On June 24, 2017 Bristol-Myers Squibb Company (NYSE:BMY) reported four-year follow-up data from the Phase 3 ELOQUENT-2 study in which Empliciti (elotuzumab) plus lenalidomide/dexamethasone (ELd) continued to demonstrate efficacy in patients with relapsed/refractory multiple myeloma (RRMM), compared to patients treated with lenalidomide/dexamethasone (Ld) alone (Press release, Bristol-Myers Squibb, JUN 24, 2017, View Source [SID1234519663]). The data also showed a safety profile consistent with prior findings. The results were presented in an oral session today during the 22nd Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Madrid, Spain and offer the longest follow-up efficacy and safety data of an Immuno-Oncology agent.

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!

ELd therapy maintained a reduction in the risk of disease progression or death of 29% (HR 0.71; 95% CI: 0.59 to 0.86). At four-years, ELd therapy continued to demonstrate a clinically meaningful and sustained relative improvement of 50% in progression-free survival (PFS) rate, 21% (95% CI: 16.6, 22.3), compared to Ld therapy, 14% (95% CI: 12.1,17.3). PFS benefits seen in patients receiving ELd therapy were consistent across certain patient subsets and sustained through two-year, three-year and four-year follow-up. Patients with high risk* (n=60 ELd, n=66 Ld) showed relative risk reduction of 36% (HR=0.64; 95% CI :0.43 to 0.97) and more than doubling of median PFS (15.2 ELd vs 7.4 Ld) with ELd in comparison to Ld.

Patients receiving ELd therapy demonstrated an overall response rate (ORR) of 79% (253/321 patients, 95% CI: 73.9 to 83.2), compared to 66% (214/325 patients, 95% CI: 60.4 to 71.0) among patients receiving Ld therapy alone. While OS was not pre-specified for the four-year follow-up, Empliciti in combination with Ld data also demonstrated a median overall survival (OS) benefit of 48 months (95% CI: 40.3 to 54.4) in favor of ELd versus a median OS of 40 months for Ld (95% CI: 33.3 to 45.4), a difference of 22% (HR 0.78; 95% CI: 0.63 to 0.96). Early separation of OS Kaplan Meier survival curves was maintained over time in favor of ELd versus Ld.

"These extended four-year follow-up data demonstrated that adding Empliciti to Ld yielded clinically relevant improvements and reductions in the risk of disease progression or death for patients with relapsed/refractory multiple myeloma, compared to Ld alone," Meletios A. Dimopoulos, M.D., ELOQUENT-2 investigator and professor and chairman of the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens School of Medicine. "This data at four-year follow-up is particularly notable as it suggests the ability of this Immuno-Oncology agent to build a sustainable immune response in some patients with advanced multiple myeloma."

The rates of adverse events (AE) were similar between patients receiving ELd or Ld therapy and consistent with those reported at two- and three-year follow-up. The most common AEs (all grades) in ELd and Ld, respectively, were diarrhea (49%, 38%), fatigue (48%, 41%), anemia (43%, 38%), pyrexia (40%, 25%), constipation (36%, 28%), neutropenia (35%, 43%), cough (34%, 19%), back pain (31%, 29%), and muscle spasm (31%, 26%).

"The long-term efficacy data for Empliciti in patients with advanced multiple myeloma shows the combination of this Immuno-Oncology agent with standard lenalidomide/dexamethasone treatment can improve patient outcomes," said Jonathan Leith, Ph.D., hematology development lead, Bristol-Myers Squibb. "These findings illustrate Bristol-Myers Squibb’s commitment to exploring how Immuno-Oncology agents might best help appropriate patients."

About ELOQUENT-2

The ELOQUENT-2 trial randomized 646 patients with RRMM who had one to three prior therapies to receive either ELd (321 patients) or Ld (325 patients) in 28-day cycles until their disease progressed, the occurrence of unacceptable toxicity or they withdrew consent. In the ELd arm, patients were administered 10 mg/kg by IV of elotuzumab for weeks one and two of the 28-day cycle and then every other week, along with 25 mg of lenalidomide by mouth for days 1-21 of the cycle and the weekly equivalent of 40 mg of dexamethasone by mouth. In the Ld arm, patients were given 25 mg of lenalidomide by mouth for days 1-21 of the cycle and the weekly equivalent of 40 mg of dexamethasone by mouth.

The occurrence of treatment-related Grade 3–4 AEs in 5% or more of patients were generally comparable between the ELd and Ld groups: vascular diseases (10% vs. 8%; mostly venous-related), second primary malignancies (9% vs. 6%), and cardiac disorders (5% vs. 8%). ELd therapy did have a slightly higher incidence of infection compared to Ld (33% vs. 26%). ELd treatment also had higher overall rates than Ld of any grade infection (84% vs. 75%) and second primary malignancies (17% vs. 11%). However, exposure to ELd was longer than to Ld, with a median treatment cycle of 19 months (9 to 42) compared to 14 months (6 to 25), respectively. While disease progression and infection were major causes of deaths in both groups, fewer were reported with ELd (165) than with Ld (186) treatment.

On November 30, 2015, the U.S. Food and Drug Administration (FDA) approved Empliciti in combination with lenalidomide and dexamethasone in patients with multiple myeloma who have received one to three prior therapies. On May 11, 2016, the European Commission approved Empliciti in combination with lenalidomide and dexamethasone in patients with multiple myeloma who have received at least one prior therapy.

Bristol-Myers Squibb & Immuno-Oncology: Advancing Oncology Research

At Bristol-Myers Squibb, patients are at the center of everything we do. Our vision for the future of cancer care is focused on researching and developing transformational Immuno-Oncology (I-O) medicines for hard-to-treat cancers that could potentially improve outcomes for these patients.

We are leading the scientific understanding of I-O through our extensive portfolio of investigational compounds and approved agents. Our differentiated clinical development program is studying broad patient populations across more than 50 types of cancers with 14 clinical-stage molecules designed to target different immune system pathways. Our deep expertise and innovative clinical trial designs position us to advance I-O/I-O, I-O/chemotherapy, I-O/targeted therapies and I-O/radiation therapies across multiple tumors and potentially deliver the next wave of therapies with a sense of urgency. We also continue to pioneer research that will help facilitate a deeper understanding of the role of immune biomarkers and how patients’ individual tumor biology can be used as a guide for treatment decisions throughout their journey.

We understand making the promise of I-O a reality for the many patients who may benefit from these therapies requires not only innovation on our part but also close collaboration with leading experts in the field. Our partnerships with academia, government, advocacy and biotech companies support our collective goal of providing new treatment options to advance the standards of clinical practice.

About Empliciti

Empliciti is an immunostimulatory antibody that specifically targets Signaling Lymphocyte Activation Molecule Family member 7 (SLAMF7), a cell-surface glycoprotein. SLAMF7 is expressed on myeloma cells independent of cytogenetic abnormalities. SLAMF7 also is expressed on Natural Killer cells, plasma cells and at lower levels on specific immune cell subsets of differentiated cells within the hematopoietic lineage.

Empliciti has a dual mechanism-of-action. It directly activates the immune system through Natural Killer cells via the SLAMF7 pathway. Empliciti also targets SLAMF7 on myeloma cells, tagging these malignant cells for Natural Killer cell-mediated destruction via antibody-dependent cellular toxicity.

Bristol-Myers Squibb and AbbVie are co-developing Empliciti, with Bristol-Myers Squibb solely responsible for commercial activities.

U.S. FDA-APPROVED INDICATION FOR EMPLICITI

EMPLICITI (elotuzumab) is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received one to three prior therapies.

IMPORTANT SAFETY INFORMATION

Infusion Reactions

EMPLICITI can cause infusion reactions. Common symptoms include fever, chills, and hypertension. Bradycardia and hypotension also developed during infusions. In the trial, 5% of patients required interruption of the administration of EMPLICITI for a median of 25 minutes due to infusion reactions, and 1% of patients discontinued due to infusion reactions. Of the patients who experienced an infusion reaction, 70% (23/33) had them during the first dose. If a Grade 2 or higher infusion reaction occurs, interrupt the EMPLICITI infusion and institute appropriate medical and supportive measures. If the infusion reaction recurs, stop the EMPLICITI infusion and do not restart it on that day. Severe infusion reactions may require permanent discontinuation of EMPLICITI therapy and emergency treatment.
Premedicate with dexamethasone, H1 Blocker, H2 Blocker, and acetaminophen prior to infusing with EMPLICITI.
Infections

In a clinical trial of patients with multiple myeloma (N=635), infections were reported in 81.4% of patients in the EMPLICITI with lenalidomide/dexamethasone arm (ERd) and 74.4% in the lenalidomide/dexamethasone arm (Rd). Grade 3-4 infections were 28% (ERd) and 24.3% (Rd). Opportunistic infections were reported in 22% (ERd) and 12.9% (Rd). Fungal infections were 9.7% (ERd) and 5.4% (Rd). Herpes zoster was 13.5% (ERd) and 6.9% (Rd). Discontinuations due to infections were 3.5% (ERd) and 4.1% (Rd). Fatal infections were 2.5% (ERd) and 2.2% (Rd). Monitor patients for development of infections and treat promptly.
Second Primary Malignancies

In a clinical trial of patients with multiple myeloma (N=635), invasive second primary malignancies (SPM) were 9.1% (ERd) and 5.7% (Rd). The rate of hematologic malignancies were the same between ERd and Rd treatment arms (1.6%). Solid tumors were reported in 3.5% (ERd) and 2.2% (Rd). Skin cancer was reported in 4.4% (ERd) and 2.8% (Rd). Monitor patients for the development of SPMs.
Hepatotoxicity

Elevations in liver enzymes (AST/ALT greater than 3 times the upper limit, total bilirubin greater than 2 times the upper limit, and alkaline phosphatase less than 2 times the upper limit) consistent with hepatotoxicity were 2.5% (ERd) and 0.6% (Rd). Two patients experiencing hepatotoxicity discontinued treatment; however, 6 out of 8 patients had resolution and continued treatment. Monitor liver enzymes periodically. Stop EMPLICITI upon Grade 3 or higher elevation of liver enzymes. After return to baseline values, continuation of treatment may be considered.
Interference with Determination of Complete Response

EMPLICITI is a humanized IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis and immunofixation assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and possibly relapse from complete response in patients with IgG kappa myeloma protein.
Pregnancy/Females and Males of Reproductive Potential

There are no studies with EMPLICITI with pregnant women to inform any drug associated risks.
There is a risk of fetal harm, including severe life-threatening human birth defects associated with lenalidomide and it is contraindicated for use in pregnancy. Refer to the lenalidomide full prescribing information for requirements regarding contraception and the prohibitions against blood and/or sperm donation due to presence and transmission in blood and/or semen and for additional information.
Adverse Reactions

Infusion reactions were reported in approximately 10% of patients treated with EMPLICITI with lenalidomide and dexamethasone. All reports of infusion reaction were Grade 3 or lower. Grade 3 infusion reactions occurred in 1% of patients.
Serious adverse reactions were 65.4% (ERd) and 56.5% (Rd). The most frequent serious adverse reactions in the ERd arm compared to the Rd arm were: pneumonia (15.4%, 11%), pyrexia (6.9%, 4.7%), respiratory tract infection (3.1%, 1.3%), anemia (2.8%, 1.9%), pulmonary embolism (3.1%, 2.5%), and acute renal failure (2.5%, 1.9%).
The most common adverse reactions in ERd and Rd, respectively (>20%) were fatigue (61.6%, 51.7%), diarrhea (46.9%, 36.0%), pyrexia (37.4%, 24.6%), constipation (35.5%, 27.1%), cough (34.3%, 18.9%), peripheral neuropathy (26.7%, 20.8%), nasopharyngitis (24.5%, 19.2%), upper respiratory tract infection (22.6%, 17.4%), decreased appetite (20.8%, 12.6%), and pneumonia (20.1%, 14.2%).
Please see the full Prescribing Information for EMPLICITI.

On June 24, 2017 Agios Pharmaceuticals, Inc. (NASDAQ:AGIO) reported new efficacy and safety data from the ongoing Phase 1/2 dose-escalation and expansion study evaluating investigational oral IDHIFA (enasidenib) in patients with relapsed or refractory acute myeloid leukemia (R/R AML) and an isocitrate dehydrogenase-2 (IDH2) mutation (Press release, Agios Pharmaceuticals, JUN 24, 2017, View Source [SID1234519654]). IDHIFA, being developed in collaboration with Celgene Corporation, is an investigational first-in-class, oral, targeted inhibitor of the mutant IDH2 enzyme. Data in an oral session at the 22nd Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) demonstrated an overall response rate (ORR) of 37 percent, including a complete response (CR) rate of 20.1 percent in 214 patients with R/R AML who received enasidenib at 100 mg daily, which was the recommended starting dose in the expansion phases of the trial.

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!

"With data from an additional 105 patients and the first look at data from the Phase 2 expansion in R/R AML patients treated at the recommended Phase 2 starting dose of 100 mg once daily, these updated results underscore the consistency and durability of response for enasidenib as a potential first-in-class therapy for patients with relapsed or refractory AML and an IDH2 mutation," said Chris Bowden, M.D., chief medical officer of Agios. "We are working with our partner Celgene to quickly bring this oral, targeted therapy to patients with limited treatment options."

As of October 14, 2016, a total of 345 patients with advanced hematologic malignances and an IDH2 mutation were enrolled into the Phase 1/2 study, which includes three parts: a Phase 1 dose escalation, a part 1 (Phase 1) expansion and a Phase 2 expansion. In the study, 281 patients had R/R AML and 214 of the R/R AML patients were treated at 100 mg daily. This is the first presentation of data from the Phase 2 expansion. Data reported include patients receiving enasidenib at total daily doses ranging from 50 mg to 650 mg in the dose-escalation arm and 100 mg daily in the Phase 1 and Phase 2 expansion arms. A maximum tolerated dose was not reached. The median age of the R/R AML patients enrolled in the study is 68 (ranging from 19-100). Patients with R/R AML received a median of two prior lines of therapy (ranging from one to 14).

The overall safety profile observed for enasidenib was consistent with previously reported data. The most common treatment-emergent AEs were nausea (48%), diarrhea (41%), fatigue (41%), decreased appetite (34%) and blood bilirubin increased (33%). For all patients in the study, 26.1 percent had treatment-related serious adverse events (SAEs), notably IDH differentiation syndrome (7%), leukocytosis (4%), tumor lysis syndrome (3%) and hyperbilirubinemia (2%).

Data from 214 of the R/R AML patients with an IDH2 mutation who were treated at the recommended Phase 2 starting dose of 100 mg daily demonstrated a 37 percent (79 of 214 patients) overall response rate, which was the primary endpoint of the study. Further, the complete response rate was 20.1 percent (43 of 214 patients). Median duration of response was 5.6 months [95% CI 4.6, 7.4] for all patients who responded and 8.8 months [95% CI 5.6, NR] for patients who achieved a CR. Median time to first response was 1.9 months (0.5-11.1) and median time to CR was 3.7 months (0.7-11.2). At the time of the data cut-off, median overall survival (OS) as observed in the study was 8.3 months [95% CI 7.5,9.4]. Additional results including qualitative improvement in response over time, improvement in hematological parameters over time, OS for patients achieving a CR and transfusion independence were also reported.

"Enasidenib’s unique profile as a targeted differentiation agent distinguishes it in a field that has seen few new medicines in decades," said Eytan Stein, M.D., lead investigator and attending physician in the leukemia service at Memorial Sloan Kettering Cancer Center. "Even in the absence of CR, some patients became transfusion independent with enasidenib treatment, suggesting a proportion of patients on study are deriving clinical benefit from an oral, single agent therapy in the relapsed/refractory setting."

Clinical Development

Enasidenib continues to be studied in the following ongoing clinical trials:

Phase III IDHENTIFY study evaluating the efficacy and safety of enasidenib versus conventional care regimens in older patients with R/R AML with an IDH2 mutation (NCT02577406)
Phase 1b study of either enasidenib or ivosidenib in combination with standard induction and consolidation chemotherapy in newly diagnosed AML (NCT02632708)
Phase 1/2 study of either enasidenib or ivosidenib in combination with azacitidine in newly diagnosed AML (NCT02677922)
The New Drug Application (NDA) for IDHIFA is currently under Priority Review with the U.S. Food and Drug Administration for the treatment of patients with relapsed or refractory AML with an IDH2 mutation. The NDA has been given a Prescription Drug User Fee Act (PDUFA) action date of August 30, 2017.

Ivosidenib (AG-120, wholly owned by Agios) is an investigational, oral, targeted inhibitor of the mutant IDH1 enzyme.

About AG221-C-001
Study AG221-C-001 includes three parts: a Phase 1 dose escalation, a part 1 (Phase 1) expansion and a Phase 2 expansion.

The Phase 1 dose escalation study was designed to determine the maximum tolerated dose and recommended Phase 2 dose, and to evaluate efficacy and safety of enasidenib (AG-221/CC-90007) in subjects with advanced hematologic malignancies with an IDH2 mutation. The Part 1 expansion further evaluated the safety, tolerability, and efficacy of enasidenib in subjects with R/R AML, untreated AML, myelodysplastic syndrome or other advanced hematologic malignancies with an IDH2 mutation. Based on the clinical activity observed in R/R AML subjects, the Phase 2 expansion was designed to assess efficacy of enasidenib at recommended 100 mg daily dose and to further evaluate safety in subjects with R/R AML and with IDH2 mutation. The study was not designed or statistically powered to reach a conclusion on OS. A phase 3 randomized controlled trial with OS as a primary endpoint has been initiated.

About Acute Myelogenous Leukemia (AML)
AML, a cancer of blood and bone marrow characterized by rapid disease progression, is the most common acute leukemia affecting adults. Undifferentiated blast cells proliferate in the bone marrow rather than mature into normal blood cells. AML incidence significantly increases with age, and according to the American Cancer Society, the median age of onset is 66. The vast majority of patients do not respond to chemotherapy and progress to relapsed/refractory AML. The five-year survival rate for AML is approximately 20 to 25 percent. IDH2 mutations are present in about 8 to 19 percent of AML cases.

On June 23, 2017 Stemline Therapeutics, Inc. (Nasdaq:STML), a clinical-stage biopharmaceutical company developing novel therapeutics for difficult to treat cancers, reported the presentation today of updated clinical data from Stages 1 and 2 of the ongoing SL-401 pivotal Phase 2 clinical trial in blastic plasmacytoid dendritic cell neoplasm (BPDCN), along with safety data from the entire SL-401 clinical program, at the 22ndCongress of the European Hematology Association (EHA) (Free EHA Whitepaper) being held in Madrid, Spain (Press release, Stemline Therapeutics, JUN 23, 2017, View Source [SID1234519681]).

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!

A summary of the presentation is as follows:

Stages 1 and 2 enrolled 32 BPDCN patients, of which 19 were first-line and 13 patients were relapsed/refractory.
Median age was 72 years (range 29-85 years).
The most common treatment-related adverse events (TRAEs) with SL-401 across BPDCN and other indications (n=134 patients) were hypoalbuminemia (43%), transaminitis (43%), and thrombocytopenia (26%), by investigator-assessment. TRAEs included capillary leak syndrome (18%), of which 3 cases were grade 5 (2.2%), as previously reported.
The overall response rate (ORR) for Stage 1 and 2 BPDCN patients (n=32) was 84%, with a complete response (CR) rate of 59%, by investigator-assessment.
Eight BPDCN patients who achieved remission on SL-401 (for ~2.5 to ~6 months duration) were subsequently bridged to stem cell transplant, including one relapsed/refractory patient.
In first-line BPDCN patients treated at 12 ug/kg/day (n=16), the median overall survival (OS) has not been reached.
The full presentation will be available on the Stemline website (www.stemline.com), under the "Scientific Presentations" tab, following delivery of today’s presentation at EHA (Free EHA Whitepaper).

Stage 3 is fully enrolled (n=13 first-line BPDCN patients) and data will be reported, along with further updated Stage 1 and 2 data, in 2H17. Depending on the results of this ongoing Phase 2 trial, the largest prospective study ever conducted in this indication (n=45 patients), we intend to file a BLA for SL-401 in BPDCN in 4Q17/1Q18.

On June 23, 2017 Syros Pharmaceuticals (NASDAQ: SYRS), a biopharmaceutical company pioneering the discovery and development of medicines to control the expression of disease-driving genes, reported preclinical data on SY-1425, its first-in-class selective retinoic acid receptor alpha (RARα) agonist currently in a Phase 2 clinical trial in genomically defined subsets of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), were presented at the European Hematology Association (EHA) (Free EHA Whitepaper) 22nd Congress in Madrid (Press release, Syros Pharmaceuticals, JUN 23, 2017, View Source [SID1234519680]).

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!

"The data presented at EHA (Free EHA Whitepaper) support our belief that SY-1425 may provide a meaningful clinical benefit as both a monotherapy and a combination therapy for defined subsets of AML and MDS patients and serve as the foundation for our rational combination strategy for SY-1425," said Nancy Simonian, M.D., Chief Executive Officer of Syros. "We are committed to broadly exploring the potential of SY-1425 through our Phase 2 clinical trial, which explores the safety and efficacy of SY-1425 as a single agent and in combination with a standard-of-care therapy, as well as through future clinical investigation of SY-1425 in combination with other targeted agents, including anti-CD38 therapies. We look forward to sharing initial clinical data from the ongoing Phase 2 trial this fall."

SY-1425 in Combination with Hypomethylating AML and MDS Therapies
Syros presented data showing that hypomethylating agents (HMAs) increase the activity of SY-1425 in in vitro and in vivo models of AML with high levels of RARA expression. HMAs including azacitidine, a therapy used as a standard-of-care in AML and MDS, prime the DNA for gene activation, thus enhancing SY-1425’s gene activation and differentiation properties. In patient-derived xenograft (PDX) models of AML with high RARA expression, SY-1425 in combination with azacitidine shows:

Greater clearance of tumor cells in bone marrow and other tissues, compared to either azacitidine or SY-1425 alone.
Greater duration of response, compared to either azacitidine or SY-1425 alone.
Based on these data, Syros expanded its ongoing Phase 2 clinical trial to include an arm assessing the safety and efficacy of SY-1425 in combination with azacitidine in newly diagnosed AML patients 60 years or older who are not suitable candidates for standard chemotherapy and who are positive for the Company’s biomarkers of high expression of the RARA-pathway associated genes RARA and IRF8. The treatment regimen for patients in the combination arm uses full doses of both agents and is consistent with the one identified in preclinical studies to maximize tumor suppression and tolerability.

SY-1425 Sensitizes RARA-High AML Cells to Anti-CD38 Therapeutic Antibody
Syros presented data demonstrating that SY-1425 induces the cell surface protein CD38 in AML cells from patient samples with high levels of RARA expression. By inducing CD38, SY-1425 sensitizes the cells to daratumumab, an anti-CD38 monoclonal antibody that targets CD38-positive tumor cells for immune cell-mediated killing. Daratumumab is approved to treat various multiple myeloma (MM) populations. The preclinical studies show SY-1425:

Induces levels of CD38 expression in RARA-high AML cells comparable to those in MM cells that are known to be responsive to daratumumab; notably, AML cells do not normally express high levels of CD38.
Triggers robust activation of natural killer cells when combined with daratumumab in RARA-high AML cells.
Leads to robust immune cell-mediated tumor cell death in RARA-high AML cells when combined with daratumumab.
Induces higher levels of CD38 expression in vivo than ATRA, a non-selective agonist of the retinoic acid receptor family.
Based on these data, Syros believes SY-1425 in combination with an anti-CD38 antibody represents a potentially promising immunotherapy approach for defined subsets of AML patients and plans to pursue clinical development of the combination in these patients.

Mechanism of Action of SY-1425
Syros presented data showing that SY-1425 regulates genes known to be associated with the proliferation of AML cells and normal myeloid differentiation. Using its proprietary gene control platform to analyze regulatory regions of the genome, Syros scientists identified changes in enhancer landscapes, gene expression and transcription factor distribution in AML cells treated with SY-1425. These changes show that SY-1425 pushes AML cells with high expression of the RARA and IRF8 genes into a more differentiated state. RARA and IRF8 code for transcription factors that work together to induce differentiation of blood and bone marrow cells and reduce proliferation of blast cells. The data show that:

In AML cells with high RARA and IRF8 expression, treatment with SY-1425 triggers a differentiation program in which a critical set of transcription factors bind to various sites on the genome to either activate or inactivate enhancers. In doing so, these transcription factors create an enhancer profile in RARA-high and IRF8-high AML cells that is similar to the enhancer profiles of normal differentiated cell types.
In RARA-high and IRF8-high AML cells treated with SY-1425, enhancers that were downregulated are enriched for binding sites for JUN and FOS, which are transcription factors known to drive proliferation, and enhancers that were upregulated are enriched for binding sites for RARα and IRF8, which are transcription factors known to be critical for differentiation.
The ongoing Phase 2 trial of SY-1425 is assessing the safety and efficacy of SY-1425 as both a monotherapy and in combination with azacitidine in subsets of AML and MDS patients who are positive for the Company’s RARA and IRF8 biomarkers. Additional details about the trial can be found using the identifier NCT02807558 at www.clinicaltrials.gov.