On December 9, 2019 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) ("Actinium") presented new findings from its pivotal Phase 3 SIERRA trial for Iomab-B (Iodine-131 apamistamab) at the 2019 American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting on Sunday, December 8, 2019 in a poster presentation (Press release, Actinium Pharmaceuticals, DEC 9, 2019, View Source [SID1234552093]). Actinium is advancing the development of low dose Iodine-131 apamistamab, a CD45 targeting antibody radiation-conjugate (ARC), as an alternative to today’s standard practice of chemotherapy-based lymphodepletion regimens like fludarabine/cyclophosphamide (Flu/Cy), which have been implicated in CAR-T toxicities including cytokine release syndrome (CRS) and neurotoxicity.

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The analysis of dosimetric results with Iomab-B in the pivotal Phase 3 SIERRA trial was conducted to model a non-myeloablative dose level to be used for lymphodepletion prior to CAR-T, as well as the time frame in which an adoptive cell therapy such as CAR-T could be administered. Based on the results from 56 evaluable patients that received a dosimetric dose of Iodine-131 apamistamab, including patients initially randomized to receive Iomab-B and those that received Iomab-B upon crossover from the control arm, it was determined that a single 75 mCi dosage of Iodine-131 apamistamab would deliver approximately 200 cGy to the bone marrow, the threshold that is considered non-myeloablative. At this dose level, it expected that an adoptive cell therapy could be administered approximately six days following Iomab-ACT lymphodepletion. Actinium intends to advance its Iomab-ACT program into human proof-of-concept clinical trials in conjunction with an adoptive cell therapy. The poster can be accessed on Actinium’s investor relations page of its website HERE.

Key findings presented in the poster include:

At fractional dose levels of Iodine-131 apamistamab (median 10mCi) used for dosimetry analysis in the SIERRA trial, approximately 1/10 of the targeted lymphodepletion dose, a significant but transient reduction in lymphocytes and white blood cells was observed compared to pre-dosimetry infusion levels
85% reduction in lymphocytes was observed at the post-dosimetry infusion time point, a 67% decrease at day 1 post-dosimetric infusion, and a 43% decrease one week later just prior to the Iomab-B therapeutic infusion, demonstrating potent yet reversible lymphodepletion at this dose level
35% reduction in peripheral leukemic blasts was observed at the post-dosimetry infusion time point, suggesting a rapid anti-leukemic effect with single-agent Iodine-131 apamistamab consistent with findings from SIERRA presented at ASCO (Free ASCO Whitepaper) 2019
The levels of platelets, red blood cells, and neutrophils did not significantly change between pre-infusion and post-dosimetry infusion
Based on the analysis of the 56 treated patients, a non-myeloablative dosage of 75 mCi has been proposed as a starting dose for human clinical testing in combination with a CAR-T
Analysis of the dosimetry data establishes that the proposed 75 mCi dosage of Iodine-131 apamistamab would be sufficiently cleared in approximately 147 hours (6.1 days) to allow for CAR-T administration
Dale Ludwig, Ph.D., Actinium’s Chief Scientific Officer, said, "CAR-T, adoptive cell therapy, and gene therapy are revolutionary medical advances with great promise. However, despite the innovation in these technologies, they continue to rely on generic chemotherapies for the necessary pre-conditioning prior to their administration, which are non-targeted and toxic. We believe this restricts the true potential of these therapies by hindering their efficacy and durability while increasing toxicities such as cytokine release syndrome and neurotoxicity. With a starting clinical dose and time to clearance defined and supported by clinical results from the SIERRA trial, we look forward to our next step of advancing this program into human clinical testing with a cell therapy while continuing to introduce the Iomab-ACT program to cell and gene therapy developers."

About the Iomab-ACT program

Iomab-ACT is a lower dose of Actinium’s lead program Iomab-B, which has been studied in over 300 patients and is currently being investigated in a pivotal Phase 3 trial for targeted conditioning prior to a Bone Marrow Transplant (BMT). Iomab-ACT targets CD45, an antigen expressed on many of the cells that are relevant to CAR-T including lymphocytes, macrophages and regulatory T-cells and that have been associated with CAR-T challenges such as durability of response, cytokine release syndrome (CRS) and neurotoxicity. Actinium has generated preclinical data that targeted lymphodepletion via Iomab-ACT has the potential to improve tumor control, selectively deplete necessary cells, and be highly differentiated in terms of tolerability compared to chemotherapy-based lymphodepletion regimens, namely fludarabine/cyclophosphamide (Flu/Cy). The Iomab-ACT program may enable lymphodepletion through a single-dose outpatient administration versus Flu/Cy or other chemo-based lymphodepletion regimens that require multiple infusions in an inpatient setting over several days.

On December 9, 2019 BerGenBio ASA (OSE:BGBIO), a clinical-stage biopharmaceutical company developing novel, selective AXL kinase inhibitors for multiple cancer indications, reported that it will provide an update from the Company’s phase II study of bemcentinib (BGB324), a first-in-class highly selective oral AXL inhibitor, in combination with low-dose cytarabine (LDAC) in elderly AML patients in a poster presentation at the 61st Annual American Society of Hematology (ASH) (Free ASH Whitepaper) Meeting, being held from 7-10 December in Orlando, Florida (Press release, BerGenBio, DEC 9, 2019, View Source [SID1234552092]).

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The bemcentinib-LDAC combination was safe and well tolerated in elderly AML patients and showed promising efficacy among both newly diagnosed and relapsed/refractory AML patients. The overall response rate and duration surpass historical benchmarks and compare favorably to other LDAC combinations. Pretreatment sAXL holds as a predictive biomarker in AML patients treated with the combination, and a new novel blood based predictive biomarker is identified and associated with clinical benefit in AML and Lung cancer patients receiving bemcentinib.

Professor Sonja Loges, attending physician and principal investigator, University Medical Centre Hamburg Eppendorf, Germany commented: "I am very encouraged by these early results. The duration of response and successful treatment beyond progression are consistent with the previously reported immunomodulatory activity of bemcentinib. I look forward to conducting a deeper analysis of AXL signalling in tumor and immune cells from patient biopsy samples to further elucidate this unique mechanism-of-action."

Richard Godfrey, Chief Executive Officer of BerGenBio, commented: "This combination trial of bemcentinib with low-dose cytarabine continues to show promising results in AML patients who are unable to tolerate intensive chemotherapy and have limited treatment options. The current data further highlight the novel tumor-immune effects of bemcentinib observed in previous cohorts and in other cancer types. Although these are early findings, we are encouraged by the response rate and duration, and we are focused on advancing our late stage development programme."

Details of the presentation are below.

Title: Durable responses observed in elderly AML patients unfit for intensive chemotherapy with first-in class selective AXL inhibitor bemcentinib (BGB324) in combination with LDAC: Phase II open-label study

Date: Monday 9th December 2019

Session Name: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Poster III

Time, Location: 6:00 PM – 8:00 PM, Orange County Convention Center, Hall B

The poster will be available at www.bergenbio.com in the section: Investors/Presentations from 14.00 CET Monday 9th December 2019.

– END –

About AML and the BGBC003 trial

Acute myeloid leukaemia (AML) is a rapidly progressing blood cancer. AML is the most common form of acute leukaemia in adults, where malignant AML blasts interfere with the normal functioning of the bone marrow leading to a multitude of complications like anaemia, infections and bleeding. AML is diagnosed in over 20,000 patients in the US annually and is rapidly lethal if left untreated. Successful treatment typically requires intensive therapy or bone marrow transplantation, and relapse and resistance are common. Consequently, there is an urgent need for effective novel therapies in relapsed/refractory patients, particularly those that are ineligible for intensive therapy or bone marrow transplant.

The BGBC003 trial is a phase Ib/II multi-centre open label study of bemcentinib in combination with cytarabine (part B2) and decitabine (part B3) in patients with AML who are unsuitable for intensive chemotherapy as a result of advanced age or existing-co-morbidities. Up to 28 patients will be enrolled at centres in the US, Norway, Germany and Italy.

For more information please access trial NCT02488408 at www.clinicaltrials.gov.

About AXL

AXL kinase is a cell membrane receptor and an essential mediator of the biological mechanisms underlying life-threatening diseases. In cancer, AXL suppresses the body’s immune response to tumours and drives cancer treatment failure across many indications. AXL inhibitors, therefore, have potential high value at the centre of cancer combination therapy, addressing significant unmet medical needs and multiple high-value market opportunities. Research has also shown that AXL mediates other aggressive diseases.

About Bemcentinib

Bemcentinib (formerly known as BGB324), is a potentially first-in-class selective AXL inhibitor in a broad phase II clinical development programme. Ongoing clinical trials are investigating bemcentinib in multiple solid and haematological tumours, in combination with current and emerging therapies (including immunotherapies, targeted therapies and chemotherapy), and as a single agent. Bemcentinib targets and binds to the intracellular catalytic kinase domain of AXL receptor tyrosine kinase and inhibits its activity. Increase in AXL function has been linked to key mechanisms of drug resistance and immune escape by tumour cells, leading to aggressive metastatic cancers.

On December 9, 2019 Agios Pharmaceuticals, Inc. (NASDAQ: AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, reported translational data describing deep and durable molecular responses to treatment of TIBSOVO (ivosidenib) and azacitidine and mechanisms of resistance and relapse to single agent treatment with TIBSOVO in acute myeloid leukemia (AML) with an IDH1 mutation (Press release, Agios Pharmaceuticals, DEC 9, 2019, View Source [SID1234552091]). The data were presented as part of the scientific program at the 2019 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

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"For 10 years, we have pioneered the science behind the role of IDH mutations in AML, while bringing to patients new oral therapies for the approximately 20% of AML patients with an IDH mutation. We’re pleased to share a robust set of translational data at ASH (Free ASH Whitepaper) that further elucidates our understanding of TIBSOVO response and resistance mechanisms in patients with IDH1 mutant AML," said Chris Bowden, M.D., chief medical officer at Agios. "These data show that combination treatment with TIBSOVO and azacitidine in newly diagnosed IDH1 mutant AML can induce deep, durable remissions in patients with a number of molecular profiles. Our translational work has further elucidated mechanisms of relapse with IDH1 monotherapy in relapsed and refractory disease that includes both IDH-related and non-IDH related pathways."

Treatment with TIBSOVO and Azacitidine Results in High Rate of IDH1 Mutation Clearance and Measurable Residual Disease Negativity in Newly Diagnosed AML
As of the February 19, 2019 data cutoff, 23 patients have been treated in the ongoing Phase 1/2 study of TIBSOVO in combination with azacitidine in patients with newly diagnosed IDH1 mutant AML ineligible for intensive chemotherapy. Results from the study show a complete response (CR) rate of 61% and a CR + CR with partial hematologic recovery (CRh) rate of 70%. Responses were durable, and the median duration of CR (95% CI 9.3 months, NE) as well as CR+CRh (95% CI 12.2 months, NE) had not been reached. In patients with CR, 10 of 14 (71%) had IDH1 mutation clearance in bone marrow mononuclear cells measured by BEAMing digital PCR (limit of detection 0.02-0.04%). Additionally, the majority of CR patients with IDH1 mutation clearance demonstrated measurable residual disease (MRD) negativity by flow cytometry or next-generation sequencing. Five patients were shown to have RTK pathway mutations (KRAS, NRAS, PTPN11), and three of these patients achieved CR/CRh with TIBSOVO and azacitidine combination therapy.

Mechanisms of Resistance to Single Agent IDH1 Inhibitors in Relapsed/Refractory AML
Comprehensive genomic profiling was conducted using patient samples from the Phase 1 study of TIBSOVO in IDH1 mutant relapsed/refractory AML to characterize the molecular predictors of response and mechanisms of relapse to TIBSOVO monotherapy. The analysis found that multiple mechanisms contribute to relapse or progression. RTK pathway mutations NRAS and PTPN11 at baseline were associated with a lower likelihood of clinical response to TIBSOVO monotherapy in relapsed/refractory AML, while patients with JAK2 mutations were more likely to achieve a response. Acquired resistance is mediated by diverse mechanisms, and mutations are acquired in multiple pathways, most frequently in RTK and 2-HG–restoring pathways (IDH2 and second-site IDH1 mutations).

Single cell mutation profiling was conducted to explore the evolution of mutant IDH2 clones under the selective pressure of TIBSOVO monotherapy in a subset of patients. The analysis revealed multiple evolutionary mechanisms by which mutant IDH2 contributes to relapse and reinforced the key role of 2-HG production in mutant IDH AML.

Taken together, these results inform the design of combination or sequential treatment strategies with TIBSOVO in IDH1 mutant AML and reinforce the importance of genomic testing for both IDH1 and IDH2 mutations at relapse.

TIBSOVO is not approved in any country for the treatment of patients with newly diagnosed AML in combination with azacitidine.

Investor Event and Webcast Information
Agios will host an investor event today at 8:00 p.m. ET in Orlando, Fla. to review the IDH and PKR data presented at ASH (Free ASH Whitepaper). The event will be webcast live and can be accessed under "Events & Presentations" in the Investors section of the company’s website at www.agios.com. The archived webcast will be available on the company’s website beginning approximately two hours after the event.

About TIBSOVO (ivosidenib)
TIBSOVO is indicated for the treatment of acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test in:

Adult patients with newly-diagnosed AML who are ≥75 years old or who have comorbidities that preclude use of intensive induction chemotherapy.
Adult patients with relapsed or refractory AML.
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, 25% (7/28) of patients with newly diagnosed AML and 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 7 patients with newly diagnosed AML who experienced differentiation syndrome, 6 (86%) patients recovered. Of the 34 patients with relapsed or refractory AML who experienced differentiation syndrome, 27 (79%) patients 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, or 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 including laboratory abnormalities (≥20%) were hemoglobin decreased (60%), fatigue (43%), arthralgia (39%), calcium decreased (39%), sodium decreased (39%), leukocytosis (38%), diarrhea (37%), magnesium decreased (36%), edema (34%), nausea (33%), dyspnea (32%), uric acid increased (32%), potassium decreased (32%), alkaline phosphatase increased (30%), mucositis (28%), aspartate aminotransferase increased (27%), phosphatase decreased (25%), electrocardiogram QT prolonged (24%), rash (24%), creatinine increased (24%), cough (23%), decreased appetite (22%), myalgia (21%), constipation (20%), and pyrexia (20%).
In patients with newly diagnosed AML, the most frequently reported Grade ≥3 adverse reactions (≥5%) were fatigue (14%), differentiation syndrome (11%), electrocardiogram QT prolonged (11%), diarrhea (7%), nausea (7%), and leukocytosis (7%). Serious adverse reactions (≥5%) were differentiation syndrome (18%), electrocardiogram QT prolonged (7%), and fatigue (7%). There was one case of posterior reversible encephalopathy syndrome (PRES).
In patients with relapsed or refractory AML, the most frequently reported Grade ≥3 adverse reactions (≥5%) were differentiation syndrome (13%), electrocardiogram QT prolonged (10%), dyspnea (9%), leukocytosis (8%), and tumor lysis syndrome (6%). 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

Because 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 Acute Myeloid Leukemia (AML)
AML is a cancer of the blood and bone marrow marked by rapid disease progression and is the most common acute leukemia affecting adults with approximately 20,000 new cases estimated in the U.S. each year. AML patients are typically older or have comorbidities that preclude the use of intensive chemotherapy. These patients typically have a worse prognosis and poor outcomes. The majority of patients with AML eventually relapse. The five-year survival rate is approximately 28%. For 6 to 10 percent of AML patients, the mutated IDH1 enzyme blocks normal blood stem cell differentiation, contributing to the genesis of acute leukemia. IDH1 mutations have been associated with negative prognosis in AML.

On December 9, 2019 Sanofi and Synthorx, Inc. (NASDAQ: THOR), a clinical-stage biotechnology company focused on prolonging and improving the lives of people suffering from cancer and autoimmune disorders, entered into a definitive agreement under which Sanofi will acquire all of the outstanding shares of Synthorx for $68 per share in cash, which represents an aggregate equity value of approximately $2.5 billion (on a fully diluted basis) (Press release, Sanofi, DEC 9, 2019, View Source [SID1234552083]). The transaction was unanimously approved by both the Sanofi and Synthorx Boards of Directors.

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"This acquisition fits perfectly with our strategy to build a portfolio of high-quality assets and to lead with innovation, as you will hear at our Capital Markets Day tomorrow, December 10. Additionally, it is aligned with our goal to build our oncology franchise with potentially practice-changing medicines and novel combinations," says Paul Hudson, Chief Executive Officer, Sanofi.

"Synthorx’s exceptionally novel discovery platform has already produced a molecule that has the potential to become a foundation of the next generation of immuno-oncology combination therapies. By selectively expanding the numbers of effector T-cells and natural killer cells in the body, THOR-707 can be combined with our current oncology medicines and our emerging pipeline of immuno-modulatory agents for treating cancer. Moreover, Synthorx’s pipeline of engineered lymphokines has great promise not only for oncology but also for addressing many autoimmune and inflammatory diseases. " says John Reed, M.D., Ph.D., Global Head of Research & Development at Sanofi.

"We are grateful that Sanofi has acknowledged the value of our Expanded Genetic Alphabet platform and the potential of our pipeline of optimized therapeutics for cancer and autoimmune disorders," says Laura Shawver, Ph.D., President and Chief Executive Officer, Synthorx. "Importantly, Sanofi has a portfolio of therapeutics that holds incredible promise for combining with our cytokine Synthorins to benefit patients around the world. I want to thank our employees and the Sanofi organization for their relentless efforts on behalf of patients."

Enhancing Sanofi’s Immuno-Oncology Franchise

Synthorx’s lead immuno-oncology product candidate, THOR-707, a variant of interleukin-2 (IL-2), is in clinical development in multiple solid tumor types as a single agent and in combination with immune checkpoint inhibitors. It has the potential to become the best-in-class IL-2 therapeutic for the treatment of solid tumors and demonstrate improved pharmacology, less frequent dosing, and therapeutic superiority when compared to other IL-2 compounds.

The addition of THOR-707 and Synthorx’s other earlier-stage cytokine programs to Sanofi’s pipeline will enhance Sanofi’s position in oncology, and in immuno-oncology. We expect IL-2 to become a foundation of future IO-IO combinations as well as offering multiple combination opportunities with Sanofi’s clinical and pre-clinical oncology assets, including with PD-1, CD-38, and molecules that modulate effector T-cells and natural killer cells.

Synergistic with Sanofi’s existing platforms

Synthorx’s Expanded Genetic Alphabet platform is expected to be a source for developing a differentiated therapeutic pipeline. Alone and in combination with other existing Sanofi platforms, including the Nanobody technology, it will enable the company to develop a wide range of novel biologics, including drug conjugates, protein fusions, and multi-specific biologics, with applications beyond oncology and extending to other therapeutic areas.

Transaction Terms

Under the terms of the merger agreement, Sanofi will commence a cash tender offer to acquire all of the outstanding shares of Synthorx common stock for $68 per share in cash for a total enterprise value of approximately $2.35 billion. The $68 per share acquisition price represents a 172% premium to Synthorx’s closing price on December 6, 2019.

The consummation of the tender offer is subject to customary closing conditions, including the tender of at least a majority of the outstanding shares of Synthorx common stock, the expiration or termination of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976, and other customary conditions. Following the successful completion of the tender offer, a wholly owned subsidiary of Sanofi will merge with Synthorx and the outstanding Synthorx shares not tendered in the tender offer will be converted into the right to receive the same $68 per share in cash paid in the tender offer. The tender offer is expected to commence in December 2019. Sanofi plans to finance the transaction with cash on hand. Subject to the satisfaction or waiver of customary closing conditions, Sanofi expects to complete the acquisition in the first quarter of 2020.

Morgan Stanley & Co. is acting as financial advisor to Sanofi and Weil, Gotshal & Manges LLP is acting as its legal counsel. Centerview Partners LLC is acting as exclusive financial advisor to Synthorx and Cooley LLP is acting as its legal counsel.

On December 8, 2019 Blueprint Medicines Corporation (NASDAQ:BPMC), a precision therapy company focused on genomically defined cancers, rare diseases and cancer immunotherapy, reported initial data from the Phase 2 PIONEER clinical trial of avapritinib in patients with indolent systemic mastocytosis (SM). Initial data from the dose-finding Part 1 of the PIONEER trial showed rapid and robust reductions in serum tryptase, a well-established measure of mast cell burden, in patients treated with 25 mg, 50 mg or 100 mg of avapritinib once daily (QD). All dose levels of avapritinib tested were well-tolerated, and no patients discontinued treatment due to an adverse event (AE). The results will be presented today in a poster presentation at the 61st American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in Orlando, Florida.

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Nearly all cases of SM, a rare mast cell disorder, are driven by the KIT D816V mutation, which aberrantly activates mast cells. Patients across all disease subtypes including indolent SM experience debilitating symptoms across multiple organ systems, while advanced SM is uniquely characterized by organ damage due to mast cell infiltration. Avapritinib, an investigational drug, is a highly potent and selective inhibitor of D816V mutant KIT.

"Patients with indolent SM often experience debilitating symptoms, including unpredictable hypersensitivity reactions and anaphylaxis, despite available symptom-directed treatments, leading to reduced quality of life, social isolation and frequent utilization of the healthcare system," said Cem Akin, M.D., Ph.D., Professor of Medicine at the University of Michigan and an investigator on the PIONEER trial. "The initial PIONEER data announced today are highly encouraging and show that low doses of avapritinib are well-tolerated and reduce elevated levels of tryptase in the blood. We believe this early indicator of mast cell response is predictive of reductions in clinical symptoms, which we hope to see confirmed with additional data from the PIONEER trial next year."

"The PIONEER data in patients with indolent SM further highlight the potential of avapritinib, a highly potent inhibitor of D816V mutant KIT, to become a new standard of care across all subtypes of SM," said Andy Boral, M.D., Ph.D., Chief Medical Officer at Blueprint Medicines. "Blueprint Medicines is committed to advancing a comprehensive clinical development program for avapritinib, with the goal of bringing a highly effective precision therapy to a broad population of patients with SM."

Blueprint Medicines plans to report additional data from Part 1 of the PIONEER trial that will inform the selection of a recommended Part 2 dose (RP2D), including the change in patient-reported disease symptoms as measured by the Indolent SM Symptom Assessment Form (ISM-SAF), in the first quarter of 2020. The registration-enabling Part 2 of the PIONEER trial is anticipated to initiate patient screening in the first half of 2020.

Highlights from the ASH (Free ASH Whitepaper) Presentation of PIONEER Trial Data in Indolent SM

The dose-finding Part 1 of the PIONEER trial was designed to test three doses of avapritinib (25 mg, 50 mg and 100 mg QD) versus placebo to determine a RP2D. Major eligibility criteria included adults with indolent SM confirmed by central pathology review and moderate to severe symptom burden, despite best available supportive care medications. Across four concurrent cohorts, 39 patients were enrolled, including 10 patients in each avapritinib dose cohort and nine patients in the placebo cohort. As of a data cutoff date of November 12, 2019, the enrolled population had a median time on study of 12 weeks (range: 1-30 weeks).

Baseline Patient Characteristics

At baseline, all patients had symptomatic disease despite best available therapy. Median ISM-SAF total symptom score (TSS) was 52 [range: 19-100 (total possible range: 0-110)]. Patients were taking a median of three medications (range: 1-7) to treat their disease. Mean serum tryptase was 84 micrograms per liter.

Clinical Activity Data

Across all avapritinib dose cohorts, reductions in serum tryptase were robust, occurred rapidly and were sustained in patients treated up to 30 weeks. The placebo cohort showed no change in serum tryptase at 12 weeks.

Tryptase is an enzyme released by activated mast cells. Elevated tryptase in blood serum is a hallmark of SM and a component of the World Health Organization diagnostic criteria. Reduction in serum tryptase is a component of the IWG-MRT-ECNM response criteria (IWG criteria) for advanced SM.

Safety Data

All doses of avapritinib tested were well-tolerated, and most reported AEs were Grade 1 or 2. There were no reported cases of intracranial bleeding, thrombocytopenia or anemia. Across all avapritinib cohorts, five patients (16.7 percent) had Grade 3 AEs, and no patients had serious AEs. In patients treated with placebo, two patients (22.2 percent) had Grade 3 AEs, and two patients (22.2 percent) had serious AEs. There was one Grade 3 cognitive effect reported in the 100 mg cohort. The event resolved following dose modification, and the patient remained on therapy as of the data cutoff date. No patients discontinued treatment due to an AE.

Top-line EXPLORER Trial Data and NDA Submission Plan for Avapritinib in Advanced SM

Blueprint Medicines plans to submit a new drug application (NDA) to the U.S. Food and Drug Administration (FDA) for avapritinib for the treatment of patients with advanced SM in the first quarter of 2020. The planned NDA will include response data for approximately 55 patients and safety data for approximately 100 patients from the EXPLORER trial and the PATHFINDER trial.

Blueprint Medicines reported top-line results from the EXPLORER trial. The company plans to report top-line data from the PATHFINDER trial in the first quarter of 2020 and expects these data will be generally consistent with the top-line EXPLORER data.

As of a data cutoff of August 30, 2019, top-line efficacy data from the EXPLORER trial showed a centrally confirmed overall response rate (ORR) of 77 percent in 48 patients evaluable for response per the modified IWG criteria. ORR was defined as complete remission with full or partial recovery of peripheral blood counts, partial remission or clinical improvement. Median duration of response (DOR) and median overall survival were not reached. Median follow-up was 21 months, with patients receiving ongoing treatment up to approximately 3.5 years.

The top-line safety results were generally consistent with previously reported data. In 80 patients evaluable for safety as of the data cutoff date, avapritinib was generally well-tolerated with most AEs reported by investigators as Grade 1 or 2. Across all grades, the most common treatment-emergent AEs reported by investigators were periorbital edema, anemia, diarrhea, fatigue, peripheral edema, nausea, thrombocytopenia, vomiting and cognitive effects. Only six patients discontinued due to treatment-related adverse events.

As of the data cutoff date, no new intracranial bleeding events had been observed in the EXPLORER trial since the company previously presented data at the 24th Congress of the European Hematology Association (EHA) (Free EHA Whitepaper). After the data cutoff date, one patient with SM and an associated hematologic neoplasm (SM-AHN) of myelodysplastic syndrome had a Grade 5 intracranial bleed. At the time of the bleeding event, the patient had severe thrombocytopenia and experienced a serious injury involving head trauma.

Investor Event and Webcast Information

Blueprint Medicines will host an investor event on Sunday, December 8, 2019 beginning at 8:30 p.m. ET in Orlando to review initial data from the PIONEER trial. The event will be webcast live and can be accessed under "Events and Presentations" in the Investors & Media section of Blueprint Medicines’ website at View Source A replay of the webcast will be available approximately two hours after the event and will be available for 30 days following the event.

About the Clinical Development Program for Avapritinib in SM

Blueprint Medicines is pursuing a broad clinical development program for avapritinib across advanced, indolent and smoldering forms of SM. Avapritinib is currently being evaluated in three ongoing, registration-enabling clinical trials for SM: the EXPLORER trial, the PATHFINDER trial and the PIONEER trial.

The EXPLORER trial is an open-label, single-arm trial designed to identify the RP2D and demonstrate proof-of-concept in patients with advanced SM. Key trial endpoints include ORR, DOR, quantitative measures of mast cell burden, patient-reported outcomes and safety. The EXPLORER trial has completed patient enrollment.

The PATHFINDER trial is an open-label, single-arm registration-enabling trial designed to confirm the clinical activity of avapritinib in approximately 60 patients with advanced SM. Key trial endpoints include ORR, DOR, quantitative measures of mast cell burden, patient-reported outcomes and safety. Patient enrollment is ongoing at sites in the United States, Canada and European Union.

The PIONEER trial is a randomized, double-blind, placebo-controlled, registration-enabling trial in approximately 112 patients with indolent and smoldering SM. The trial includes three parts: dose-finding Part 1, registration-enabling Part 2 and long-term treatment Part 3. All patients who complete Parts 1 or 2 will have an opportunity to continue to receive treatment with avapritinib in Part 3. Key trial endpoints include the change in patient-reported disease symptoms as measured by the ISM-SAF TSS, quantitative measures of mast cell burden and safety. Part 1 has completed patient enrollment. Part 2 is anticipated to initiate patient screening in the first half of 2020 at sites in the United States, Canada and European Union.

SM patients and clinicians interested in ongoing or planned clinical trials can contact the Blueprint Medicines study director at [email protected] or 1-617-714-6707. Additional details are available at www.pathfindertrial.com, www.pioneertrial.com or www.clinicaltrials.gov.

About SM

SM is one disease driven by the KIT D816V mutation. The majority of patients have indolent SM with symptoms that range from burdensome to life-threatening. A minority of patients have advanced SM, which encompasses a group of high-risk SM subtypes, including aggressive SM (ASM), SM-AHN and mast cell leukemia (MCL), which are associated with organ damage due to mast cell infiltration and poor overall survival. In nearly all SM patients, the KIT

D816V mutation aberrantly activates mast cells. Aberrant mast cell activation and proliferation results in chronic, severe and often unpredictable symptoms, such as pruritus, flushing, headaches, bone pain, nausea, vomiting, diarrhea, anaphylaxis, abdominal pain and fatigue. Currently, there are no approved therapies that selectively inhibit D816V mutant KIT.

About Avapritinib

Avapritinib is an investigational, oral precision therapy that selectively and potently inhibits KIT and PDGFRA mutant kinases. It is a type 1 inhibitor designed to target the active kinase conformation; all oncogenic kinases signal via this conformation. Avapritinib has demonstrated broad inhibition of KIT and PDGFRA mutations associated with gastrointestinal stromal tumors (GIST), including potent activity against activation loop mutations that are associated with resistance to currently approved therapies.

Blueprint Medicines is initially developing avapritinib for the treatment of advanced GIST, advanced SM, and indolent and smoldering SM. The FDA has granted Breakthrough Therapy Designation to avapritinib for two indications: one for the treatment of unresectable or metastatic GIST harboring the PDGFRA D842V mutation and one for the treatment of advanced SM, including the subtypes of aggressive SM, SM with an associated hematologic neoplasm and mast cell leukemia.

Blueprint Medicines has an exclusive collaboration and license agreement with CStone Pharmaceuticals for the development and commercialization of avapritinib and certain other drug candidates in Mainland China, Hong Kong, Macau and Taiwan. Blueprint Medicines retains development and commercial rights for avapritinib in the rest of the world.