On December 10, 2017 Incyte Corporation (Nasdaq:INCY) reported new 208-week (4-year) follow-up data from the ongoing, global, multi-center, open-label Phase 3 RESPONSE study of Jakafi (ruxolitinib) comparing the efficacy and safety of Jakafi with best available therapy (BAT) in patients with polycythemia vera (PV) who are resistant to or intolerant of hydroxyurea (HU) (Press release, Incyte, DEC 10, 2017, View Source;p=RssLanding&cat=news&id=2321950 [SID1234522490]). The pre-planned data analysis showed a durable primary response to Jakafi in patients with PV who are resistant to or intolerant of HU and the overall safety profile for Jakafi remained consistent with previously reported 80-week RESPONSE data.1 The results were shared in an oral presentation today at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting 2017 in Atlanta, Georgia.

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"With 30 months of additional follow-up, the four-year RESPONSE data analysis presented today at ASH (Free ASH Whitepaper) further reinforces the potential of Jakafi as a long-term option for patients with PV," said Peg Squier, M.D., Ph.D., Head of U.S. Medical Affairs at Incyte. "Given the few treatment options available to treat this chronic and progressive blood cancer, these long-term safety and efficacy data are meaningful to patients with uncontrolled PV."

The 80-week follow-up results from RESPONSE confirmed that among patients who initially responded to Jakafi treatment, the probability of maintaining primary and hematocrit (Hct) responses for ≥ 80 weeks was 92% and 89%, respectively, and hence Jakafi could be an effective long-term treatment option for patients with PV who are HU-resistant or intolerant.

At the week 208 analysis, the overall long-term safety profile remained consistent with the 80-week data analysis and the response was durable. In both the Jakafi arm and the crossover population, around 30% of patients completed the study treatment and 37% of patients were still receiving treatment.

"These are clinically relevant long-term safety and efficacy results, and further support the use of Jakafi in PV patients who have an inadequate response to or are intolerant of hydroxyurea," said Srdan Verstovsek, M.D., Ph.D., medical oncologist and professor, Department of Leukemia at The University of Texas MD Anderson Cancer Center, Houston, Texas.

About the RESPONSE Trial

RESPONSE is an ongoing, global, multi-center, open-label, Phase 3 trial comparing the efficacy and safety of Jakafi (ruxolitinib) with BAT in 222 patients (Jakafi, 110; BAT, 112) with PV who are resistant to or intolerant of hydroxyurea (HU).2

The primary response was a composite endpoint of the proportion of patients who achieved both hematocrit (Hct) control (defined as no phlebotomy eligibility from week 8 through week 32, with no more than 1 post-randomization phlebotomy eligibility up to week 8) and a spleen volume reduction of at least 35% from baseline at week 32. Phlebotomy eligibility was defined as an Hct >45% and at least 3 percentage points greater than baseline or an Hct >48%. Patients randomized to BAT could crossover (CO) to ruxolitinib at week 32 if they did not meet the primary endpoint, or after week 32 in case of disease progression (PBT eligibility, splenomegaly progression, or both).2

The primary endpoint of the RESPONSE study was achieved, demonstrating that Jakafi was superior to BAT at controlling Hct and reducing spleen volume at week 32.2 The 80-week follow-up results from RESPONSE have been published previously and confirmed that ruxolitinib could be an effective long-term therapy option for HU-resistant/intolerant (R/I) patients with PV.3

Durability of the primary response, overall clinicohematologic (CLHM) response (defined as Hct control, platelet count ≤ 400 × 109/L, white blood cell count ≤ 10 × 109/L, and spleen volume reduction ≥ 35% by imaging), as well as long-term safety were updated at week 208.1

At week 208, the Kaplan-Meier (KM) estimate of duration of primary response was 0.73 (95% CI: 0.49, 0.87), and the KM estimate of duration of absence of PBT eligibility was 0.73 (95% CI: 0.60, 0.83). The KM estimate of duration of at least 35% reduction in spleen volume was 0.86 (95% CI: 0.61, 0.95). Median duration of primary and CLHM responses has not been reached.1

Out of the 70 patients (63.6%) in the Jakafi arm who achieved an overall CLHM response at week 32, 21 had progressed by week 208. The KM estimate of duration of complete hematological remission (defined as Hct control, platelet count ≤ 400 × 109/L, and white blood cell count ≤ 10 × 109/L) at 208-weeks was 0.54 (95% CI: 0.31, 0.72). RESPONSE data also demonstrated that the KM estimate for overall survival at 5-years was 90.6% (95% CI: 80.1, 95.7) for patients treated with Jakafi compared to 87.7% (95% CI: 74.8, 94.3) for patients treated with BAT.1

At the week 208 analysis, 41 patients (37%) originally randomized to the Jakafi arm were still receiving therapy (median exposure, 225 weeks) versus no patients on BAT (median exposure, 34 weeks). Among patients in the Jakafi arm, 29% completed the treatment as per protocol. Of the 98 patients who crossed over to Jakafi after week 32, 38% remained on Jakafi (median exposure, 189 weeks) and 31% completed treatment. Other main reasons for the study drug discontinuations (Jakafi + CO patients) were disease progression (11% + 8%), patient decision (6% + 6%), and adverse events (14% + 14%).1

The most common adverse events in the Jakafi randomized arm (week 208 vs week 80) per 100 patient-years of exposure were anemia (9.3 vs 13.2), pruritus (7.3 vs 9.7), diarrhea (7.1 vs 9.7), headache (6.1 vs 10.5), arthralgia (5.9 vs 6.1), increased weight (5.6 vs 7.5) and muscle spasms (5.4 vs 7.9).

The 208-week results (Abstract #322) were presented as a part of an oral session (#634) on Sunday, December 10, 2017, 7:30-9:00 AM Eastern Time (8:15 AM), Building C, Level 2, C208-C210.

About Polycythemia Vera (PV)

Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) and is typically characterized by elevated hematocrit, the percent volume of red blood cells in the blood, which can lead to a thickening of the blood and an increased risk of blood clots. An elevated white blood cell and/or platelet count may also be present.4 Patients with PV who fail to consistently maintain appropriate hematocrit levels have a four times higher risk of major thrombosis (blood clots) or cardiovascular death.5 Patients with PV can also suffer from an enlarged spleen and a significant symptom burden which may be attributed to thickening of the blood and lack of oxygen to parts of the body.6 Signs and symptoms of PV commonly include fatigue, itching, night sweats, bone pain, fever, and unexplained weight loss.7

Approximately 100,000 patients in the U.S. are living with PV.8 Current standard treatment for PV is phlebotomy (the removal of blood from the body) plus aspirin. When phlebotomy can no longer control PV, chemotherapy such as hydroxyurea, or interferon, is utilized in high-risk patients.9,10 Approximately one in four patients with PV are considered uncontrolled11,12 because they have an inadequate response to or are intolerant of hydroxyurea, the most commonly used chemotherapeutic agent for the treatment of PV.

About Jakafi (ruxolitinib)

Jakafi is a first-in-class JAK1/JAK2 inhibitor approved by the U.S. Food and Drug Administration for treatment of people with polycythemia vera (PV) who have had an inadequate response to or are intolerant of hydroxyurea.

Jakafi is also indicated for treatment of people with intermediate or high-risk myelofibrosis (MF), including primary MF, post–polycythemia vera MF, and post–essential thrombocythemia MF.

Jakafi is marketed by Incyte in the United States and by Novartis as Jakavi (ruxolitinib) outside the United States. Jakafi is a registered trademark of Incyte Corporation. Jakavi is a registered trademark of Novartis AG in countries outside the United States.

Important Safety Information

Jakafi can cause serious side effects, including:

Low blood counts: Jakafi (ruxolitinib) may cause your platelet, red blood cell, or white blood cell counts to be lowered. If you develop bleeding, stop taking Jakafi and call your healthcare provider. Your healthcare provider will perform blood tests to check your blood counts before you start Jakafi and regularly during your treatment. Your healthcare provider may change your dose of Jakafi or stop your treatment based on the results of your blood tests. Tell your healthcare provider right away if you develop or have worsening symptoms such as unusual bleeding, bruising, tiredness, shortness of breath, or a fever.

Infection: You may be at risk for developing a serious infection during treatment with Jakafi. Tell your healthcare provider if you develop any of the following symptoms of infection: chills, nausea, vomiting, aches, weakness, fever, painful skin rash or blisters.

Skin cancers: Some people who take Jakafi have developed certain types of non-melanoma skin cancers. Tell your healthcare provider if you develop any new or changing skin lesions.

Increases in Cholesterol: You may have changes in your blood cholesterol levels. Your healthcare provider will do blood tests to check your cholesterol levels during your treatment with Jakafi.

The most common side effects of Jakafi include: low platelet count, low red blood cell counts, bruising, dizziness, headache.

These are not all the possible side effects of Jakafi. Ask your pharmacist or healthcare provider for more information. Tell your healthcare provider about any side effect that bothers you or that does not go away.

Before taking Jakafi, tell your healthcare provider about: all the medications, vitamins, and herbal supplements you are taking and all your medical conditions, including if you have an infection, have or had tuberculosis (TB), or have been in close contact with someone who has TB, have or had hepatitis B, have or had liver or kidney problems, are on dialysis, had skin cancer or have any other medical condition. Take Jakafi exactly as your healthcare provider tells you. Do not change or stop taking Jakafi without first talking to your healthcare provider. Do not drink grapefruit juice while on Jakafi.

Women should not take Jakafi while pregnant or planning to become pregnant, or if breast-feeding.

Full Prescribing Information, which includes a more complete discussion of the risks associated with Jakafi, is available at www.jakafi.com.

On December 10, 2017 Acceleron Pharma Inc. (NASDAQ:XLRN), a leading biopharmaceutical company in the discovery and development of TGF-beta therapeutics to treat serious and rare diseases, reported preliminary results from the ongoing Phase 2 trials with luspatercept in patients with lower-risk myelodysplastic syndromes (MDS) at the 59th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in Atlanta, Georgia (Press release, Acceleron Pharma, DEC 10, 2017, View Source [SID1234522480]). Luspatercept is being developed as part of a global collaboration between Acceleron and Celgene.

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"As the Phase 2 results in MDS mature, we are excited to see luspatercept achieving a clinically meaningful erythroid response in over 50% of patients. Luspatercept continues to provide long-term benefit to multiple patients now nearing three years on treatment. These results further reinforce luspatercept’s potential to be a transformative treatment option for patients living with lower-risk MDS," said Habib Dable, President and Chief Executive Officer of Acceleron. "We look forward to the upcoming MEDALIST and BELIEVE Phase 3 trial top-line data readouts in mid-2018, and we and Celgene continue to make considerable progress toward initiating the COMMANDS Phase 3 trial during the first half of 2018."

Phase 2 Results

A total of 99 lower-risk MDS patients have been treated with therapeutic dose levels of luspatercept (≥ 0.75 mg/kg) in the ongoing Phase 2 trials.

53% (52 of 99 patients) achieved a clinically meaningful erythroid response of an increase in hemoglobin or reduction in red blood cell (RBC) transfusion burden as per the International Working Group’s Hematologic Improvement Erythroid (IWG HI-E) response criteria.
43% (29 of 67 patients) with an RBC transfusion burden at baseline of ≥ 2 units per 8 weeks achieved RBC transfusion independence (RBC-TI) for ≥ 8 weeks.
In an updated analysis of the 23 RBC-TI responders previously reported at EHA (Free EHA Whitepaper) 2017, the median duration of treatment increased to 19.0 months from 14.7 months. The current duration of treatment for RBC-TI responders ranges from 2.8 months to 37.3 months.
Patients with a low transfusion burden at baseline ( < 4 RBC units per 8 weeks and hemoglobin < 10 g/dL) demonstrated a clinically meaningful increase in hemoglobin for up to 34 months, with multiple ongoing.
The results presented at ASH (Free ASH Whitepaper) 2017 confirm and extend previously reported results across the lower-risk MDS patient subpopulations, showing erythroid responses regardless of prior use of erythropoiesis-stimulating agents (ESA), baseline erythropoietin (EPO) levels, and ring sideroblast (RS) status.

Phase 2 Safety Summary

A total of 106 lower-risk MDS patients have been treated with luspatercept in the ongoing Phase 2 trials (all dose levels).

The majority of adverse events (AEs) were Grade 1 or 2. AEs possibly or probably related to study drug that occurred in at least three patients during the studies were headache, hypertension, fatigue, bone pain, diarrhea, arthralgia, injection site erythema, myalgia, and edema peripheral.
Grade 3 non-serious AEs possibly related to study drug were ascites, blast cell count increase, blood bilirubin increase, bone pain, hypertension, mucosal inflammation, platelet count increase, and pleural effusion. These Grade 3 non-serious AEs occurred in seven individual patients with one patient reporting both the ascites and pleural effusion.
Serious AEs (SAEs) possibly related to study drug were general physical health deterioration, muscular weakness, musculoskeletal pain, and myalgia. These SAEs occurred in three individual patients with one patient reporting both the muscular weakness and musculoskeletal pain.
The MEDALIST trial, a global Phase 3 trial of luspatercept in lower-risk MDS patients, is fully enrolled with top-line results expected in mid-2018. The MEDALIST trial enrolled patients who are RS-positive, RBC transfusion dependent, and are ESA-refractory or ESA-treatment ineligible, based on EPO levels greater than 200 units per liter at baseline. Acceleron and Celgene plan to initiate the COMMANDS Phase 3 trial in first-line, lower-risk MDS patients during the first half of 2018.

The MDS clinical poster presentation is available under the Science page of the Company’s website at www.acceleronpharma.com.

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

Acceleron ASH (Free ASH Whitepaper) Conference Call Information

Acceleron will host a conference call and live webcast to discuss data presented at the ASH (Free ASH Whitepaper) meeting on December 11, 2017, at 7:00 a.m. EST.

Individuals can participate in the conference call by dialing 877-312-5848 (domestic) or 253-237-1155 (international) and refer to the "Acceleron ASH (Free ASH Whitepaper) 2017 Update."

The webcast will be accessible under "Events & Presentations" in the Investors/Media page of the Company’s website at www.acceleronpharma.com.

A replay of the webcast will be available approximately two hours after the event.

About the Ongoing MDS Phase 2 Studies

Data from two Phase 2 trials were presented at the conference: the base study in which patients received treatment with luspatercept for three months and the long-term extension study in which patients who completed the base study may receive treatment with luspatercept for up to an additional five years. In both the three-month base study and the long-term extension study, lower-risk MDS patients were enrolled and treated with open-label luspatercept, dosed subcutaneously once every three weeks.

The outcome measures for the trials included the proportion of patients who had an erythroid response (IWG HI-E) or achieved RBC transfusion independence (RBC-TI). IWG HI-E was defined as hemoglobin increase ≥ 1.5 g/dL sustained for ≥ 8 weeks in patients with < 4 units RBC / 8 weeks transfusion burden at baseline and hemoglobin levels below 10 g/dL. For patients with a ≥ 4 units RBC / 8 weeks transfusion burden at baseline, erythroid response was defined as a reduction of ≥ 4 units RBC sustained for ≥ 8 weeks. RBC-TI was defined as receiving no RBC transfusions for ≥ 8 weeks in patients with a ≥ 2 units RBC / 8 weeks baseline transfusion burden.

About Luspatercept

Luspatercept is a modified activin receptor type IIB fusion protein that acts as a ligand trap for members of the TGF-beta superfamily involved in the late stages of erythropoiesis (red blood cell production). Luspatercept is a first-in-class erythroid maturation agent (EMA) that regulates late-stage erythrocyte (red blood cell) precursor cell differentiation. This mechanism of action is distinct from that of erythropoiesis stimulating agents (ESAs), which stimulate the proliferation of early-stage erythrocyte precursor cells. Acceleron and Celgene are jointly developing luspatercept as part of a global collaboration. Phase 3 clinical trials are underway to evaluate the safety and efficacy of luspatercept in patients with myelodysplastic syndromes (the MEDALIST trial) and in patients with beta-thalassemia (the BELIEVE trial). A Phase 3 trial is being planned in first-line, lower-risk, myelodysplastic syndromes patients (the COMMANDS trial). For more information, please visit www.clinicaltrials.gov.

On December 10, 2017 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported positive results from the randomised phase II GO29365 study that compared polatuzumab vedotin in combination with bendamustine plus MabThera/Rituxan (rituximab) (BR) against BR alone in people with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are not candidates for haematopoietic stem cell transplant (Press release, Hoffmann-La Roche, DEC 10, 2017, View Source [SID1234522488]). The study met its primary endpoint, demonstrating that the addition of polatuzumab vedotin to BR increased complete response (CR) rates from 15% to 40% (p=0.012) at the end of treatment, as measured by positron emission tomography (PET) and assessed by an independent review committee (IRC). No unexpected safety signals were observed with the addition of polatuzumab vedotin to BR.

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"As many as forty percent of people with diffuse large B-cell lymphoma do not respond to initial therapy or experience the return of their disease, at which point their treatment options are limited and the prognosis is poor," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "The promising efficacy observed for polatuzumab vedotin in this study supports its potential as a new treatment option for people previously treated for this aggressive blood cancer, and we look forward to discussing the results with health authorities."

The data will be presented in a poster session on Sunday, 10 December at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting by Laurie Sehn, MD, British Columbia Cancer Agency/University of British Columbia.
The results showed:

Polatuzumab vedotin plus BR significantly improved CR rates from 15% with BR alone to 40% (p=0.012), as measured by PET and assessed by IRC. A CR means no cancer could be detected at that time.
The benefit observed was consistent across secondary endpoints, including improvements in investigator-assessed best objective response (OR; CR and partial response, PR) and CR with polatuzumab vedotin plus BR (70.0% OR, 57.5% CR) compared to BR alone (32.5% OR, CR 20.0%).

Exploratory endpoints also improved with the addition of polatuzumab vedotin to BR:
Patients treated with polatuzumab vedotin plus BR lived longer than those receiving BR alone (median overall survival; 11.8 months vs. 4.7 months; HR 0.35; 95% CI 0.19-0.67; p=0.0008).
The addition of polatuzumab vedotin also increased the time until disease worsening or death (median progression-free survival: 6.7 months vs. 2.0 months; HR 0.31; 95% CI 0.18-0.55; p<0. 0001), and the time between first response to treatment and disease worsening (duration of response: 8.8 months vs. 3.7 months).
No unexpected safety signals were observed with the addition of polatuzumab vedotin to BR. The most common Grade 3-4 adverse events with polatuzumab vedotin plus BR compared to BR alone, respectively, were low white blood cell count (46.2% vs. 35.9%), low white blood cell count with fever (10.3% vs. 5.1%), low platelet count (33.3% vs. 20.5%), anaemia (25.6% vs. 12.8%) and infections (17.9% vs. 17.9%).
Based on results from this study, polatuzumab vedotin was recently granted Breakthrough Therapy Designation by the US Food and Drug Administration and PRIME (PRIority MEdicines) designation by the European Medicines Agency for the treatment of people with relapsed or refractory DLBCL. There are a number of ongoing studies evaluating the efficacy and safety of polatuzumab vedotin for several types of non-Hodgkin lymphoma, including combinations with Gazyva /Gazyvaro (obinutuzumab), MabThera/Rituxan, Venclexta/Venclyxto (venetoclax) and Tecentriq (atezolizumab).

About the GO29365 study
GO29365 is a global, phase Ib/II randomised study evaluating the safety, tolerability and activity of polatuzumab vedotin in combination with MabThera /Rituxan (rituximab) or Gazyva /Gazyvaro (obinutuzumab) plus bendamustine in relapsed or refractory (R/R) follicular lymphoma or diffuse large B-cell lymphoma (DLBCL). The phase II stage randomised 80 patients with heavily pre-treated R/R DLBCL to receive either bendamustine plus MabThera/Rituxan (BR), or BR in combination with polatuzumab vedotin. Patients enrolled had received a median of two prior therapies (a range of 1-7 prior therapies in the polatuzumab vedotin arm and range of 1-5 prior therapies in the BR alone arm). The primary endpoint was complete response (CR) at the end of treatment, as measured by positron emission tomography (PET) and assessed by an independent review committee (IRC). Secondary endpoints included objective response (OR; CR and partial response, PR) by investigator assessment and best objective response at the end of treatment by investigator and IRC assessment. Exploratory endpoints included duration of response (DOR), progression-free survival (PFS), event-free survival (EFS) and overall survival (OS).

About polatuzumab vedotin
Polatuzumab vedotin is a first-in-class anti-CD79b antibody drug conjugate (ADC) currently being investigated for the treatment of several types of non-Hodgkin lymphoma (NHL). The CD79b protein is highly specific and expressed in the majority of types of B-cell NHL, making it a promising target for the development of new therapies.1 Polatuzumab vedotin binds to CD79b and destroys these B-cells via a targeted approach, which is thought to minimise the effects on normal cells while maximising tumour cell death. Polatuzumab vedotin is being developed by Roche utilising Seattle Genetics ADC technology.

About diffuse large B-cell lymphoma
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL), accounting for about one in three cases of NHL.2 DLBCL is an aggressive (fast-growing) type of NHL, which is generally responsive to treatment in the frontline.3 However, as many as 40% of patients will relapse, at which time salvage therapy options are limited and survival is short.3 Approximately 123,000 people worldwide are estimated to be diagnosed with DLBCL each year.

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.

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 that updated clinical results from HGB-206, the company’s ongoing Phase 1 multicenter study of its LentiGlobin gene therapy product candidate in patients with severe sickle cell disease (SCD), will be discussed in an oral presentation during the 59th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) (Press release, bluebird bio, DEC 10, 2017, View Source [SID1234522485]). In addition, a poster on the feasibility and potential benefits of plerixafor-mediated peripheral blood stem cell collection and drug product (DP) manufacturing in patients with SCD was presented yesterday at ASH (Free ASH Whitepaper).

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"The promising early results from the first two patients treated under the amended HGB-206 study protocol indicate that the manufacturing and patient management changes we implemented may have a meaningful impact on patient outcomes," said Dave Davidson, chief medical officer, bluebird bio. "These two patients have maintained higher levels of gene-marked cells in the blood following treatment compared to the previous patients in HGB-206. This improvement corresponds with increased production of the anti-sickling hemoglobin, HbAT87Q, made from LentiGlobin. We are hopeful that this high-level expression of HbAT87Q will lead to a sustained clinical benefit for these patients. The next group of patients in the study will be treated using LentiGlobin made from stem cells obtained from plerixafor-mobilized peripheral blood. Plerixafor mobilization in place of direct bone marrow harvest is less burdensome for patients, and our results suggest that this approach may be able to obtain a greater quantity of higher quality cells."

Interim Results from a Phase 1/2 Clinical Study of LentiGlobin Gene Therapy for Severe Sickle Cell Disease (Oral Abstract #527)
Presenter: Julie Kanter, M.D., Medical University of South Carolina, Charleston, SC
Date & Time: Sunday, December 10 at 5:30 p.m.
Location: Bldg C, Level 1, C101 Auditorium

"People with sickle cell disease have a genetic disease that causes the protein in red blood cells, called hemoglobin, to be misshapen. As a result of this abnormal hemoglobin, many affected individuals live with low blood counts and severe, recurrent pain crises that lead to organ damage and shortened life spans," said Dr. Kanter. "It is also a disease that has been historically under-researched and under-resourced, with few treatment options beyond pain management. These early results with the revised study protocol indicate that gene therapy with LentiGlobin may allow people with SCD to produce substantial levels of normal, anti-sickling, adult hemoglobin. We are hopeful about the possibility that this could substantially reduce the painful and damaging crises that are a hallmark of this disease, potentially allowing patients to live longer, healthier lives."

HGB-206 is an ongoing, open-label study designed to evaluate the safety and efficacy of LentiGlobin DP in the treatment of adults with severe SCD. Patients in this study are divided into three cohorts: A, B and C. Patients in Group A were treated under the original study protocol. Patients in Group B were treated under an amended study protocol that included changes intended to increase DP vector copy number (VCN) and improve engraftment of gene-modified stem cells. Patients in both Group A and B had DP made from stem cells collected using bone marrow harvest. Patients in Group C are also treated under the amended study protocol, but receive LentiGlobin made from stem cells collected from peripheral blood after mobilization with plerixafor rather than via bone marrow harvest. As of November 30, 2017, ten patients had been treated in the study and follow‑up data were available on nine patients from groups A and B, with a median of 21 (6-27) months since transplantation. Key results include:

Group A
N=7

Median (min-max)

Group B
N=2

Patient 1312 Patient 1313
Transduced CD34+ cells (%) 25 (8-42)
951, 901

46, 831
Drug product Cell Dose (x106 CD34+ cells) 2.1 (1.6-5.1) 3.2 2.2
Drug product VCN (copies per diploid genome) 0.6 (0.3-1.3) 2.91, 5.01 1.4, 3.31
VCN in peripheral blood (copies per diploid genome at last measurement) 0.1 (0.1-0.2) 2.5 (M6) 0.5 (M9)
HbAT87Q (g/dL at last measurement) 0.7 (0.5-2.0) 6.4 (M6) 3.0 (M9)
HbAT87Q (% of total, at last measurement) 7.9 (5.3-18.2) 51% (M6) 28% (M9)

1 LentiGlobin DP manufactured using refined process

Both patients in Group B were treated with two DP lots. Information from each of these LentiGlobin DP lots is reflected in the chart above.
Patient 1313 received LentiGlobin manufactured using a combination of the original and the refined manufacturing processes.
Patient 1312 received LentiGlobin manufactured entirely using the refined manufacturing process.
LentiGlobin DP has been manufactured for four patients in Group C:
Median transduced CD34+ cells: 80%
Median DP cell dose: 6.9 x106 CD34+ cells
Median DP VCN (copies per diploid genome): 3.3
The first patient treated with LentiGlobin (Group C) made using plerixafor-mobilized stem cells had a VCN in peripheral blood of 2.5 at one month.
The toxicity profile observed from drug product infusion to latest follow-up was generally consistent with myeloablative conditioning with single-agent busulfan.
Successful Plerixafor-Mediated Mobilization, Apheresis, and Lentiviral Vector Transduction of Hematopoietic Stem Cells in Patients with Severe Sickle Cell Disease (Poster Abstract #990)
Presenter: John Tisdale, M.D., National Heart, Lung and Blood Institute (NHLBI), Bethesda, MD
Date & Time: Saturday, December 9 at 5:30 p.m.
Location: Bldg A, Level 1, Hall A2

"Historically, harvesting stem cells from people with SCD required bone marrow harvest, a painful approach for obtaining cells that often yields a suboptimal dose level and cell quality," said Dr. Tisdale. "The data we presented at ASH (Free ASH Whitepaper) suggest that not only is this new approach using plerixafor mobilization generally tolerable for patients, but it may enable us to obtain a larger cell dose with a higher concentration of primitive stem cells. Cells with this primitive phenotype are more likely to become long-term sources of gene-modified red blood cells. We believe that providing more primitive hematopoietic stem cells that carry more copies of the gene therapy vector may be critical to realizing the full promise of gene therapy for people with SCD, and we look forward to getting more data on this new cohort of patients in the coming months."

Results as of November 30, 2017:

Bone Marrow Harvest Plerixafor
Number of Patients 9 (26 BMHs) 7 (10 mobilization cycles)
Adverse Events
17 Grade 3 AEs following BMH in 5 patients, 4 were SAEs (1 procedural pain, 3 SCD pain crisis)

5 Grade 3 events included 2 non-serious (hypomagnesemia and non-cardiac chest pain) and 3 SAEs (1 patient each) of SCD pain crisis
CD34+ cells collected per harvest, median (min-max) cells/kg 5.0 (0.3-10.8) x 106 10.4 (5.1-20.0) x 106

Webcast Information
bluebird bio will host a webcast at 8:30 p.m. ET today, 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 SCD
Sickle cell disease (SCD) is an inherited disease caused by a mutation in the beta-globin gene, that produces βS-globin. High levels of HbS in patients with SCD are responsible for the characteristic chronic anemia, vaso-occlusive crises, and other acute and chronic manifestations of SCD which lead to significant morbidity and early mortality.

Where adequate medical care is available, common treatments for patients with SCD largely revolve around prevention of infection and management and prevention of acute sickling episodes. Chronic management may include hydroxyurea and, in certain cases, chronic transfusions. Allogeneic hematopoietic stem cell transplant (HSCT) is currently the only available option to address the underlying genetic cause of SCD, though it carries significant risk. 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 allogeneic HSCT.

On December 10, 2017 Immune Design (Nasdaq:IMDZ), a clinical-stage immunotherapy company focused on oncology, reported data from the randomized Phase 2 trial of its investigational intratumoral TLR4 agonist G100 plus low-dose radiation (G100 Monotherapy) with or without KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 therapy, in follicular non-Hodgkin’s lymphoma (FL) patients (Press release, Immune Design, DEC 10, 2017, View Source [SID1234522489]). The G100 Monotherapy and pembrolizumab combination resulted in a 39% objective response rate (ORR), with a 57% ORR in those patients who expressed a potential predictive biomarker. These data were presented at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual meeting in Atlanta, Georgia on Sunday, December 10, 2017.

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"We have been developing two immuno-oncology platforms in parallel: an intratumoral immunization approach with G100 as the lead therapeutic candidate, and novel cancer vaccines from the Dendritic cell-targeting RNA vector platform, ZVex. We believe these data presented at ASH (Free ASH Whitepaper) confirm that G100 is an active and safe agent that results in systemic tumor responses, which are further enhanced in combination with KEYTRUDA," said Carlos Paya, M.D., Ph.D., President and Chief Executive Officer of Immune Design. "In light of the fact that some inhibitors of the anti-PD-1 class are viewed to have limited activity in this type of hematological malignancy, these positive data support further investigation of the potential synergy of G100 with anti-PD-1/L1 agents and the use of TLR4 expression as a potential predictive biomarker."

The randomized Phase 2 trial was designed to examine intratumoral (IT) administration of G100 Monotherapy vs. G100 Monotherapy + pembrolizumab (G+P) in either treatment naïve or recurrent/refractory FL patients (13 patients/arm). Highlights from the study include:

Clinical Benefit
Patients receiving G+P showed a 39% ORR, as compared to 15% in the G100 Monotherapy arm.
Pembrolizumab monotherapy in a similar recurrent/refractory FL study showed 11% ORR (Ding, ASH (Free ASH Whitepaper) 2017 abstract).
Patients receiving G+P also had more frequent and deeper abscopal tumor shrinkage and a trend toward a better progression free survival (PFS).
Safety: Adverse events considered possibly related to G100 were Grade 1 or 2, with no related serious adverse events. The safety experience in the G+P arm did not suggest any unexpected or worsening toxicity compared to what has been reported previously with pembrolizumab alone.
Potential Predictive Biomarker: A strong association between baseline tumor TLR4 expression and objective clinical response was observed. Reported ORR in patients with a >50% TLR4 expression by IHC (TLR4high) receiving G+P increased to 57%, including patients with recurrent/refractory disease.
Potential Further Development: Because clinical responses were observed in patients with recurrent/refractory disease, treatment failure <2 years after rituximab-containing chemotherapy, and high-risk patients based on GELF criteria, G+P may provide a therapeutic option in this unmet medical need population. Enrichment of patients more likely to respond may be attained by selecting for high expression of TLR4.
Additional subtypes of indolent lymphomas with injectable lesions are known to express TLR4, which expands the potential of this combination of G100 and pembrolizumab in hematological malignancies beyond FL. Likewise, many solid tumors are known to express TLR4.

G100 has been granted orphan drug designation by the U.S. Food and Drug Administration and the European Medicines Agency for the treatment of FL.

Conference Call Information

Immune Design will hold a conference call on Monday, December 11, 2017 at 8:00 a.m. EST. Ahmad S Halwani, MD, Assistant Professor of Medicine, Huntsman Cancer Institute, University of Utah, and a Principal Investigator on the trial, will join the call.

The live call may be accessed by dialing 844-266-9538 for domestic callers and 216-562-0391 for international callers. The audience passcode is 3258589. A live webcast of the call will be available online from the investor relations section of the company website at View Source and will be archived there for 30 days. A telephone replay of the call will be available for five days by dialing 855-859-2056 for domestic callers or 404-537-3406 for international callers and entering the conference code: 3258589.

ASH Presentation Details:

Intratumoral G100 Induces Systemic Immunity and Abscopal Tumor Regression in Patients with Follicular Lymphoma: Results of a Phase 1/2 Study Examining G100 Alone and in Combination with Pembrolizumab (Abstract # 2771)

Presenter: Christopher R. Flowers, M.D.
Session Name: 623. Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma—Clinical Studies: Poster II
Poster Discussion: Sunday, December 10, 2017, 6:00 PM – 8:00 PM Eastern
Location: Georgia World Congress Center, Bldg A, Lvl 1, Hall A2

About G100

G100 is a product candidate from Immune Design’s GLAAS discovery platform. It contains a potent synthetic small molecule toll-like receptor-4 (TLR-4) agonist, Glucopyranosyl Lipid A (GLA), and is the lead product candidate in Immune Design’s Antigen Agnostic approach. G100 activates innate and adaptive immunity in the tumor microenvironment to generate an immune response against the tumor’s preexisting diverse set of antigens. A growing set of clinical and preclinical data have demonstrated the ability of G100 to activate tumor-infiltrating lymphocytes, macrophages and dendritic cells, and promote antigen-presentation and the recruitment of T cells to the tumor. The induction of local and systemic immune responses has been shown in preclinical studies to result in local and abscopal (shrinking of tumors outside the scope of the localized treatment) tumor control.

About Follicular Non-Hodgkin’s Lymphoma

Follicular lymphoma is a malignancy affecting the lymph nodes and may spread to the bone marrow or spleen. The most common type of slow-growing (indolent) non-Hodgkin’s lymphoma (NHL), it represents approximately 20% of all NHL cases. Despite advances in treatment options in recent decades, FL is considered incurable. Currently, patients who do not respond to initial treatment or whose disease progresses within two years of diagnoses after treatment have a worse survival prognosis and may constitute an unmet medical need population. In 2017, it is estimated that more than 14,000 new cases of FL will be diagnosed in the United States alone.