Post by stcks on Sept 16, 2017 1:57:52 GMT
ARRY business
Array BioPharma Inc. is a biopharmaceutical company focused on the discovery, development and commercialization of targeted small molecule drugs to treat patients afflicted with cancer. Eight registration studies are currently advancing related to seven Array-owned or partnered drugs: binimetinib (MEK162), encorafenib (LGX818), selumetinib (partnered with AstraZeneca), danoprevir (partnered with Roche), ipatasertib (partnered with Genentech), larotrectinib (partnered with Loxo Oncology) and tucatinib (partnered with Cascadian Therapeutics).
Binimetinib and encorafenib
In March 2015, we regained development and commercialization rights to binimetinib, a MEK inhibitor, under the Termination and Asset Transfer Agreement with Novartis Pharma AG and Novartis Pharmaceutical Ltd. and to encorafenib, a BRAF inhibitor, under the Asset Transfer Agreement with Novartis Pharma AG (which we collectively refer to as the "Novartis Agreements"). Along with global ownership of both assets, we received an up-front payment of $85.0 million from Novartis. We believe these programs present significant opportunity to us in the area of oncology.
Binimetinib and encorafenib are currently being studied in Phase 3 trials in advanced cancer patients, including the COLUMBUS trial studying encorafenib in combination with binimetinib in patients with BRAF-mutant melanoma and the BEACON colorectal cancer (or "CRC") trial studying encorafenib in combination with binimetinib and cetuximab in patients with BRAF V600E-mutant CRC ("BRAFm CRC"). On July 5, 2017, we announced the submission of two NDAs to the U.S. Food and Drug Administration (or the "FDA") to support use of the combination of binimetinib 45 mg twice daily and encorafenib 450 mg once daily (or "COMBO450") for the treatment of patients with BRAF-mutant advanced, unresectable or metastatic melanoma. On September 12, 2017, the FDA notified us that it has accepted the NDAs for review, with a Prescription Drug User Fee Act ("PDUFA") date of June 30, 2018. Binimetinib and encorafenib are investigational medicines and are not currently approved in any country.
Novartis continues to substantially fund all ongoing trials with binimetinib and encorafenib that were active or planned as of the close of the Novartis Agreements in 2015, including the COLUMBUS Phase 3 trial. Reimbursement revenue from Novartis was approximately $107.2 million for the previous 12 months.
We have also entered into agreements with Pierre Fabre Medicament SAS, (or "Pierre Fabre" or "PFM") and Ono Pharmaceutical Co., Ltd. (or "Ono") related to the binimetinib and encorafenib programs.
Pierre Fabre agreement
On November 10, 2015, we entered into a Development and Commercialization Agreement (the "PF Agreement") with Pierre Fabre pursuant to which we granted Pierre Fabre rights to commercialize binimetinib and encorafenib in all countries except for the United States, Canada, Japan, Korea and Israel. The PF Agreement satisfies our commitment to secure a development and commercialization partner for the European market for both encorafenib and binimetinib acceptable to European Commission regulatory agencies made in connection with the Novartis Agreements.
The PF Agreement closed in December 2015. All clinical trials involving binimetinib and encorafenib that were ongoing or planned at the Effective Date, including the NEMO and COLUMBUS trials and other then-ongoing Novartis sponsored and investigator sponsored clinical studies, continue to be conducted pursuant to the terms of the Novartis Agreements. Further worldwide development activities will be governed by a Global Development Plan (or "GDP") with Pierre Fabre. Pierre Fabre and we will jointly fund worldwide development costs under the GDP, with us covering 60% and Pierre Fabre covering 40% of such costs. The initial GDP includes multiple trials, including the BEACON CRC trial, and Pierre Fabre and we have agreed to commit at least €100 million in combined funds for these studies in CRC and melanoma.
Pierre Fabre is responsible for seeking regulatory and pricing and reimbursement approvals in the European Economic Area and its other licensed territories. The companies will also enter into a clinical and commercial supply agreement pursuant to which we will supply or procure the supply of clinical and commercial supplies of drug substance and drug product for Pierre Fabre, the costs of which will be borne by Pierre Fabre. We have also agreed to cooperate with Pierre Fabre to ensure the supply of companion diagnostics for use with binimetinib and encorafenib in certain indications.
Each party has also agreed not to distribute, sell or promote competing products in each party's respective markets during a period of exclusivity. Each party has also agreed to indemnify the other party from certain liabilities specified in the PF Agreement.In connection with the PF Agreement, we received $30.0 million as a non-refundable up-front payment during the year ended June 30, 2016. The PF Agreement contains substantive potential milestone payments of up to $35.0 million for achievement of three regulatory milestones relating to European Commission marketing approvals for three specified indications and of up to $390.0 million for achievement of seven commercialization milestones if certain net sales amounts are achieved for any licensed indications. We are also entitled to double-digit royalties that are tiered between 20% and 35% of net sales under the agreement.
Ono agreement
Effective May 31, 2017, we entered into a License, Development and Commercialization Agreement (the "Ono Agreement") with Ono, a company duly organized and existing under the laws of Japan, pursuant to which we granted Ono exclusive rights to commercialize binimetinib and encorafenib, in Japan and the Republic of Korea (the "Ono Territory"), along with the right to develop these products in the Ono Territory. We retain all rights outside the Ono Territory, as well as the right to conduct development and manufacturing activities in the Ono Territory, except for rights we have granted to Pierre Fabre under the PF Agreement.
Under the terms of the Ono Agreement, we received a non-refundable up-front cash payment of ¥3.5 billion, or $31.2 million. We retain all rights to conduct, either by ourselves or through third parties, all clinical studies and file related regulatory filings with respect to binimetinib and encorafenib and to develop, manufacture and commercialize binimetinib and encorafenib outside the Ono Territory (subject to rights we have granted to Pierre Fabre in certain countries). We are entitled to receive up to ¥1.8 billion in milestone payments from Ono if certain development goals are achieved, ¥5.0 billion in milestone payments from Ono if certain regulatory milestones are achieved, and ¥10.5 billion in milestone payments from Ono if certain sales milestones are achieved. A portion of these milestones represent Ono's co-funding obligation as part of Ono's participation in the Phase 3 BEACON CRC trial. We are further eligible for tiered double-digit royalties on annual net sales of binimetinib and encorafenib in the Ono Territory, starting at 22% for annual net sales under ¥10.0 billion and increasing to 25% for annual net sales in excess of ¥10.0 billion subject to certain adjustments. As of September 1, 2017, ¥1.0 billion was the equivalent of approximately $9.1 million (based on the exchange rate published by Oanda).
All ongoing clinical trials involving binimetinib and encorafenib, including the BEACON CRC and COLUMBUS trials, continue as planned as of the effective date of the Ono Agreement, and Ono is entitled to the data derived from such studies. As part of the agreement, Ono obtained the right to participate in any future global development of binimetinib and encorafenib by contributing 12% of those future costs. Ono is responsible for seeking, and for any development of binimetinib and encorafenib specifically necessary to obtain, regulatory and marketing approvals for products in the Ono Territory. We will furnish clinical supplies of drug substance to Ono for use in Ono's development efforts, and Ono may elect to have us provide commercial supplies of drug product to Ono pursuant to a commercial supply agreement to be entered into by us and Ono, in each case the costs of which will be borne by Ono. We have also agreed to discuss and agree on a strategy with Ono to ensure the supply to Ono of companion diagnostics for use with binimetinib and encorafenib in certain indications in the Ono Territory.
Each party has also agreed not to distribute, sell or promote competing MEK or RAF products in the Ono Territory during the term of the Ono Agreement. Each party has also agreed to indemnify the other party from customary matters specified in the Ono Agreement.
COLUMBUS
COLUMBUS is a global Phase 3 study comparing binimetinib and encorafenib versus vemurafenib being conducted in BRAF-mutant melanoma patients.
On July 5, 2017, we announced the submission of two NDAs to the FDA to support use of COMBO450 for the treatment of patients with BRAF-mutant advanced, unresectable or metastatic melanoma. In addition, our European partner, Pierre Fabre, filed the marketing authorization applications (or "MAAs") for binimetininb and encorafenib with the EMA in July 2017. The submissions are supported by data from Part 1 of the pivotal Phase 3 COLUMBUS study, which showed that patients who received binimetinib and encorafenib had a significantly longer progression free survival (or "PFS") compared to patients receiving vemurafenib, and from COLUMBUS Part 2, which demonstrated the contribution of binimetinib to the combination of binimetinib and encorafeinib.
COLUMBUS Part 1: As presented at the 2016 Society for Melanoma Research Annual Congress, results from Part 1 of the COLUMBUS study, based on data cut off as of May 19, 2016, showed that COMBO450 significantly extended PFS in patients with advanced BRAF-mutant melanoma, with a PFS of 14.9 months compared with 7.3 months observed with vemurafenib [hazard ratio (or "HR") 0.54, (95% CI 0.41-0.71, P<0.001)]. As part of the trial design, the primary analysis was based on a Blinded Independent Central Review (or "BICR") of patient scans, while results by local review at the investigative site were also analyzed. The table below outlines the median PFS (or "mPFS") results, as determined by both assessments, for COMBO450 versus vemurafenib, COMBO450 versus encorafenib, and encorafenib versus vemurafenib:
In this study, COMBO450 was generally well-tolerated, with a median duration of treatment of 51 weeks and median relative dose intensity for encorafenib and binimetinib of 100% and 99.6%, respectively, compared with median duration of treatment of 31 weeks and 27 weeks for encorfenib alone and vemurafenib, respectively, and median relative dose intensity of 86.2% and 94.5% for encorfenib alone and vemurafenib, respectively. Grade 3 / 4 adverse events (or "AEs") that occurred in more than 5% of patients receiving COMBO450 were increased gamma-glutamyltransferase (or "GGT") (9%), increased blood creatine phosphokinase (or "CK") (7%) and hypertension (6%). The incidence of selected any grade AEs of special interest, defined based on toxicities commonly associated with commercially available MEK+BRAF-inhibitor treatments for patients receiving COMBO450 included: rash (23%), pyrexia (18%), retinal pigment epithelial detachment (13%) and photosensitivity (5%). Full safety results of COLUMBUS Part 1 were presented at the 2016 Society for Melanoma Research Annual Congress.
COLUMBUS Part 2: COLUMBUS Part 2 was designed specifically to assess the contribution of binimetinib to the combination of binimetinib and encorafenib by reducing the dose of encorafenib to 300mg in the combination arm to allow for a comparison of equal doses across arms. In COLUMBUS Part 2, PFS in patients treated with binimetinib 45mg twice daily plus encorafenib 300mg daily (or "COMBO300") was compared with PFS in patients treated with encorafenib 300mg daily as a single agent. Enrollment in COLUMBUS Part 2 is complete, and patients on study continue to be followed.
Results from COLUMBUS Part 2 were presented at the 2017 European Society for Medical Oncology Congress on September 9, 2017 in Madrid, Spain. In this analysis, based on data cut off as of November 9, 2016, the median PFS for patients treated with COMBO300 was 12.9 months compared to 9.2 months for patients treated with single agent encorafenib, with HR of 0.77 [95% CI 0.61-0.97, P=0.029]. As part of the trial design, the analysis was based on a BICR of patient scans, while results by local review at the investigative site were also analyzed. COMBO300 has been generally well-tolerated to date and reported dose intensity and AEs were consistent with binimetinib 45 mg twice daily plus encorafenib 450 mg daily (COMBO450) results in COLUMBUS Part 1. Grade 3 / 4 AEs that have occurred in 5% or more of patients receiving COMBO300 include increased GGT (5%), increased blood CK (5%) and increased alanine aminotransferase (5%). The incidence of selected any grade AEs of special interest, defined based on toxicities commonly associated with commercially available MEK+BRAF-inhibitor treatments for patients receiving COMBO300 included: pyrexia (17%), rash (15%), retinal pigment epithelial detachment (9%) and photosensitivity (2%).
BEACON CRC
BEACON CRC is a global Phase 3 trial of encorafenib and Erbitux (cetuximab), with or without binimetinib, versus standard of care in patients with BRAF V600E -mutant CRC (BRAFm CRC) whose disease has progressed after one or two prior regimens in the metastatic setting. BRAFm CRC represents a difficult-to-treat subtype of CRC that impacts 10 to 15% of CRC patients. Based on the attractive safety profile and with early encouraging clinical activity observed in the safety lead-in, the randomized portion of the trial was initiated.
The primary endpoint of the BEACON CRC trial is overall survival (or "OS") of the triplet therapy compared to the control arm. The secondary endpoints address efficacy of the doublet therapy compared to the control arm, and the triplet therapy compared to the doublet therapy. Other secondary endpoints include PFS, objective response rate (or "ORR"), duration of response, safety and tolerability. Health related quality of life data will also be assessed. The trial will be conducted at over 250 investigational sites in North America, South America, Europe and the Asia Pacific region. Patient enrollment is expected to be completed in 2018.
On September 9, 2017, we announced interim results based on data cut off as of August 9, 2017 regarding safety and initial clinical activity from the safety lead-in of the Phase 3 BEACON CRC study. These data were presented at the ESMO Congress in Madrid, Spain on September 9 (Abstract No. #517P).
As of August 9, 2017, 30 patients have been treated in the safety lead-in and received the triplet combination of binimetinib, encorafenib and cetuximab (BINI 45 mg twice daily, ENCO 300 mg daily and CETUX per label). Out of the 30 patients, 29 had a BRAF V600E mutation. Microsatellite instability-high (resulting from defective DNA mismatch repair) was detected in only one patient. The triplet demonstrated an acceptable safety profile, supporting initiation of the randomized portion of the study. In addition, favorable clinical activity has been observed to date, with a confirmed ORR of 41% in patients with the BRAF V600Emutation, a group of patients with historically poor outcomes. The observed ORR was 59% in the 17 patients with the BRAF V600E mutation with only one prior therapy. Out of 28 patients with both a BRAF V600E mutation and a post-baseline assessment, 27 showed tumor regression.
In the safety lead-in, the triplet combination has been generally well-tolerated. The most common grade 3 or 4 AEs seen in at least 10% of patients include nausea (10%), vomiting (10%), increased blood CK (10%) and urinary tract infection (10%). Three patients discontinued treatment due to AEs with only one considered related to treatment. At the time of the analysis, 76% of patients remain on study treatment with a median duration of treatment of 5.6 months (range 1.0 - 9.3 months).
BEACON CRC was initiated based on results from a Phase 2 study which included the combination of encorafenib and cetuximab in 50 patients with advanced BRAF-mutant CRC. These results were presented at the 2016 ASCO annual meeting. In this arm, median OS for these patients exceeded one year, which is more than double several separate historical standard of care published benchmarks for this population. The ORR was 22%; historical published benchmarks in this patient population using standard of care regimens range between 4% to 8%.
The Phase 2 data for these treatment regimens showed promising clinical activity in patients:
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Median OS was 12.4 and 13.1 months for the doublet and alpelisib-containing triplet regimens, respectively.
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Median PFS was 4.2 and 5.4 months for the doublet and alpelisib-containing triplet regimens, respectively.
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ORR was 22% and 27% for the doublet and alpelisib-containing triplet regimens, respectively.
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Grade 3 or 4 AEs occurred in greater than 10% of patients and included anemia, hyperglycemia and increased lipase.
Historical results from other published studies show median PFS and median OS after first-line treatment for BRAFm CRC patients range from 1.8 to 2.5 months and 4 to 6 months, respectively, and published ORR from various studies in this population range between 6% to 8%. The study showed that alpelisib added toxicity with only marginal additional activity, therefore the BEACON CRC trial will replace it with binimetinib in the triplet arm.
We are the global sponsor of the BEACON CRC study. Pursuant to the PF Agreement with Pierre Fabre, Pierre Fabre has elected to co-fund 40% of the cost of the BEACON CRC trial. Merck KGaA, Darmstadt, Germany, is the owner of Erbitux outside the United States and Canada, and will supply Erbitux to all trial sites outside the United States and Canada as part of the collaboration. If successful, results would support regulatory submissions for all three parties as well as Ono.
Colorectal cancer is the second most common cancer among men and third most common cancer among women in the United States, with more than 135,000 new cases and more than 50,000 deaths from the disease projected in 2017. In the United States, BRAF mutations occur in 10 to 15% of patients with CRC and represent a poor prognosis for these patients.
Bristol-Myers Squibb collaboration
We entered into a clinical research collaboration with Bristol-Myers Squibb in May 2017 to investigate the safety, tolerability and efficacy of binimetinib in combination with Bristol-Myers Squibb's Opdivo (nivolumab) and Opdivo + Yervoy (ipilimumab) regimen as a potential treatment for metastatic CRC in patients with microsatellite stable tumors.
We and Bristol-Myers Squibb will jointly support, with us acting as the sponsor, a multicenter, open-label Phase 1/2 study that is expected to establish maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) and to assess the safety, efficacy, and pharmacokinetics of binimetinib administered in combination with nivolumab or nivolumab plus ipilimumab in approximately 90 patients with previously treated microsatellite stable metastatic CRC (or "MSS CRC") with documented RAS mutation. The study will include a dose-finding period in Phase 1b followed by a randomized Phase 2 period. Results from this first study will be used to determine optimal approaches to further clinical development of these combinations.
In Phase 1b, Arm A will evaluate binimetinib plus nivolumab and Arm B will evaluate binimetinib with nivolumab plus ipilimumab. In Phase 2, Arm A will evaluate binimetinib plus nivolumab and Arm B will evaluate binimetinib with nivolumab plus ipilimumab. The study start date is September 2017 and the estimated primary completion date is August 2018.
Merck collaboration
We entered into a clinical trial collaboration agreement with Merck in May 2017 to investigate the safety and efficacy of binimetinib with Merck's anti-PD-1 therapy, KEYTRUDA (pembrolizumab), in metastatic CRC patients with microsatellite stable tumors. The companies entered into this collaboration based on the growing body of preclinical and clinical evidence that the immune activity of an anti-PD-1 therapy, such as KEYTRUDA, can be enhanced when combined with a MEK inhibitor, such as binimetinib.
Under the agreement, we and Merck will collaborate on a clinical trial to investigate the safety and efficacy of the combination of binimetinib with KEYTRUDA, in CRC patients with microsatellite stable tumors. The trial is expected to establish a recommended dose regimen of binimetinib and KEYTRUDA, as well as explore the preliminary anti-tumor activity of several novel regimens. The study is expected to begin in the second half of 2017. Results from this first study will be used to determine optimal approaches to further clinical development of these combinations.
Merck will act as the sponsor of this clinical trial, and we will supply Merck with binimetinib for use in the trial. This agreement does not include a non-competition provision that generally prohibits Merck or us from entering into agreements with third parties to perform other clinical studies.
SECOMBIT
The SECOMBIT trial is a randomized study designed to assess the sequencing strategies for targeted agents and immunotherapies in 230 patients with metastatic melanoma and BRAF V600 mutation. The trial will evaluate the combination of targeted agents (encorafenib + binimetinib) and the combination of immunomodulatory antibodies (ipilimumab + nivolumab). SECOMBIT is a multicenter, international cooperative group trial sponsored by Clinical Research Technology and Fondazione Melanoma Onlus, and supported jointly by Bristol-Myers Squibb and us (via Novartis). The primary endpoint is OS and a key secondary endpoint is PFS.
IMMU-TARGET
IMMU-TARGET is a 140-patient open-label, prospective, Phase 1 / 2 study, with a safety run in Phase 1 followed by a randomized Phase 2 part. In Phase 1 (one arm / dose finding), the safety of antibody treatment in combination with encorafenib/ binimetinib therapy will be evaluated. In the randomized two-armed Phase 2, all patients will be treated for 6 months with the triple therapy (encorafenib/ binimetinib/ pembrolizumab) with the doses determined in Phase 1. Patients with disease control (CR, PR, SD) will then be randomly assigned in a 1:1 ratio for maintenance therapy to receive either encorafenib plus binimetinib plus pembrolizumab further on or pembrolizumab only. The trial sponsor is Dr. Dirk Schadendorf, University Hospital, Essen, Germany.
ARRY-382
We are advancing a Phase 1/2 immuno-oncology trial of ARRY-382 in combination with pembrolizumab (Keytruda), a Programmed Cell Death Receptor 1 (or "PD-1") antibody, in patients with advanced solid tumors. ARRY-382 is a wholly-owned, highly selective and potent, small molecule inhibitor of CSF-1R kinase activity. Our current plans to expand development of ARRY-382 include treatment for patients with melanoma and non-small cell lung cancer.
The Phase 1/2 study is an open-label, multicenter study to determine the maximum tolerated dose and/or recommended Phase 2 dose of ARRY-382 in combination with pembrolizumab in adult patients with selected advanced solid tumors (Phase 1b), to assess the pharmacodynamic and pharmacokinetic effects of the combination and to describe the preliminary antitumor activity of the combination in patients with advanced unresectable/metastatic melanoma (Phase 2 expansion), and to estimate the efficacy of the combination in patients with PD-L1—positive non-small cell lung cancer (Phase 2 expansion). The Phase 1b trial is expected to enroll up to 18 patients.
ARRY-797
Based on data to date from a Phase 2 study of ARRY-797, an oral, selective p38 mitogen-activated protein kinase inhibitor, in patients with LMNA-related DCM, a serious rare, degenerative cardiovascular disease caused by mutations in the LMNA gene and characterized by poor prognosis. We plan to initiate a Phase 3 trial of ARRY-797 later in 2017. We continue to evaluate options regarding the asset, including advancing it internally, partnering the program for further development and commercialization or creating a separate company.
The Phase 2 study evaluated the effectiveness and safety of ARRY-797 in 12 patients with LMNA A/C-related DCM. By age 45, approximately 70% of patients with LMNA A/C-related DCM will have died, suffered a major cardiac event, or will have undergone a heart transplant. The primary endpoint of the trial was mean change in six-minute walk test, or 6MWT, at 12 weeks relative to baseline. The trial results were presented at the European Society of Cardiology meeting on August 30, 2016. The results demonstrated an absolute mean change from baseline of 69 meters on the 6MWT at week 12, the study's primary endpoint (baseline 6MWT ranged from 246 to 412 meters). This magnitude of improvement exceeded historical benchmarks for 6MWT that has served as the basis for recent approvals of drugs in other rare diseases. ARRY-797 administration also resulted in sustained improvements in N-terminal pro-brain natriuretic peptide, or NT-proBNP, functional capacity and cardiac function through 48 weeks in LMNA-related DCM patients. Patients who rolled over to a continuing treatment protocol maintained improvements in the 6MWT and NT-proBNP levels through 72 weeks of treatment. Other secondary endpoints measured including echocardiographic measures of left and right ventricular function and patient-reported outcomes using the Kansas City Cardiomyopathy Questionnaire. Both mirrored the favorable improvements seen with the 6MWT. Taken together, the data to date suggest a path forward for this program, and we have met with regulators to discuss the design of a study that could be the basis for marketing approval.
Preclinical drug discovery programs
We also have a portfolio of proprietary and partnered preclinical drug discovery programs, including collaborations with Amgen, Asahi Kasei Pharma Corporation, Loxo Oncology and Mirati Therapeutics, Inc.
Array BioPharma Inc. is a biopharmaceutical company focused on the discovery, development and commercialization of targeted small molecule drugs to treat patients afflicted with cancer. Eight registration studies are currently advancing related to seven Array-owned or partnered drugs: binimetinib (MEK162), encorafenib (LGX818), selumetinib (partnered with AstraZeneca), danoprevir (partnered with Roche), ipatasertib (partnered with Genentech), larotrectinib (partnered with Loxo Oncology) and tucatinib (partnered with Cascadian Therapeutics).
Binimetinib and encorafenib
In March 2015, we regained development and commercialization rights to binimetinib, a MEK inhibitor, under the Termination and Asset Transfer Agreement with Novartis Pharma AG and Novartis Pharmaceutical Ltd. and to encorafenib, a BRAF inhibitor, under the Asset Transfer Agreement with Novartis Pharma AG (which we collectively refer to as the "Novartis Agreements"). Along with global ownership of both assets, we received an up-front payment of $85.0 million from Novartis. We believe these programs present significant opportunity to us in the area of oncology.
Binimetinib and encorafenib are currently being studied in Phase 3 trials in advanced cancer patients, including the COLUMBUS trial studying encorafenib in combination with binimetinib in patients with BRAF-mutant melanoma and the BEACON colorectal cancer (or "CRC") trial studying encorafenib in combination with binimetinib and cetuximab in patients with BRAF V600E-mutant CRC ("BRAFm CRC"). On July 5, 2017, we announced the submission of two NDAs to the U.S. Food and Drug Administration (or the "FDA") to support use of the combination of binimetinib 45 mg twice daily and encorafenib 450 mg once daily (or "COMBO450") for the treatment of patients with BRAF-mutant advanced, unresectable or metastatic melanoma. On September 12, 2017, the FDA notified us that it has accepted the NDAs for review, with a Prescription Drug User Fee Act ("PDUFA") date of June 30, 2018. Binimetinib and encorafenib are investigational medicines and are not currently approved in any country.
Novartis continues to substantially fund all ongoing trials with binimetinib and encorafenib that were active or planned as of the close of the Novartis Agreements in 2015, including the COLUMBUS Phase 3 trial. Reimbursement revenue from Novartis was approximately $107.2 million for the previous 12 months.
We have also entered into agreements with Pierre Fabre Medicament SAS, (or "Pierre Fabre" or "PFM") and Ono Pharmaceutical Co., Ltd. (or "Ono") related to the binimetinib and encorafenib programs.
Pierre Fabre agreement
On November 10, 2015, we entered into a Development and Commercialization Agreement (the "PF Agreement") with Pierre Fabre pursuant to which we granted Pierre Fabre rights to commercialize binimetinib and encorafenib in all countries except for the United States, Canada, Japan, Korea and Israel. The PF Agreement satisfies our commitment to secure a development and commercialization partner for the European market for both encorafenib and binimetinib acceptable to European Commission regulatory agencies made in connection with the Novartis Agreements.
The PF Agreement closed in December 2015. All clinical trials involving binimetinib and encorafenib that were ongoing or planned at the Effective Date, including the NEMO and COLUMBUS trials and other then-ongoing Novartis sponsored and investigator sponsored clinical studies, continue to be conducted pursuant to the terms of the Novartis Agreements. Further worldwide development activities will be governed by a Global Development Plan (or "GDP") with Pierre Fabre. Pierre Fabre and we will jointly fund worldwide development costs under the GDP, with us covering 60% and Pierre Fabre covering 40% of such costs. The initial GDP includes multiple trials, including the BEACON CRC trial, and Pierre Fabre and we have agreed to commit at least €100 million in combined funds for these studies in CRC and melanoma.
Pierre Fabre is responsible for seeking regulatory and pricing and reimbursement approvals in the European Economic Area and its other licensed territories. The companies will also enter into a clinical and commercial supply agreement pursuant to which we will supply or procure the supply of clinical and commercial supplies of drug substance and drug product for Pierre Fabre, the costs of which will be borne by Pierre Fabre. We have also agreed to cooperate with Pierre Fabre to ensure the supply of companion diagnostics for use with binimetinib and encorafenib in certain indications.
Each party has also agreed not to distribute, sell or promote competing products in each party's respective markets during a period of exclusivity. Each party has also agreed to indemnify the other party from certain liabilities specified in the PF Agreement.In connection with the PF Agreement, we received $30.0 million as a non-refundable up-front payment during the year ended June 30, 2016. The PF Agreement contains substantive potential milestone payments of up to $35.0 million for achievement of three regulatory milestones relating to European Commission marketing approvals for three specified indications and of up to $390.0 million for achievement of seven commercialization milestones if certain net sales amounts are achieved for any licensed indications. We are also entitled to double-digit royalties that are tiered between 20% and 35% of net sales under the agreement.
Ono agreement
Effective May 31, 2017, we entered into a License, Development and Commercialization Agreement (the "Ono Agreement") with Ono, a company duly organized and existing under the laws of Japan, pursuant to which we granted Ono exclusive rights to commercialize binimetinib and encorafenib, in Japan and the Republic of Korea (the "Ono Territory"), along with the right to develop these products in the Ono Territory. We retain all rights outside the Ono Territory, as well as the right to conduct development and manufacturing activities in the Ono Territory, except for rights we have granted to Pierre Fabre under the PF Agreement.
Under the terms of the Ono Agreement, we received a non-refundable up-front cash payment of ¥3.5 billion, or $31.2 million. We retain all rights to conduct, either by ourselves or through third parties, all clinical studies and file related regulatory filings with respect to binimetinib and encorafenib and to develop, manufacture and commercialize binimetinib and encorafenib outside the Ono Territory (subject to rights we have granted to Pierre Fabre in certain countries). We are entitled to receive up to ¥1.8 billion in milestone payments from Ono if certain development goals are achieved, ¥5.0 billion in milestone payments from Ono if certain regulatory milestones are achieved, and ¥10.5 billion in milestone payments from Ono if certain sales milestones are achieved. A portion of these milestones represent Ono's co-funding obligation as part of Ono's participation in the Phase 3 BEACON CRC trial. We are further eligible for tiered double-digit royalties on annual net sales of binimetinib and encorafenib in the Ono Territory, starting at 22% for annual net sales under ¥10.0 billion and increasing to 25% for annual net sales in excess of ¥10.0 billion subject to certain adjustments. As of September 1, 2017, ¥1.0 billion was the equivalent of approximately $9.1 million (based on the exchange rate published by Oanda).
All ongoing clinical trials involving binimetinib and encorafenib, including the BEACON CRC and COLUMBUS trials, continue as planned as of the effective date of the Ono Agreement, and Ono is entitled to the data derived from such studies. As part of the agreement, Ono obtained the right to participate in any future global development of binimetinib and encorafenib by contributing 12% of those future costs. Ono is responsible for seeking, and for any development of binimetinib and encorafenib specifically necessary to obtain, regulatory and marketing approvals for products in the Ono Territory. We will furnish clinical supplies of drug substance to Ono for use in Ono's development efforts, and Ono may elect to have us provide commercial supplies of drug product to Ono pursuant to a commercial supply agreement to be entered into by us and Ono, in each case the costs of which will be borne by Ono. We have also agreed to discuss and agree on a strategy with Ono to ensure the supply to Ono of companion diagnostics for use with binimetinib and encorafenib in certain indications in the Ono Territory.
Each party has also agreed not to distribute, sell or promote competing MEK or RAF products in the Ono Territory during the term of the Ono Agreement. Each party has also agreed to indemnify the other party from customary matters specified in the Ono Agreement.
COLUMBUS
COLUMBUS is a global Phase 3 study comparing binimetinib and encorafenib versus vemurafenib being conducted in BRAF-mutant melanoma patients.
On July 5, 2017, we announced the submission of two NDAs to the FDA to support use of COMBO450 for the treatment of patients with BRAF-mutant advanced, unresectable or metastatic melanoma. In addition, our European partner, Pierre Fabre, filed the marketing authorization applications (or "MAAs") for binimetininb and encorafenib with the EMA in July 2017. The submissions are supported by data from Part 1 of the pivotal Phase 3 COLUMBUS study, which showed that patients who received binimetinib and encorafenib had a significantly longer progression free survival (or "PFS") compared to patients receiving vemurafenib, and from COLUMBUS Part 2, which demonstrated the contribution of binimetinib to the combination of binimetinib and encorafeinib.
COLUMBUS Part 1: As presented at the 2016 Society for Melanoma Research Annual Congress, results from Part 1 of the COLUMBUS study, based on data cut off as of May 19, 2016, showed that COMBO450 significantly extended PFS in patients with advanced BRAF-mutant melanoma, with a PFS of 14.9 months compared with 7.3 months observed with vemurafenib [hazard ratio (or "HR") 0.54, (95% CI 0.41-0.71, P<0.001)]. As part of the trial design, the primary analysis was based on a Blinded Independent Central Review (or "BICR") of patient scans, while results by local review at the investigative site were also analyzed. The table below outlines the median PFS (or "mPFS") results, as determined by both assessments, for COMBO450 versus vemurafenib, COMBO450 versus encorafenib, and encorafenib versus vemurafenib:
In this study, COMBO450 was generally well-tolerated, with a median duration of treatment of 51 weeks and median relative dose intensity for encorafenib and binimetinib of 100% and 99.6%, respectively, compared with median duration of treatment of 31 weeks and 27 weeks for encorfenib alone and vemurafenib, respectively, and median relative dose intensity of 86.2% and 94.5% for encorfenib alone and vemurafenib, respectively. Grade 3 / 4 adverse events (or "AEs") that occurred in more than 5% of patients receiving COMBO450 were increased gamma-glutamyltransferase (or "GGT") (9%), increased blood creatine phosphokinase (or "CK") (7%) and hypertension (6%). The incidence of selected any grade AEs of special interest, defined based on toxicities commonly associated with commercially available MEK+BRAF-inhibitor treatments for patients receiving COMBO450 included: rash (23%), pyrexia (18%), retinal pigment epithelial detachment (13%) and photosensitivity (5%). Full safety results of COLUMBUS Part 1 were presented at the 2016 Society for Melanoma Research Annual Congress.
COLUMBUS Part 2: COLUMBUS Part 2 was designed specifically to assess the contribution of binimetinib to the combination of binimetinib and encorafenib by reducing the dose of encorafenib to 300mg in the combination arm to allow for a comparison of equal doses across arms. In COLUMBUS Part 2, PFS in patients treated with binimetinib 45mg twice daily plus encorafenib 300mg daily (or "COMBO300") was compared with PFS in patients treated with encorafenib 300mg daily as a single agent. Enrollment in COLUMBUS Part 2 is complete, and patients on study continue to be followed.
Results from COLUMBUS Part 2 were presented at the 2017 European Society for Medical Oncology Congress on September 9, 2017 in Madrid, Spain. In this analysis, based on data cut off as of November 9, 2016, the median PFS for patients treated with COMBO300 was 12.9 months compared to 9.2 months for patients treated with single agent encorafenib, with HR of 0.77 [95% CI 0.61-0.97, P=0.029]. As part of the trial design, the analysis was based on a BICR of patient scans, while results by local review at the investigative site were also analyzed. COMBO300 has been generally well-tolerated to date and reported dose intensity and AEs were consistent with binimetinib 45 mg twice daily plus encorafenib 450 mg daily (COMBO450) results in COLUMBUS Part 1. Grade 3 / 4 AEs that have occurred in 5% or more of patients receiving COMBO300 include increased GGT (5%), increased blood CK (5%) and increased alanine aminotransferase (5%). The incidence of selected any grade AEs of special interest, defined based on toxicities commonly associated with commercially available MEK+BRAF-inhibitor treatments for patients receiving COMBO300 included: pyrexia (17%), rash (15%), retinal pigment epithelial detachment (9%) and photosensitivity (2%).
BEACON CRC
BEACON CRC is a global Phase 3 trial of encorafenib and Erbitux (cetuximab), with or without binimetinib, versus standard of care in patients with BRAF V600E -mutant CRC (BRAFm CRC) whose disease has progressed after one or two prior regimens in the metastatic setting. BRAFm CRC represents a difficult-to-treat subtype of CRC that impacts 10 to 15% of CRC patients. Based on the attractive safety profile and with early encouraging clinical activity observed in the safety lead-in, the randomized portion of the trial was initiated.
The primary endpoint of the BEACON CRC trial is overall survival (or "OS") of the triplet therapy compared to the control arm. The secondary endpoints address efficacy of the doublet therapy compared to the control arm, and the triplet therapy compared to the doublet therapy. Other secondary endpoints include PFS, objective response rate (or "ORR"), duration of response, safety and tolerability. Health related quality of life data will also be assessed. The trial will be conducted at over 250 investigational sites in North America, South America, Europe and the Asia Pacific region. Patient enrollment is expected to be completed in 2018.
On September 9, 2017, we announced interim results based on data cut off as of August 9, 2017 regarding safety and initial clinical activity from the safety lead-in of the Phase 3 BEACON CRC study. These data were presented at the ESMO Congress in Madrid, Spain on September 9 (Abstract No. #517P).
As of August 9, 2017, 30 patients have been treated in the safety lead-in and received the triplet combination of binimetinib, encorafenib and cetuximab (BINI 45 mg twice daily, ENCO 300 mg daily and CETUX per label). Out of the 30 patients, 29 had a BRAF V600E mutation. Microsatellite instability-high (resulting from defective DNA mismatch repair) was detected in only one patient. The triplet demonstrated an acceptable safety profile, supporting initiation of the randomized portion of the study. In addition, favorable clinical activity has been observed to date, with a confirmed ORR of 41% in patients with the BRAF V600Emutation, a group of patients with historically poor outcomes. The observed ORR was 59% in the 17 patients with the BRAF V600E mutation with only one prior therapy. Out of 28 patients with both a BRAF V600E mutation and a post-baseline assessment, 27 showed tumor regression.
In the safety lead-in, the triplet combination has been generally well-tolerated. The most common grade 3 or 4 AEs seen in at least 10% of patients include nausea (10%), vomiting (10%), increased blood CK (10%) and urinary tract infection (10%). Three patients discontinued treatment due to AEs with only one considered related to treatment. At the time of the analysis, 76% of patients remain on study treatment with a median duration of treatment of 5.6 months (range 1.0 - 9.3 months).
BEACON CRC was initiated based on results from a Phase 2 study which included the combination of encorafenib and cetuximab in 50 patients with advanced BRAF-mutant CRC. These results were presented at the 2016 ASCO annual meeting. In this arm, median OS for these patients exceeded one year, which is more than double several separate historical standard of care published benchmarks for this population. The ORR was 22%; historical published benchmarks in this patient population using standard of care regimens range between 4% to 8%.
The Phase 2 data for these treatment regimens showed promising clinical activity in patients:
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Median OS was 12.4 and 13.1 months for the doublet and alpelisib-containing triplet regimens, respectively.
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Median PFS was 4.2 and 5.4 months for the doublet and alpelisib-containing triplet regimens, respectively.
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ORR was 22% and 27% for the doublet and alpelisib-containing triplet regimens, respectively.
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Grade 3 or 4 AEs occurred in greater than 10% of patients and included anemia, hyperglycemia and increased lipase.
Historical results from other published studies show median PFS and median OS after first-line treatment for BRAFm CRC patients range from 1.8 to 2.5 months and 4 to 6 months, respectively, and published ORR from various studies in this population range between 6% to 8%. The study showed that alpelisib added toxicity with only marginal additional activity, therefore the BEACON CRC trial will replace it with binimetinib in the triplet arm.
We are the global sponsor of the BEACON CRC study. Pursuant to the PF Agreement with Pierre Fabre, Pierre Fabre has elected to co-fund 40% of the cost of the BEACON CRC trial. Merck KGaA, Darmstadt, Germany, is the owner of Erbitux outside the United States and Canada, and will supply Erbitux to all trial sites outside the United States and Canada as part of the collaboration. If successful, results would support regulatory submissions for all three parties as well as Ono.
Colorectal cancer is the second most common cancer among men and third most common cancer among women in the United States, with more than 135,000 new cases and more than 50,000 deaths from the disease projected in 2017. In the United States, BRAF mutations occur in 10 to 15% of patients with CRC and represent a poor prognosis for these patients.
Bristol-Myers Squibb collaboration
We entered into a clinical research collaboration with Bristol-Myers Squibb in May 2017 to investigate the safety, tolerability and efficacy of binimetinib in combination with Bristol-Myers Squibb's Opdivo (nivolumab) and Opdivo + Yervoy (ipilimumab) regimen as a potential treatment for metastatic CRC in patients with microsatellite stable tumors.
We and Bristol-Myers Squibb will jointly support, with us acting as the sponsor, a multicenter, open-label Phase 1/2 study that is expected to establish maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) and to assess the safety, efficacy, and pharmacokinetics of binimetinib administered in combination with nivolumab or nivolumab plus ipilimumab in approximately 90 patients with previously treated microsatellite stable metastatic CRC (or "MSS CRC") with documented RAS mutation. The study will include a dose-finding period in Phase 1b followed by a randomized Phase 2 period. Results from this first study will be used to determine optimal approaches to further clinical development of these combinations.
In Phase 1b, Arm A will evaluate binimetinib plus nivolumab and Arm B will evaluate binimetinib with nivolumab plus ipilimumab. In Phase 2, Arm A will evaluate binimetinib plus nivolumab and Arm B will evaluate binimetinib with nivolumab plus ipilimumab. The study start date is September 2017 and the estimated primary completion date is August 2018.
Merck collaboration
We entered into a clinical trial collaboration agreement with Merck in May 2017 to investigate the safety and efficacy of binimetinib with Merck's anti-PD-1 therapy, KEYTRUDA (pembrolizumab), in metastatic CRC patients with microsatellite stable tumors. The companies entered into this collaboration based on the growing body of preclinical and clinical evidence that the immune activity of an anti-PD-1 therapy, such as KEYTRUDA, can be enhanced when combined with a MEK inhibitor, such as binimetinib.
Under the agreement, we and Merck will collaborate on a clinical trial to investigate the safety and efficacy of the combination of binimetinib with KEYTRUDA, in CRC patients with microsatellite stable tumors. The trial is expected to establish a recommended dose regimen of binimetinib and KEYTRUDA, as well as explore the preliminary anti-tumor activity of several novel regimens. The study is expected to begin in the second half of 2017. Results from this first study will be used to determine optimal approaches to further clinical development of these combinations.
Merck will act as the sponsor of this clinical trial, and we will supply Merck with binimetinib for use in the trial. This agreement does not include a non-competition provision that generally prohibits Merck or us from entering into agreements with third parties to perform other clinical studies.
SECOMBIT
The SECOMBIT trial is a randomized study designed to assess the sequencing strategies for targeted agents and immunotherapies in 230 patients with metastatic melanoma and BRAF V600 mutation. The trial will evaluate the combination of targeted agents (encorafenib + binimetinib) and the combination of immunomodulatory antibodies (ipilimumab + nivolumab). SECOMBIT is a multicenter, international cooperative group trial sponsored by Clinical Research Technology and Fondazione Melanoma Onlus, and supported jointly by Bristol-Myers Squibb and us (via Novartis). The primary endpoint is OS and a key secondary endpoint is PFS.
IMMU-TARGET
IMMU-TARGET is a 140-patient open-label, prospective, Phase 1 / 2 study, with a safety run in Phase 1 followed by a randomized Phase 2 part. In Phase 1 (one arm / dose finding), the safety of antibody treatment in combination with encorafenib/ binimetinib therapy will be evaluated. In the randomized two-armed Phase 2, all patients will be treated for 6 months with the triple therapy (encorafenib/ binimetinib/ pembrolizumab) with the doses determined in Phase 1. Patients with disease control (CR, PR, SD) will then be randomly assigned in a 1:1 ratio for maintenance therapy to receive either encorafenib plus binimetinib plus pembrolizumab further on or pembrolizumab only. The trial sponsor is Dr. Dirk Schadendorf, University Hospital, Essen, Germany.
ARRY-382
We are advancing a Phase 1/2 immuno-oncology trial of ARRY-382 in combination with pembrolizumab (Keytruda), a Programmed Cell Death Receptor 1 (or "PD-1") antibody, in patients with advanced solid tumors. ARRY-382 is a wholly-owned, highly selective and potent, small molecule inhibitor of CSF-1R kinase activity. Our current plans to expand development of ARRY-382 include treatment for patients with melanoma and non-small cell lung cancer.
The Phase 1/2 study is an open-label, multicenter study to determine the maximum tolerated dose and/or recommended Phase 2 dose of ARRY-382 in combination with pembrolizumab in adult patients with selected advanced solid tumors (Phase 1b), to assess the pharmacodynamic and pharmacokinetic effects of the combination and to describe the preliminary antitumor activity of the combination in patients with advanced unresectable/metastatic melanoma (Phase 2 expansion), and to estimate the efficacy of the combination in patients with PD-L1—positive non-small cell lung cancer (Phase 2 expansion). The Phase 1b trial is expected to enroll up to 18 patients.
ARRY-797
Based on data to date from a Phase 2 study of ARRY-797, an oral, selective p38 mitogen-activated protein kinase inhibitor, in patients with LMNA-related DCM, a serious rare, degenerative cardiovascular disease caused by mutations in the LMNA gene and characterized by poor prognosis. We plan to initiate a Phase 3 trial of ARRY-797 later in 2017. We continue to evaluate options regarding the asset, including advancing it internally, partnering the program for further development and commercialization or creating a separate company.
The Phase 2 study evaluated the effectiveness and safety of ARRY-797 in 12 patients with LMNA A/C-related DCM. By age 45, approximately 70% of patients with LMNA A/C-related DCM will have died, suffered a major cardiac event, or will have undergone a heart transplant. The primary endpoint of the trial was mean change in six-minute walk test, or 6MWT, at 12 weeks relative to baseline. The trial results were presented at the European Society of Cardiology meeting on August 30, 2016. The results demonstrated an absolute mean change from baseline of 69 meters on the 6MWT at week 12, the study's primary endpoint (baseline 6MWT ranged from 246 to 412 meters). This magnitude of improvement exceeded historical benchmarks for 6MWT that has served as the basis for recent approvals of drugs in other rare diseases. ARRY-797 administration also resulted in sustained improvements in N-terminal pro-brain natriuretic peptide, or NT-proBNP, functional capacity and cardiac function through 48 weeks in LMNA-related DCM patients. Patients who rolled over to a continuing treatment protocol maintained improvements in the 6MWT and NT-proBNP levels through 72 weeks of treatment. Other secondary endpoints measured including echocardiographic measures of left and right ventricular function and patient-reported outcomes using the Kansas City Cardiomyopathy Questionnaire. Both mirrored the favorable improvements seen with the 6MWT. Taken together, the data to date suggest a path forward for this program, and we have met with regulators to discuss the design of a study that could be the basis for marketing approval.
Preclinical drug discovery programs
We also have a portfolio of proprietary and partnered preclinical drug discovery programs, including collaborations with Amgen, Asahi Kasei Pharma Corporation, Loxo Oncology and Mirati Therapeutics, Inc.