On December 3, 2018 Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, reported its data from a Phase 1 study evaluating ivosidenib or enasidenib in combination with standard induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia (AML) and an isocitrate dehydrogenase (IDH)1 or IDH2 mutation (Press release, Agios Pharmaceuticals, DEC 3, 2018, View Source [SID1234531864]). The data were featured in an oral presentation at the 60thAmerican Society of Hematology Annual Meeting in San Diego.

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"These data demonstrate that combining full doses of standard induction and consolidation chemotherapy with ivosidenib or enasidenib is well tolerated and has the potential to provide benefit for AML patients in the frontline setting," said Eytan Stein, M.D., study investigator and attending physician in the leukemia service at Memorial Sloan Kettering Cancer Center. "The addition of an IDH inhibitor to induction and consolidation followed administration as single-agent maintenance therapy for patients with newly diagnosed AML will be evaluated further in a Phase 3 randomized study."

"The molecular remissions observed in these newly diagnosed AML patients is encouraging," said Chris Bowden, M.D., chief medical officer at Agios. "In conjunction with Celgene, we will provide support of the Phase 3 HOVON 150 AML/AMLSG 29-18 study, which is planned to initiate by year-end. HOVON 150 AML/AMLSG 29-18 is an intergroup sponsored, global, registration-enabling trial combining ivosidenib or enasidenib with standard induction and consolidation chemotherapy followed by a maintenance therapy period in frontline AML patients with an IDH1 or IDH2 mutation, respectively."

About the Ongoing Phase 1 Study
As of the August 1, 2018 data cut-off, 60 newly diagnosed AML patients with mIDH1 received 500 mg of ivosidenib and standard induction chemotherapy (daunorubicin 60 mg/m2/day or idarubicin 12 mg/m2/day x 3 days with cytarabine 200 mg/m2/day x 7 days) and 93 newly diagnosed AML patients with mIDH2 received 100 mg of enasidenib and standard induction chemotherapy. After induction, patients received up to four cycles of consolidation chemotherapy while continuing ivosidenib (n=28) or enasidenib (n=45). Patients who achieved a complete response (CR) or a complete response with incomplete neutrophil or platelet recovery (CRi/CRp) after consolidation could continue taking single agent ivosidenib or enasidenib daily until the end of the study which is up to two years from the last patient dosed.

70% of ivosidenib-treated patients and 63% of enasidenib-treated patients had de novo AML, while the remaining had secondary AML (sAML).
In patients with sAML, 22% in the ivosidenib cohort and 50% in the enasidenib cohort had received prior hypomethylating agent therapy.
The median age of patients was 62.5 years (range 24-76) in the ivosidenib cohort and 63 years (range 27-77) in the enasidenib cohort.
The most commonly occurring baseline co-mutations in ivosidenib-treated patients were DNMT3A, NPM1, ASXL1 and BCOR while in enasidenib-treated patients, the most commonly occurring baseline mutations were DNMT3A, SRSF2, ASXL1 and RUNX1.
Ivosidenib Results

Safety Data

The frequency of Grade 3 or higher adverse events of interest, regardless of attribution, during the induction period were: IDH differentiation syndrome in 3% (2/60) of patients, QT interval prolongation in 2% (1/60) of patients and blood bilirubin increased in 7% (4/60) of patients.
The 30-day mortality rate was 5% and the 60-day mortality rate was 8%.
Efficacy Data

An overall best response of CR+CRi/CRp was achieved in 80% (39/49) of efficacy evaluable patients.
The CR+CRi/CRp rate for de novo patients was 91% (31/34) and 53% (8/15) for sAML patients.
In a subset of patients who achieved a CR or CRi/CRp, elimination of measurable residual disease (MRD) by flow cytometry was observed in 88% (15/17) of patients.
In patients whose best response was CR or CRi/CRp, IDH1 mutation clearance by digital PCR was achieved in 41% (12/29) of patients.
At the time of the data cut-off, the probability of survival at one-year was 79% and median overall survival (OS) was not yet estimable.
The median time to absolute neutrophil count (ANC) recovery (>500/µL) from induction therapy (n=38) was 28 days (95% CI 28, 30). Median time to platelet recovery (>50,000/µL) from induction therapy (n=38) was 28 days (95% CI 27, 30).
Enasidenib Results

Safety Data

The frequency of Grade 3 or higher adverse events of interest, regardless of attribution, during the induction period were: IDH differentiation syndrome in 1% (1/93) of patients and blood bilirubin increased in 14% (13/93) of patients.
The 30-day mortality rate was 5% and the 60-day mortality rate was 9%.
Efficacy Data

An overall best response of CR+CRi/CRp was achieved in 72% (64/89) of efficacy evaluable patients.
The CR+CRi/CRp rate for de novo patients was 77% (43/56) and 64% (21/33) for sAML patients.
In a subset of patients who achieved a CR or CRi/CRp, elimination of MRD by flow cytometry was observed in 45% (9/20) of patients.
In patients whose best response was CR or CRi/CRp, IDH2 mutation clearance by digital PCR was achieved in 25% (15/59) of patients.
At the time of the data cut-off, the probability of survival at one-year was 75% and median OS was not yet estimable.
The median time to ANC recovery (>500/µL) from induction therapy (n=46) was 34 days (95% CI 31, 36). Median time to platelet recovery (>50,000/µL) from induction therapy (n=46) was 30 days (95% CI 29, 34).
Neither IDHIFA nor TIBSOVO are approved for the treatment of patients with newly diagnosed AML or approved in combination with induction and consolidation chemotherapy.

About TIBSOVO (ivosidenib)

TIBSOVO (ivosidenib) is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test. For more information, visit TIBSOVO.com.

IMPORTANT SAFETY INFORMATION

WARNING: DIFFERENTIATION SYNDROME

Patients treated with TIBSOVO have experienced symptoms of differentiation syndrome, which can be fatal if not treated. Symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.
WARNINGS AND PRECAUTIONS

Differentiation Syndrome: See Boxed WARNING. In the clinical trial, 19% (34/179) of patients with relapsed or refractory AML treated with TIBSOVO experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms of differentiation syndrome in patients treated with TIBSOVO included noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and creatinine increased. Of the 34 patients who experienced differentiation syndrome, 27 (79%) recovered after treatment or after dose interruption of TIBSOVO. Differentiation syndrome occurred as early as 1 day and up to 3 months after TIBSOVO initiation and has been observed with or without concomitant leukocytosis.

If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or an equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until improvement. If concomitant noninfectious leukocytosis is observed, initiate treatment with hydroxyurea or leukapheresis, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms and administer corticosteroids for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid and/or hydroxyurea treatment. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt TIBSOVO until signs and symptoms are no longer severe.

QTc Interval Prolongation: Patients treated with TIBSOVO can develop QT (QTc) prolongation and ventricular arrhythmias. One patient developed ventricular fibrillation attributed to TIBSOVO. Concomitant use of TIBSOVO with drugs known to prolong the QTc interval (e.g., anti-arrhythmic medicines, fluoroquinolones, triazole anti-fungals, 5-HT3 receptor antagonists) and CYP3A4 inhibitors may increase the risk of QTc interval prolongation. Conduct monitoring of electrocardiograms (ECGs) and electrolytes. In patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or in those who are taking medications known to prolong the QTc interval, more frequent monitoring may be necessary.

Interrupt TIBSOVO if QTc increases to greater than 480 msec and less than 500 msec. Interrupt and reduce TIBSOVO if QTc increases to greater than 500 msec. Permanently discontinue TIBSOVO in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.

Guillain-Barré Syndrome: Guillain-Barré syndrome occurred in <1% (2/258) of patients treated with TIBSOVO in the clinical study. Monitor patients taking TIBSOVO for onset of new signs or symptoms of motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing. Permanently discontinue TIBSOVO in patients who are diagnosed with Guillain-Barré syndrome.

ADVERSE REACTIONS

The most common adverse reactions (≥20%) of any grade were fatigue (39%), leukocytosis (38%), arthralgia (36%), diarrhea (34%), dyspnea (33%), edema (32%), nausea (31%), mucositis (28%), electrocardiogram QT prolonged (26%), rash (26%), pyrexia (23%), cough (22%), and constipation (20%).
The most frequently reported ≥Grade 3 adverse reactions (≥5%) were electrocardiogram QT prolonged (10%), dyspnea (9%), leukocytosis (8%), tumor lysis syndrome (6%), and differentiation syndrome (5%).
Serious adverse reactions (≥5%) were differentiation syndrome (10%), leukocytosis (10%), and electrocardiogram QT prolonged (7%). There was one case of progressive multifocal leukoencephalopathy (PML).
DRUG INTERACTIONS

Strong or Moderate CYP3A4 Inhibitors: Reduce TIBSOVO dose with strong CYP3A4 inhibitors. Monitor patients for increased risk of QTc interval prolongation.

Strong CYP3A4 Inducers: Avoid concomitant use with TIBSOVO.

Sensitive CYP3A4 Substrates: Avoid concomitant use with TIBSOVO.

QTc Prolonging Drugs: Avoid concomitant use with TIBSOVO. If co-administration is unavoidable, monitor patients for increased risk of QTc interval prolongation.

LACTATION

Many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with TIBSOVO and for at least 1 month after the last dose.

Please see full Prescribing Information, including Boxed WARNING.

About IDHIFA (enasidenib)

IDHIFA (enasidenib) is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase-2 mutation as detected by an FDA-approved test.

Important Safety Information

WARNING: DIFFERENTIATION SYNDROME
Patients treated with IDHIFA have experienced symptoms of differentiation syndrome, which can be fatal if not treated. Symptoms may include fever, dyspnea, acute respiratory distress, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, lymphadenopathy, bone pain, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.
WARNINGS AND PRECAUTIONS

Differentiation Syndrome: See Boxed WARNING. In the clinical trial, 14% of patients treated with IDHIFA experienced differentiation syndrome. Differentiation syndrome has been observed with and without concomitant hyperleukocytosis, as early as 10 days and at up to 5 months after IDHIFA initiation. If differentiation syndrome is suspected, initiate systemic corticosteroids and hemodynamic monitoring until improvement. Taper corticosteroids only after resolution of symptoms. Differentiation syndrome symptoms may recur with premature discontinuation of corticosteroids. If severe pulmonary symptoms requiring intubation or ventilator support and/or renal dysfunction persist for more than 48 hours after initiation of corticosteroids, interrupt IDHIFA until signs and symptoms are no longer severe. Hospitalization for close observation and monitoring of patients with pulmonary and/or renal manifestation is recommended.

Embryo-Fetal Toxicity: Based on animal embryo-fetal toxicity studies, IDHIFA can cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with IDHIFA and for at least 1 month after the last dose. Pregnant women, patients becoming pregnant while receiving IDHIFA, or male patients with pregnant female partners should be apprised of the potential risk to the fetus.

ADVERSE REACTIONS

The most common adverse reactions (≥20%) included total bilirubin increased (81%), calcium decreased (74%), nausea (50%), diarrhea (43%), potassium decreased (41%), vomiting (34%), decreased appetite (34%), and phosphorus decreased (27%)
The most frequently reported ≥Grade 3 adverse reactions (≥5%) included total bilirubin increased (15%), potassium decreased (15%), phosphorus decreased (8%), calcium decreased (8%), diarrhea (8%), differentiation syndrome (7%), non-infectious leukocytosis (6%), tumor lysis syndrome (6%), and nausea (5%)
Serious adverse reactions were reported in 77.1% of patients. The most frequent serious adverse reactions (≥2%) were leukocytosis (10%), diarrhea (6%), nausea (5%), vomiting (3%), decreased appetite (3%), tumor lysis syndrome (5%), and differentiation syndrome (8%). Differentiation syndrome events characterized as serious included pyrexia, renal failure acute, hypoxia, respiratory failure, and multi-organ failure
LACTATION
Many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed infants, advise women not to breastfeed during treatment with IDHIFA and for at least 1 month after the last dose.

On December 3, 2018 AOP Orphan Pharmaceuticals AG (AOP Orphan) reported latest follow-up results on Ropeginterferon alfa-2b in patients with Polycythemia Vera (PV) from CONTINUATION-PV presented at ASH (Free ASH Whitepaper) 2018 (Press release, AOP Orphan Pharmaceuticals, DEC 3, 2018, View Source [SID1234531862]).

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CONTINUATION-PV is an open-label, multicenter, phase IIIb study assessing the long-term efficacy and safety of Ropeginterferon alfa-2b versus hydroxyurea (HU) or best available treatment (BAT) in patients with PV who previously participated in the PROUD-PV study.

Ropeginterferon alfa-2b is a novel, long-acting, mono-pegylated proline interferon (ATC L03AB15). It is administered once every 2 weeks initially, or monthly after stabilization of hematological parameters. It is expected to be the first interferon approved for PV worldwide. AOP Orphan´s submission for marketing authorization in the EU is in the final stage of EMA review.

Clinical evidence:

Previously, at 12 months of treatment, Ropeginterferon alfa-2b was shown to be non-inferior to hydroxyurea (HU) in Complete Hematologic Response (CHR) and to have a significantly better safety and tolerability profile. . At 24 months Ropeginterferon alfa-2b achieved a significantly higher CHR of 70.5% versus 49.3% compared with HU/BAT (p=0.0101).

After 36 months of treatment Ropeginterferon alfa-2b sustained higher CHR response rates compared to HU/BAT (70.5% vs. 51.4%; p=0.0122). Further, the composite endpoint, CHR including disease symptom improvement was higher in patients treated with Ropeginterferon alfa-2b compared to HU/BAT (52.6% vs. 37.8%; p=0.0437).

Disease modification evidence:


66.0% of PV patients treated with Ropeginterferon alfa-2b, but only 27.0% having received HU/BAT showed a mutant JAK2 molecular response (p<0.0001) after 36 months. Importantly, molecular response strongly correlated with CHR, emphasizing the clinical relevance of mutant JAK2 allele burden reduction.

Analysis of additional non-JAK2 mutations, which are believed to contribute to disease progression revealed that Ropeginterferon alfa-2b, but not HU was able to reduce their respective mutant allele burden. This suggests that only Ropeginterferon alfa-2b but not HU has the ability to suppress additional clones with different mutations and modify the disease at the molecular level.

In line with molecular findings, disease or treatment related secondary malignancies occurred only in patients receiving HU/BAT, including 2 cases of acute myeloid leukemia, 1 melanoma and 2 basaliomas, whereas 3 malignancies (glioblastoma, seminoma, adrenal neoplasm) most likely unrelated to treatment were reported for patients treated with Ropeginterferon alfa-2b.

A similar number of patients experienced adverse events (89.8% for Ropeginterferon alfa-2b, 90.6% for HU) and treatment-related adverse events (74.8% for Ropeginterferon alfa-2b, 78.7% for HU). The most common (>10%) treatment-related adverse events anemia, thrombocytopenia and leukopenia occurred more frequently with HU, whereas liver enzyme increase was mainly observed with Ropeginterferon alfa-2b.

No new safety signals appeared in the third year of treatment.

Professor Heinz Gisslinger from the Medical University of Vienna, Austria presenting the results at ASH (Free ASH Whitepaper) stated, "The observed superior efficacy of Ropeginterferon alfa-2b over hydroxyurea/best-available-therapy after 36 months, is a clear proof of the long-term value of this treatment modality. Thus, Ropeginterferon alfa-2b will provide a valuable and safe new first line therapy for PV patients".

Professor Jean-Jacques Kiladjian from the Saint-Louis Hospital & Paris Diderot University in France, concluded, "The disease modification capability of Ropeginterferon alfa-2b suggested by a significant reduction of not only mutant JAK2, but also non-JAK2 allele burden and the specific targeting of the malignant clone, holds promise for improvement of progression-free survival and long-term patient benefit."

About Ropeginterferon alfa-2b


Ropeginterferon alfa-2b is a novel, long-acting, mono-pegylated proline interferon (ATC L03AB15) with improved pharmacokinetic properties offering improved tolerability and convenience. It is administered once every 2 weeks, or monthly during long-term maintenance, and is expected to be the first interferon approved for PV worldwide. AOP Orphan´s submission for marketing authorization in the EU is currently under EMA review.

Ropeginterferon alfa-2b was discovered by PharmaEssentia, a long-term partner of AOP Orphan. Ropeginterferon alfa-2b has Orphan Drug designation in the European Union, Switzerland and the United States of America.


In 2009, AOP Orphan has in-licensed from PharmaEssentia Corporation the exclusive rights to develop and commercialize Ropeginterferon alfa-2b in PV, other MPNs and CML for European, Commonwealth of Independent States (CIS), and Middle Eastern markets.

About Polycythemia Vera


Polycythemia Vera (PV) is a cancer of the blood-building cells in the bone marrow resulting in a chronic increase of red blood cells, white blood cells and platelets. This condition may result in circulatory disorders such as thrombosis and embolism, as well as malignant transformation to myelofibrosis or leukemia. While the molecular mechanism underlying PV is still subject of intense research, current results point to a set of acquired mutations, the most important being a mutant form of JAK2 that make the malignant clone.

On December 3, 2018 The National Comprehensive Cancer Network (NCCN) Oncology Research Program (ORP) reported plans to solicit and oversee research projects that evaluate cyclin dependent kinase (CDK)4 & 6 inhibitors in the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer and underlying mechanisms of resistance (Press release, Eli Lilly, DEC 3, 2018, View Source [SID1234531861]). Research funding will be provided by a $2 million grant from Eli Lilly and Company (NYSE: LLY).

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"This program is part of our ongoing efforts to improve the lives of people with cancer," said Wui-Jin Koh, MD, Chief Medical Officer, NCCN. "The NCCN ORP facilitates clinical investigation into important questions. In this instance, we’re managing research to understand mechanisms of resistance to CDK4 & 6 inhibitor treatment in metastatic breast cancer."

"We are excited to support NCCN to further understand the mechanisms of resistance to CDK4 & 6 inhibitors in advanced breast cancer, which is a central and critically important issue in this treatment landscape," said Maura Dickler, MD, Vice President of Late Phase Development, Lilly Oncology. "This work with NCCN is an example of our ongoing commitment to optimize treatment for people living with metastatic breast cancer."

CDK4 & 6 inhibitors have emerged as a key treatment in many patients with HR+ and HER2- metastatic breast cancer. However, resistance to CDK4 & 6 inhibitors, either intrinsic or acquired, can limit their effectiveness. This project seeks to support preclinical and clinical studies that elucidate mechanisms of resistance to CDK4 & 6 inhibitors and provide insights into how this resistance can be overcome or mitigated, resulting in potentially greater efficacy. Lilly will provide abemaciclib, a CDK4 & 6 inhibitor, for studies when needed. This endeavor by the NCCN ORP will utilize the scientific expertise from investigators across the 28 NCCN Member Institutions, and proposals will be reviewed and awarded by a scientific steering committee made up of experts from these NCCN institutions.

Earlier this year, the NCCN ORP was engaged by Lilly for a separate project, seeking scalable, reproducible interventions to address gaps in clinical care for treating gastric cancer. To learn more about the NCCN ORP, including ongoing clinical trials, recent publications, and shared resources, visit NCCN.org/ORP.

On December 3, 2018 Amgen (NASDAQ:AMGN) reported that it will present at the Citi Global Healthcare Conference at 12:35 p.m. ET on Thursday, Dec. 6, 2018, in New York City (Press release, Amgen, DEC 3, 2018, View Source;p=RssLanding&cat=news&id=2379134 [SID1234531860]). Elliott M. Levy, M.D., senior vice president of Global Development at Amgen, will present at the conference. Live audio of the presentation can be accessed from the Events Calendar on Amgen’s website, www.amgen.com, under Investors. A replay of the webcast will also be available on Amgen’s website for at least 90 days following the event

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On December 3, 2018 Alexion Pharmaceuticals, Inc. (NASDAQ:ALXN) reported the presentation of comprehensive positive Phase 3 data for ALXN1210, the company’s investigational long-acting C5 complement inhibitor, at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, taking place December 1-4, 2018 (Press release, Alexion, DEC 3, 2018, View Source [SID1234531858]). The presentations included both previously announced and new data from the two large Phase 3 studies in patients with paroxysmal nocturnal hemoglobinuria (PNH) who had either never been treated with a complement inhibitor before or who had been stable on Soliris treatment. The conference presentations coincided with publications in Blood of the positive results on all primary and key secondary endpoints from these two studies.

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"We are excited by the increasing body of data from our two active comparator-controlled Phase 3 studies, the largest PNH Phase 3 program ever conducted, on clinically meaningful endpoints in this devastating and potentially life-threatening disease. We are particularly pleased by the positive data in patients converting to ALXN1210 from Soliris," said John Orloff, M.D., Executive Vice President and Head of Research & Development at Alexion. "Our ambition is to make ALXN1210 the new standard of care for patients with PNH."

Results from a Phase 3, Multicenter, Non-Inferiority Study of Ravulizumab (ALXN1210) Versus Eculizumab in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria Currently Treated with Eculizumab – ASH (Free ASH Whitepaper), Session 101, Oral Presentation 625, Abstract ID# 119147, December 3, 2018 1
The conference presentation of these previously announced data coincided with their peer-reviewed publication in Blood.2

A Phase 3 Study of Ravulizumab (ALXN1210) versus Eculizumab in Adults with Paroxysmal Nocturnal Hemoglobinuria Naïve to Complement Inhibitors: Results of a Subgroup Analysis with Patients Stratified by Baseline Hemolysis Level, Transfusion History, and Demographics – ASH (Free ASH Whitepaper), Session 101, Oral Presentation 627, Abstract ID# 110623, December 3, 2018 3
These new results add to previously announced results on the co-primary and key secondary endpoints of this study, which have now also been published in Blood.4

A Prospective Analysis of Breakthrough Hemolysis in 2 Phase 3 Randomized Studies of Ravulizumab (ALXN1210) versus Eculizumab in Adults with Paroxysmal Nocturnal Hemoglobinuria – ASH (Free ASH Whitepaper), Oral and Poster Abstracts, Poster 2330, Abstract ID# 110874, December 2, 2018 5

Ravulizumab (ALXN1210) versus Eculizumab in Adults with Paroxysmal Nocturnal Hemoglobinuria: Pharmacokinetics and Pharmacodynamics Observed in Two Phase 3 Randomized, Multicenter Studies – ASH (Free ASH Whitepaper) Session 101, Oral Presentation 626, Abstract ID# 110858, December 3, 2018 6

About Paroxysmal Nocturnal Hemoglobinuria (PNH)

Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic, progressive, debilitating and life-threatening ultra-rare blood disorder characterized by hemolysis (destruction of red blood cells) that is mediated by an uncontrolled activation of the complement system, a component of the body’s immune system.7,8,9 PNH can strike men and women of all races, backgrounds and ages without warning, with an average age of onset in the early 30s.7,10 PNH often goes unrecognized, with delays in diagnosis ranging from one to more than five years.11 Patients with PNH may experience a wide range of signs and symptoms, such as fatigue, difficulty swallowing, shortness of breath, abdominal pain, erectile dysfunction, dark-colored urine and anemia.9,12,13,14,15,16,17 The most devastating consequence of chronic hemolysis is thrombosis, which can occur in blood vessels throughout the body, damage vital organs and cause premature death.18 The first thrombotic event can be fatal.8,10,19 Despite historical supportive care, including transfusion and anticoagulation management, 20 to 35 percent of patients with PNH die within five to 10 years of diagnosis.20,21 Patients with certain types of hemolytic anemia, bone marrow disorders and unexplained venous or arterial thrombosis are at increased risk of PNH.9,22,23,24,25,26

About ALXN1210

ALXN1210 is an innovative, investigational, long-acting C5 inhibitor discovered and developed by Alexion that works by inhibiting the C5 protein in the terminal complement cascade, a part of the body’s immune system that, when activated in an uncontrolled manner, plays a role in severe ultra-rare disorders like paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and anti-acetylcholine receptor (AchR) antibody-positive myasthenia gravis (MG). In Phase 3 clinical studies in complement inhibitor-naïve patients with PNH, and patients with PNH who had been stable on Soliris, intravenous treatment with ALXN1210 every eight weeks demonstrated non-inferiority to intravenous treatment with Soliris every two weeks, with numeric results for all primary and key secondary endpoints favoring ALXN1210. ALXN1210 is also currently being evaluated in a Phase 3 clinical study in complement inhibitor-naïve patients with aHUS, administered intravenously every eight weeks. In addition, Alexion plans to initiate a Phase 3 clinical study of ALXN1210 delivered subcutaneously once per week as a potential treatment for patients with PNH and aHUS. Alexion is also planning to initiate the development of ALXN1210, intravenously administered every eight weeks, as a potential treatment for patients with generalized MG (gMG).

ALXN1210 has received Orphan Drug Designation (ODD) for the treatment of patients with PNH in the U.S., EU, and Japan, and for the subcutaneous treatment of patients with aHUS in the U.S.

About Soliris (eculizumab)

Soliris is a first-in-class complement inhibitor that works by inhibiting the C5 protein in the terminal part of the complement cascade, a part of the immune system that, when activated in an uncontrolled manner, plays a role in severe rare and ultra-rare disorders like paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and anti-acetylcholine receptor (AchR) antibody-positive myasthenia gravis (MG). Soliris is approved in the U.S., EU, Japan, and other countries as the first and only treatment for patients with PNH and aHUS, in the EU as the first and only treatment of refractory generalized MG (gMG) in adults who are anti-AchR antibody-positive, in the U.S. for the treatment of adult patients with gMG who are anti-AchR antibody-positive, and in Japan for the treatment of patients with gMG who are AChR antibody-positive and whose symptoms are difficult to control with high-dose intravenous immunoglobulin (IVIG) therapy or plasmapheresis (PLEX). Soliris is not indicated for the treatment of patients with Shiga-toxin E. coli-related hemolytic uremic syndrome (STEC-HUS).

Soliris has received Orphan Drug Designation (ODD) for the treatment of patients with PNH in the U.S., EU, Japan, and many other countries, for the treatment of patients with aHUS in the U.S., EU, and many other countries, for the treatment of patients with MG in the U.S. and EU, for the treatment of patients with refractory gMG in Japan, and for the treatment of patients with neuromyelitis optica spectrum disorder (NMOSD) in the U.S., EU, and Japan. Alexion and Soliris have received some of the pharmaceutical industry’s highest honors for the medical innovation in complement inhibition: the Prix Galien USA (2008, Best Biotechnology Product) and France (2009, Rare Disease Treatment).

For more information on Soliris, please see full prescribing information for Soliris, including BOXED WARNING regarding risk of serious meningococcal infection, available at www.soliris.net.

Important Soliris Safety Information

The U.S. prescribing information for Soliris includes the following warnings and precautions: 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. Comply with the most current Centers for Disease Control (CDC)’s Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients with complement deficiencies. Immunize patients with meningococcal vaccines 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. 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. Enrollment in the Soliris REMS program and additional information are available by telephone: 1-888-SOLIRIS (1-888-765-4747) or at www.solirisrems.com.

Patients may have increased susceptibility to infections, especially with encapsulated bacteria. Aspergillus infections have occurred in immunocompromised and neutropenic patients. Children treated with Soliris may be at increased risk of developing serious infections due to Streptococcus pneumoniae and Haemophilus influenza type b (Hib). 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. Administration of Soliris may result in infusion reactions, including anaphylaxis or other hypersensitivity reactions.

In patients with PNH, the most frequently reported adverse events observed with Soliris treatment in clinical studies were headache, nasopharyngitis, back pain, and nausea. 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. In patients with gMG who are anti-AchR antibody-positive, the most frequently reported adverse reaction observed with Soliris treatment in the placebo-controlled clinical study (≥10%) was musculoskeletal pain.