On December 9, 2017 Kadmon Holdings, Inc. (NYSE: KDMN) reported additional positive findings from an ongoing Phase 2 clinical trial demonstrating that KD025, its Rho-associated coiled-coil kinase 2 (ROCK2) inhibitor, was well tolerated and resulted in clinically meaningful responses in patients with chronic graft-versus-host disease (cGVHD) (Press release, , DEC 10, 2017, View Source [SID1234522516]). The results are being presented today in a poster at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Atlanta (Poster #3256).

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!

New data from Cohort 2 of the trial (KD025 200 mg BID; n=16) showed an Overall Response Rate (ORR) of 63%, as of a data cutoff date of November 20, 2017. Updated data from Cohort 1 (KD025 200 mg QD; n=17) showed an ORR of 65%. While data from Cohort 2 continue to mature, responses were durable in Cohort 1, lasting five months or longer in 70% of patients. Responses were also rapid: 71% of patients across Cohorts 1 and 2 achieved response by the first assessment (after 8 weeks of treatment). Responses were observed across all affected organs, including Complete Responses (CRs) in upper and lower gastrointestinal (GI) tract, mouth, skin, joints, esophagus, eyes and liver. In addition, 64% of patients from Cohorts 1 and 2 were able to reduce steroid dose, and four patients completely discontinued steroids. Eighty-three percent (83%) of patients were able to reduce dose of tacrolimus, another immunosuppressive agent used to treat cGVHD. KD025 was well tolerated, with no drug-related serious adverse events (SAEs) in either cohort.

"Treatment with KD025 has demonstrated clinical activity across multiple organs affected by cGVHD, including CRs in difficult-to-treat fibrotic manifestations such as those in eyes and joints," said Madan Jagasia, MD, MS, MMHC, Professor of Medicine; Chief, Section of Hematology-SCT, Medical Director, Division of Hematology-Oncology, Vanderbilt University Medical Center; Co-Leader, Translational Research and Interventional Oncology; Vanderbilt-Ingram Cancer Center; and study investigator. "In addition, KD025 has been well tolerated, with no drug-related SAEs, and does not appear to increase risk of infection, a common consequence of immunosuppressants frequently used to treat cGVHD."

"The overall response and durability of response observed are particularly compelling in this complex patient population, the majority of which had cGVHD involvement in four or more organs," said Harlan W. Waksal, M.D., President and CEO at Kadmon. "We will continue to observe response rate, durability and safety in this ongoing clinical trial as well as in future planned studies of KD025 in cGVHD."

The ASH (Free ASH Whitepaper) poster is now available on the Investors section of Kadmon.com, under "Presentations & Events." Additional data and analysis from the KD025-208 study will be provided on Monday, December 11, 2017, after market close (4:00 p.m. ET), via slides that will be available on the Investors section of Kadmon.com.

About KD025-208
KD025-208 is an ongoing Phase 2 clinical trial of KD025 for the treatment of cGVHD. The trial is being conducted in adults with steroid-dependent or steroid-refractory cGVHD and active disease. The dose-finding trial includes 48 patients divided into three cohorts at different dose levels (KD025 200 mg QD, 200 mg BID and 400 mg QD), enrolled sequentially following a safety assessment of each cohort. An expansion cohort of approximately 40 patients will be enrolled after the optimal dose has been determined. In October 2017, KD025 received orphan drug designation from the U.S. Food and Drug Administration for cGVHD.

About cGVHD
cGVHD is a common and often fatal complication following hematopoietic stem cell transplantation, a procedure that is often used to treat patients with cancers such as myeloma or leukemia. With cGVHD, transplanted immune cells (graft) attack the patient’s cells (host), leading to inflammation and fibrosis in multiple tissues, including skin, mouth, eye, joints, liver, lung, esophagus and GI tract.

On December 10, 2017 Novartis reported updated results from the JULIET clinical trial demonstrating sustained responses with KymriahTM (tisagenlecleucel) suspension for intravenous infusion, formerly CTL019, in adult patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) (Press release, Novartis, DEC 10, 2017, View Source [SID1234522495]). The data from this pivotal trial, led by researchers from the University of Pennsylvania (Penn), show an overall response rate (ORR) of 53% (95% confidence interval [CI], 42% – 64%; p<0.0001), with 40% achieving a complete response (CR) and 14% achieving a partial response (PR) among 81 infused patients with three or more months of follow-up or earlier discontinuation. At six months from infusion, the ORR was 37% with a CR rate of 30%. The median duration of response was not reached. Results from this study of Kymriah, the first-ever FDA-approved chimeric antigen receptor T cell (CAR-T) therapy, were included in the US and EU regulatory filings for Kymriah in r/r DLBCL and will be presented in an oral presentation at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting (Abstract #577; Monday, December 11, 7:00 AM EST)[1].

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!

"At the time of trial enrollment, these patients with DLBCL had been through multiple rounds of chemotherapy and many had unsuccessful stem cell transplants, leaving them with few options and a poor prognosis," said the study’s principal investigator Stephen J. Schuster, MD, the Robert and Margarita Louis-Dreyfus Professor in Chronic Lymphocytic Leukemia and Lymphoma Clinical Care and Research in the University of Pennsylvania’s (Penn) Perelman School of Medicine and director of the Lymphoma Program at the Abramson Cancer Center. "With tisagenlecleucel, we have been able to significantly increase their chance of achieving and maintaining a sustained response without stem cell transplant, demonstrating the therapy’s benefit in the treatment of this lethal blood cancer."

At month three, the CR rate was 32% and the PR rate was 6%, which remained consistent to month six (30% CR, 7% PR). Response rates were also consistent among prognostic subgroups, including patients who received prior autologous stem cell transplant (ASCT) and those with a subtype of DLBCL known as double-hit lymphoma, who historically have poor outcomes. No patients in response following treatment with Kymriah proceeded to stem cell transplant[1].

In the JULIET study, the relapse-free probability at six months after first response was 74% (95% CI, 52%-87%), and median duration of response was not reached. Median overall survival was also not reached (95% CI: 6.5 months to NE [not estimable]), and the median time from infusion to data cutoff was 5.6 months[1].

"While immediate response to treatment is a marker for efficacy, patients and physicians need treatment options that provide sustained responses over time with a consistent safety profile," said Samit Hirawat, MD, Head, Novartis Oncology Global Drug Development. "We look forward to continuing to work with health authorities to bring Kymriah to patients with relapsed or refractory DLBCL."

In the JULIET study, cytokine release syndrome (CRS) occurred in 58% of all treated patients, with 23% of patients experiencing grade 3/4 CRS (15% grade 3; 8% grade 4) using the Penn Grading Scale, a rigorous scale for grading CRS. CRS is a known complication of CAR-T therapy that may occur when the engineered cells become activated in the patient’s body. CRS was managed globally using prior site education on implementation of the CRS treatment algorithm[1].

Twenty one percent of patients experienced any grade neurologic events, and 12% of patients had grade 3/4 neurologic adverse events, which were managed with supportive care. Grade 3/4 cytopenias lasting more than 28 days, grade 3/4 infections and grade 3/4 febrile neutropenia occurred in 27%, 20% and 13% of patients, respectively. Three patients died from disease progression within 30 days of infusion. There were no deaths attributed to Kymriah, CRS or neurological events. No cerebral edema events were reported[1].

In the JULIET trial, 26 patients (26%) were infused in the outpatient setting; of those, 20 patients (77%) remained outpatient for three or more days after infusion. Forty-three patients discontinued before infusion and the majority did so due to rapid progression of their disease or deterioration in their clinical status. This reflects the acute and progressive nature of relapsed or refractory DLBCL. Only 9 of 147 (6.1%) enrolled patients could not be infused due to inability to manufacture an adequate dose of CAR-T cells. Over the course of JULIET, with continuous process improvements, manufacturing success rate improved to 97% for the last 30 patients.

JULIET is the first multi-center global registration study for Kymriah in adult patients with r/r DLBCL and the second global CAR-T cell therapy trial, following the Novartis ELIANA study of Kymriah in children and young adults with r/r B-cell acute lymphoblastic leukemia (ALL). JULIET was conducted in collaboration with Penn and enrolled patients from 27 sites in 10 countries across the US, Canada, Europe, Australia and Japan. In 2012, Novartis and Penn entered into a global collaboration to further research, develop and commercialize CAR-T cell therapies, including Kymriah, for the investigational treatment of cancers.

The results from JULIET build upon a pilot study of Kymriah in r/r DLBCL and follicular lymphoma published online today in the New England Journal of Medicine, which was led by and conducted at Penn and supported by Novartis and grants from the National Institutes of Health, as well as through philanthropic support. Among patients with r/r DLBCL, the study demonstrated an ORR and safety profile similar to results seen in JULIET. The study demonstrated sustained remissions at a follow up of 28.6 months among patients who responded at six months[2].

In April 2017, the US Food and Drug Administration (FDA) granted Breakthrough Therapy designation to Kymriah based on data from the JULIET study. In October 2017, Novartis submitted an application to the FDA for Kymriah in adult patients with r/r DLBCL who are ineligible for or relapse after ASCT, followed shortly by an application to the European Medicines Agency (EMA) in November for Kymriah for the treatment of adult patients with r/r DLBCL who are ineligible for ASCT, and for children and young adults with r/r B-cell ALL. Additional filings beyond the US and EU are anticipated in 2018.

Economic and Societal Value of Kymriah in ALL Presented at ASH (Free ASH Whitepaper)
Results of a cost-effectiveness analysis of Kymriah for the treatment of r/r B-cell ALL in the US will be presented in an oral presentation at the meeting (Abstract #609; Monday, December 11, 7:30 AM EST).

The analysis showed that, based on the current US list price of $475,000, Kymriah is cost-effective compared to standard of care. The analysis compared the life years and quality-adjusted life years gained with Kymriah compared to clofarabine monotherapy, clofarabine combination therapy, blinatumomab, other salvage chemotherapies and allogeneic stem cell transplant. Quality-adjusted life years is a measure of value of health outcomes based on disease burden, including both the quality and quantity of life lived[3].

In addition, results of another analysis to determine the potential societal value of Kymriah to patients with r/r ALL in the United Kingdom were presented in a poster presentation at the meeting (Abstract #1330; Saturday, December 9, 5:30 PM EST).

To quantify the societal value of Kymriah, the analysis looked at the economic value of the incremental quality adjusted life years gained along with the patient’s expected productivity using nationally representative data on employment rates and earnings. Results show that therapies such as Kymriah have the potential to provide benefit to patients and society, particularly through gains in survival, contributing to productivity[4].

About Kymriah
In August 2017, Kymriah became the first available chimeric antigen receptor T cell (CAR-T) therapy when it received FDA approval for children and young adults with B-cell acute lymphoblastic leukemia (ALL) that is refractory or has relapsed at least twice. Kymriah is a novel immunocellular therapy and a one-time treatment that uses a patient’s own T cells to fight cancer. Kymriah uses the 4-1BB costimulatory domain in its chimeric antigen receptor to enhance cellular expansion and persistence.

About Kymriah Manufacturing
Kymriah will be manufactured for each individual patient using their own cells at the Novartis Morris Plains, New Jersey facility. Novartis has successfully demonstrated a 22-day turnaround time for manufacturing Kymriah in the commercial setting, and this will continue to be the target. The reliable and integrated manufacturing and supply chain platform for Kymriah allows for an individualized treatment approach on a global scale. The process includes cryopreservation of a patient’s harvested (or leukapheresed) cells, giving treating physicians and centers the flexibility to initiate therapy with Kymriah based on the individual patient’s condition. Building on the company’s experience, having manufactured CAR-T cells for over 250 patients from 11 countries across various indications in clinical trials, it has demonstrated a high-quality and reproducible product. Novartis continues to advance its CAR-T manufacturing expertise and make investments to support the anticipated demand to meet the needs of patients.

About DLBCL
DLBCL is the most common form of non-Hodgkin lymphoma, a cancer of the lymphatic system, with an estimated 27,650 new cases diagnosed in 2016[5],[6]. Ten to 15% of DLBCL patients fail to respond to initial therapy or relapse within three months of treatment, and an additional 20% to 25% relapse after initial response to therapy[5]. Nearly 40% of patients with DLBCL will die of relapsed or refractory disease[7].

KymriahTM (tisagenlecleucel) Important Safety information (for pediatric and young adult patients with B-cell precursor acute lymphoblastic leukemia)
The full prescribing information, including Boxed WARNING, for Kymriah can be found at:
View Source

Kymriah may cause side effects that are severe or life-threatening, such as Cytokine Release Syndrome (CRS) or Neurological Toxicities. Patients with CRS may experience symptoms including high fever, difficulty breathing, chills/shaking chills, severe nausea, vomiting and diarrhea, severe muscle or joint pain, very low blood pressure, or dizziness/lightheadedness. Patients may be admitted to the hospital for CRS and treated with other medications.

Patients with neurological toxicities may experience symptoms such as altered or decreased consciousness, headaches, delirium, confusion, agitation, anxiety, seizures, difficulty speaking and understanding, or loss of balance. Patients should be advised to call their health care provider or get emergency help right away if they experience any of these signs and symptoms of CRS or neurological toxicities.

Because of the risk of CRS and neurological toxicities, Kymriah is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) in the US called Kymriah REMS.

Serious allergic reactions, including anaphylaxis, may occur after Kymriah infusion.
Kymriah can increase the risk of life-threatening infections that may lead to death. Patients should be advised to tell their health care provider right away if they develop fever, chills, or any signs or symptoms of an infection.

Patients may experience prolonged low blood cell counts (cytopenia), where one or more types of blood cells (red blood cells, white blood cells, or platelets) are decreased. The patient’s health care provider will do blood tests to check all of their blood cell counts after treatment with Kymriah. Patients should be advised to tell their health care provider right away if they get a fever, are feeling tired, or have bruising or bleeding.

Patients may experience hypogammaglobulinemia, a condition in which the level of immunoglobulins (antibodies) in the blood is low and the risk of infection is increased. It is expected that patients may develop hypogammaglobulinemia with Kymriah, and may need to receive immunoglobulin replacement for an indefinite amount of time following treatment with Kymriah. Patients should tell their health care provider about their treatment with Kymriah before receiving a live virus vaccine.

After treatment with Kymriah, patients will be monitored life-long by their health care provider, as they may develop secondary cancers or recurrence of their leukemia.

Patients should not drive, operate heavy machinery, or do other dangerous activities for 8 weeks after receiving Kymriah because the treatment can cause temporary memory and coordination problems, including sleepiness, confusion, weakness, dizziness, and seizures.

Some of the most common side effects of Kymriah are difficulty breathing, fever (100.4°F/38°C or higher), chills/shaking chills, confusion, severe nausea, vomiting and diarrhea, severe muscle or joint pain, very low blood pressure, and dizziness/lightheadedness. However, these are not all of the possible side effects of Kymriah. Patients should talk to their health care provider for medical advice about side effects.

Prior to a female patient starting treatment with Kymriah, their health care provider may do a pregnancy test. There is no information available for Kymriah use in pregnant or breast-feeding women. Therefore, Kymriah is not recommended for women who are pregnant or breast feeding. If either sex partner has received Kymriah, patients should talk to their health care provider about birth control and pregnancy.

Patients should tell their health care provider about all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

After receiving Kymriah, patients should be advised that some commercial HIV tests may cause a false positive test result. Patients should also be advised not to donate blood, organs, or tissues and cells for transplantation after receiving Kymriah.

Disclaimer
This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as "potential," "can," "will," "plan," "expect," "anticipate," "look forward," "believe," "committed," "investigational," "pipeline," "launch," or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for Kymriah, regarding our ability to scale and sustain commercial manufacturing for Kymriah, regarding our ability to build and sustain a network of treatment centers to offer Kymriah, or regarding potential future revenues from Kymriah. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that Kymriah will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Neither can there be any guarantee that Novartis will successfully scale and sustain commercial manufacturing for Kymriah, or successfully build and sustain a network of treatment centers to offer Kymriah. Nor can there be any guarantee that Kymriah will be commercially successful in the future. In particular, our expectations regarding Kymriah could be affected by, among other things, our ability to successfully scale and sustain commercial manufacturing and build and sustain a network of treatment centers; the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures; general economic and industry conditions, including the effects of the persistently weak economic and financial environment in many countries; safety, quality or manufacturing issues, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

On December 10, 2017 Agios Pharmaceuticals, Inc. (Nasdaq:AGIO) reported updated data today from its wholly owned pyruvate kinase-R (PKR) activator, AG-348, demonstrating its potential as the first disease-modifying treatment for patients with pyruvate kinase (PK) deficiency at the 2017 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Press release, Agios Pharmaceuticals, DEC 10, 2017, View Source [SID1234522569]). PK deficiency is a rare, potentially debilitating, congenital anemia.

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!

DRIVE PK is an ongoing global open-label, Phase 2, safety and efficacy trial evaluating AG-348 in 52 adult, transfusion-independent patients with PK deficiency. As of the July 14, 2017 data cut-off 43 patients had completed the six-month core dosing period and 9 patients discontinued treatment during the core dosing period. Of the 52 patients enrolled, 26 (50%) experienced a maximum hemoglobin (Hb) increase from baseline of >1.0 gram per deciliter (g/dL) during the six-month core period. For the 42 patients enrolled with at least 1 missense mutation, 25 (60%) experienced a maximum Hb increase from baseline of >1.0 g/dL. AG-348 remains well-tolerated with the majority of adverse events (AEs) being Grade 1 or 2. The median treatment duration was 37.5 weeks, with a maximum of 92.4 weeks.

"With some patients approaching two years of treatment, we are encouraged that AG-348 continues to be well-tolerated and demonstrates clinically relevant, sustained increases in hemoglobin in adults with PK deficiency," said Rachael Grace, M.D., of the Dana-Farber Boston Children’s Cancer and Blood Disorder Center and a principal investigator for the study. "AG-348 has the potential to be the first therapy for patients with PK deficiency that targets the underlying cause of this chronic anemia and its associated complications."

Patients in DRIVE PK were randomized to a starting dose of 50 mg or 300 mg twice daily, treated for six months in a core treatment period and then offered treatment in an extension period. Enrollment was completed in November 2016 with 52 patients. Nine subjects discontinued during the core treatment period. Thirty-six of 43 patients who completed the six month core treatment period entered the extension period. As of the data cut-off, 29 patients remain on treatment in the extension period.

"DRIVE PK has established a clear signal of activity for AG-348 in PK deficiency and was instrumental in informing the design of the pivotal program we are on track to initiate in the first half of 2018," said Chris Bowden, M.D., chief medical officer at Agios. "In addition to this clinical work, our planned global PKD patient registry will complement our patient finding efforts and further advance our understanding of the disease burden for this rare anemia."

Safety Data

A safety analysis conducted for all 52 treated patients as of the data cut-off shows that AG-348 continues to be well tolerated.

The majority of treatment-related AEs were Grade 1-2; the most frequent were headache, insomnia and nausea.
As previously reported, four patients experienced treatment-related AEs leading to discontinuation: pleural effusion (n=1), hypertriglyceridemia (n=1), pharyngitis/nausea (n=1) and anemia (n=1).
As previously reported, four patients experienced treatment-related serious adverse events: withdrawal hemolysis followed by anemia (n=1), anemia (n=1), osteoporosis (n=1) and hypertriglyceridemia (n=1).
A previously reported case of drug-related pharyngitis (n=1) was subsequently deemed unrelated to study drug.
Measurements of hormone levels in men at doses ≤50 mg BID suggest mild aromatase inhibition by AG-348; ongoing follow-up will continue to assess potential clinical significance.
Efficacy Data

In the efficacy analysis 26 of 52 patients (50%) overall and 25 of 42 patients (60%) with at least one missense mutation achieved rapid and sustained Hb increases from baseline of >1.0 g/dL as of the data cut-off.

In patients who had Hb increases of >1.0 g/dL, the mean maximum Hb increase was 3.4 g/dL (range 1.1-5.8 g/dL).
The median time to first Hb increase of >1.0 g/dL was 10 days (range 7–187 days).
As previously reported, the median baseline Hb in patients who experienced a maximum Hb increase of >1.0 g/dL was 9.7 g/dL (range 7.3–12.3 g/dL) vs. 8.0 g/dL (range 6.5–10.1 g/dL) in patients who did not experience the increase.
Pivotal Development Plan

Agios plans to initiate two global, pivotal trials in adults with PK deficiency in the first half of 2018 based on transfusion status:

A randomized, placebo-controlled trial with a 1:1 randomization known as ACTIVATE is expected to enroll approximately 80 patients who do not receive regular transfusions. The primary endpoint of the trial is the proportion of patients who achieve a sustained hemoglobin increase ≥1.5 g/dL.
A single arm trial of approximately 20 regularly transfused patients known as ACTIVATE-T will have a primary endpoint of reduction in transfusion burden over six months.
About Pyruvate Kinase Deficiency and Genetic Background

PK deficiency is a rare inherited disease that presents as hemolytic anemia, which is the accelerated destruction of red blood cells. The inherited mutations in PKR enzymes cause a deficit in cellular energy within the red blood cell, as evidenced by lower pyruvate kinase enzyme activity and a decline in ATP (adenosine triphosphate) levels and a build-up of upstream metabolites, including 2,3-DPG (2,3-diphosphoglycerate).

The current standard of care for PK deficiency is supportive, including blood transfusions, splenectomy, chelation therapy to address iron overload and/or interventions for other treatment- and disease-related morbidities. There is no approved therapy to treat the underlying cause of PK deficiency.

PK deficiency is an autosomal recessive disease whereby all patients inherit two mutations, one from each parent. More than 250 different mutations have been identified to date. The mutations observed in PK deficiency patients are classified in two main categories. A missense mutation causes a single amino acid change in the protein, generally resulting in some functional protein. A non-missense mutation is any mutation other than a missense mutation, generally resulting in little functional protein. It is estimated that 58 percent of patients with PK deficiency have two missense mutations, 27 percent have one missense and one non-missense mutation, and 15 percent have two non-missense mutations1.

Boston Children’s Hospital, in collaboration with Agios, is conducting a Natural History Study to better understand the symptoms and complications of PK deficiency, identify patients and treatment centers, and capture other clinical data, including quality of life measures and genetic information.

On December 10, 2017 Seattle Genetics, Inc. (Nasdaq: SGEN) reported final five-year survival results from a phase 1 clinical trial evaluating ADCETRIS (brentuximab vedotin) in mature T-cell lymphoma (MTCL) 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 10, 2017, View Source;p=RssLanding&cat=news&id=2321959 [SID1234522496]). The presentation highlighted durability data from a phase 1 clinical trial of ADCETRIS in combination with chemotherapy for the treatment of patients with newly diagnosed MTCL, also known as peripheral T-cell lymphoma (PTCL). ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, which is expressed on the surface of Hodgkin lymphoma cells and several types of non-Hodgkin lymphoma. ADCETRIS is currently not approved for the frontline treatment of MTCL.

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!

"Approximately 4,000 patients are diagnosed with MTCL each year. The current standard of care for frontline MTCL treatment has not changed for several decades and there remains a significant need for improved therapeutic options. The results of this phase 1 trial support the ongoing phase 3 ECHELON-2 clinical trial and our goal to redefine frontline MTCL treatment with a novel ADCETRIS combination regimen," said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. "The final results from the phase 1 study were presented today, with five-year progression-free survival and overall survival rates of 52 and 80 percent, respectively. No patients have experienced any disease progression events since the three-year follow-up results. Importantly, after more than five years of follow-up, patients who remain in remission have the potential to be cured. These data continue to support the phase 3 ECHELON-2 trial, from which we anticipate reporting data in 2018."

Five-Year Survival Results: Frontline Brentuximab Vedotin in Combination with CHP in Patients with CD30-Expressing Peripheral T-Cell Lymphomas (Abstract #2790, poster presentation on Sunday, December 10, 2017)

Data were reported from 26 frontline MTCL patients who received the combination regimen of ADCETRIS plus cyclophosphamide, doxorubicin and prednisone (CHP). Patients who achieved at least a partial remission with combination therapy following six cycles of ADCETRIS plus CHP were eligible to receive up to ten additional cycles of single-agent ADCETRIS treatment. The median age of patients was 56 years. Nineteen patients (73 percent) had a subtype of MTCL called systemic anaplastic large cell lymphoma (sALCL), including 16 patients with anaplastic lymphoma kinase (ALK)-negative disease, which is typically associated with a poor prognosis. Seven patients (27 percent) had a diagnosis of other types of MTCL. The majority of patients had advanced stage disease and were considered high risk. All patients on the trial achieved an objective response, including 92 percent with a complete response and eight percent with a partial response.

Updated key findings based on a median observation time of 60 months from first dose of therapy include:

At five-year follow-up, there have been no progression events or deaths in this trial since the three-year follow up.
The estimated five-year progression-free survival rate was 52 percent, with no patients receiving a consolidative stem cell transplant in first remission. The median progression-free survival has not yet been reached.
The estimated five-year overall survival rate was 80 percent. The median overall survival has not yet been reached.
Seventy-three percent of patients (19 of 26) experienced peripheral neuropathy, the majority of which was Grade 1 or 2. Ninety-five percent of these patients had complete resolution or some improvement of their symptoms at last follow-up with a median time to resolution of 4.2 months and median time to improvement of symptoms was 2.6 months.
A global phase 3 study called ECHELON-2 completed enrollment in November 2016. The ECHELON-2 trial is a randomized, double-blind, placebo-controlled, multi-center trial designed to investigate ADCETRIS plus CHP versus CHOP as frontline therapy in patients with CD30-expressing MTCL. The trial enrolled 452 patients (approximately 225 patients per treatment arm) randomized to receive ADCETRIS plus CHP or CHOP every three weeks for six to eight cycles. Data from the ECHELON-2 trial are expected in 2018.

About T-Cell Lymphomas

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. Non-Hodgkin lymphomas are broadly divided into two major groups: B-cell lymphomas, which develop from abnormal B-lymphocytes, and T-cell lymphomas, which develop from abnormal T-lymphocytes. T-cell lymphomas account for approximately 15 percent of all non-Hodgkin lymphoma in the United States. There are many different forms of T-cell lymphomas, some of which are extremely rare. T-cell lymphomas can be aggressive (fast-growing) or indolent (slow-growing). Almost all types of T-cell lymphoma fall under the category of mature T-cell lymphoma, also known as peripheral T-cell lymphoma. According to the American Cancer Society and analysis of literature sources, approximately 4,300 patients will be diagnosed with CD30-expressing mature T-cell lymphoma in the United States during 2017.

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 10, 2017 bluebird bio, Inc. (Nasdaq: BLUE), a clinical-stage company committed to developing potentially transformative gene therapies for severe genetic diseases and T cell-based immunotherapies for cancer, reported data from two studies of its LentiGlobin gene therapy product candidate in patients with transfusion-dependent β-thalassemia (TDT) (Press release, bluebird bio, DEC 10, 2017, View Source [SID1234522484]). Data from the Northstar (HGB-204) and Northstar-2 (HGB-207) studies were presented today at the 59th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) by Janet Kwiatkowski, M.D., MSCE, of Children’s Hospital of Philadelphia, and Mark C. Walters, M.D., of UCSF Benioff Children’s Hospital, respectively.

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!

"Addressing the underlying genetic cause of TDT to restore production of functional hemoglobin can potentially eliminate or reduce the need for chronic blood transfusions in people with this disease, which we expect will reduce the risk of iron overload and associated long-term complications of TDT, and may allow cessation of chelation therapy," said Dave Davidson, chief medical officer, bluebird bio. "Northstar-2 is the first clinical trial to use our refined manufacturing process for LentiGlobin drug product. Early data from this study demonstrates consistently higher in vivo vector copy numbers and HbAT87Q hemoglobin levels, potentially enabling patients to consistently achieve near-normal or normal total hemoglobin levels. It is important to demonstrate the long-term benefit of gene therapy, and follow-up data of up to three years from the first Northstar study show that nearly all patients with non-β0/β0 genotypes were transfusion-free. We are engaged with the regulatory authorities in the context of the Breakthrough Designation from FDA, and PRIME and Adaptive Pathways from EMA, and look forward to submitting these data to seek marketing approval for LentiGlobin in TDT."

"People with transfusion-dependent thalassemia need regular blood transfusions to survive, but chronic transfusions lead to unavoidable iron overload that can result in multi-organ damage and shortened life span. Eliminating or reducing the need for transfusions can reduce the risk of these long-term complications," said Janet L. Kwiatkowski, MD, MSCE, Director of the Thalassemia Program at the Children’s Hospital of Philadelphia and Associate Professor of Pediatrics at the Perelman School of Medicine of the University of Pennsylvania, and a primary investigator of the Northstar and Northstar-2 studies. "The growing body of data from the Northstar studies indicate LentiGlobin gene therapy may enable transfusion independence for the majority of patients with non-β0/β0 genotypes – and that this effect has been durable during the 3 years of follow-up."

Clinical Outcomes up to 3 Years Following LentiGlobin Gene Therapy for Transfusion-Dependent β-Thalassemia in the Northstar HGB-204 Study (Oral Abstract #360)
Presenter: Janet Kwiatkowski, M.D., MSCE, Children’s Hospital of Philadelphia, Philadelphia, PA
Date and Time: Sunday, December 10 at 10:45 a.m.
Location: Building B, Level 2, B213-B214

The Northstar study is an open-label, single-dose, international, multi-center Phase 1/2 study designed to evaluate the efficacy and safety of LentiGlobin for the treatment of patients with TDT. The study has completed its treatment phase and 18 patients with TDT (eight with β0/β0 and 10 with non-β0/β0 genotypes) received LentiGlobin drug product (DP). Results as of September 21, 2017 include:

All 18 patients have ≥18 months follow up, with 10 completing two-year analysis. Three patients have three years of follow up (median follow-up: 27.4 months; min-max: 17.5-36.5 months).
Nine of ten patients with non-β0/β0 genotypes were free from chronic transfusions for a median of 29 months (range: 14.7-33.1 months).
Patients with non-β0/β0 genotypes who were able to achieve freedom from chronic transfusions had HbAT87Q concentrations of 3.6-9.3.
The one patient with a non-β0/β0 genotype who still required periodic transfusions was treated with LentiGlobin with a VCN in the lower range (VCN: 0.3 copies/diploid genome).
Two of eight patients with β0/β0 genotypes have not received a transfusion in more than a year (16.7 months and 15.7 months). At the patients’ last study visits (Month 36 and Month 18, respectively), total hemoglobin levels were 10.2 and 10.3 g/dL and HbAT87Q levels were 9.7 and 7.0 g/dL, respectively.
Clinically meaningful reductions in transfusion volume and frequency were observed in five of the six patients with β0/β0 genotypes who have continued to receive transfusions.
For the 18 study participants, the median DP vector copy number (VCN) was 0.7 (range: 0.3-1.5) copies/diploid genome, the median cell dose was 8.1 (range: 5.2-18.1) x 106 CD34+ cells/kg, and the proportion of transduced CD34+ cells was 17-58 percent.
The safety profile of LentiGlobin DP continues to be consistent with myeloablative conditioning with single-agent busulfan. No Grade 3 or higher DP-related adverse events (AEs) have been observed, and there is no evidence of clonal dominance.
All study participants remain enrolled in the trial, and there have been no reports of graft versus host disease (GVHD).
Results from the HGB-207 (Northstar-2) Trial: A Phase 3 Study to Evaluate Safety and Efficacy of LentiGlobin Gene Therapy for Transfusion-Dependent β-thalassemia (TDT) in Patients with non-β0/β0 Genotypes (Oral Abstract #526)
Presenter: Mark C. Walters, M.D., UCSF Benioff Children’s Hospital, Oakland, Calif.

Date and Time: Sunday, December 10 at 5:15 p.m.
Location: Building C, Level 1, C101 Auditorium

The Northstar-2 study is an ongoing, open-label, single-dose, international, multicenter Phase 3 study designed to evaluate the efficacy and safety of LentiGlobin for the treatment of patients with TDT and non-β0/β0 genotypes. As of December 1, 2017, drug product had been manufactured for 10 patients. The median LentiGlobin DP VCN these patients received was 3.3 (range: 2.4-5.4) copies/diploid genome) compared to a median DP VCN of 0.7 (range: 0.3-1.5) copies/diploid genome in the Phase 1/2 Northstar study. Results in treated patients, ages 15 to 24 years, include:

Seven patients had been infused with LentiGlobin as of October 13, 2017. The median follow-up was 3 months (range: 1-9 months).
All three patients who have ≥6 months follow-up are transfusion-free, and 2/3 have achieved or are approaching a normal total hemoglobin level (up to 12.5 g/dl total Hb; range in three patients: 8.4 – 12.5) without transfusions (up to 10.2 g/dL vector-derived HbAT87Q).
Five of six patients treated in the study with ≥3 months follow-up data available as of December 1, 2017 are making at least 6 g/dL of HbAT87Q.
The safety profile of LentiGlobin to date is similar to that observed in the Northstar study, and consistent with myeloablative conditioning with single-agent busulfan. No DP-related AEs have been observed.
All study participants remain enrolled in the trial, and there have been no reports of graft failure or graft versus host disease (GVHD).
Webcast Information
bluebird bio will host a webcast at 8:30 p.m. ET on Sunday, December 10, 2017. The webcast can be accessed under "Calendar of Events" in the Investors and Media section of the company’s website at www.bluebirdbio.com.

About TDT
Transfusion-dependent β-thalassemia (TDT) is a severe genetic disease characterized by reduced or absent hemoglobin levels that results in severe anemia and ineffective red blood cell production. Supportive care for people with TDT consists of a lifelong regimen of chronic blood transfusions to enable survival and suppress symptoms of the disease, and iron chelation therapy to manage iron overload that results from the transfusions. Despite the availability of supportive care, many people with TDT experience serious complications and organ damage due to underlying disease and iron overload.

Allogeneic hematopoietic stem cell transplant (HSCT) is currently the only available option to address the underlying genetic cause of TDT, though it carries significant risks. Complications of allogeneic HSCT include a risk of treatment-related mortality, graft failure, graft-versus-host disease (GvHD) and opportunistic infections, particularly in patients who undergo non-sibling matched allogenic HSCT.