature T-cell lymphomas, and the ongoing CHECKMATE 812 trial of ADCETRIS in combination with Opdivo (nivolumab) for relapsed/refractory Hodgkin lymphoma.

ADCETRIS is an ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.

ADCETRIS injection for intravenous infusion has received FDA approval for four indications: (1) regular approval for adult patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy, (2) regular approval for the treatment of patients with classical Hodgkin lymphoma after failure of autologous hematopoietic stem cell transplantation (auto-HSCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates, (3) regular approval for the treatment of classical Hodgkin lymphoma patients at high risk of relapse or progression as post-auto-HSCT consolidation, and (4) accelerated approval for the treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen. The sALCL indication is approved under accelerated approval based on overall response rate. Continued approval for the sALCL indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Health Canada granted ADCETRIS approval with conditions for relapsed or refractory Hodgkin lymphoma and sALCL in 2013, and non-conditional approval for post-ASCT consolidation treatment of Hodgkin lymphoma patients at increased risk of relapse or progression.

ADCETRIS was granted conditional marketing authorization by the European Commission in October 2012 for two indications: (1) for the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin lymphoma following autologous stem cell transplant (ASCT), or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, and (2) the treatment of adult patients with relapsed or refractory sALCL. The European Commission extended the current conditional marketing authorization of ADCETRIS and approved ADCETRIS for the treatment of adult patients with CD30-positive Hodgkin lymphoma at increased risk of relapse or progression following ASCT.

ADCETRIS has received marketing authorization by regulatory authorities in 69 countries for relapsed or refractory Hodgkin lymphoma and sALCL. See important safety information below.

Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

On December 9, 2017 ImmunoGen, Inc. (Nasdaq: IMGN), a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, reported that new data from the Company’s ongoing Phase 1 study of IMGN779, a next-generation CD33-targeting ADC, in patients with relapsed or refractory adult acute myeloid leukemia (AML) were presented at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Atlanta (Press release, ImmunoGen, DEC 9, 2017, View Source [SID1234522464]). Poster presentations on preclinical data for IMGN779 in combination with cytarabine and CD123-targeting IMGN632 in acute lymphoblastic leukemia (ALL) are also being presented at the meeting.

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The Phase 1 data presented at ASH (Free ASH Whitepaper) demonstrate that IMGN779 was well-tolerated with no dose-limiting toxicities (DLTs) observed in patients with relapsed or refractory AML across nine dose levels administered once every two weeks (Q2W) and one dose level administered once a week (QW). In addition, anti-leukemia activity was seen at doses ≥0.39 mg/kg in both schedules in patients with poor prognostic features. The maximum tolerated dose has not been reached and dose escalation continues. Data across the first seven dose levels on the Q2W schedule were presented in June at the 22nd Congress of the European Hematology Association (EHA) (Free EHA Whitepaper).

"The data at ASH (Free ASH Whitepaper) build on the initial safety and anti-leukemia data presented earlier this year at EHA (Free EHA Whitepaper), and further support continued dose escalation of IMGN779, a novel, next-generation treatment for AML," said Anna Berkenblit, M.D., vice president and chief medical officer of ImmunoGen. "Given investigator enthusiasm and high unmet need, the dosing cohorts have been rapidly enrolling and we are very encouraged by the initial findings with IMGN779. We are continuing to dose escalate on the every two week schedule and, to evaluate the potential of continuous exposure, we have opened a weekly dosing schedule in parallel. We look forward to establishing the optimal dose and schedule, and quickly moving this compound into later stages of development."

Phase 1 Data on IMGN779 in AML

Key findings presented from the Phase 1 study of IMGN779 at ASH (Free ASH Whitepaper) (Abstract #1312) include the following:

IMGN779 displays a tolerable safety profile.
No DLTs were observed on either administration schedule at doses examined – up to 0.91 mg/kg Q2W and 0.39 mg/kg QW.
No increase in the nature, frequency, or severity of any treatment-emergent adverse event was observed with increasing dose.
This profile has enabled repeat dosing, with one patient showing a 93% reduction in bone marrow blasts with extended treatment and who remains on therapy through Cycle 14.
Pharmacokinetic (PK) exposures and pharmacodynamic (PD) CD33 saturation continue to increase with dose, and support further escalation and exploration of both the QW and Q2W schedules.
Anti-leukemia activity was seen at doses ≥0.39 mg/kg in both schedules with:
16 of 17 patients showing a decrease in peripheral blasts within 10 days after first dose with a median maximal decrease of 71%; and
Seven of 17 patients showing a 48%-96% reduction in bone marrow blasts. These seven patients had poor prognostic features (e.g., prior intense therapy, primary refractory disease, RAS/TP53/FLT3/IDH mutations).
This ongoing Phase 1 trial is designed to establish the maximum tolerated dose and determine the recommended Phase 2 dose for IMGN779 administered as monotherapy. The trial is also intended to evaluate safety and tolerability, and characterize PK, PD, and preliminary anti-leukemia activity in relapsed or refractory AML.

Preclinical Presentations on IMGN779 in Combination with Cytarabine and IMGN632 in ALL

Supporting data evaluating the mechanism, anti-leukemia efficacy, and tolerability of repeated dosing of IMGN779 in combination with cytarabine using in vitro and in vivo human AML preclinical models were also presented. Key findings from the poster presentation (Abstract #1357) include:

The combination of IMGN779 and cytarabine increased DNA damage response, cell cycle arrest, and apoptosis in vitro when compared to single agent treatment.
The combination of IMGN779 and cytarabine lead to increased survival and greater numbers of complete responses in in vivo preclinical AML models.
Use of cytarabine increased cell surface CD33 levels on AML cells, suggesting a novel mechanism for potentiating IMGN779 uptake.
Preclinical data (Abstract #2718) on IMGN632 reporting the prevalence of CD123 expression in acute lymphoblastic leukemia (ALL), and assessing the anti-leukemia activity of IMGN632 on ALL cells will also be presented. Among the findings:

CD123 expression is prevalent across ALL subtypes including 90% of B-cell ALL (B-ALL) and nearly half of T-cell ALL patient samples.
IMGN632 demonstrates promising activity against B-ALL cell lines and patient samples in vitro, including the elimination of more than 90% of B-ALL blasts in 6 out of 8 patient samples. Normal cells were not affected by IMGN632 at 100-fold higher concentrations.
More information can be found at www.hematology.org, including abstracts.

Poster Session Schedule and Details

Title (Abstract #1312): "IMGN779, a Next-Generation CD33-Targeting Antibody-Drug Conjugate (ADC) Demonstrates Initial Antileukemia Activity in Patients with Relapsed or Refractory Acute Myeloid Leukemia"
Poster session #613: Saturday, December 9, 5:30 – 7:30 PM ET.
Title (Abstract #1357): "IMGN779, a Next Generation CD33-Targeting ADC, Combines Effectively With Cytarabine in Acute Myeloid Leukemia (AML) Preclinical Models, Resulting in Increased DNA Damage Response, Cell Cycle Arrest and Apoptosis In Vitro, and Prolonged Survival In Vivo"
Poster session #616: Saturday, December 9, 5:30 – 7:30 PM ET.
Title (Abstract #2718): "CD123 Expression Patterns and Potential of IMGN632, a CD123-Targeted Antibody Drug Conjugate, in Acute Lymphoblastic Leukemia"
Poster session #618: Sunday, December 10, 6:00 – 8:00 PM ET.
About IMGN779
IMGN779 is a novel ADC that combines a high-affinity, humanized anti-CD33 antibody, a cleavable disulfide linker, and one of ImmunoGen’s novel indolino-benzodiazepine payloads, called IGNs, which alkylate DNA without crosslinking, resulting in potent preclinical anti-leukemia activity with relative sparing of normal hematopoietic progenitor cells.1,2 IMGN779 is in Phase 1 clinical testing for the treatment of AML.

About IMGN632
IMGN632 is a humanized anti-CD123 antibody-drug conjugate that is a potential treatment for AML, blastic plasmacytoid dendritic cell neoplasm (BPDCN), myelodysplastic syndrome, B-cell acute lymphocytic leukemia, and other CD123-positive malignancies. IMGN632 uses a novel IGN payload, linker and antibody technology and in AML xenograft models has demonstrated a large therapeutic index.3 ImmunoGen has filed an investigational new drug (IND) application for IMGN632 and expects to open a Phase I study before year end.

About IGNs
Indolino-benzodiazepine cancer-killing agents, or IGNs, are a new class of cancer-killing agent developed by ImmunoGen for use in ADCs. These ultra-potent, DNA-acting IGNs alkylate DNA without crosslinking, which preclinically has resulted in potent anti-leukemia activity with relative sparing of normal hematopoietic progenitor cells.4,5 IMGN779, a CD33-targeting ADC in Phase 1 testing for AML, was the first IGN ADC to enter clinical testing. IMGN632, a CD123-targeting ADC entering Phase 1 testing for AML and BPDCN, deploys a novel IGN payload.

About Acute Myeloid Leukemia (AML)
AML is a cancer of the bone marrow cells that produce white blood cells. It causes the marrow to increasingly generate abnormal, immature white blood cells (blasts) that do not mature into effective infection-fighting cells. The blasts quickly fill the bone marrow, impacting the production of normal platelets and red blood cells. The resulting deficiencies in normal blood cells leave the patient vulnerable to infections, bleeding problems and anemia.

It is estimated that, in the U.S. alone, 21,380 patients will be diagnosed with AML this year and 10,590 patients will die from the disease.6

On December 9, 2017 H3 Biomedicine Inc., a clinical stage biopharmaceutical company specializing in the discovery and development of precision medicines for oncology and a member of Eisai’s global Oncology Business Group, reported that data from the company’s academic collaborations in RNA splicing biology will be presented over the next three days at the 2017 American Society of Hematology (ASH) (Free ASH Whitepaper) meeting in Atlanta, GA (Press release, H3 Biomedicine, DEC 9, 2017, View Source [SID1234522463]). The presentations are part of three academic research collaborations and will detail pre-clinical studies evaluating the role of RNA splicing in cancer biology and potential approaches for therapeutic intervention.

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Participating in these studies with H3 Biomedicine are Memorial Sloan Kettering Cancer Center, Cold Spring Harbor Laboratory, the University of Manchester, Institute Gustave Roussy, Université Paris-Saclay, the University of Texas, Dana Farber Cancer Institute, University of California, Center for Molecular Medicine of the Austrian Academy of Sciences, MD Anderson Cancer Center, Broad Institute, Beckman Research Institute and Harvard Medical School.

"We are grateful to the academic centers that have become a key aspect of our research efforts, and we are pleased to continue these ongoing relationships," said Markus Warmuth, M.D., Chief Executive Officer and President of H3 Biomedicine. "We look forward to exploring the potential of our RNA splicing platform and expand our insights on how best to target the spliceosome, in order to help H3 enhance its mission to develop important new cancer drugs."

The details of the presentations are as follows:

Title 1: Splicing Modulation Perturbs Key Survival Pathways and Sensitizes Chronic Lymphocytic Leukemia to Venetoclax Treatment
Program: Oral and Poster Abstracts
Type: Oral
Session: 641. CLL: Biology and Pathophysiology, excluding Therapy: Therapeutic Resistance in CLL
Date/Time: Saturday, December 9, 2017: 5:15 PM. Building C, Level 1, Room C101
Location: Auditorium of the Georgia World Congress Center

Title 2: Spliceosomal Dysfunction Is a Critical Mediator of IDH2 Mutant Leukemogenesis
Program: Oral and Poster Abstracts
Type: Oral
Session: 617. Acute Myeloid Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis I
Date/Time: Sunday, December 10, 2017: 5:30 PM
Location: Building C, Level 2, C202-C204 of the Georgia World Congress Center

Title 3: 289 Dynamic BH3 Profiling to Assess the Effects of Novel Agents on Anti-Apoptotic Protein Dependence of CLL Cells
Program: Oral and Poster Abstracts
Session: 641. CLL: Biology and Pathophysiology, excluding Therapy: Poster III
Date/Time: Monday, December 11, 2017, 6:00-8:00 p.m.
Location: Building A, Level 1, Hall A2 of the Georgia World Congress Center

"H3 is exploring the potential of targeting the spliceosome, which has become an integral part of our research and development efforts," said Pete Smith, Ph.D., Chief Scientific Officer for H3 Biomedicine. "A critical component of our research and translational work is undertaken in strong collaboration with leading investigators and academic centers. This work will be exemplified through the presentations at the ASH (Free ASH Whitepaper) meeting."

On December 9, 2017 Fate Therapeutics, Inc. (NASDAQ:FATE), a biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for cancer and immune disorders, reported the generation of chimeric antigen receptor (CAR)-targeted CD8αβ+ T cells from a clonal engineered master pluripotent cell line (MPCL) (Press release, Fate Therapeutics, DEC 9, 2017, View Source [SID1234522462]). The clonal engineered MPCL was created from an induced pluripotent stem cell (iPSC), which was modified in a one-time engineering event using CRISPR/Cas9 to both insert a CAR into the T-cell receptor α constant (TRAC) locus and eliminate T-cell receptor (TCR) expression. The groundbreaking development enables the renewable production of CAR-targeted, TCR-null CD8αβ+ T cells that are not restricted to an individual patient for off-the-shelf administration.

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The breakthrough was reported today at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition by scientists from the laboratories of Michel Sadelain, M.D., Ph.D., Director, Center for Cell Engineering, Memorial Sloan Kettering Cancer Center and Fate Therapeutics. In September 2016, Fate Therapeutics and Memorial Sloan Kettering Cancer Center launched a multi-year partnership led by Dr. Sadelain to develop off-the-shelf T-cell product candidates using clonal engineered MPCLs. The collaborators are currently conducting preclinical studies and finalizing current good manufacturing practice protocols for the development of CAR-targeted, TCR-null T-cell immunotherapies. A first-in-human clinical trial of FT819, a CAR19 T-cell product candidate derived from a clonal engineered MPCL with complete elimination of TCR expression and TRAC-regulated CAR expression, is being planned.

"The use of a clonal engineered master pluripotent cell line enables cost-effective manufacture, timely availability and reliable off-the-shelf delivery of targeted T-cell cancer immunotherapy without patient restriction," said Scott Wolchko, President and Chief Executive Officer of Fate Therapeutics. "Additionally, unlike conventional allogeneic CAR T-cell approaches that involve billions of heterogeneous engineering events to modify the genomic function of primary T cells, an engineered iPSC clone is defined by a single uniform engineering event. As a result, a T-cell product generated from a clonal engineered master pluripotent cell line is homogeneous with respect to genomic modification and cell product composition. This revolutionary approach has the potential to mediate safer, more effective pharmacologic activity, including in combination with cycles of other cancer treatments."

In February 2017, Dr. Sadelain and colleagues published a set of preclinical studies in the journal Nature using primary T cells demonstrating that directing a CD19-specific CAR to the TRAC locus with CRISPR/Cas9 resulted in uniform CAR expression and enhanced T-cell potency as compared to conventional CAR T cells. Scientists from the laboratories of Sadelain and Fate Therapeutics advanced the observation by instead engineering iPSCs and generating CD8αβ+ T cells from a clonal engineered MPCL with a CD19-targeted CAR inserted into the TRAC locus and complete elimination of TCR expression. The collaborators demonstrated that the CAR-targeted, TCR-null CD8αβ+ T cells display antigen-specific anti-tumor potency, including cytokine release and targeted cellular cytotoxicity.

Fate Therapeutics has built an extensive intellectual property portfolio broadly covering the genomic engineering of iPSCs and off-the-shelf engineered T- and NK cell cancer immunotherapies. Its proprietary portfolio includes compositions and methods for editing iPSCs to modify their biological properties using CRISPR and other nucleases, including the use of CRIPSR to insert a CAR in the TRAC locus for endogenous transcriptional control, and for manufacturing cells of all hematopoietic lineages from iPSCs including T cells. In addition, the Company has an exclusive license from Memorial Sloan Kettering covering iPSC-derived T cells expressing chimeric antigen receptors for human therapeutic use, and maintains an option to exclusively license intellectual property arising from all research and development activities under the collaboration.

About Fate Therapeutics’ iPSC Product Platform
The Company’s proprietary induced pluripotent stem cell (iPSC) product platform enables large-scale generation of off-the-shelf, engineered, homogeneous cell products that can be administered in repeat doses to mediate more effective pharmacologic activity. Human iPSCs possess the unique dual properties of unlimited self-renewal and differentiation potential into all cell types of the body. The Company’s first-of-kind approach involves engineering human iPSCs in a one-time genetic modification event, and selecting a single iPSC for maintenance as a clonal master pluripotent cell line (MPCL). Similar to master cell lines used for the manufacture of monoclonal antibodies, clonal MPCLs can serve as a renewable cell source for the consistent and repeated manufacture of homogeneous cell products with the potential to treat many different diseases and many thousands of patients in an off-the-shelf manner. Fate Therapeutics’ iPSC product platform is supported by an intellectual property portfolio of over 90 issued patents and 100 pending patent applications.

On December 9, 2017 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that new data from the ongoing Hemlibra (emicizumab) clinical development programme were presented at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, Hoffmann-La Roche, DEC 9, 2017, View Source [SID1234522459]). These data include longer-term results from the pivotal HAVEN 1 and HAVEN 2 studies in people with haemophilia A with inhibitors to factor VIII, showing once-weekly subcutaneous Hemlibra prophylaxis demonstrated superior efficacy compared to prior treatment with bypassing agents (BPAs) as prophylaxis or on-demand. These new data from the largest pivotal studies in people with haemophilia A with inhibitors further support Hemlibra as an important new treatment option for these adults, adolescents and children.

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In updated results from the HAVEN 2 study with six additional months of data and 40 more children (younger than 12 years of age), 94.7% (95% CI: 85.4; 98.9) of children with haemophilia A with inhibitors who received Hemlibra prophylaxis had zero treated bleeds (n=57). The intra-patient analysis comparing the effects of different therapies in the same child (n=13) showed a 99% reduction in treated bleeds with Hemlibra prophylaxis compared to prior treatment with a BPA, either as prophylaxis (n=12) or on-demand (n=1). Substantial improvements in health-related quality of life and aspects of caregiver burden, measured by the haemophilia-specific quality of life short form (Haemo-QoL-SF) and adapted health-related quality of life in haemophilia patients with inhibitors (Inhib-QoL) questionnaires, were also observed with Hemlibra prophylaxis compared to prior BPA prophylaxis. These data were featured today in the official press programme of the ASH (Free ASH Whitepaper) Annual Meeting.

With nearly ten additional months of follow-up, updated results from the HAVEN 1 intra-patient analysis of adults and adolescents showed an 88% (risk rate [RR]=0.12, 95% CI: 0.05; 0.28) reduction in treated bleeds with Hemlibra prophylaxis compared to prior BPA prophylaxis (n=24). The results also showed a 95% (RR=0.05, 95% CI: 0.02; 0.12) reduction in treated bleeds in patients who received Hemlibra prophylaxis compared to prior on-demand BPA treatment (n=24). After more than one year, substantially more patients continued to experience zero bleeds with Hemlibra prophylaxis compared to their prior prophylaxis or on-demand BPA treatment across bleed endpoints, including treated bleeds and all bleeds. The previously reported improvement in health status after 24 weeks, measured by the haemophilia-specific quality of life (Haem-A-QoL) and EuroQol 5-Dimensions 5-level (EQ-5D-5L) questionnaires, was also maintained with longer follow-up.

"These data demonstrate the continued reduction in bleeds over time with Hemlibra prophylaxis and reinforce the potential of this medicine, recently approved by the FDA for haemophilia A with inhibitors, to redefine the standard of care," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "We are continuing to study Hemlibra in a robust clinical development programme to help advance care for all people with haemophilia A, regardless of age or inhibitor status, and provide even less frequent dosing options."

Data from the run-in cohort of the ongoing phase III HAVEN 4 study showed that Hemlibra prophylaxis dosed once every four weeks in people 12 years of age or older with haemophilia A, with or without inhibitors, resulted in levels of Hemlibra in the blood (pharmacokinetics) that were consistent with predictions. These data supported opening the expansion cohort of the study to further evaluate this dosing regimen. After a median observation time of eight weeks, 85.7% of patients (six out of seven) had zero bleeds while receiving Hemlibra prophylaxis once every four weeks. These data follow the recent announcement that an interim analysis of the phase III HAVEN 4 study showed a clinically meaningful control of bleeding in people 12 years of age or older with haemophilia A who received Hemlibra prophylaxis once every four weeks.

The most common adverse events (AEs) in the HAVEN 1 and HAVEN 2 studies at the time of these follow-up data were consistent with those observed previously in the studies. No unexpected safety findings were observed in the run-in cohort of the HAVEN 4 study. No new cases of thrombotic microangiopathy (TMA) or thrombotic events were observed in HAVEN 1, and no cases occurred in HAVEN 2 or HAVEN 4.

Based on earlier results from the HAVEN 1 and HAVEN 2 studies, Hemlibra was approved by the US Food and Drug Administration (FDA) for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children with haemophilia A with inhibitors. Data from HAVEN 1 and HAVEN 2 are also being reviewed under accelerated assessment by the European Medicines Agency (EMA) and submissions to health authorities around the world are ongoing. The clinical development programme also includes the ongoing phase III HAVEN 4 study and the phase III HAVEN 3 study, which showed a statistically significant and clinically meaningful reduction in the number of treated bleeds over time in people aged 12 years or older with haemophilia A without inhibitors who received Hemlibra prophylaxis every week or every other week, compared to those receiving no prophylaxis.

About HAVEN 1 (NCT02622321)
HAVEN 1 is a randomised, multicentre, open-label, phase III study evaluating the efficacy, safety and pharmacokinetics of once-weekly subcutaneous administration of Hemlibra prophylaxis compared to no prophylaxis in adults and adolescents with haemophilia A with inhibitors to factor VIII. The study included 113 patients (12 years of age and older) with haemophilia A with inhibitors to factor VIII, who were previously treated with BPAs on-demand or as prophylaxis. Patients previously treated with on-demand BPAs were randomised in a 2:1 ratio to receive Hemlibra prophylaxis (Arm A) or no prophylaxis (Arm B). Patients previously treated with BPAs as prophylaxis received Hemlibra prophylaxis (Arm C). Additional patients previously treated with on-demand BPAs were also enrolled in a separate arm (Arm D). On-demand treatment of breakthrough bleeds with BPAs was allowed per protocol in all arms.
The updated HAVEN 1 intra-patient analysis data presented at ASH (Free ASH Whitepaper) comparing treatment with Hemlibra prophylaxis to prior BPAs as prophylaxis or on-demand showed:

No new AEs resulted in treatment discontinuation. No new cases of TMA or thrombotic events were observed. As previously reported, three people experienced TMA events and two people experienced serious thrombotic events in the HAVEN 1 study when on average a cumulative amount of >100 U/kg/24 hours of activated prothrombin complex concentrate (aPCC) was administered for 24 hours or more to patients receiving Hemlibra prophylaxis.

About HAVEN 2 (NCT02795767)
HAVEN 2 is a single-arm, multicentre, open-label, clinical study in children younger than 12 years of age with haemophilia A with inhibitors to factor VIII. The study is evaluating the efficacy, safety and pharmacokinetics of once-weekly subcutaneous administration of Hemlibra prophylaxis.
The updated HAVEN 2 analysis after a median of nine weeks of treatment (range 1.6-41.6 weeks) included 60 children with haemophilia A with inhibitors to factor VIII. The updated data presented at ASH (Free ASH Whitepaper) showed:

The most common AEs related to Hemlibra were injection-site reactions. Six patients experienced serious AEs, including bleeding in the muscles (muscle haemorrhage), eye pain, catheter site infection, device-related infection, bleeding of the mouth or gums (mouth haemorrhage) and appendicitis. No cases of TMA or thrombotic events occurred in the study.

About HAVEN 4 (NCT03020160)
HAVEN 4 is a single-arm, multicentre, open-label, phase III study evaluating the efficacy, safety and pharmacokinetics (PK) of subcutaneous administration of Hemlibra dosed every four weeks. The study included 48 patients (12 years of age or older) with haemophilia A with or without inhibitors to factor VIII who were previously treated with either factor VIII or bypassing agents, on-demand or as prophylaxis.

The study was conducted in two parts: a PK run-in; and an expansion cohort. All patients in the PK run-in (n=7) were previously treated on-demand, and received subcutaneous Hemlibra at 6 mg/kg to fully characterise the PK profile after a single dose during four weeks, followed by 6 mg/kg every four weeks for at least 24 weeks. Patients in the expansion cohort (n=41) received subcutaneous Hemlibra prophylaxis at 3 mg/kg/wk for four weeks, followed by 6 mg/kg every four weeks for at least 24 weeks. Episodic treatment of breakthrough bleeds with factor VIII therapy or bypassing agents, depending on a patient’s inhibitor status, was allowed per study protocol.

About Hemlibra (emicizumab)
Hemlibra is a bispecific factor IXa- and factor X-directed antibody. It is designed to bring together factor IXa and factor X, proteins required to activate the natural coagulation cascade and restore the blood clotting process for haemophilia A patients. Hemlibra is a prophylactic (preventative) treatment that can be administered by an injection of a ready-to-use solution under the skin (subcutaneously). The clinical development programme is assessing the safety and efficacy of Hemlibra and its potential to help overcome current clinical challenges: the short-lasting effects of existing treatments, the development of factor VIII inhibitors and the need for frequent venous access. Hemlibra was created by Chugai Pharmaceutical Co., Ltd. and is being co-developed by Chugai, Roche and Genentech. It is marketed in the United States as Hemlibra (emicizumab-kxwh) for patients with factor VIII inhibitors, with kxwh as the suffix designated in compliance with Nonproprietary Naming of Biological Products Guidance for Industry issued by the US Food and Drug Administration.

About haemophilia A
Haemophilia A is an inherited, serious disorder in which a person’s blood does not clot properly, leading to uncontrolled and often spontaneous bleeding. Haemophilia A affects around 320,000 people worldwide,1,2 approximately 50-60% of whom have a severe form of the disorder.3 People with haemophilia A either lack or do not have enough of a clotting protein called factor VIII. In a healthy person, when a bleed occurs, factor VIII brings together the clotting factors IXa and X, which is a critical step in the formation of a blood clot to help stop bleeding. Depending on the severity of their disorder, people with haemophilia A can bleed frequently, especially into their joints or muscles.1 These bleeds can present a significant health concern as they often cause pain and can lead to chronic swelling, deformity, reduced mobility, and long-term joint damage.4 In addition to impacting a person’s quality of life,5 these bleeds can be life threatening if they go into vital organs, such as the brain.6,7 A serious complication of treatment is the development of inhibitors to factor VIII replacement therapies.8 Inhibitors are antibodies developed by the body’s immune system that bind to and block the efficacy of replacement factor VIII,9 making it difficult, if not impossible to obtain a level of factor VIII sufficient to control bleeding.

About Roche in haematology
For more than 20 years, Roche has been developing medicines that redefine treatment in haematology. Today, we are investing more than ever in our effort to bring innovative treatment options to people with diseases of the blood. In addition to approved medicines MabThera/Rituxan (rituximab), Gazyva/Gazyvaro (obinutuzumab), and Venclexta/Venclyxto (venetoclax) in collaboration with AbbVie, Roche’s pipeline of investigational haematology medicines includes Tecentriq (atezolizumab), an anti-CD79b antibody drug conjugate (polatuzumab vedotin/RG7596) and a small molecule antagonist of MDM2 (idasanutlin/RG7388). Roche’s dedication to developing novel molecules in haematology expands beyond malignancy, with the development of Hemlibra (emicizumab), a bispecific monoclonal antibody for the treatment of haemophilia A.