On December 6, 2020 AstraZeneca reported that Long-term follow-up results from the positive ACE-LY-004 Phase II trial showed patients with relapsed or refractory mantle cell lymphoma (MCL) treated with Calquence (acalabrutinib) remained progression free for a median of 22 months, with median overall survival not yet reached at three years of follow-up (Press release, AstraZeneca, DEC 6, 2020, View Source [SID1234572229]). The safety and tolerability profile remained consistent.1 These results were presented at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition on 6 December 2020.

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MCL is typically an aggressive, rare form of non-Hodgkin lymphoma (NHL) that accounts for nearly 6% of all NHL cases and is mostly found in males during their early sixties.2,3

At a median follow up of 38.1 months (range: 0.3-59.5), 55 patients (44%) either remained on treatment (24 patients) or continued to be followed for survival (31 patients). The safety profile remained largely unchanged from the last analysis at 26 months, with only 14 patients (11%) having discontinued treatment due to adverse events (AE).1

Michael L. Wang, MD, Professor, Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, and principal investigator of the ACE-LY-004 Phase II trial, said: "Mantle cell lymphoma is an aggressive, difficult-to-treat blood cancer that is typically diagnosed at an advanced stage and often becomes resistant to treatment. This data shows that patients treated with acalabrutinib experienced deep responses over time, while the safety profile remained largely the same, including low rates of Grade 3/4 events, cardiac events and bleeding events, which are important in this patient population."

José Baselga, Executive Vice President, Oncology R&D, said: "These results add to the mounting evidence that Calquence can provide sustained responses in patients over more than three years. Calquence is an important chemo-free treatment option for relapsed or refractory mantle cell lymphoma and is rapidly being embraced across the clinical and patient community."

Summary of efficacy results1

Median follow up of 38.1 months (range: 0.3-59.5)

Efficacy measure

Result (N=124; 95% CI)

ORR (investigator-assessed PR or better per Lugano classification), %

81 (74, 88)

CR, %

48 (39, 57)

Median DOR, months

28.6 (17.5, 39.1)

Estimated DOR rate at 36 months, %

41.9 (31.7, 51.8)

Median PFS, months

22.0 (16.6, 33.3)

Estimated PFS rate at 36 months, %

37.2 (28.2, 46.1)

CI, confidence interval; ORR, overall response rate; PR, partial response; CR, complete response; DOR, duration of response; PFS, progression-free survival; DOR was measured in the 101 subjects who achieved a CR or PR

Figure. Progression-free survival1

graph
CR, complete response; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease

Additionally, an exploratory analysis of 30 patients meeting the criteria for minimal residual disease (MRD) evaluation showed six patients (20%) achieved a complete response and undetectable MRD (uMRD) and maintained uMRD at last assessment.1

AEs in the trial remained largely unchanged with an additional year of follow up. The most frequent AEs of any grade (greater than or equal to 20% of patients) included headache (39%), diarrhoea (37%), fatigue (30%), cough (23%), myalgia (22%) and nausea (22%), and were primarily Grade 1/2. Grade 3/4 AEs included neutropenia (11%), anaemia (10%) and pneumonia (6%).1

Overall, 16 patients (13%) had cardiac AEs (11 with prior cardiac risk factors), with three of the 16 cardiac AEs occurring in the last year of follow up (two were Grade 3/4). Overall, six patients (5%) had Grade 3/4 cardiac AEs. One patient had Grade 3/4 hypertension in the last year (total any grade, n=5 [4%]; total Grade 3/4, n=2 [2%]), and five patients had bleeding AEs in the last year (total any grade, n=46 [37%]). Three patients had Grade 3/4 infections in the last year.1

Initial results from the ACE-LY-004 Phase II trial were presented on 9 December 2017 at the 59th ASH (Free ASH Whitepaper) Annual Meeting and Exposition and served as the basis for the first FDA approval of Calquence in adult patients with MCL who have received at least one prior therapy.4 Calquence is approved for this indication in many other countries. The US MCL indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Mantle cell lymphoma
Mantle cell lymphoma (MCL) is an uncommon type of B-cell non-Hodgkin lymphoma.5 MCL comprises 3% to 6% of non-Hodgkin lymphomas, with an annual incidence of 0.5 per 100,000 population in Western countries; in the US, it was estimated that approximately 3,300 new cases of MCL were diagnosed in 2016.5,6 The median age at diagnosis is 68 years, with MCL occurring more often in men than women. While MCL patients initially respond to treatment, there is a high relapse rate.5

ACE-LY-004
ACE-LY-004 is an open-label, single-arm Phase II clinical trial evaluating Calquence in adult patients with relapsed or refractory MCL.7 Adults with MCL and ECOG PS ≤2 who had relapsed or were refractory to 1-5 prior therapies, had no prior BTK/BCL-2 inhibitor exposure, and did not require warfarin/vitamin K antagonists, received oral Calquence 100mg twice-daily until progressive disease or toxicity. Overall response rate (investigator-assessed partial response or better per Lugano classification), duration of response, progression-free survival, overall survival, and safety were assessed. Minimal residual disease was analysed in formalin-fixed, paraffin-embedded samples and peripheral blood by next-generation sequencing (5×10-6) in patients with available paired samples.1

Calquence
Calquence (acalabrutinib) is a next-generation, selective inhibitor of Bruton’s tyrosine kinase (BTK). Calquence binds covalently to BTK, thereby inhibiting its activity.4,8 In B-cells, BTK signalling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.4

Calquence is approved for the treatment of chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma in the US and is approved for CLL in the EU and several other countries worldwide. Calquence is also approved for the treatment of adult patients with MCL who have received at least one prior therapy in the US and several other countries. Calquence is not currently approved for the treatment of MCL in Europe.

As part of an extensive clinical development programme, AstraZeneca and Acerta Pharma are currently evaluating Calquence in more than 20 company-sponsored clinical trials. Calquence is being developed for the treatment of multiple B-cell blood cancers including CLL, MCL, diffuse large B-cell lymphoma, Waldenström’s macroglobulinaemia, follicular lymphoma, and other haematologic malignancies.

AstraZeneca in haematology
Leveraging its strength in oncology, AstraZeneca has established haematology as one of four key oncology disease areas of focus. The Company’s haematology franchise includes two medicines approved by the US Food and Drug Administration and a robust global development programme for a broad portfolio of potential blood cancer treatments. Acerta Pharma serves as AstraZeneca’s haematology research and development arm. AstraZeneca partners with like-minded science-led companies to advance the discovery and development of therapies to address unmet need.

AstraZeneca in oncology
AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With seven new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers.

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

On December 6, 2020 MacroGenics, Inc. (NASDAQ: MGNX), a clinical-stage biopharmaceutical company focused on discovering and developing innovative monoclonal antibody-based therapeutics for the treatment of cancer, reported updated results from a single-arm, registrational study of flotetuzumab, an investigational, bispecific CD123 × CD3 DART molecule, in patients with primary induction failure (PIF) and early relapsed (less than six months, or ER6) acute myeloid leukemia (AML) (Press release, MacroGenics, DEC 6, 2020, View Source [SID1234572227]). The data were presented at the 62nd Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) taking place December 5-8, 2020.

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In the open label study of flotetuzumab, 44 AML patients had disease classified as either PIF or ER6. Of these patients, 72.7% (32 of 44) had adverse risk cytogenetics by ELN Risk Stratification (2017). Patients were treated with flotetuzumab at the recommended Phase 2 dose (RP2D) of 500 ng/kg/day by continuous infusion. Data were reported as of the cut-off date of November 10, 2020. The study is currently ongoing, with a total of up to 200 patients planned for enrollment for registrational purposes.

The median time to achieve a response to flotetuzumab was one cycle (range of 1-3 cycles). Responses, including complete remission (CR), CRh (CR with partial hematological recovery) and CRi (CR with incomplete hematological improvement) per a modified International Working Group (IWG) Response Criteria for AML, are summarized in the table below.

PIF/ER (n=44) PIF (n=27) ER6 (n=17)
CR/CRh 25.0% (11) 33.3% (9) 11.8% (2)
CR/CRh/Cri 31.8% (14) 37.0% (10) 23.5% (4)
HSCT 57.1% (8/14) 70.0% (7/10) 25.0% (1/4)
Median Duration of Response 8.13 mos.
(n=14) 15.2 mos.
(n=10) 2.4 mos.
(n=4)
As shown in the table, over 50% of responders (8 of 14) successfully received allogeneic hematopoietic stem cell transplantation (HSCT) as consolidation therapy with durable remission (median not reached). Also, among those PIF/ER6 patients who achieved remission (CR, CRh or CRi), the median duration of response was 8.13 months, with a median overall survival of 10.7 months. Within the PIF/ER6 population, five of ten patients with TP53MUT AML achieved CR/CRh/CRi responses, three of whom went on to receive HSCT. More detailed flotetuzumab clinical data in the TP53MUT AML population is available via a separate poster presentation at ASH (Free ASH Whitepaper) (see "TP53 Abnormalities Correlate with Immune Infiltration and Associate with Response to Flotetuzumab Immunotherapy in Acute Myeloid Leukemia", Session 617).

The most common treatment-related adverse event (TRAE) was infusion-related reaction/cytokine release syndrome (IRR/CRS), which occurred in all patients. However, most CRS events observed were of short duration and mild to moderate (Grade 1 or 2) in severity, with only a single Grade 3 event reported.

"For the approximately 50% of AML patients who fail primary induction therapy or relapse within six months of an initial response, there is no standard of care among the available treatment regimens. Historically, these patients have CR/CRh rates to subsequent interventions in the range of only 5-12% with a median overall survival of approximately 3.5 months. A remission rate of 32% with good duration and a manageable safety profile observed to date in the ongoing registrational study of flotetuzumab in this extremely challenging patient population is very encouraging," said Ibrahim Aldoss, M.D., Assistant Professor of Hematology/HCT at City of Hope Comprehensive Cancer Center.

In addition to the above data provided in an oral presentation, five additional presentations related to flotetuzumab and AML have or will be presented at ASH (Free ASH Whitepaper).

"We are very encouraged by the updated results from this study, and continue to enroll patients in this single arm, registrational trial," said Scott Koenig, M.D., Ph.D., President and CEO of MacroGenics. "Especially encouraging is the duration of response we’ve seen to date in this otherwise fragile population of patients for whom no approved therapies exist."

About Acute Myeloid Leukemia

AML is a hematological malignancy characterized by differentiation arrest and uncontrolled clonal proliferation of neoplastic precursors that prevent normal bone marrow hematopoiesis. Nearly 20,000 new cases of AML are diagnosed in the U.S. each year, with a median age of 69 years at diagnosis. Approximately 40-50% of newly diagnosed patients fail to achieve a complete remission with intensive induction therapy (primary induction failure, or PIF) or experience disease recurrence after a short remission duration (<6 months; early relapsed, or ER6). A very small number of these patients are expected to respond to salvage therapy. Although new targeted agents have been approved for the treatment of frontline or relapsed/refractory AML in recent years, approximately 50% of patients have no known targetable mutations.

About Flotetuzumab

Flotetuzumab (previously known as MGD006) is a clinical-stage bispecific, investigational DART molecule that recognizes both CD123 and CD3. CD123, the interleukin-3 receptor alpha chain, has been reported to be over-expressed on malignant cells in AML and other hematologic malignancies. The primary mechanism of action of flotetuzumab is believed to be its ability to redirect T lymphocytes to kill CD123-expressing cells. To achieve this, the DART molecule combines a portion of an antibody recognizing CD3, an activating molecule expressed by T cells, with an arm that recognizes CD123 on the target cells. MacroGenics is conducting a single-arm, registration-enabling clinical study to evaluate flotetuzumab in up to 200 patients with PIF/ER AML, with complete remission (CR) and CR with partial hematological recovery (CRh) as the primary endpoint. The study will be conducted as a continuation of the ongoing Phase 1/2 study (NCT02152956). The FDA has granted orphan drug designation to flotetuzumab for the treatment of AML. MacroGenics retains global development and commercialization rights to flotetuzumab.

On December 6, 2020 Fate Therapeutics, Inc. (NASDAQ: FATE), a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for cancer and immune disorders, reported a patient case study from the Company’s Phase 1 clinical trial of FT596, its universal, off-the-shelf, CD19-targeted chimeric antigen receptor (CAR) natural killer (NK) cell product candidate, at the 62nd Annual Society of Hematology Annual Meeting and Exposition (Press release, Fate Therapeutics, DEC 6, 2020, View Source [SID1234572226]).

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The case study described a heavily pre-treated patient with diffuse large B-cell lymphoma (DLBCL) who achieved a partial response following administration of a single-dose treatment cycle of FT596 as a monotherapy in the first dose cohort of 30 million cells. The patient subsequently received a second single-dose treatment cycle of FT596, which resulted in a deepening response as evidenced by further decrease in both tumor size and metabolic activity. No dose-limiting toxicities, no FT596-related serious adverse events, and no events of any grade of cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or graft-versus-host disease were reported by the investigator. The patient had previously received seven prior treatment regimens, including five rituximab-containing regimens as well as autologous stem cell transplantation, and was most recently refractory to an experimental cellular therapy.

"The safety, pharmacokinetics and clinical activity observed following both the first and second single-dose treatment cycles of FT596 are compelling, especially when considering that the administered cell dose was significantly lower than the recommended cell dose of FDA-approved autologous CD19-targeted CAR T-cell therapies and that the heavily pre-treated patient was refractory to last prior therapy," said Dr. Wayne Chu, Senior Vice President, Clinical Development of Fate Therapeutics. "We are excited the CAR component of FT596 has shown clinical activity at this low dose level, and we continue to enroll patients in dose escalation with FT596 as a monotherapy and in combination with rituximab. Our recent Phase 1 clinical data with FT516 in combination with rituximab, which demonstrate the potential of our novel hnCD16 Fc receptor to potentiate ADCC and drive complete responses, support our belief that the multi-antigen targeting functionality of FT596 may offer best-in-class potential for patients with B-cell malignancies."

FT596 is derived from a clonal master induced pluripotent stem cell (iPSC) line engineered with three anti-tumor modalities: a proprietary CAR optimized for NK cell biology that targets CD19; a novel high-affinity, non-cleavable CD16 (hnCD16) Fc receptor that enhances antibody-dependent cellular cytotoxicity (ADCC), a potent anti-tumor mechanism by which NK cells recognize, bind and kill antibody-coated cancer cells; and an IL-15 receptor fusion that augments NK cell activity. The open-label, multi-center Phase 1 clinical trial is designed to assess the safety and activity of a single-dose treatment cycle of FT596 in up to four dose cohorts (30 million cells; 90 million cells; 300 million cells and 900 million cells) as a monotherapy and in combination with CD20-targeted monoclonal antibody therapy for the treatment of relapsed / refractory B-cell malignancies. Under the clinical protocol, the Company may seek consent of the U.S. Food and Drug Administration (FDA) for administration of a second single-dose treatment cycle.

Patient History
The patient, a 76 year old woman with refractory DLBCL, had received seven prior lines of therapy, which included five rituximab-containing regimens, autologous stem cell transplantation, and two experimental cellular therapies. Of note, the patient was most recently refractory to an experimental NK cell therapy regimen comprised of fludarabine and cyclophosphamide lympho-conditioning followed by ex vivo expanded, donor-derived NK cells (≥1 billion cells), IL-2, and rituximab. Approximately 3.5 months from last prior therapy, the patient enrolled into the first dose cohort of FT596 as a monotherapy at 30 million cells.

Safety
The patient underwent fludarabine and cyclophosphamide lympho-conditioning and was administered a single dose of FT596 as a monotherapy at 30 million cells (Study Day 1). Following FDA consent for continued treatment based on review of the clinical data from the first FT596 treatment cycle, the patient underwent another round of lympho-conditioning and was administered a second dose of FT596 as a monotherapy at 30 million cells (Study Day 47). No dose-limiting toxicities, and no cases of any grade of cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or graft-versus-host disease, were observed. No FT596-related serious adverse events (SAEs) were reported, and the only Grade ≥3 adverse events deemed possibly related to FT596 were neutrophil count decreased, white blood cell count decreased, and lymphocyte count decreased. All other Grade ≥3 adverse events were consistent with lympho-conditioning chemotherapy and prior treatment regimens. No evidence of anti-product T- or B-cell mediated host-versus-product alloreactivity was detected.

Clinical Response & Pharmacokinetics
The patient achieved a partial response as of the Day 29 protocol-defined response assessment (Study Day 29), with a greater than 50% reduction in tumor size and a substantial reduction in metabolic activity as assessed by PET-CT scan per Lugano 2014 criteria. The protocol-defined response assessment following the second FT596 treatment cycle (Study Day 75) showed a deepening response, with an additional 33% reduction in tumor size and further reduction in metabolic activity. The duration of response, which was not aided by further therapeutic intervention, was 3.8 months and is comparable to that of FDA-approved autologous CD19 CAR-T cell therapy among patients who achieve partial response as best overall response (2.1-3.4 months; Yescarta USPI; Kymriah USPI). The pharmacokinetic profile of both FT596 treatment cycles was consistent and indicative of cell expansion, with peak peripheral blood exposure observed on the eighth day following administration of FT596 (1732 and 1150 vector transgene copies per µg of genomic DNA, respectively), which further validates that retreatment with FT596 conferred additional clinical benefit.

Dose escalation in the FT596 Phase 1 study is currently ongoing in the second dose cohort of 90 million cells as monotherapy and in combination with CD20-targeted monoclonal antibody therapy for patients with relapsed / refractory B-cell lymphoma. In addition, for patients with relapsed / refractory chronic lymphocytic leukemia, the Company has initiated enrollment in the first dose cohort of 30 million cells as monotherapy and plans to begin enrollment in combination with obinutuzumab upon dose-limiting toxicity clearance of monotherapy in the first dose cohort.

FT596 is also currently being evaluated in an investigator-initiated Phase 1 clinical trial sponsored by investigators from the Masonic Cancer Center, University of Minnesota for patients with B-cell lymphoma who have undergone autologous hematopoietic stem cell transplant and are considered high risk for early relapse (NCT04555811). Up to three dose cohorts of FT596, beginning at 90 million cells per dose, in combination with CD20-targeted monoclonal antibody will be assessed.

About Fate Therapeutics’ iPSC Product Platform
The Company’s proprietary induced pluripotent stem cell (iPSC) product platform enables mass production of off-the-shelf, engineered, homogeneous cell products that can be administered with multiple doses to deliver more effective pharmacologic activity, including in combination with other cancer treatments. 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 engineered iPSC for maintenance as a clonal master iPSC line. Analogous to master cell lines used to manufacture biopharmaceutical drug products such as monoclonal antibodies, clonal master iPSC lines are a renewable source for manufacturing cell therapy products which are well-defined and uniform in composition, can be mass produced at significant scale in a cost-effective manner, and can be delivered off-the-shelf for patient treatment. As a result, the Company’s platform is uniquely capable of overcoming numerous limitations associated with the production of cell therapies using patient- or donor-sourced cells, which is logistically complex and expensive and is subject to batch-to-batch and cell-to-cell variability that can affect clinical safety and efficacy. Fate Therapeutics’ iPSC product platform is supported by an intellectual property portfolio of over 300 issued patents and 150 pending patent applications.

About FT596
FT596 is an investigational, universal, off-the-shelf natural killer (NK) cell cancer immunotherapy derived from a clonal master induced pluripotent stem cell (iPSC) line engineered with three anti-tumor functional modalities: a proprietary chimeric antigen receptor (CAR) optimized for NK cell biology that targets B-cell antigen CD19; a novel high-affinity 158V, non-cleavable CD16 (hnCD16) Fc receptor, which has been modified to prevent its down-regulation and to enhance its binding to tumor-targeting antibodies; and an IL-15 receptor fusion (IL-15RF) that augments NK cell activity. In preclinical studies of FT596, the Company has demonstrated that dual activation of the CAR19 and hnCD16 targeting receptors enhances cytotoxic activity, indicating that multi-antigen engagement may elicit a deeper and more durable response. Additionally, in a humanized mouse model of lymphoma, FT596 in combination with the anti-CD20 monoclonal antibody rituximab showed enhanced killing of tumor cells in vivo as compared to rituximab alone. FT596 is being investigated in an open-label, multi-center Phase 1 clinical trial for the treatment of relapsed / refractory B-cell lymphoma as a monotherapy and in combination with rituximab, and for the treatment of relapsed / refractory chronic lymphocytic leukemia (CLL) as a monotherapy and in combination with obinutuzumab (NCT04245722).

On December 6, 2020 Arch Oncology, Inc., a clinical-stage immuno-oncology company focused on the discovery and development of anti-CD47 antibody therapies, reported the presentation of new preclinical data on AO-176 at the ASH (Free ASH Whitepaper) Annual Meeting 2020 (Press release, Arch Oncology, DEC 6, 2020, View Source;utm_medium=rss&utm_campaign=arch-oncology-presents-new-preclinical-data-on-highly-differentiated-anti-cd47-antibody-ao-176-at-ash-2020 [SID1234572225]). AO-176 is an anti-CD47 antibody with a potential best-in-class profile that works by blocking the "don’t eat me" signal and also by directly killing tumor cells, with preferential binding to tumor versus normal cells. Currently, AO-176 is being evaluated in Phase 1/2 clinical trials for the treatment of patients with select solid tumors and multiple myeloma, both as monotherapy and in combination with standard therapies.

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"At ASH (Free ASH Whitepaper) this year, we are pleased to highlight the growing body of preclinical data on AO-176, demonstrating a breadth of efficacy data in models of lymphoma, AML, and multiple myeloma," said Daniel Pereira, Ph.D., Chief Scientific Officer of Arch Oncology. "In our multiple myeloma preclinical studies, AO-176 shows potent tumor inhibition and complete durable responses as a monotherapy, as well as in combination with several standard therapies, including proteasome inhibitors, IMIDs, and anti-CD38 antibodies."

Poster Presentations at ASH (Free ASH Whitepaper) Annual Meeting & Exposition 2020

Date: December 5, 2020 7:00 am – 3:30 pm PT
Abstract Title: Pre-clinical Combination of AO-176, a Highly Differentiated Clinical Stage CD47 Antibody, with Either Azacitidine or Venetoclax Significantly Enhances DAMP Induction and Phagocytosis of Acute Myeloid Leukemia

Date: December 6, 2020 7:00 am – 3:30 pm PT
Abstract Title: AO-176, a Highly Differentiated Clinical Stage Anti-CD47 Antibody, Exerts Potent Anti-Tumor Activity in Preclinical Models of Multiple Myeloma as a Single Agent and in Combination With Approved Therapeutics

A copy of these poster presentations will be available at the beginning of each session at View Source

About AO-176

AO-176 is a humanized anti-CD47 IgG2 antibody with a potential best-in-class profile. AO-176 is highly differentiated, with the potential to improve upon the safety and efficacy profile relative to other agents in this class of innate checkpoint inhibitors. AO-176 works by blocking the "don’t eat me" signal, the standard mechanism of anti-CD47 antibodies. Beyond blocking this signal, AO-176 has additional mechanisms, including directly killing tumor cells and inducing DAMPs (Damage Associated Molecular Patterns), resulting in Immunogenic Cell Death. Importantly, AO-176 binds preferentially to tumor cells, instead of to normal cells, and binds even more potently to tumors in their acidic microenvironment (low pH). Publications and presentations on AO-176 can be found at View Source

AO-176 is being evaluated in Phase 1/2 clinical trials for the treatment of patients with select solid tumors and multiple myeloma, both as monotherapy and in combination with standard therapies. In a Phase 1 trial in solid tumors, AO-176 demonstrated encouraging safety and evidence of anti-tumor activity when administered as a single agent. Additional information about these trials may be found at www.clinicaltrials.gov using the trial identification number NCT03834948 (solid tumors) or NCT04445701 (multiple myeloma).

On December 6, 2020 Constellation Pharmaceuticals, Inc. (Nasdaq: CNST) reported that two oral presentations and three posters relating to the Phase 2 MANIFEST and the Phase 3 MANIFEST-2 clinical trials of CPI-0610 in myelofibrosis (MF) were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Press release, Constellation Pharmaceuticals, DEC 6, 2020, View Source [SID1234572224]). The preliminary data in these presentations are based on a data cutoff of September 29, 2020, and reflect an analysis of clinical activity in 63 first-line (1L) and 94 second-line (2L) or later patients.

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"We are pleased both with the response rates and consistency of the results we are seeing in MANIFEST," said Jigar Raythatha, president and chief executive officer of Constellation Pharmaceuticals. "In addition, we are excited by results from our translational studies that suggest that CPI-0610 may potentially be a disease modifying therapy that affects all four hallmarks of myelofibrosis. We are pleased to have initiated MANIFEST-2, our global registrational study of CPI-0610, in JAK-inhibitor-naïve MF patients."

Data Highlights

Arm 3 (1L) – CPI-0610 + ruxolitinib in JAK-inhibitor-naïve patients

42 of 63 evaluable patients (67%) achieved a ≥35% reduction in spleen volume (SVR35) at 24 weeks (the primary endpoint for Arm 3). The median spleen volume reduction was 50%
34 of 60 evaluable patients (57%) achieved a ≥50% reduction in Total Symptom Scores (TSS50) at 24 weeks. The median TSS reduction was 59%
Arm 1 (2L or later) – CPI-0610 monotherapy in JAK-inhibitor-experienced or -ineligible patients

7 of 23 (30%) evaluable patients that were not transfusion dependent at baseline (non-TD) achieved SVR35 at 24 weeks, the primary endpoint for cohort 1B. 10 of 21 (48%) evaluable non-TD patients achieved TSS50 at 24 weeks
10 of 20 (50%) evaluable non-TD patients who did not receive transfusions 12 weeks prior to treatment achieved a ≥1.5 g/dL increase in hemoglobin
3 of 14 (21%) evaluable transfusion-dependent (TD) patients converted to transfusion independence (TI), the primary endpoint for cohort 1A
Arm 2 (2L) – CPI-0610 + ruxolitinib in ruxolitinib-experienced patients

6 of 21 (29%) evaluable non-TD patients achieved SVR35 at 24 weeks, the primary endpoint for cohort 2B. 8 of 21 (38%) evaluable non-TD patients achieved TSS50 at 24 weeks
13 of 36 (36%) evaluable TD patients converted to transfusion independence, the primary endpoint for cohort 2A
Translational data

In samples from patients in Arm 3, 16 of 48 evaluable patients (33%) had at least one grade improvement in bone marrow fibrosis and in 88% (14/16) of these patients, improvements occurred within six months of starting treatment. Only 2 of 48 patients had worsening in bone marrow fibrosis
38 of 116 (33%) patients with evaluable samples across all three treatment arms had a one grade or greater improvement in bone marrow fibrosis. In 84% (32/38) of these patients, improvements occurred within six months of treatment. Only 7 of 116 patients had worsening in bone marrow fibrosis
Analysis of evaluable patient samples from MANIFEST suggests that CPI-0610 promotes normalization of megakaryocyte and erythroid differentiation and proliferation, which the Company believes may improve bone marrow function and hemoglobin levels, and may ultimately be disease-modifying in patients
Safety

CPI-0610 was generally well tolerated in MANIFEST, both as monotherapy and in combination with ruxolitinib, and in both JAK-inhibitor-naïve and -ineligible as well as JAK-inhibitor-experienced patients.

Among the most common treatment-emergent adverse events (TEAEs) for CPI-0610 monotherapy in 46 safety-evaluable patients in Arm 1, those that were Grade 3 were thrombocytopenia (15%), anemia (13%), diarrhea (4%), constipation (2%), respiratory tract infection (2%), and decreased weight (2%). Other Grade 3/4 TEAEs (≥ 5%) include hyperuricemia (9%), hyperkalemia (6%) and dyspnea (6%). Nine patients discontinued treatment because of TEAEs.

Among the most common TEAEs in 78 safety-evaluable patients in Arm 2, those that were Grade 3 were thrombocytopenia (23%), anemia (10%), respiratory tract infections (5%), diarrhea (4%), asthenic conditions (4%), and nausea (3%). Grade 4 TEAEs included thrombocytopenia (3%) and anemia (1%). Nine patients discontinued treatment due to TEAEs, including six Grade 5 TEAEs, which were acute kidney injury, traumatic subdural hematoma, brain stem hemorrhage (no concomitant thrombocytopenia), disease progression, congestive heart failure, and transformation to AML.

Among the most common TEAEs in 78 safety-evaluable patients in Arm 3, those that were Grade 3 were anemia (28%) and thrombocytopenia (5%). Grade 4 TEAEs included thrombocytopenia (3%), anemia (1%), and respiratory tract infection (1%). Two patients discontinued treatment due to TEAEs. In addition, there were two Grade 5 TEAEs, each resulting from multi-organ failure due to sepsis.

ASH Oral Presentations

Title: CPI-0610, a Bromodomain and Extraterminal Domain Protein (BET) Inhibitor, in Combination with Ruxolitinib, in JAK-Inhibitor-Naïve Myelofibrosis Patients: Update of MANIFEST Phase 2 Study
Oral Session: 634. Myeloproliferative Syndromes: Clinical: New Therapies and JAKi-based Combinations for Myelofibrosis
Date and Time: December 5, 2020, 11:30 AM EST
Presenter: Dr. John Mascarenhas, Associate Professor of the Icahn School of Medicine at Mount Sinai

Title: CPI-0610, Bromodomain and Extraterminal Domain Protein (BET) Inhibitor, As "Add-on" to Ruxolitinib, in Advanced Myelofibrosis Patients with Suboptimal Response: Update of MANIFEST Phase 2 Study
Oral Session: 634. Myeloproliferative Syndromes: Clinical: New Therapies and JAKi-based Combinations for Myelofibrosis
Date and Time: December 5, 2020, 11:45 AM EST
Presenter: Dr. Srdan Verstovsek, Medical Oncologist, MD Anderson Cancer Center

ASH Poster Presentations

Title: CPI-0610, a Bromodomain and Extraterminal Domain Protein (BET) Inhibitor, As Monotherapy in Advanced Myelofibrosis Patients Refractory / Intolerant to JAK Inhibitor: Update from Phase 2 MANIFEST Study
Session: 634. Myeloproliferative Syndromes: Clinical: Poster II
Date and Time: Sunday, December 6, 2020, 10:00 AM-6:30 PM EST
Presenter: Dr. Moshe Talpaz, Professor of Leukemia Research and Professor of Internal Medicine, University of Michigan Medical School

Title: MANIFEST-2, a Global, Phase 3, Randomized, Double-Blind, Active-Control Study of CPI-0610 and Ruxolitinib vs. Placebo and Ruxolitinib in JAK-Inhibitor-Naïve Myelofibrosis Patients
Session: 634. Myeloproliferative Syndromes: Clinical: Poster III
Date and Time: Monday, December 7, 2020, 10:00 AM-6:30 PM EST
Presenter: Dr. John Mascarenhas, Associate Professor of the Icahn School of Medicine at Mount Sinai

Title: The BET Inhibitor, CPI-0610, Promotes Myeloid Differentiation in Myelofibrosis Patient Bone Marrow and Peripheral CD34+ Hematopoietic Stem Cells
Session: 634. Myeloproliferative Syndromes: Clinical: Poster III
Date and Time: Monday, December 7, 2020, 10:00 AM-6:30 PM EST
Presenter: Dr. Mohamed Salama, Professor of Pathology and Laboratory Medicine, Mayo Clinic School of Medicine and Chief Medical Officer at Mayo Clinic Laboratories

Title: LSD1 Inhibitor CPI-482 Shows Efficacy and Prolongs Survival in Mouse Models of AML and post-MPN AML in the context of constitutive JAK-STAT pathway activation
Session: 635. Myeloproliferative Syndromes: Basic Science: Poster III
Date and Time: Monday, December 7, 2020, 10:00 AM-6:30 PM EST
Presenter: Dr. Raajit Rampal, Clinical Director of Leukemia Service at Memorial Sloan Kettering Cancer Center

Conference Call

Constellation will host a virtual analyst/investor event and conference call on December 7, 2020 at 8:00 AM EDT to discuss the data relating to the MANIFEST clinical trial for CPI-0610 being presented at the ASH (Free ASH Whitepaper) meeting. The agenda of the event will include:

An overview of MF and the potential impact of Constellation’s BET inhibitor, CPI-0610, in treating MF
A review of the clinical and translational data from MANIFEST presented at ASH (Free ASH Whitepaper)
A physician panel discussion and question-and-answer session with Dr. John Mascarenhas, Associate Professor of Medicine at the Icahn School of Medicine at Mount Sinai – New York and Dr. Serge Verstovsek, Professor of Medicine at University of Texas MD Anderson Cancer Center
The event will be webcast live and can be accessed on the Investor Relations section of Constellation’s website at View Source To participate in the live question-and-answer session, please dial (877) 473-2077 (domestic) or (661) 378-9662 (international) and refer to conference ID 7164095.

About MANIFEST

MANIFEST is an open-label Phase 2 clinical trial of CPI-0610 in patients with myelofibrosis (MF), a rare cancer of the bone marrow that disrupts the body’s normal production of blood cells. Constellation is evaluating CPI-0610 in combination with ruxolitinib in JAK-inhibitor-naïve MF patients (Arm 3), with a primary endpoint of the proportion of patients with a ≥35% spleen volume reduction from baseline (SVR35) after 24 weeks of treatment. Constellation is also evaluating CPI-0610, either as a monotherapy in patients who are resistant to, intolerant of, or ineligible for ruxolitinib and no longer on the drug (Arm 1), or as add-on therapy in combination with ruxolitinib in patients with a sub-optimal response to ruxolitinib or MF progression (Arm 2). Patients in Arms 1 and 2 are being stratified based on TD status. The primary endpoint for the patients in cohorts 1A and 2A, who were TD at baseline, is conversion to TI for 12 consecutive weeks. The primary endpoint for the patients in cohorts 1B and 2B, who were not TD at baseline, is the proportion of patients with a ≥35% spleen volume reduction from baseline after 24 weeks of treatment.

About MANIFEST-2

MANIFEST-2 is a global, double-blind, randomized Phase 3 clinical study with CPI-0610 in combination with ruxolitinib versus placebo plus ruxolitinib in JAK-inhibitor-naïve patients with primary myelofibrosis or post-ET or post-PV myelofibrosis who have splenomegaly and symptoms requiring therapy. It is designed to enroll approximately 310 patients, randomized 1:1 to the CPI-0610 + ruxolitinib arm or the placebo + ruxolitinib arm. The primary endpoint of the study is a ≥35% reduction in spleen volume (SVR35) from baseline at 24 weeks. A key secondary endpoint of the study is 50% or greater improvement in Total Symptom Score (TSS50) from baseline at 24 weeks. Other endpoints include bone marrow fibrosis grade improvements, duration of transfusion independence, rate of red-blood-cell transfusion for the first 24 weeks, and hemoglobin response.