UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 8-K
CURRENT REPORT
Pursuant to Section 13 or 15(d)
of the Securities Exchange Act of 1934
Date of Report (Date of Earliest Event Reported): June 14, 2019
Blueprint Medicines Corporation
(Exact name of registrant as specified in its charter)
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Delaware |
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001-37359 |
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26-3632015 |
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(State or other jurisdiction of incorporation) |
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(Commission File Number) |
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(I.R.S. Employer |
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45 Sidney Street Cambridge, Massachusetts |
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02139 |
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(Address of principal executive offices) |
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(Zip Code) |
Registrant’s telephone number, including area code: (617) 374-7580
(Former name or former address, if changed since last report)
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:
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Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425) |
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Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12) |
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Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b)) |
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Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c)) |
Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).
Emerging growth company ☐
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐
Securities registered pursuant to Section 12(b) of the Exchange Act:
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Title of each class |
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Name of each exchange on which registered |
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Common stock, par value $0.001 per share |
BPMC |
Nasdaq Global Select Market |
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Item 7.01 Regulation FD Disclosure.
On June 14, 2019, Blueprint Medicines Corporation (the “Company”) issued a press release announcing the submission of a new drug application (“NDA”) to the U.S. Food and Drug Administration (“FDA”) for avapritinib for the treatment of adult patients with PDGFRA Exon 18 mutant gastrointestinal stromal tumors (“GIST”), regardless of prior therapy, and fourth-line GIST. The Company has requested priority review for the application, which, if granted, could result in a six-month review process. The FDA has a 60-day filing review period to determine whether the NDA is complete and acceptable for filing. A copy of the press release is furnished as Exhibit 99.1 to this Current Report on Form 8-K.
On June 15, 2019, the Company announced updated data from its Phase 1 EXPLORER clinical trial evaluating avapritinib for the treatment of patients with advanced systemic mastocytosis (“SM”). The data were presented on Saturday, June 15, 2019 in an oral presentation at the 24th Congress of the European Hematology Association (“EHA Annual Meeting”) in Amsterdam, The Netherlands. A copy of the press release is furnished as Exhibit 99.2 to this Current Report on Form 8-K, and a copy of the presentation is furnished as Exhibit 99.3 to this Current Report on Form 8-K.
On June 17, 2019, the Company will host an investor call and live webcast to discuss the updated data from its Phase 1 EXPLORER clinical trial, which were presented at the EHA Annual Meeting, and its NDA submission to the FDA for avapritinib for the treatment of adult patients with PDGFRA Exon 18 mutant GIST, regardless of prior therapy, and fourth-line GIST. A copy of the presentation from the investor call is furnished as Exhibit 99.4 to this Current Report on Form 8-K.
The information in Item 7.01 of this Current Report on Form 8-K, including Exhibits 99.1, 99.2, 99.3 and 99.4, is intended to be furnished and shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended, or the Exchange Act, except as expressly set forth by specific reference in such filing.
Item 9.01 Financial Statements and Exhibits.
(d) Exhibits.
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SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
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BLUEPRINT MEDICINES CORPORATION |
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Date: June 17, 2019 |
By: |
/s/ Tracey L. McCain |
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Tracey L. McCain |
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Chief Legal Officer |
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Exhibit 99.1
Blueprint Medicines Submits New Drug Application to U.S. Food and Drug Administration for Avapritinib for the Treatment of PDGFRA Exon 18 Mutant GIST and Fourth-Line GIST
CAMBRIDGE, Mass., June 14, 2019 – Blueprint Medicines Corporation (NASDAQ: BPMC), a precision therapy company focused on genomically defined cancers, rare diseases and cancer immunotherapy, today announced it has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for avapritinib for the treatment of adult patients with PDGFRA Exon 18 mutant gastrointestinal stromal tumors (GIST), regardless of prior therapy, and fourth-line GIST. Currently, no effective therapy exists for either population. Avapritinib is an investigational, potent and highly selective KIT and PDGFRA inhibitor for patients with advanced GIST.
Avapritinib has received Breakthrough Therapy Designation from the FDA for the treatment of patients with unresectable or metastatic GIST harboring the PDGFRα D842V mutation, as well as Fast Track Designations for the treatment of patients with GIST harboring a PDGFRα D842V mutation regardless of prior therapy, and patients with GIST who have progressed following treatment with imatinib and a second tyrosine kinase inhibitor.
Blueprint Medicines has requested priority review for the application, which, if granted, could result in a six-month review process. The FDA has a 60-day filing review period to determine whether the NDA is complete and acceptable for filing.
“There is an important need for new treatment options that offer durable responses for PDGFRA Exon 18 mutant and fourth-line GIST patients,” said Andy Boral, M.D., Ph.D., Chief Medical Officer at Blueprint Medicines. “By targeting the underlying molecular drivers of GIST, avapritinib has the potential to help these patients realize the benefits of precision therapy. We plan to work closely with the FDA to bring avapritinib to appropriate GIST patients as quickly as possible.”
About GIST
GIST is a sarcoma, or tumor of bone or connective tissue, of the gastrointestinal (GI) tract. Tumors arise from cells in the wall of the GI tract and occur most often in the stomach or small intestine. Most patients are diagnosed between the ages of 50 to 80, and diagnosis is typically triggered by GI bleeding, incidental findings during surgery or imaging and, in rare cases, tumor rupture or GI obstruction.
Most GIST cases are caused by a spectrum of clinically relevant mutations that force the KIT or PDGFRA protein kinases into an increasingly active state. Because currently available therapies primarily bind to the inactive protein conformations, certain primary and secondary mutations typically lead to treatment resistance and disease progression.
In unresectable or metastatic GIST, clinical benefits from existing treatments can vary by mutation type. Mutational testing is critical to tailor therapy to the underlying disease driver and is recommended in expert guidelines. Currently, there are no approved therapies for patients with KIT-driven GIST whose disease progresses beyond imatinib, sunitinib and regorafenib. In patients with metastatic PDGFRα D842V-driven GIST, progression occurs in a median of approximately three to four months with available therapy.
CONFIDENTIAL
CONFIDENTIAL
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 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 systemic mastocytosis (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 PDGFRα 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.
About Blueprint Medicines
Blueprint Medicines is a precision therapy company striving to improve human health. With a focus on genomically defined cancers, rare diseases and cancer immunotherapy, we are developing transformational medicines rooted in our leading expertise in protein kinases, which are proven drivers of disease. Our uniquely targeted, scalable approach empowers the rapid design and development of new treatments and increases the likelihood of clinical success. We are currently advancing four investigational medicines in clinical development, along with multiple research programs. For more information, visit www.BlueprintMedicines.com and follow us on Twitter (@BlueprintMeds) and LinkedIn.
Cautionary Note Regarding Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, statements regarding the potential benefits of avapritinib in treating patients with GIST; plans, timelines and expectations for interactions with the FDA; plans, timelines and expectations for the commercialization of avapritinib for the treatment of GIST, if approved by the FDA; and Blueprint Medicines’ strategy, goals and anticipated milestones, business plans and focus. The words “may,” “will,” “could,” “would,” “should,” “expect,” “plan,” “anticipate,” “intend,” “believe,” “estimate,” “predict,” “project,” “potential,” “continue,” “target” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements in this press release are based on management’s current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation, risks and uncertainties related to the delay of any current or planned clinical trials or the development of Blueprint Medicines’ drug candidates, including avapritinib, BLU-667, BLU-554 and BLU-782; Blueprint Medicines’ advancement of multiple early-stage efforts; Blueprint
CONFIDENTIAL
CONFIDENTIAL
Medicines’ ability to successfully demonstrate the safety and efficacy of its drug candidates and gain approval of its drug candidates on a timely basis, if at all; the preclinical and clinical results for Blueprint Medicines’ drug candidates, which may not support further development of such drug candidates; actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials; Blueprint Medicines’ ability to develop and commercialize companion diagnostic tests for its current and future drug candidates; and the success of Blueprint Medicines’ current and future collaborations, including its cancer immunotherapy collaboration with F. Hoffmann-La Roche Ltd and Hoffmann-La Roche Inc. and its collaboration with CStone Pharmaceuticals. These and other risks and uncertainties are described in greater detail in the section entitled “Risk Factors” in Blueprint Medicines’ Quarterly Report on Form 10-Q for the period ended March 31, 2019, as filed with the Securities and Exchange Commission (SEC) on May 9, 2019, and any other filings that Blueprint Medicines has made or may make with the SEC in the future. Any forward-looking statements contained in this press release represent Blueprint Medicines’ views only as of the date hereof and should not be relied upon as representing its views as of any subsequent date. Except as required by law, Blueprint Medicines explicitly disclaims any obligation to update any forward-looking statements.
Investor Relations Contact
Kristin Hodous
617-714-6674
ir@blueprintmedicines.com
Media Relations Contact
Andrew Law
617-844-8205
media@blueprintmedicines.com
Exhibit 99.2
Blueprint Medicines Presents Updated EXPLORER Trial Data for Avapritinib in Patients with Systemic Mastocytosis at 24th EHA Congress
-- Confirmed 77% ORR per central review in advanced SM --
-- Consistent and profound improvements on measures of mast cell burden across all disease subtypes, including in 15 indolent and smoldering SM patients --
-- Median overall survival not reached with ongoing treatment durations up to 34 months --
-- Updated data support plans to submit NDA to FDA in advanced SM in first quarter of 2020 --
-- Blueprint Medicines to host investor conference call and webcast on Monday, June 17, 2019 at 8:30 a.m. ET --
CAMBRIDGE, Mass., June 15, 2019 – Blueprint Medicines Corporation (NASDAQ: BPMC), a precision therapy company focused on genomically defined cancers, rare diseases and cancer immunotherapy, today announced updated data from the ongoing, registration-enabling EXPLORER trial of avapritinib in patients with systemic mastocytosis (SM). The updated data showed a confirmed overall response rate (ORR) of 77 percent in advanced SM patients, as assessed by a central review committee of SM clinical experts. In addition, the data showed durable clinical activity across advanced, smoldering and indolent forms of SM, with patients on therapy up to 34 months and responses continuing to deepen over time. Avapritinib was generally well-tolerated, with most adverse events (AEs) reported by investigators as Grade 1 or 2. The results are being presented today in an oral presentation at the 24th Congress of the European Hematology Association (EHA) in Amsterdam, The Netherlands.
These updated data from the EXPLORER trial support 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 advanced SM in the first quarter of 2020, subject to continued discussions with the FDA regarding the data required to support an NDA submission. Avapritinib has received FDA Breakthrough Therapy Designation for the treatment of patients with advanced SM, including the subtypes of aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL).
“I believe that potently and selectively targeting KIT D816V, the disease driver in nearly all systemic mastocytosis patients, represents a promising therapeutic approach,” said Dr. Deepti Radia, a hematologist and an investigator on the EXPLORER trial. “These new data showed avapritinib led to profound reductions of objective mast cell burden and durable clinical responses across a broad patient population. In advanced systemic mastocytosis, I am particularly encouraged by the strong activity shown in patients with especially poor survival rates, such as those with mast cell leukemia or high-risk genotypes. These data further reinforce the broad potential of avapritinib to address important medical needs across the spectrum of the disease.”
“These results highlight the promise of avapritinib, a potent and selective KIT D816V inhibitor, to be an important disease-modifying treatment in patients with systemic mastocytosis,” said Andy Boral, M.D., Ph.D., Chief Medical Officer at Blueprint Medicines. “The updated data, including high confirmed
response rates per central review, support our plans to submit a New Drug Application for advanced systemic mastocytosis in the first quarter of 2020. Avapritinib had strong activity in patients with indolent or smoldering systemic mastocytosis as well, providing further confidence in our approach for our ongoing registration-enabling PIONEER trial. By selectively targeting the common driver across all forms of systemic mastocytosis, avapritinib has the potential to address the spectrum of disease manifestations that significantly affect patients with different subtypes.”
Highlights from EHA Presentation of EXPLORER Trial Data
As of the data cutoff date of January 2, 2019, 69 patients were treated with avapritinib in the Phase 1 EXPLORER clinical trial, including seven patients with ASM, 37 patients with SM-AHN, nine patients with MCL, 15 patients with indolent or smoldering SM, and one patient without SM who had chronic myelomonocytic leukemia. Diagnoses were centrally reviewed by a committee of SM experts following an initial assessment by local investigators. Forty-two patients (61 percent) had a prior treatment, including 15 patients (22 percent) who had previously received the multi-kinase inhibitor midostaurin.
Clinical Activity Data
Thirty-nine patients with advanced SM (three ASM, 28 SM-AHN, eight MCL) were evaluable for response by the modified IWG-MRT-ECNM criteria, a rigorous method for assessing clinical response in advanced SM patients with regulatory precedent in the U.S. and Europe. Confirmation of response was defined as a response duration of at least 12 weeks. Evaluable patients generally had more advanced disease at baseline than the overall trial population.
In evaluable patients across all doses studied, the confirmed ORR was 77 percent. Nine patients had complete remission with a full or partial recovery of peripheral blood counts (CR/CRh; 23 percent), 18 patients had partial remission (46 percent) and three patients had clinical improvement (8 percent). No patients had progressive disease as the initial response. In addition, the 12-month duration of response (DOR) rate was 74 percent, and 49 patients (71 percent) remained on treatment with durations up to nearly three years (34 months).
Across all enrolled patients, the median overall survival (OS) was not reached. The estimated 24-month OS rate was 78 percent in all advanced SM patients: 100 percent in ASM patients, 70 percent in SM-AHN patients and 88 percent in MCL patients.
Avapritinib demonstrated strong clinical activity in patients with SRSF2, ASXL1 and/or RUNX1 (S/A/R) mutation positive genotypes, who historically have particularly poor prognoses. In 22 evaluable patients with S/A/R genotypes, the confirmed ORR was 73 percent and five patients had a CR/CRh (23 percent).
Nearly all patients had significant declines on objective measures of mast cell burden. Across all patients evaluable on these measures, 100 percent had a ≥50 percent decline in serum tryptase, 93 percent had a ≥50 percent reduction in bone marrow mast cells, 84 percent had palpable spleens become non-palpable, and 88 percent had a ≥50 percent reduction in KIT D816V mutation allele fraction.
Clinical Activity Data – Indolent or Smoldering SM
Avapritinib showed strong clinical activity in patients with indolent or smoldering SM. Nearly all patients had ≥50 percent reductions in serum tryptase, bone marrow mast cells and KIT D816V mutation allele
fraction. In addition, improvements on these measures were deep and rapid. Thirteen of 15 evaluable patients had normalized serum tryptase levels, and 12 of 13 evaluable patients had complete clearance of mast cell aggregates from the bone marrow. All indolent and smoldering SM patients achieved a ≥50 percent reduction in serum tryptase by the first post-baseline assessment.
Safety Data
Avapritinib was generally well-tolerated with most AEs reported by investigators as Grade 1 or 2. Across all grades, the most common non-hematologic treatment-emergent AEs (regardless of relationship to avapritinib) reported by investigators (>15 percent) were periorbital edema, diarrhea, nausea, fatigue, peripheral edema, vomiting, cognitive effects, hair color changes, arthralgia, abdominal pain, dizziness, decreased appetite, pruritis, constipation and dysgeusia. The most common hematologic treatment-emergent AEs reported by investigators (>10 percent) were anemia, thrombocytopenia and neutropenia. In addition, intracranial bleeding occurred in six patients with pre-existing thrombocytopenia, a known risk factor for intracranial bleeding, and one patient who had a life-threatening fall prior to intracranial bleeding. Five of these patients resumed and remain on treatment with avapritinib following dose modifications. Updated dose modification procedures have been implemented for patients with thrombocytopenia, and to date, no new intracranial bleeding events have been observed. Cytopenias were the most common Grade 3 and 4 treatment-related AEs. No Grade 5 treatment-related AEs were reported by investigators.
Only three patients (4 percent) discontinued treatment with avapritinib due to treatment-related AEs. Nine patients (13 percent) discontinued treatment with avapritinib due to disease progression, with the majority due to either acute myeloid leukemia (n=3) or associated hematologic neoplasm (n=3).
These updated data on avapritinib are being presented at the 24th Congress of EHA on Saturday, June 15 (Abstract Number: S830). A copy of the oral presentation is available in the “Science—Publications and Presentations” section of Blueprint Medicines’ website at www.BlueprintMedicines.com.
Conference Call Information
Blueprint Medicines will host a live conference call and webcast on Monday, June 17, 2019 at 8:30 a.m. ET to review the updated data for avapritinib in SM, as well as the recently announced NDA submission to the FDA for avapritinib for the treatment of PDGFRA Exon 18 mutant gastrointestinal stromal tumors (GIST), regardless of prior therapy, and fourth-line GIST. The conference call may be accessed by dialing (855) 728-4793 (domestic) or (503) 343-6666 (international) and referring to conference ID 8549897. A live webcast of the conference call will be available under the “Investors & Media—Events & Presentations” section of Blueprint Medicines’ website at www.BlueprintMedicines.com. A replay of the webcast will be available approximately two hours after the call and will be available for 30 days following the call.
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 Phase 1 EXPLORER trial, the Phase 2 PATHFINDER trial and the Phase 2 PIONEER trial.
The Phase 1 EXPLORER trial was designed to identify the recommended Phase 2 dose for further study and demonstrate proof-of-concept in advanced SM, including patients with ASM, SM-AHN and MCL. The dose escalation portion is complete, and the expansion portion of the trial is ongoing at multiple sites in the United States and United Kingdom. Trial objectives include assessing safety and tolerability, response per modified IWG-MRT-ECNM criteria and patient-reported outcomes.
The Phase 2 PATHFINDER trial is an open-label, single-arm, registration-enabling trial in patients with advanced SM. Patient dosing is ongoing in the trial, which is designed to enroll up to 60 advanced SM patients at sites in the United States, Canada and European Union. The primary efficacy endpoints are ORR and DOR based on modified IWG-MRT-ECNM criteria.
The Phase 2 PIONEER trial is a randomized, placebo-controlled, registration-enabling trial in patients with indolent and smoldering SM. Patient dosing is ongoing in the trial, which is designed to enroll up to 112 indolent and smoldering SM patients at sites in the United States, Canada and European Union. The primary endpoint is symptom reductions for avapritinib versus placebo based on the Indolent and Smoldering SM Assessment Form Total Symptom Score. All patients who complete the dose-finding (part 1) and placebo-controlled efficacy (part 2) portions of this trial will have an opportunity to receive avapritinib in an open-label extension (part 3).
SM patients and clinicians interested in ongoing clinical trials can contact the Blueprint Medicines study director at SM@blueprintmedicines.com or 1-617-714-6707. Additional details are available at www.blueprintclinicaltrials.com/SM/ or www.clinicaltrials.gov.
About SM
SM results from the abnormal proliferation and survival of mast cells, which mediate allergic responses. The clinical presentation of SM is heterogeneous, ranging from indolent or smoldering SM to three advanced subtypes – ASM, SM-AHN and MCL. The KIT D816V mutation drives approximately 95 percent of all SM cases, causing debilitating and difficult-to-manage symptoms such as pruritus, flushing, headaches, bone pain, nausea, vomiting, diarrhea, anaphylaxis, abdominal pain and fatigue. While these effects occur across SM patients, symptom burden and poor quality of life are the predominant disease manifestations of indolent and smoldering SM. Advanced SM patients experience organ damage and a median overall survival of about 3.5 years in ASM, two years in SM-AHN and less than six months in MCL.
Currently, there are no approved therapies that selectively inhibit KIT D816V in advanced SM, and no approved therapies for indolent and smoldering SM. New treatments are needed that are more effective and better tolerated than existing advanced SM therapy, as well as for indolent and smoldering SM patients whose symptoms are often not well controlled with symptom-directed therapies.
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 GIST, including potent activity against activation loop mutations that are associated with resistance to currently approved therapies. In contrast to approved multi-kinase inhibitors, avapritinib has shown marked selectivity for KIT and PDGFRA over other kinases. In addition,
avapritinib is uniquely designed to selectively bind and inhibit D816V mutant KIT, the common driver of disease in approximately 95 percent of all SM patients. Preclinical studies have shown avapritinib potently inhibited KIT D816V at sub-nanomolar potencies with minimal off-target activity.
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 PDGFRα D842V mutation and one for the treatment of advanced SM, including the subtypes of ASM, SM-AHN and MCL.
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.
Blueprint Medicines is a precision therapy company striving to improve human health. With a focus on genomically defined cancers, rare diseases and cancer immunotherapy, we are developing transformational medicines rooted in our leading expertise in protein kinases, which are proven drivers of disease. Our uniquely targeted, scalable approach empowers the rapid design and development of new treatments and increases the likelihood of clinical success. We are currently advancing four investigational medicines in clinical development, along with multiple research programs. For more information, visit www.BlueprintMedicines.com and follow us on Twitter (@BlueprintMeds) and LinkedIn.
Cautionary Note Regarding Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, statements regarding plans and timelines for the clinical development of avapritinib and Blueprint Medicines’ ability to implement those plans; expectations regarding the potential for Blueprint Medicines’ current or future clinical trials to be registration-enabling; plans, timelines and expectations for interactions with the FDA and other regulatory authorities; plans and timelines for submitting an NDA to the FDA for avapritinib for the treatment of advanced SM; expectations regarding the potential benefits of avapritinib in treating patients with SM; and Blueprint Medicines’ strategy, goals and anticipated milestones, business plans and focus. The words “may,” “will,” “could,” “would,” “should,” “expect,” “plan,” “anticipate,” “intend,” “believe,” “estimate,” “predict,” “project,” “potential,” “continue,” “target” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements in this press release are based on management’s current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation, risks and uncertainties related to the delay of any current or planned clinical trials or the development of Blueprint Medicines’ drug candidates, including avapritinib, BLU-667, BLU-554 and BLU-782; Blueprint Medicines’ advancement of multiple early-stage efforts; Blueprint Medicines’ ability to successfully demonstrate the safety and efficacy of its drug candidates and gain approval of its drug candidates on a timely basis, if at all; the preclinical and clinical results for Blueprint Medicines’ drug candidates, which
may not support further development of such drug candidates; actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials; Blueprint Medicines’ ability to develop and commercialize companion diagnostic tests for its current and future drug candidates; and the success of Blueprint Medicines’ current and future collaborations, including its cancer immunotherapy collaboration with F. Hoffmann-La Roche Ltd and Hoffmann-La Roche Inc. and its collaboration with CStone Pharmaceuticals. These and other risks and uncertainties are described in greater detail in the section entitled “Risk Factors” in Blueprint Medicines’ Quarterly Report on Form 10-Q for the period ended March 31, 2019, as filed with the Securities and Exchange Commission (SEC) on May 9, 2019, and any other filings that Blueprint Medicines has made or may make with the SEC in the future. Any forward-looking statements contained in this press release represent Blueprint Medicines’ views only as of the date hereof and should not be relied upon as representing its views as of any subsequent date. Except as required by law, Blueprint Medicines explicitly disclaims any obligation to update any forward-looking statements.
Investor Relations Contact
Kristin Hodous
617-714-6674
ir@blueprintmedicines.com
Media Relations Contact
Andrew Law
617-844-8205
media@blueprintmedicines.com
Exhibit 99.3
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Avapritinib, a Potent and Selective Inhibitor of KIT D816V, Induces Complete and Durable Responses in Patients with Advanced Systemic Mastocytosis European Hematology Association Annual Meeting Amsterdam, Netherlands, 15 June 2019 Deepti Radia, Michael W. Deininger, Jason Gotlib, Prithviraj Bose, Mark W Drummond, Elizabeth O. Hexner, William A. Robinson, Albert T Quiery, Elliott Winton, Tracy I. George, Hans-Peter Horny, Ronny Oren, Hongliang Shi, Oleg Schmidt-Kittler, Brenton Mar, Daniel J. DeAngelo EXPLORER Advanced SM |
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Disclosures 2 Dr. Deepti Radia is an investigator for Blueprint Medicines’ ongoing phase 1 and phase 2 studies in advanced, indolent and smoldering systemic mastocytosis Dr. Radia has the following disclosures: Consulting or advisory role: Blueprint Medicines, Novartis Speaker’s Bureau: Novartis Avapritinib is an investigational agent discovered by and currently in development by Blueprint Medicines Corporation (Blueprint Medicines) |
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Systemic mastocytosis (SM) is a clonal mast cell disease 3 SM subtyping is based on clinicopathologic features and predicts survival1-3 Mast cell leukemia (MCL) mOS: 2 months SM with an associated hematological neoplasm (SM-AHN) mOS: 24 months Aggressive SM (ASM) mOS: 41 months Indolent SM (ISM) mOS: 198 months* Smoldering SM (SSM) mOS: 120 months 1. Pardanani A. Am J Hematol. 2016;91(11):1146-1159. 2. Lim KH et al. Blood. 2009;113(23):5727-5736 3. Valent P et al. Cancer Res. 2017;77(6):1261-1270. *Expected US survival for age mOS: median Overall Survival Mast cell activation leads to debilitating symptoms Advanced SM (AdvSM) – organ damage KIT D816V drives mast cell growth and activation in ~95% of cases |
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Biochemical binding by DiscoverRX at 3uM KIT D816V biochemical IC50 avapritinib* imatinib* masitinib# midostaurin* ripretinib# 0.27 nM 8150 nM >1000 nM 2.9 nM 2.6 nM Avapritinib potently and selectively targets KIT D816V Kinome illustrations reproduced courtesy of Cell Signaling Technology, Inc. (CSTI) (www.cellsignal.com). Blueprint Medicines is not responsible for the content of the CSTI site. 4 Binding to other kinases (size is proportional to binding) avapritinib imatinib midostaurin Binding to KIT ripretinib *Evans EK et al. Sci Transl Med. 2017;9(414) #Blueprint Medicines internal data on file masitinib |
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Phase 1 EXPLORER clinical trial design AdvSM AdvSM, mIWG-MRT-ECNM evaluable Cohort 1: 300 mg QD Cohort 2: 200 mg QD Part 1: Dose escalation (N=32) Part 2: Expansion (N=37) avapritinib 30-400 mg QD Key entry criteria: AdvSM (ASM, SM-AHN or MCL) or relapsed/refractory myeloid malignancy per local assessment Age ≥18 years, ECOG performance status 0-3, platelets ≥25 x109/L Study objectives: RP2D, safety, ORR per m-IWG-MRT-ECNM, patient-reported outcomes AdvSM or relapsed/refractory myeloid malignancy All data in this presentation are based on a cut-off of January 2, 2019; QD, once daily RP2D, recommended Phase 2 dose, ECOG, Eastern Cooperative Oncology Group 5 EXPLORER Advanced SM |
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Central pathology and adjudication implemented Central Assessments Central tryptase and imaging Central pathology and mutation assessment Central adjudication of diagnosis and response EXPLORER trial now performing central adjudication for confirmation of diagnosis and consistency of response evaluation Only responses confirmed ≥12 weeks considered 45% of local subtyping changed during central adjudication Found AHN on central pathology (i.e., ASM SM-AHN, 20%) WHO C-findings not present/documented upon review (ie. ASM ISM, 19%) Other central pathology discordance (i.e., MCL found, AHN not found, 6%) 6 |
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WHO C-findings are complex and mis-subtyping common 13 of 34 local diagnoses of ASM were adjudicated to be ISM (12) or SSM (1) due to lack of WHO C-findings upon central review* Presence of WHO C-findings in ASM correlates with higher mast cell burden Mast cell burden ASM ISM/SSM n 7 15 Median tryptase, ng/mL 270 116 Median marrow biopsy mast cells, % 30 20 *Bone findings that were not large osteolytic lesions, weight loss that was <10% of body weight, splenomegaly, but without hypersplenism (ie. platelets <100K/uL) were most common 7 Best Change from Baseline (%) Serum Trypase 0 -20 -40 -60 -80 -100 ASM ISM or SSM >50% decrease in tryptase tryptase decreased to < 20 ng/ml# tryptase normalized to < 11.4ng/ML Marrow Mast Cells 40 20 0 -20 -40 -60 -80 -100 ASM ISM or SSM <50% decrease in mast cells (MC) >50% decrease in MC MC aggregates cleared from marrow |
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Parameter All patients (N=69) mIWG Evaluable* pts (N=39) Median age, years (range) / Female, n (%) 62 (34 – 83) / 33 (48) 66 (34 – 83) / 21 (54) SM subtype per central assessment, n (%)* AdvSM ASM SM-AHN MCL ISM or SSM Not SM (CMML) 53 (77) 7 (10) 37 (54) 9 (13) 15 (22) 1 (1) 39 (100) 3 (8) 28 (72) 8 (20) 0 0 ECOG performance status, n (%) 0-1 2-3 50 (75) 17 (25) 26 (67) 13 (33) KIT mutation, per central assays#, n (%) D816V positive D816Y positive KIT mutation negative 62 (90) 2 (3) 5 (7) 37 (95) 2 (5) 0 SRSF2, ASXL1 and/or RUNX1 (S/A/R) mutation positive, n (%), n=64 31 (45) 22 (56) Prior anti-neoplastic therapy Median # of therapies (range) Any, n (%) Midostaurin Cladribine 1 (0 – 4) 42 (61) 15 (22) 11 (16) 1 (0 – 4) 23 (59) 10 (26) 6 (15) Bone marrow mast cell (MC) burden (%), median (range) 35 (5 – 95) 50 (5 – 95) Serum tryptase (µg/L), median (range) 163 (12 – 1414) 182 (21 – 765) KIT D816V allele fraction, median % (range) 9 (0 – 81) 16 (0 – 81) Baseline characteristics *mIWG Evaluable patients have central diagnosis of AdvSM and adjudicated baseline mIWG-MRT-ECNM C-finding(s) (or MCL) and at least 25 weeks follow up (or EOS) 8 |
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65% of patients return to normal tryptase levels ≥50% tryptase reduction in every patient treated normal serum tryptase is defined as <11.4ng/mL # < 20ng/mL is a criterion for complete remission per mIWG-MRT-ECNM 9 Serum Tryptase (central) Best Change from Baseline (%) 0 -20 -40 -60 -80 -100 >50% decrease in tryptase tryptase decreased to <20ng.mL# tryptase normalized to <11.4ng/mL ISM ASM SM-AHN SSM MCL CMML S/A/R genotype |
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79% of patients clear marrow mast cell aggregates ≥50% marrow cells reduction in 93% of patients Only patients with MC aggregates at baseline who have post-baseline assessments included * Clearance of marrow MC aggregates, but necessarily interstitial MC, is a criterion for complete remission per mIWG-MRT-ECNM 10 Bone marrow mast cells (central) Best change from Baseline (%) 40 20 0 -20 -40 -60 -80 -100 n=58 <50% decrease in mast cells (MC) >50% decrease in MC MC aggregates cleared from marrow* ISM ASM SM-AHN SSM MCL S/A/R genotype |
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84% of palpable spleens become non-palpable Only patients with measurable spleens at baseline who have post-baseline assessments included *Of 44 palpable spleens at baseline, 37 (84%) become non-palpable. One not shown on figure as no post-baseline scan yet ≥35% reduction in spleen volume in 81% of patients 11 Spleen volume (central) Best Change from Baseline (%) 0 -20 -40 -60 -80 -100 <35% decrease in spleen volume from baseline ≥35% decrease in spleen volume from baseline Palpable spleen at baseline becomes non-palpable ISM ASM SM-AHN SSM MCL CMML S/A/R genotype -35% reduction n-63 |
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64% of patients return to normal tryptase levels ≥50% tryptase reduction in every patient treated normal serum tryptase is defined as <11.4ng/mL # < 20ng/mL is a criterion for complete remission per mIWG-MRT-ECNM 79% of patients clear marrow mast cell aggregates ≥50% marrow cells reduction in 93% of patients Only patients with MC aggregates at baseline who have post-baseline assessments included * Clearance of marrow MC aggregates, but necessarily interstitial MC, is a criterion for complete remission per mIWG-MRT-ECNM 84% of palpable spleens become non-palpable Only patients with measurable spleens at baseline who have post-baseline assessments included *Of 44 palpable spleens at baseline, 37 (84%) become non-palpable. One not shown on figure as no post-baseline scan yet ≥35% reduction in spleen volume in 81% of patients 12 >50% reduction in marrow KIT D816V in 88% of patients Marrow KIT D816V becomes undetectable in 33% of patients Only patients with marrow KIT D816V at baseline who have post-baseline assessments included *Allele fraction is below validated reliable threshold of detection for KIT D816V ddPCR assay of 0.17% Marrow KIT D816V ddPCR (central) Best Change from Baseline (%) 0 -20 -40 -60 -80 -100 <50% decrease from baseline >50% decrease from baseline Decreases to <1% Becomes undetectable* ISM ASM SM-AHN SSM MCL CMML S/A/R genotype n=60 |
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High rate of confirmed mIWG-MRT-ECNM responses across all AdvSM subtypes 1 CRh: Requires all criteria for CR be met and response duration must be ≥12 weeks (to be confirmed); however, patient may have residual cytopenias. The following are required for CRh: ANC > 0.5 × 109/L with normal differential (absence of neoplastic MCs and blasts < 1%) and Platelet count > 50 × 109/L and Hgb level > 8.0 g/dL Best confirmed central response, n (%) All evaluable (n=39) mIWG ORR (CR + CRh + PR + CI) 30 (77) CR or CRh1 9 (23) Complete Remission (CR) 3 (8) CR, partial hematologic recovery1 (CRh) 6 (15) Partial Remission (PR) 18 (46) Clinical Improvement (CI) 3 (8) Stable Disease (SD) 9 (23) Progressive Disease* (PD) 0 All responses (CR, CRh, PR, CI) confirmed at ≥12 weeks ASM (n=3) SM-AHN (n=28) MCL (n=8) 3 (100) 21 (75) 6 (75) 0 7 (25) 2 (25) 0 2 (7) 1 (13) 0 5 (18) 1 (13) 3 (100) 13 (46) 2 (25) 0 1 (4) 2 (25) 0 7 (25) 2 (25) 0 0 0 S/A/R genotype (n=22) 16 (73) 5 (23) 1 (5) 4 (18) 9 (41) 2 (9) 6 (27) 0 13 S/A/R: A poor prognosis SRSF2, ASXL1 or RUNX1 mutation detected at baseline *No patients were primary progressors within the first 12 weeks |
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Responses occur rapidly and deepen over time Median time to initial response 2 months 74% of patients maintain response for at least 12 months Median time to CR/CRh is 16 months On therapy up to 34 months 14 *Only 3 pts met the mIWG-MRT-ECNM PD response criteria (all transformation to AML), however 6 additional clinical progressions also occurred Patients (%) marrow assessments 100 90 80 70 60 50 40 30 20 10 0 months 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 n=39 39 39 39 39 37 31 29 27 24 23 21 19 18 15 13 13 12 12 10 9 9 8 8 6 6 5 5 3 PD* SD CI PR CRh CR |
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Median overall survival not reached for any subtype ISM/SSM + ASM MCL SM-AHN Subtype % All AdvSM 78 ASM 100 SM-AHN 70 MCL 88 ISM or SSM 100 Estimated 24 month OS rate 15 Only patients with a central diagnosis of SM shown (n=68) Overall Survival Probability (%) CENSORED 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 ASM SM-AHN MCL ISM/SSM 7 37 9 15 0 7 36 8 15 3 7 29 8 15 6 6 23 6 14 9 5 17 6 12 12 3 10 6 9 15 2 10 4 8 18 2 8 2 7 21 1 7 1 5 24 1 4 1 3 27 1 3 0 1 30 0 1 0 0 33 36 Months from First Dose ASM SM-AHN MCL ISM/SSM |
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Treatment-emergent adverse events (AEs) Adverse event, n (%) Any Grade Grade 3/4 Anemia 38 (55) 20 (29) Thrombocytopenia 24 (35) 16 (23) Neutropenia 8 (12) 7 (10) Periorbital edema 52 (75) 3 ( 4) Diarrhea 28 (41) 1 ( 1) Nausea 26 (38) 3 ( 4) Fatigue 25 (36) 5 ( 7) Peripheral Edema 23 (33) 0 Vomiting 22 (32) 3 ( 4) Cognitive effects* 22 (32) 3 ( 4) Hair color changes 20 (29) 1 ( 1) Arthralgia 14 (20) 1 ( 1) Abdominal pain 13 (19) 1 ( 1) Dizziness 13 (19) 1 ( 1) Decreased appetite 12 (17) 0 Pruritis 12 (17) 0 Constipation 11 (16) 1 (1) Dysgeusia 11 (16) 0 NON-HEMATOLOGICAL AEs >15% (N=69) HEMATOLOGICAL AEs >10% (N=69) AEs of note: ascites (n=6 [9%]; n=1 [1%] at ≥ grade 3), pleural effusion (n=9 [13%], n= 1[1%] at ≥ grade 3) *Cognitive effects include: cognitive disorder, confusional state, memory impairment and encephalopathy **1 ICB was in setting of severe head trauma 4% (3/69) discontinued due to treatment-related AEs Refractory ascites, encephalopathy and ICB 13% (9/69) discontinued due to clinical progression 3 AMLs, 3 AHNs, 3 SM Intracranial bleeding (ICB) occurred in 7 patients** 5 of 7 patients resumed therapy No new ICB events reported since implementing dose modifications for thrombocytopenia 71% (49/69) remain on treatment 16 Most AEs were grade 1 or 2 Cytopenias were most common ≥ grade 3 treatment-related AE No grade 5 treatment-related AEs |
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45yo woman with SM-AHN (MDS/MPN-U) 17 Patient permission granted for use of photos Bone Marrow Mast Cells (%) 70 60 50 40 30 20 10 0 SD PR CR Mast cell aggregates Only interestitial mast cells Serum Tryptase 0 1 2 3 4 5 6 7 8 9 10 12 14 16 18 20 22 24 26 28 30 32 months on therapy 600 550 500 450 400 350 300 250 200 150 100 50 0 20 Serum Tryptase (ng/mL) KIT D816V VAF by ddPCR (%) 13 12 11 10 9 8 7 6 5 4 3 2 1 0 C1D1 - 1 0 1 2 3 4 5 6 7 8 9 10 12 14 16 18 20 22 24 26 28 30 32 months on therapy Bllod Marrow baseline 6 months 29 months |
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77% confirmed central ORR by mIWG-MRT-ECNM criteria in AdvSM Responses across all subtypes and poor prognosis S/A/R genotype Responses occur at a median time of 2 mos and deepen over time Dose escalation patients (even cohort 1) still on therapy up to 34 months KIT D816V eventually becomes undetectable in the marrow in 33% of patients Only 4% discontinued for related AEs and 71% remain on treatment Starting dose of 200mg QD and platelet dose modifications implemented to improve long term safety and tolerability Granted Breakthrough Designation for AdvSM and Orphan Designation for Mastocytosis Phase 2 trials for AdvSM and ISM/SSM are enrolling in Europe and North America Avapritinib induces complete and durable responses across SM spectrum 18 |
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Acknowledgements Phase I Investigators Daniel DeAngelo Michael Deininger Jason Gotlib Srdan Verstovsek Prithvi Bose Elizabeth Hexner Albert Quiery William Robinson Mark Drummond Elliott Winton Maria Kremyanskaya Tracy George Hans-Peter Horny 19 Guys and St. Thomas Trust Deimante Drasutyte Monika Ciesielska Thompson Olaoni Clare Oni Natalia Curto-Garcia Claire Woodley Yvonne Francis Donal McLornan Claire Harrison Patients & Families EXPLORER Advanced SM |
Exhibit 99.4
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R.S. Living with advanced systemic mastocytosis Avapritinib program update teleconference Monday, June 17, 2019 blueprint TM MEDICINES |
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Blueprint Medicines call agenda and participants Introduction Kristin Hodous, Senior Manager, Investor Relations Corporate update Jeff Albers, Chief Executive Officer Systemic mastocytosis data presented at 24th EHA Congress Andy Boral, MD, PhD, Chief Medical Officer Avapritinib program next steps Jeff Albers, Chief Executive Officer Q&A 2 blueprint TM MEDICINES |
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Forward-looking statements 3 This presentation contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, as amended. The words “may,” “will,” “could,” “would,” “should,” “expect,” “plan,” “anticipate,” “intend,” “believe,” “estimate,” “predict,” “project,” “potential,” “continue,” “target” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. In this presentation, forward-looking statements include, without limitation, statements regarding plans, timelines and expectations for the development and, if approved by the FDA or other regulatory authorities, commercialization of avapritinib and the ability of Blueprint Medicines Corporation (the “Company”) to implement those plans; the potential benefits of Blueprint Medicines’ current and future drug candidates in treating patients, including the potential benefits of avapritinib in treating patients with gastrointestinal stromal tumors or systemic mastocytosis; plans and timelines for new drug applications for avapritinib in the United States; plans and timelines for presenting data from current or future clinical trials; plans, timelines and expectations for the initiation of additional clinical trials for the Company’s current or future drug candidates; and the Company’s strategy, key goals and anticipated milestones, business plans and focus. The Company has based these forward-looking statements on management’s current expectations, assumptions, estimates and projections. While the Company believes these expectations, assumptions, estimates and projections are reasonable, such forward-looking statements are only predictions and involve known and unknown risks, uncertainties and other important factors, many of which are beyond the Company’s control and may cause actual results, performance or achievements to differ materially from those expressed or implied by any forward-looking statements. These risks and uncertainties include, without limitation, risks and uncertainties related to the delay of any current or planned clinical trials or the development of the Company's drug candidates, including avapritinib, BLU-667, BLU-554 and BLU-782; the Company's advancement of multiple early-stage efforts; the Company's ability to successfully demonstrate the efficacy and safety of its drug candidates and gain approval of its drug candidates on a timely basis, if at all; the preclinical and clinical results for the Company's drug candidates, which may not support further development of such drug candidates; actions or decisions of regulatory agencies or authorities, which may affect the initiation, timing and progress of clinical trials; the Company’s ability to obtain, maintain and enforce patent and other intellectual property protection for any drug candidates it is developing; the Company's ability to develop and commercialize companion diagnostic tests for its current and future drug candidates; and the success of the Company’s current and future collaborations, including its cancer immunotherapy collaboration with F. Hoffmann-La Roche Ltd and Hoffmann-La Roche Inc. and its collaboration with CStone Pharmaceuticals. These and other risks and uncertainties are described in greater detail under “Risk Factors” in the Company’s Quarterly Report on Form 10-Q for the period ended March 31, 2019, as filed with the Securities and Exchange Commission (“SEC”) on May 9, 2019, and any other filings the Company has made or may make with the SEC in the future. The Company cannot guarantee future results, outcomes, levels of activity, performance, developments, or achievements, and there can be no assurance that the Company’s expectations, intentions, anticipations, beliefs, or projections will result or be achieved or accomplished. The forward-looking statements in this presentation are made only as of the date hereof, and except as required by law, the Company undertakes no obligation to update any forward-looking statements contained in this presentation as a result of new information, future events or otherwise. This presentation also contains estimates, projections and other statistical data made by independent parties and by the Company relating to market size and growth and other data about the Company’s industry. These data involve a number of assumptions and limitations, and you are cautioned not to give undue weight to such estimates. In addition, projections, assumptions and estimates of the Company’s future performance and the future performance of the markets in which the Company operates are necessarily subject to a high degree of uncertainty and risk. blueprint TM MEDICINES |
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3L GIST 4L GIST PDGFRA Exon 18 mutant GIST First new drug application for avapritinib submitted to FDA * Trial planned to initiate 2H 2019. Target GIST populations have unresectable or metastatic disease. Kinome illustration reproduced courtesy of Cell Signaling Technology, Inc. (www.cellsignal.com) (CSTI). The foregoing website is maintained by CSTI, and Blueprint Medicines is not responsible for its content. 4 2L GIST* Advanced SM Indolent and smoldering SM U.S. REGULATORY SUBMISSION PLANS 2020 Q1 2020 LATE CLINICAL DEVELOPMENT 4 Submitted Submitted Avapritinib Potent and highly selective KIT and PDGFRA inhibitor blueprint TM MEDICINES |
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Avapritinib, a Potent and Selective Inhibitor of KIT D816V, Induces Complete and Durable Responses in Patients with Advanced Systemic Mastocytosis European Hematology Association Annual Meeting Amsterdam, Netherlands, 15 June 2019 Deepti Radia, Michael W. Deininger, Jason Gotlib, Prithviraj Bose, Mark W Drummond, Elizabeth O. Hexner, William A. Robinson, Albert T Quiery, Elliott Winton, Tracy I. George, Hans-Peter Horny, Ronny Oren, Hongliang Shi, Oleg Schmidt-Kittler, Brenton Mar, Daniel J. DeAngelo EXPLORER Advanced SM |
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Phase 1 EXPLORER clinical trial design AdvSM AdvSM, mIWG-MRT-ECNM evaluable Cohort 1: 300 mg QD Cohort 2: 200 mg QD Part 1: Dose escalation (N=32) Part 2: Expansion (N=37) avapritinib 30-400 mg QD Key entry criteria: AdvSM (ASM, SM-AHN or MCL) or relapsed/refractory myeloid malignancy per local assessment Age ≥18 years, ECOG performance status 0-3, platelets ≥25 x109/L Study objectives: RP2D, safety, ORR per m-IWG-MRT-ECNM, patient-reported outcomes AdvSM or relapsed/refractory myeloid malignancy All data in this presentation are based on a cut-off of January 2, 2019; QD, once daily RP2D, recommended Phase 2 dose, ECOG, Eastern Cooperative Oncology Group 6 EXPLORER Advanced SM |
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Central pathology and adjudication implemented Central Assessments Central tryptase and imaging Central pathology and mutation assessment Central adjudication of diagnosis and response EXPLORER trial now performing central adjudication for confirmation of diagnosis and consistency of response evaluation Only responses confirmed ≥12 weeks considered 45% of local subtyping changed during central adjudication Found AHN on central pathology (i.e., ASM SM-AHN, 20%) WHO C-findings not present/documented upon review (ie. ASM ISM, 19%) Other central pathology discordance (i.e., MCL found, AHN not found, 6%) 7 |
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Parameter All patients (N=69) mIWG Evaluable* pts (N=39) Median age, years (range) / Female, n (%) 62 (34 – 83) / 33 (48) 66 (34 – 83) / 21 (54) SM subtype per central assessment, n (%)* AdvSM ASM SM-AHN MCL ISM or SSM Not SM (CMML) 53 (77) 7 (10) 37 (54) 9 (13) 15 (22) 1 (1) 39 (100) 3 (8) 28 (72) 8 (20) 0 0 ECOG performance status, n (%) 0-1 2-3 50 (75) 17 (25) 26 (67) 13 (33) KIT mutation, per central assays#, n (%) D816V positive D816Y positive KIT mutation negative 62 (90) 2 (3) 5 (7) 37 (95) 2 (5) 0 SRSF2, ASXL1 and/or RUNX1 (S/A/R) mutation positive, n (%), n=64 31 (45) 22 (56) Prior anti-neoplastic therapy Median # of therapies (range) Any, n (%) Midostaurin Cladribine 1 (0 – 4) 42 (61) 15 (22) 11 (16) 1 (0 – 4) 23 (59) 10 (26) 6 (15) Bone marrow mast cell (MC) burden (%), median (range) 35 (5 – 95) 50 (5 – 95) Serum tryptase (µg/L), median (range) 163 (12 – 1414) 182 (21 – 765) KIT D816V allele fraction, median % (range) 9 (0 – 81) 16 (0 – 81) Baseline characteristics *mIWG Evaluable patients have central diagnosis of AdvSM and adjudicated baseline mIWG-MRT-ECNM C-finding(s) (or MCL) and at least 25 weeks follow up (or EOS) 8 |
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65% of patients return to normal tryptase levels ≥50% tryptase reduction in every patient treated normal serum tryptase is defined as <11.4ng/mL # < 20ng/mL is a criterion for complete remission per mIWG-MRT-ECNM 9 Serum Tryptase (central) Best Change from Baseline (%) 0 -20 -40 -60 -80 -100 >50% decrease in tryptase decreased to <20 ng/mL# tryptase normalized to < 11.4ng/mL ISM ASM SM-AHN SSM MCL CMML S/A/R Genotype n=69 |
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79% of patients clear marrow mast cell aggregates ≥50% marrow cells reduction in 93% of patients Only patients with MC aggregates at baseline who have post-baseline assessments included * Clearance of marrow MC aggregates, but necessarily interstitial MC, is a criterion for complete remission per mIWG-MRT-ECNM 10 Bone marrow mast cells (central) Best Change from Baseline (%) 40 20 0 -20 -40 -60 -80 -100 <50% decrease in mast cells (MC) >50% decrease in MC MC aggregates cleared from marrow* ISM ASM SM-AHN SSM MCL S/A/R genotype n=58 |
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84% of palpable spleens become non-palpable Only patients with measurable spleens at baseline who have post-baseline assessments included *Of 44 palpable spleens at baseline, 37 (84%) become non-palpable. One not shown on figure as no post-baseline scan yet ≥35% reduction in spleen volume in 81% of patients 11 Spleen volume (central) Best Change from Baseline (%) 0 -20 -40 -60 -80 -100 <35% decrease in spleen volume from baseline ≥35% decrease in spleen volume from baseline Palpable spleen at baseline becomes non-palpable ISM ASM SM-AHN SSM MCL CMML S/A/R/ genotype -35% reduction n=63 |
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64% of patients return to normal tryptase levels ≥50% tryptase reduction in every patient treated normal serum tryptase is defined as <11.4ng/mL # < 20ng/mL is a criterion for complete remission per mIWG-MRT-ECNM 79% of patients clear marrow mast cell aggregates ≥50% marrow cells reduction in 93% of patients Only patients with MC aggregates at baseline who have post-baseline assessments included * Clearance of marrow MC aggregates, but necessarily interstitial MC, is a criterion for complete remission per mIWG-MRT-ECNM 84% of palpable spleens become non-palpable Only patients with measurable spleens at baseline who have post-baseline assessments included *Of 44 palpable spleens at baseline, 37 (84%) become non-palpable. One not shown on figure as no post-baseline scan yet ≥35% reduction in spleen volume in 81% of patients 12 >50% reduction in marrow KIT D816V in 88% of patients Marrow KIT D816V becomes undetectable in 33% of patients Only patients with marrow KIT D816V at baseline who have post-baseline assessments included *Allele fraction is below validated reliable threshold of detection for KIT D816V ddPCR assay of 0.17% Marrow KIT D816V ddPCR (central) Best Change from Baseline (%) 0 -20 -40 -60 -80 -100 <50% decrease from baseline >50% decrease from baseline Decreases to <1% Becomes undetectable* ISM ASM SM-AHN SSM MCL CMML S/A/R genotype n=60 |
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High rate of confirmed mIWG-MRT-ECNM responses across all AdvSM subtypes 1 CRh: Requires all criteria for CR be met and response duration must be ≥12 weeks (to be confirmed); however, patient may have residual cytopenias. The following are required for CRh: ANC > 0.5 × 109/L with normal differential (absence of neoplastic MCs and blasts < 1%) and Platelet count > 50 × 109/L and Hgb level > 8.0 g/dL Best confirmed central response, n (%) All evaluable (n=39) mIWG ORR (CR + CRh + PR + CI) 30 (77) CR or CRh1 9 (23) Complete Remission (CR) 3 (8) CR, partial hematologic recovery1 (CRh) 6 (15) Partial Remission (PR) 18 (46) Clinical Improvement (CI) 3 (8) Stable Disease (SD) 9 (23) Progressive Disease* (PD) 0 All responses (CR, CRh, PR, CI) confirmed at ≥12 weeks ASM (n=3) SM-AHN (n=28) MCL (n=8) 3 (100) 21 (75) 6 (75) 0 7 (25) 2 (25) 0 2 (7) 1 (13) 0 5 (18) 1 (13) 3 (100) 13 (46) 2 (25) 0 1 (4) 2 (25) 0 7 (25) 2 (25) 0 0 0 S/A/R genotype (n=22) 16 (73) 5 (23) 1 (5) 4 (18) 9 (41) 2 (9) 6 (27) 0 13 S/A/R: A poor prognosis SRSF2, ASXL1 or RUNX1 mutation detected at baseline *No patients were primary progressors within the first 12 weeks |
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Responses occur rapidly and deepen over time Median time to initial response 2 months 74% of patients maintain response for at least 12 months Median time to CR/CRh is 16 months On therapy up to 34 months 14 *Only 3 pts met the mIWG-MRT-ECNM PD response criteria (all transformation to AML), however 6 additional clinical progressions also occurred Patients (%) marrow assessments PD* SD CI PR CRh CR |
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Median overall survival not reached for any subtype ISM/SSM + ASM MCL SM-AHN Subtype % All AdvSM 78 ASM 100 SM-AHN 70 MCL 88 ISM or SSM 100 Estimated 24 month OS rate 15 Only patients with a central diagnosis of SM shown (n=68) Overall Survival Probability (%) ASM SM-AHN MCL ISM/SSM Months from First Dose ASM SM-AHN MCL ISM/SSM |
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45yo woman with SM-AHN (MDS/MPN-U) 16 Patient permission granted for use of photos Bone Marrow Mast Cells (%) KIT D816V VAF by ddPCR (%) Mast cell aggregates Only interstitial mast cells Serum Tryptase Serum Tryptase (ng/mL) months on therapy months on therapy baseline 6 months 29 months Blood Marrow |
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Treatment-emergent adverse events (AEs) Adverse event, n (%) Any Grade Grade 3/4 Anemia 38 (55) 20 (29) Thrombocytopenia 24 (35) 16 (23) Neutropenia 8 (12) 7 (10) Periorbital edema 52 (75) 3 ( 4) Diarrhea 28 (41) 1 ( 1) Nausea 26 (38) 3 ( 4) Fatigue 25 (36) 5 ( 7) Peripheral Edema 23 (33) 0 Vomiting 22 (32) 3 ( 4) Cognitive effects* 22 (32) 3 ( 4) Hair color changes 20 (29) 1 ( 1) Arthralgia 14 (20) 1 ( 1) Abdominal pain 13 (19) 1 ( 1) Dizziness 13 (19) 1 ( 1) Decreased appetite 12 (17) 0 Pruritis 12 (17) 0 Constipation 11 (16) 1 (1) Dysgeusia 11 (16) 0 NON-HEMATOLOGICAL AEs >15% (N=69) HEMATOLOGICAL AEs >10% (N=69) AEs of note: ascites (n=6 [9%]; n=1 [1%] at ≥ grade 3), pleural effusion (n=9 [13%], n= 1[1%] at ≥ grade 3) *Cognitive effects include: cognitive disorder, confusional state, memory impairment and encephalopathy **1 ICB was in setting of severe head trauma 4% (3/69) discontinued due to treatment-related AEs Refractory ascites, encephalopathy and ICB 13% (9/69) discontinued due to clinical progression 3 AMLs, 3 AHNs, 3 SM Intracranial bleeding (ICB) occurred in 7 patients** 5 of 7 patients resumed therapy No new ICB events reported since implementing dose modifications for thrombocytopenia 71% (49/69) remain on treatment 17 Most AEs were grade 1 or 2 Cytopenias were most common ≥ grade 3 treatment-related AE No grade 5 treatment-related AEs |
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77% confirmed central ORR by mIWG-MRT-ECNM criteria in AdvSM Responses across all subtypes and poor prognosis S/A/R genotype Responses occur at a median time of 2 mos and deepen over time Dose escalation patients (even cohort 1) still on therapy up to 34 months KIT D816V eventually becomes undetectable in the marrow in 33% of patients Only 4% discontinued for related AEs and 71% remain on treatment Starting dose of 200mg QD and platelet dose modifications implemented to improve long term safety and tolerability Granted Breakthrough Designation for AdvSM and Orphan Designation for Mastocytosis Phase 2 trials for AdvSM and ISM/SSM are enrolling in Europe and North America Avapritinib induces complete and durable responses across SM spectrum 18 |
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ISM and SSM patients have deep reductions in mast cell burden 19 Best Change from Baseline (%) Serum Tryptase Marrow mast cells Spleen Volume Marrow KIT D816V n=15 n=13 n=15 n=10 >50% decrease in tryptase tryptase decreased to <20 ng/mL* tryptase normalized to < 11.4ng/mL >50% decrease in MC MC aggregates cleared from marrow* <35% decrease in volume from baseline ≥ 35% decrease in volume from baseline** Palpable spleen becomes non-palpable** <50% decrease from baseline>50% decrease from baseline Decreases to <1% Becomes undetectable# ISM SSM S/A/R genotype |
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ISM patients rapidly achieve normal tryptase levels Over half have normal tryptase by 2 months and every patient by 11 months in ISM 20 Patients(%) AdvSM baseline median: 176 ng/mL ISM or SSM baseline median: 116 ng/mL Patients (%) month months <50% decrease in tryptase >50% decrease in tryptase tryptase decreased to <20ng/mL tryptase normalized to < 11.4ng/mL |
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Key avapritinib program next steps in systemic mastocytosis Data presented at 24th EHA Congress in June 2019. Data cut-off date: January 2, 2019. Avapritinib granted Breakthrough Therapy Designation for the treatment of advanced SM, including the subtypes of aggressive SM, SM with an associated hematologic neoplasm and mast cell leukemia. 21 Status Planned next steps Submit NDA for advanced SM in Q1 2020, based on full data from the Phase 1 EXPLORER trial and initial data from the Phase 2 PATHFINDER trial Present initial data from Part 1 (dose finding) of the Phase 2 PIONEER trial in 2H 2019 Advanced SM All patients have benefit on measures of mast cell burden Confirmed 77% ORR per central review 71% still on treatment with durations up to nearly 3 years Well-tolerated to date FDA breakthrough therapy designation Indolent SM Activity at the lowest dose levels tested in advanced SM Profound reductions on measures of mast cell burden in all ISM patients enrolled in the Phase 1 EXPLORER trial Well-tolerated to date |
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DRUG CANDIDATE (TARGET) DISCOVERY EARLY CLINICAL DEVELOPMENT LATE CLINICAL DEVELOPMENT REGULATORY SUBMISSION APPROVED COMMERCIAL RIGHTS Avapritinib (KIT & PDGFRA) BLU-667 (RET) BLU-554 (FGFR4) BLU-782 (ALK2) 4 undisclosed targets Immunokinase targets Rapidly advancing pipeline of investigational precision therapies EGFR-m, EGFR mutant; FOP, fibrodysplasia ossificans progressive; GIST, gastrointestinal stromal tumors; HCC, hepatocellular carcinoma; NSCLC, non-small cell lung cancer; MTC, medullary thyroid cancer; SM, systemic mastocytosis. 1 Unresectable or metastatic disease. 2 Phase 1 trial in healthy volunteers ongoing. Phase 2 trial in patients with FOP planned Q4 2019. * CStone Pharmaceuticals has exclusive rights to develop and commercialize avapritinib, BLU-554 and BLU-667 in Mainland China, Hong Kong, Macau and Taiwan. Blueprint Medicines retains all rights in the rest of the world. ** Blueprint Medicines has U.S. commercial rights for up to two programs. Roche has worldwide commercialization rights for up to three programs and ex-U.S. commercialization rights for up to two programs. 22 ** * FOP2 Up to 5 cancer immunotherapy programs; development stage undisclosed HCC (+CS-1001) 1 – trial planned 2H 2019 3L GIST1 2L GIST1 Advanced SM 2L RET-fusion NSCLC1 2L RET-mutant MTC1 EGFR-m NSCLC (+osimertinib)1 – trial planned 2H 2019 Advanced HCC (+CS-1001) – trial planned 2H 2019 trial planned 2H 2019 NDA planned Q1 2020 NDA planned Q1 2020 NDA planned 1H 2020 NDA planned 2020 PDGFRA Exon 18 mutant GIST1 4L GIST1 NDA submitted NDA submitted Other RET-altered solid tumors1 Advanced HCC 1L RET-fusion NSCLC1 – trial planned 2H 2019 Indolent and smoldering SM |
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Thank you blueprint TM MEDICINES |
