On June 11, 2016 Janssen-Cilag International NV reported results from the international Phase 3, randomised, double-blind, placebo-controlled, multicentre study, EPOANE 3021 (Press release, Janssen-Cilag International, JUN 11, 2016, View Source [SID:1234513282]).The study demonstrated the efficacy and safety of EPREX (epoetin alfa) as a treatment for anaemia, in adult patients with low or intermediate-1 risk myelodysplastic syndromes (MDS), as classified by an International Prognostic Scoring System (IPSS).1 EPOANE 3021 data were presented at the 21st Annual Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) (Abstract P248).

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These data, along with three registry studies from across Europe, have been submitted to the French health authority Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM), as the reference health authority for EPREX (epoetin alfa) within the mutual recognition procedure, to extend the existing marketing authorisation in Europe. A decision is expected in the coming months.

EPOANE 3021 was designed to evaluate whether epoetin alfa improves anaemia in patients with MDS, versus placebo over 24-weeks of treatment. It consisted of 130 randomised patients, with 85 patients receiving epoetin alfa. Results showed that compared to placebo, patients in the epoetin alfa arm demonstrated a statistically significantly higher erythroid response rate (according to IWG2006 criteria) in the first 24 weeks, the primary endpoint of the study (31.8 percent vs. 4.4 percent, p<0.001). Significantly fewer patients required transfusion on epoetin alfa (24.7 percent vs. 54.1 percent).1 Additional analysis, accounting for dose adjustments within the protocol, also confirmed a statistically significant erythroid response for epoetin alfa (45.9 percent) compared to placebo (4.4 percent) (p<0.001).1 Quality of life for responding patients in the epoetin alfa arm improved significantly compared to non-responders (FACT-An p=0.025, EQ-5D index score p=0.007, EQ-5D VAS p=0.037). There were no new safety signals for epoetin alfa from the study and safety findings were consistent with the known safety profile of epoetin alfa.1

"Anaemia affects the vast majority of patients with MDS and contributes substantially to their symptoms. However, there are currently no approved erythropoiesis stimulating agents approved for treating anaemia in lower-risk MDS patients," said Pierre Fenaux, M.D., PhD., principal investigator of EPOANE 3021, and Professor of Hematology, Hôpital St Louis/Université, Paris, France. "These data provide important evidence that epoetin alfa can effectively manage lower risk MDS-related anaemia, beyond transfusion, and without any impact on progression to acute myeloid leukaemia (AML)."

"EPREX (epoetin alfa) has shown great potential across a range of indications throughout its clinical development programme. We are excited to be building on this evidence base once again, with the findings of this new study demonstrating the meaningful difference this medicine can make to patients with MDS-related anaemia. We’re also extremely pleased to see the improvements in quality of life offered by EPREX, where alternative treatment options have so far been limited," said Jane Griffiths, Company Group Chairman, Janssen Europe, Middle East and Africa.

For more information on the EPOANE 3021 data presented at EHA (Free EHA Whitepaper) 2016, please view the abstract online.

About the EPOANE 3021 Study1

EPOANE 3021 was a randomised, double-blind, placebo-controlled, multicentre clinical trial investigating the efficacy and safety of EPREX (epoetin alfa) as a treatment for anaemia, in adult patients with low or Intermediate-1 risk myelodysplastic syndromes (MDS), as classified by an International Prognostic Scoring System (IPSS). Results demonstrated that 31.8 percent of patients treated with epoetin alfa achieved the primary endpoint of erythroid response versus 4.4 percent of placebo patients (p<0.001). An ad hoc analysis, accounting for the dose adjustments as per the protocol, confirmed a statistically significant erythroid response for epoetin alfa, with 45.9 percent of epoetin alfa patients, versus 4.4 percent of placebo patients achieving an erythroid response (p<0.001). Median erythroid response duration for epoetin alfa patients was 197 days. The number of patients needing transfusion in the epoetin alfa arm steadily decreased from 51.8 percent in the 8 weeks prior to baseline, to 24.7 percent by week-24. Transfusion need remained unchanged in the placebo patients (48.9 percent – 54.1 percent) over the same interval. Time to first transfusion was longer in the epoetin alfa group (p=0.046). Epoetin alfa demonstrated a statistically significant improvement of quality of life in responding patients.

There were no new safety signals for epoetin alfa from the study and safety findings are consistent with the known safety profile of epoetin alfa. The proportion of patients with at least one treatment emergent adverse event (TEAE) was numerically higher in the placebo group compared with the epoetin alfa group (88.9 percent vs. 77.6 percent). Drug discontinuation due to adverse events was 10.6 percent in the epoetin alfa group versus 13.3 percent in placebo. Four patients in the epoetin alfa arm (4.7 percent) and none in placebo reported a thrombovascular event (TVE). There were four fatal outcomes in the epoetin alfa arm versus one in the placebo arm; none were reported to be related to the study drug. During the study, progression to acute myeloid leukaemia (AML) was similar between groups (3.5 percent in epoetin alfa; 4.4 percent in placebo).

About Myelodysplastic Syndromes (MDS)

Myelodysplastic syndromes (MDS) are a group of diverse bone marrow disorders in which the bone marrow does not produce enough healthy blood cells.2 The low numbers of normal blood cells (cytopenias) eventually cause symptoms, including infection, anaemia, spontaneous bleeding, or easy bruising.2,3 The natural course of MDS is highly variable, with overall survival ranging from a few weeks to several years.4 MDS is primarily a disease of the elderly with a median age at diagnosis of 70 years, but it can affect younger patients as well.4 The incidence in Europe is about four cases per 100,000 per year, reaching 40-50 per 100,000 in patients aged 70 years and over.4

Approximately 60-80 percent of patients with MDS experience symptomatic anaemia,5 which can significantly reduce quality of life and often requires repeated blood transfusions.2 Controlling anaemia and improving quality of life are the principal aims of treatment in lower risk MDS patients.4 At present, blood transfusions are currently the only approved treatment option; however these lead to iron overload, which is associated with significant morbidity and mortality.4,5

About EPREX (epoetin alfa)

EPREX (epoetin alfa) is an erythreopoiesis-stimulating agent (ESA) that works by stimulating the production of red blood cells (RBCs).6 ESAs are an important treatment option for patients with certain types of anaemia, including chemotherapy-induced anaemia and anaemia due to chronic kidney disease. Without ESAs, patients with certain types of anaemia may require regular blood transfusions to maintain RBCs at concentrations necessary to sustain normal oxygen levels throughout the body.4

EPREX is currently indicated for the treatment of:6

Symptomatic anaemia associated with chronic renal failure (CRF):
In adult and paediatric patients aged 1 to 18 years on haemodialysis and adult patients on peritoneal dialysis.
In adults with renal insufficiency not yet undergoing dialysis for the treatment of severe anaemia of renal origin accompanied by clinical symptoms in patients.
Adults receiving chemotherapy for solid tumours, malignant lymphoma or multiple myeloma, and at risk of transfusion as assessed by the patient’s general status (e.g. cardiovascular status, pre-existing anaemia at the start of chemotherapy) for the treatment of anaemia and reduction of transfusion requirements.
Adults in a predonation programme to increase the yield of autologous blood. Treatment should only be given to patients with moderate anaemia (haemoglobin concentration range between 10 to 13 g/dl [6.2 to 8.1 mmol/l], no iron deficiency) if blood saving procedures are not available or insufficient when the scheduled major elective surgery requires a large volume of blood (4 or more units of blood for females or 5 or more units for males).
Non-iron deficient adults prior to major elective orthopaedic surgery having a high perceived risk for transfusion complications to reduce exposure to allogeneic blood transfusions. Use should be restricted to patients with moderate anaemia (e.g. haemoglobin concentration range between 10 to 13 g/dl) who do not have an autologous predonation programme available and with expected moderate blood loss (900 to 1,800 ml).
About the Janssen Pharmaceutical Companies

On June 11, 2016 Boehringer Ingelheim reported that the results of the Phase III POLO-AML-2 trial investigating volasertib plus chemotherapy (low dose cytarabine, LDAC), in the treatment of elderly acute myeloid leukemia (AML) patients, did not meet the primary endpoint of objective response (Press release, Boehringer Ingelheim, JUN 11, 2016, View Source [SID:1234513209]). Boehringer Ingelheim is committed to further investigating volasertib with a revised research strategy based on the learnings of the trial, which demonstrated the compound’s anti-leukemic activity and an increased response rate.

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The results, presented at the 21st Annual Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) 2016, showed the percentage of patients with an objective response was higher with volasertib plus LDAC, compared to placebo plus LDAC, but the difference was statistically not significant. The data showed an unfavorable overall survival trend for the experimental treatment arm, with the safety profile of the volasertib plus LDAC dosing regimen considered as the main reason for the trend.

Martin Stefanic, Medical Head, Early Clinical Development, Boehringer Ingelheim commented: "We are disappointed with the findings of the POLO-AML-2 trial after the encouraging results we observed in the Phase II trial. However, we believe in the potential of volasertib and new clinical studies have been initiated for AML patients, in addition to other areas of high unmet need such as higher risk myelodysplastic syndromes (MDS). The goal of these studies is to improve tolerability with modified dosing and scheduling of volasertib, while not compromising on efficacy, in order to achieve the best outcome for patients."

POLO-AML-2 (NCT01721876) is a randomized, double-blind, multi-center, controlled Phase III clinical trial of volasertib in combination with LDAC in 666 patients aged 65 years and older with newly diagnosed AML, not suitable for intensive induction therapy. The primary analysis showed a higher number of patients responded to volasertib plus LDAC (25.2%) than placebo plus LDAC (16.8%) but the overall result was not statistically significant.

There was a higher incidence of severe adverse events with volasertib plus LDAC, with a fatal infection frequency of 16.6% (volasertib plus LDAC) vs 5.1% (placebo plus LDAC) which was considered the main reason for a negative overall survival trend in the volasertib plus LDAC treatment arm compared to placebo plus LDAC (primary OS analysis: HR 1.26 [95% CI 0.95–1.67; p=0.113]; updated OS analysis (Nov 2015): HR 1.06 [95% CI 0.88–1.28; p=0.552]). The unblinded trial is still ongoing and updated results will be presented at a future scientific meeting when they are available.

Boehringer Ingelheim has a substantial program in hematological cancers with five investigational compounds in early clinical development.

About volasertib
Volasertib is an investigational compound that inhibits enzymes called Polo-like kinases (PLKs). Inhibition of PLK1 by volasertib ultimately results in cell death (apoptosis). By inhibiting PLK1 activity, the extremely high cell division that is characteristic of AML should be blocked, which may result in cancer regression.

On June 11, 2016 Seattle Genetics, Inc. (NASDAQ: SGEN) reported data at the 21st Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) taking place in Copenhagen, Denmark, June 9-12, 2016, evaluating vadastuximab talirine (SGN-CD33A; 33A) in combination with hypomethylating agents (HMAs; azacitidine, decitabine) in frontline patients with acute myeloid leukemia (AML) who had declined intensive therapy (Press release, Seattle Genetics, JUN 11, 2016, View Source;p=RssLanding&cat=news&id=2176948 [SID:1234513211]). 33A is an investigational antibody-drug conjugate (ADC) targeted to CD33 utilizing Seattle Genetics’ newest technology, comprising an engineered cysteine antibody (EC-mAb) stably linked to a highly potent DNA binding agent called a pyrrolobenzodiazepine (PBD) dimer. CD33 is expressed on leukemic blasts in nearly all AML patients with expression generally consistent regardless of age, cytogenetic abnormalities or underlying mutations.

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Based on data from the ongoing phase 1 clinical trial, a phase 3 clinical trial, called CASCADE, was recently initiated evaluating 33A in combination with HMAs in previously untreated AML patients not candidates for intensive induction chemotherapy. Seattle Genetics is also evaluating 33A broadly across multiple lines of therapy in patients with myeloid malignancies, including ongoing and planned phase 1 and 2 clinical trials for newly diagnosed or relapsed AML and for previously untreated myelodysplastic syndrome (MDS). More information about 33A and ongoing clinical trials can be found at www.ADC-CD33.com.

"Hypomethylating agents, or HMAs, are the current standard of care for AML patients who are not able to tolerate intensive therapy. HMAs have limited benefit, with low response rates and median overall survival of 10 months or less," said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. "We believe that adding 33A to HMAs may improve efficacy and has the potential to redefine the treatment of AML. The clinical data at ASH (Free ASH Whitepaper) showing high response rate, manageable tolerability profile and low early mortality reported have been maintained in this larger data set, and support our recently initiated phase 3 CASCADE clinical trial, which is now enrolling patients."

"There is a dire need to improve outcomes for patients with AML," said Amir Fathi, M.D., investigator of the phase 1 trial who will present the data at EHA (Free EHA Whitepaper). "The anti-leukemic activity we have observed in the phase 1 clinical trial evaluating 33A combination therapy in AML patients continues to be encouraging. This is an incredibly difficult disease to treat and the results to-date continue to show a balance of activity and tolerability together with low early mortality rates. The data presented suggest that the addition of 33A improves the rates of response and durable remissions in comparison to that seen historically from using the current standard of care alone."

SGN-CD33A in Combination with Hypomethylating Agents: A Novel, Well-Tolerated Regimen with High Remission Rate in Older Patients with AML (Abstract #S503, oral presentation on Saturday, June 11, 2016 at 4:30 p.m. CEST)

Outcomes for AML patients who are not candidates for intensive chemotherapy or allogeneic stem cell transplant are dismal. Low intensity treatment options, including HMAs (azacitidine and decitabine), are limited. Interim results from the first 25 patients in the ongoing phase 1 study evaluating 33A in combination with HMAs in frontline AML were presented at the 2015 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition. Updated interim results from the ongoing phase 1 study were presented in an oral session at EHA (Free EHA Whitepaper).

Data were reported from 53 frontline unfit AML patients with a median age of 75 years and intermediate or adverse cytogenetic risk who had declined intensive therapy. Forty-five percent of patients had evidence of underlying myelodysplasia. Key findings presented by Dr. Fathi include:

Of 49 efficacy-evaluable patients treated with 33A combined with either azacitidine or decitabine, the overall response rate was 76 percent. Complete remission (CR) or complete remission with incomplete platelet or neutrophil recovery (CRi) was observed in 35 patients (71 percent). The remission rate (CR+CRi) was similar between the two 33A and HMA combination treatment groups (71 percent combined with azacitidine and 72 percent combined with decitabine).
Responses were observed in higher-risk patients, with remissions achieved in 16 of 22 patients (73 percent) with underlying myelodysplasia and 15 of 18 patients (83 percent) with adverse cytogenetics.
Patients who achieved minimal residual disease included eight of 19 (42 percent) CR patients and five of 15 (33 percent) CRi patients.
The median overall survival for all patients in the phase 1 trial is interim and expected to evolve. The estimated median overall survival for the first 25 patients enrolled in the study was 12.75 months, with a median follow-up of 12.58 months.
Median relapse-free survival was 7.7 months (range, 0.0+ and 11.3+) with 27 patients (51 percent) remaining alive and on study as of last follow-up. The 30- and 60-day mortality rates were two and eight percent, respectively.
The most common treatment-related adverse events of any grade occurring in 20 percent or more of patients were fatigue (57 percent), thrombocytopenia (53 percent), nausea (49 percent), febrile neutropenia (45 percent), and constipation and anemia (42 percent each). The most common Grade 3 or 4 treatment-emergent adverse events occurring in 20 percent or more of patients were febrile neutropenia, thrombocytopenia, neutropenia, anemia and fatigue.
About Acute Myeloid Leukemia
Acute myeloid leukemia, also called acute myelocytic leukemia or AML, is an aggressive type of cancer of the bone marrow and blood that progresses rapidly without treatment. AML is a cancer that starts in the cells that are supposed to mature into different types of blood cells. AML starts in the bone marrow (the interior part of bones, where new blood cells are made) and quickly moves into the blood. According to the American Cancer Society, in 2016 approximately 20,000 new cases of AML (mostly in adults) will be diagnosed and nearly 10,500 deaths will occur from AML (almost all will be in adults).

About Vadastuximab Talirine (SGN-CD33A)
Vadastuximab talirine (SGN-CD33A; 33A) is a novel investigational ADC targeted to CD33 utilizing Seattle Genetics’ newest ADC technology. CD33 is expressed on most AML and MDS blast cells. The CD33 antibody is attached to a highly potent DNA binding agent, a pyrrolobenzodiazepine (PBD) dimer, via a proprietary site-specific conjugation technology to a monoclonal antibody with engineered cysteines (EC-mAb). PBD dimers are significantly more potent than systemic chemotherapeutic drugs and the site-specific conjugation technology (EC-mAb) allows uniform drug-loading of the cell-killing PBD agent to the anti-CD33 antibody. The ADC is designed to be stable in the bloodstream and to release its potent DNA binding agent upon internalization into CD33-expressing cells.

33A was granted Orphan Drug Designation by both the U.S. Food and Drug Administration (FDA) and the European Commission for the treatment of AML. FDA orphan drug designation is intended to encourage companies to develop therapies for the treatment of diseases that affect fewer than 200,000 individuals in the United States.

On June 10, 2016 Alexion Pharmaceuticals, Inc. (NASDAQ:ALXN) reported that interim data were presented from a Phase 1/2 study of ALXN1210, an investigational, highly innovative longer-acting anti-C5 antibody, in patients with paroxysmal nocturnal hemoglobinuria (PNH), a debilitating, ultra-rare blood disorder characterized by complement-mediated hemolysis (destruction of red blood cells) (Press release, Alexion, JUN 10, 2016, View Source [SID:1234513201]).1 In this study, once-monthly dosing of ALXN1210 achieved rapid and sustained reductions in mean levels of lactate dehydrogenase (LDH), a marker of hemolysis, in 100 percent of treated patients, which were observed through up to five once-monthly dosing intervals. Researchers also reported that, at this time, 80 percent of patients who required at least 1 blood transfusion in the 12 months prior to treatment with ALXN1210 did not require transfusions while on treatment.2 These findings were presented in a late-breaking poster at the 21st Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Copenhagen, Denmark.

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In a separate late-breaking poster at EHA (Free EHA Whitepaper), additional interim results were presented from a Phase 2 trial evaluating ALXN1007, a novel anti-inflammatory antibody targeting complement protein C5a, in patients with acute graft-versus-host disease of the lower GI tract (GI-GVHD). Acute GI-GVHD is a severe and life-threatening rare autoimmune disease that can occur as a complication of stem cell or bone marrow transplantation.3,4,5 The study showed an overall 28-day response rate—defined as improvement from diagnosis in any organ by ≥1 stage, without progression in any other organ and no need for additional therapy—of 77 percent in ALXN1007-treated patients.6

"Alexion has more than 20 years of experience in complement research and discovery, and we are pleased to have late-breaking data from two of our highly innovative, investigational complement inhibitors, ALXN1210 and ALXN1007, presented at EHA (Free EHA Whitepaper)," said Martin Mackay, Ph.D., Executive Vice President and Global Head of R&D at Alexion. "Interim results from the Phase 1/2 study of ALXN1210 in patients with PNH showed rapid, complete, and sustained complement inhibition, as measured by reductions in LDH levels, with a once-monthly dosing regimen in all treated patients. A Phase 2 study is ongoing to evaluate the safety and efficacy of ALXN1210 in additional dosing cohorts evaluating longer dosing intervals."

ALXN1210, a Long-Acting C5 Inhibitor, Results in Rapid and Sustained Reduction of LDH with a Monthly Dosing Interval in Patients with PNH: Preliminary Data from a Dose-Escalation Study (Abstract LB2247) 2

In a poster session, interim results were presented from a Phase 1/2, open-label, 24-week dose-escalating study of ALXN1210 in patients with PNH. The primary efficacy endpoint was the percent change in LDH levels from baseline; other efficacy endpoints included change in blood transfusion requirements and change in hematologic parameters from baseline. Patients with PNH (aged 18 and older; n=13) with mean LDH levels ≥3 times the upper limit of normal and who were complement inhibitor-naïve were separated into two study cohorts. Patients in Cohort 1 (n=6) received either 400 mg or 600 mg induction doses of ALXN1210, followed by a 900 mg maintenance dose once-monthly. Patients in Cohort 2 (n=7) received 600 mg and 900 mg induction doses of ALXN1210, followed by an 1,800 mg maintenance dose once-monthly.

All patients showed rapid reductions in mean LDH levels at Day 8 (the first evaluable time point of the study), which were sustained for up to five once-monthly dosing intervals. At the most recent evaluable time point, the mean percentage reduction in LDH levels from baseline was 85.4 percent in Cohort 1 (Day 148) and 86.0 percent in Cohort 2 (Day 85). Among five patients with one or more transfusions in the year prior to the study, only one patient, from Cohort 1, required a transfusion during treatment with ALXN1210. This patient received two units of packed red blood cells (RBC) while receiving ALXN1210, compared to 12 units of RBC in the six months prior to ALXN1210. In addition, mean levels of hemoglobin, another direct marker of intravascular hemolysis, were improved or stable in both cohorts.

"PNH is a devastating, ultra-rare blood disorder caused by uncontrolled activation of complement, putting patients at risk for severe and life-threatening consequences," said lead author Jong-Wook Lee, M.D., of The Catholic University of Korea, Seoul St. Mary’s Hospital, Seoul, Korea. "The interim data presented at EHA (Free EHA Whitepaper) suggest that treatment with ALXN1210 results in effective blockade of complement-mediated hemolysis and reduces transfusion requirements in patients with PNH. All patients achieved rapid decreases in LDH levels that were sustained through extended, once-monthly dosing intervals, consistent with the longer half-life of ALXN1210."

No serious adverse events or study withdrawals were observed in either patient cohort. The most common treatment-related adverse events were headache and upper respiratory tract infection (each occurring in 3 patients), which resolved during ongoing treatment with ALXN1210.

Phase 2A Study of ALXN1007, A Novel C5a Inhibitor, in Subjects with Newly Diagnosed Acute Graft-Versus-Host Disease (GVHD) Involving the Lower Gastrointestinal Tract (Abstract LB2269) 6

In a poster session, additional interim results were presented from an ongoing Phase 2, open-label study of ALXN1007 in patients with newly diagnosed acute GI-GVHD. The primary efficacy endpoint is the overall acute GVHD response rate at Day 28. Other efficacy endpoints include complete GI-GVHD response rate at Day 28 and Day 56. Patients were treated once-weekly with 10 mg/kg of ALXN1007 for eight weeks in combination with methylprednisolone or equivalent, with one year of follow-up.

At both Day 28 and Day 56, the overall acute GVHD response rate was 77 percent in 13 evaluable patients. Complete GI-GVHD response rates at Days 28 and 56 were 69 percent and 77 percent, respectively. Additionally, at Day 180, the non-relapse mortality rate from causes other than the underlying malignancy was 12.5 percent, and the overall survival rate was 69.2 percent, among 13 evaluable patients.

The study also evaluated the degree of C5a inhibition relative to PK and acute GI-GVHD response suggesting that higher doses and frequency may be needed to optimize C5a inhibition and maximize clinical response. The trial protocol was subsequently amended to evaluate an ALXN1007 dose of 20 mg/kg weekly and twice-weekly.

Two patients (13 percent) experienced serious treatment-related adverse events and one patient had a grade 2 infusion-related reaction. There were no grade 3 or higher non-serious adverse events related to treatment with ALXN1007. One patient withdrew from the study due to a treatment-emergent adverse event (relapse of T-cell lymphoma). Six deaths were reported, none of which were considered related to treatment with ALXN1007.

About Paroxysmal Nocturnal Hemoglobinuria (PNH)

PNH is an ultra-rare blood disorder in which chronic, uncontrolled activation of complement, a component of the normal immune system, results in hemolysis (destruction of the patient’s red blood cells). PNH strikes people of all ages, with an average age of onset in the early 30s.1 Approximately 10 percent of all patients first develop symptoms at 21 years of age or younger.7 PNH develops without warning and can occur in men and women of all races, backgrounds and ages. PNH often goes unrecognized, with delays in diagnosis ranging from one to more than 10 years.8 In the period of time before Soliris (eculizumab) was available, it had been estimated that approximately one-third of patients with PNH did not survive more than five years from the time of diagnosis.1 PNH has been identified more commonly among patients with disorders of the bone marrow, including aplastic anemia (AA) and myelodysplastic syndromes (MDS).9,10,11 In patients with thrombosis of unknown origin, PNH may be an underlying cause.1

About ALXN1210

ALXN1210 is a highly innovative, longer-acting C5 antibody being evaluated by Alexion for the treatment of patients with PNH. In early studies, ALXN1210 has demonstrated rapid, complete, and sustained reduction of free C5 activity and a terminal half-life of more than 30 days, which may facilitate a monthly or longer dosing interval.12 Alexion is conducting two clinical studies of ALXN1210 in patients with PNH—a Phase 1/2 dose-escalating study and an open-label, multi-dose Phase 2 study.

About Graft-Versus-Host Disease of the Lower GI tract (GI-GVHD)

GI-GVHD is an immune-mediated disease that affects 10 to 12 percent of patients who receive an allogeneic hematopoietic stem cell transplant.3,4 Patients with severe, acute GI-GVHD have a 30 to 40 percent mortality rate within the first six months post-transplant.13 There are no approved treatments for GI-GVHD.

About ALXN1007

ALXN1007 is a novel anti-inflammatory antibody targeting complement protein C5a being evaluated in a Phase 2 trial for patients with acute GI-GVHD.

About Soliris (eculizumab)

Soliris is a first-in-class terminal complement inhibitor developed from the laboratory through regulatory approval and commercialization by Alexion. Soliris is approved in the U.S. (2007), European Union (2007), Japan (2010) and other countries as the first and only treatment for patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis. PNH is a debilitating, ultra-rare and life-threatening blood disorder, characterized by complement-mediated hemolysis (destruction of red blood cells). Soliris is also approved in the U.S. (2011), European Union (2011), Japan (2013) and other countries as the first and only treatment for patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy, or TMA (blood clots in small vessels). aHUS is a debilitating, ultra-rare and life-threatening genetic disorder characterized by complement-mediated TMA. Soliris is not indicated for the treatment of patients with Shiga-toxin E. coli-related hemolytic uremic syndrome (STEC-HUS). For the breakthrough medical innovation in complement inhibition, Alexion and Soliris have received some of the pharmaceutical industry’s highest honors: the Prix Galien USA (2008, Best Biotechnology Product) and France (2009, Rare Disease Treatment).

More information, including the full U.S. prescribing information, on Soliris is available at www.soliris.net.

Important Safety Information

The U.S. product label for Soliris includes a boxed warning: "Life-threatening and fatal meningococcal infections have occurred in patients treated with Soliris. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early [see Warnings and Precautions (5.1)]. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients with complement deficiencies. Immunize patients with a meningococcal vaccine at least two weeks prior to administering the first dose of Soliris, unless the risks of delaying Soliris therapy outweigh the risk of developing a meningococcal infection. [See Warnings and Precautions (5.1) for additional guidance on the management of the risk of meningococcal infection]. Monitor patients for early signs of meningococcal infections and evaluate immediately if infection is suspected. Soliris is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Under the Soliris REMS, prescribers must enroll in the program [see Warnings and Precautions (5.2)]. Enrollment in the Soliris REMS program and additional information are available by telephone: 1-888-SOLIRIS (1-888-765-4747)."

In patients with PNH, the most frequently reported adverse events observed with Soliris treatment in clinical studies were headache, nasopharyngitis (runny nose), back pain and nausea. Soliris treatment of patients with PNH should not alter anticoagulant management because the effect of withdrawal of anticoagulant therapy during Soliris treatment has not been established. In patients with aHUS, the most frequently reported adverse events observed with Soliris treatment in clinical studies were headache, diarrhea, hypertension, upper respiratory infection, abdominal pain, vomiting, nasopharyngitis, anemia, cough, peripheral edema, nausea, urinary tract infections, and pyrexia. Soliris is not indicated for the treatment of patients with Shiga-toxin E. coli-related hemolytic uremic syndrome (STEC-HUS). Please see full prescribing information for Soliris, including BOXED WARNING regarding risk of serious meningococcal infection.

On June 10, 2016 Syros Pharmaceuticals reported that SY-1425, its potent and selective retinoic acid receptor alpha (RARα) agonist, was observed to inhibit the growth of cancer cells and prolong survival in an in vivo model of acute myeloid leukemia (AML) with a novel RARA biomarker discovered by the Company (Press release, Syros Pharmaceuticals, JUN 10, 2016, View Source [SID:1234513202]). Syros also announced that SY-1365, its first-in-class potent and selective cyclin-dependent kinase 7 (CDK7) inhibitor, was observed to selectively kill acute leukemia cells over non-cancerous cells and induce complete tumor regression and a significant survival benefit in in vivo models of AML. These data are being presented this week at the 21st Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Copenhagen, Denmark.

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"The presentations at EHA (Free EHA Whitepaper) highlight the potential of our gene control platform to systematically analyze the non-coding, regulatory region of the genome to advance a new wave of medicines designed to control the expression of disease-causing genes"
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"The presentations at EHA (Free EHA Whitepaper) highlight the potential of our gene control platform to systematically analyze the non-coding, regulatory region of the genome to advance a new wave of medicines designed to control the expression of disease-causing genes," said Nancy Simonian, MD, Chief Executive Officer of Syros. "By pioneering the understanding of this previously unexploited region of the genome, we believe we can identify novel disease drivers in specific patient populations and develop drugs that influence multiple disease-driving genes to provide patients with a more profound and durable benefit than many of today’s targeted therapies. Based on these strong preclinical data, we are currently advancing SY-1425 into a Phase 2 trial in genomically defined subsets of relapsed or refractory AML and relapsed high-risk MDS patients and plan to advance SY-1365 into a clinical trial for acute leukemia in the first half of 2017."

SY-1425 for Novel Genomically Defined Subsets of AML and MDS Patients
The data on SY-1425, which will be detailed in an oral presentation Sunday at EHA (Free EHA Whitepaper), shows that a biomarker for a highly specialized regulatory region of non-coding DNA, known as a super-enhancer, that is associated with the RARA gene is predictive of response to treatment with SY-1425 in AML cell lines and a patient-derived xenograft (PDX) model of AML. Treatment with SY-1425 was observed to inhibit cancer growth and prolong survival in a PDX model of AML with the RARA biomarker but not in a model of AML without the biomarker. Syros found the biomarker in approximately 25 percent of AML and myelodysplastic syndrome (MDS) patient tissue samples analyzed. Highlights of the data include:

Greatly reduced tumor burden in the blood, bone marrow and spleen in a PDX mouse model with the RARA biomarker treated with SY-1425 compared to untreated mice; by contrast, no effect was seen in a PDX model of AML without the biomarker.
Prolonged survival with 100 percent of mice with the RARA biomarker treated with SY-1425 alive at the end of the 35-day study; by contrast, none of the untreated mice survived beyond 25 days; notably, no survival benefit was seen in a PDX model of AML without the biomarker.
No anti-tumor or survival benefit seen with ATRA, a less potent and non-selective retinoid, in a PDX model with the RARA biomarker.
Differentiation of AML cells with the RARA biomarker treated with SY-1425.
Using its gene control platform, Syros identified subsets of AML and MDS patients whose tumors have the RARA super-enhancer. The super-enhancer is believed to lead to over-production of the RARα transcription factor, locking cells in an immature, undifferentiated and proliferative state. Treatment with SY-1425 inhibits cancer growth by promoting differentiation of AML cells with the RARA super-enhancer. Syros is on track to initiate a Phase 2 clinical trial of SY-1425 in mid-2016 in subsets of relapsed or refractory AML and relapsed high-risk MDS patients with the RARA biomarker.

CDK7 Inhibition as a Novel Treatment Strategy for Acute Leukemia
In the preclinical studies being presented Saturday at EHA (Free EHA Whitepaper), SY-1365 was observed to preferentially kill AML and acute lymphoblastic leukemia (ALL) cells over non-cancerous cells and induce tumor regression and significantly prolong survival in models of AML. Highlights of the in vitro and in vivo data include:

Complete tumor regression, which was maintained through the end of the 38-day study, in 100 percent of treated mice in a cell-line derived xenograft model of AML.
Strong survival benefit, with treated mice surviving up to 7-1/2 weeks beyond untreated mice in a PDX model of treatment-resistant AML.
Robust, sustained and dose-dependent apoptosis in AML and ALL cells treated with SY-1365 while not inducing apoptosis in non-cancerous cells.
Potent and selective inhibition of CDK7, with only six other kinases exhibiting greater than 90 percent binding when profiled across a panel of 468 kinases at a concentration of 1μM; notably, SY-1365 was not observed to significantly bind to members of the CDK family involved in cell cycle.
Minimal effect on blood cell counts, including white blood cells, lymphocytes, neutrophils and reticulocytes, in an in vivo model, demonstrating a more favorable profile than a non-selective CDK inhibitor.
Reduced expression of cancer-contributing genes associated with super-enhancers, including oncogenic transcription factors MYB and MYC, in an AML cell line.
Synergistic activity when combined with other targeted agents in AML, including Flt3, Bcl-2 and pan-Brd inhibitors.
Certain cancers, including AML and ALL, are dependent on high and constant expression of transcription factors for their growth and survival and have been shown to be particularly responsive to selective inhibition of CDK7. Syros has generated several selective CDK7 inhibitors, which have been observed to delay tumor progression in in vivo models of additional transcriptionally addicted cancers, including MYCN-amplified neuroblastoma, small cell lung cancer and triple negative breast cancer. Syros selected SY-1365 as its development candidate based on its strong preclinical efficacy and safety and plans to begin a Phase 1/2 clinical trial of SY-1365 in acute leukemia in the first half of 2017.