On November 9, 2016 Merrimack Pharmaceuticals, Inc. (Nasdaq: MACK) reported its third quarter 2016 financial results (Press release, Merrimack, NOV 9, 2016, View Source [SID1234516467]).

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Merrimack will host a live conference call and webcast today, Wednesday, November 9 at 4:30 p.m., Eastern time, to provide an update on Merrimack’s progress as well as a summary of these results.

Investors and the general public are invited to listen to the call by dialing (877) 564-1301 (domestic) or (224) 357-2394 (international) five minutes prior to the start of the call and providing the passcode 89606889. A listen-only webcast of the call can be accessed in the Investors section of Merrimack’s website, investors.merrimack.com, and a replay of the call will be archived there for six weeks following the call.

ONIVYDE (irinotecan liposome injection) Update

ONIVYDE updates include:

Receipt by Shire plc of European Marketing Authorization for ONIVYDE for the treatment of patients with metastatic adenocarcinoma of the pancreas following gemcitabine-based therapy;
Establishment of an initial tolerable dose for ONIVYDE in combination with 5-FU/LV and oxaliplatin in an ongoing study evaluating its use in patients with previously untreated metastatic pancreatic cancer;
Issuance by the Centers for Medicare & Medicaid Services (CMS) of a unique, permanent J-code for ONIVYDE, which will streamline the billing and reimbursement process for healthcare providers. The new J-code, J9205 (Injection, irinotecan liposome, 1mg), will become effective for dates of service beginning January 1, 2017 and supersedes all other temporary codes;
Shipments of ONIVYDE from specialty distributors to individual accounts and facilities, a measure of product demand, grew 18% in the third quarter of 2016 as compared to shipments in the second quarter of 2016; and
Recognition of $16.8 million of gross product revenues, or $14.5 million of net product revenues, from U.S. commercial sales of ONIVYDE for the third quarter of 2016. This is compared to $14.8 million of gross product revenues, or $12.9 million of net product revenues for the second quarter of 2016, which represents an increase in net product revenues of 13% over the prior quarter.
Key Recent Events

Merrimack’s key recent events include:

Acceptance for review of an Abbreviated New Drug Application (ANDA) filed by Actavis LLC for generic doxorubicin hydrochloride (HCl) liposome injection (DOXIL). This is the first product developed by Merrimack under a development, license and supply agreement with Actavis pursuant to which Merrimack is responsible for the development and commercial supply of bulk drug product. If the product is approved, Merrimack is eligible to receive a percentage share of net profits in the mid-twenties on future sales of doxorubicin HCl liposome injection in the United States.
Announcement on October 3, 2016, of a 22% reduction in headcount as part of a major corporate restructuring with the objective of prioritizing its research and development on a focused set of systems biology-derived oncology products and strengthening its financial runway. On this same date, Merrimack also announced the resignation of Robert Mulroy, its former President and Chief Executive Officer.
Initiation, in connection with the corporate restructuring, of a strategic review of the company’s pipeline, including the clinical and financial prioritization of its programs. This review may result in amendments to Merrimack’s ongoing clinical trials and other changes to its programs. The company expects to complete this review by the end of 2016. In the absence of clinical trial amendments, Merrimack believes that the data readouts of trials for its lead product candidates, including potentially MM-302, MM-121 and ONIVYDE in front-line metastatic pancreatic cancer, will likely extend beyond its prior guidance. As part of this strategic review, the company will continue to assess these data timelines and the potential impact of any such clinical trial amendments, and will report these findings by year end.
Third Quarter 2016 Financial Results

The following summarizes Merrimack’s financial results from the quarter ended September 30, 2016:

Product revenues from the commercial sale of ONIVYDE, net of discounts, allowances and reserves, were $14.5 million for the third quarter of 2016, compared to $12.9 million for the second quarter of 2016. This represents an increase of $1.6 million, or 13%, over the prior quarter;
License and collaboration revenues were $12.4 million for the third quarter of 2016, compared to $19.3 million for the second quarter of 2016. This represents a decrease of $6.9 million from the prior quarter. The majority of this decrease was related to a $10.0 million substantive milestone achieved during the second quarter of 2016 offset by increased revenue that was recognized under the proportional performance revenue recognition model;
Aggregate research and development and selling, general and administrative expenses were $50.1 million for the third quarter of 2016, compared to $61.7 million for the second quarter of 2016. This represents a decrease of $11.6 million, or 19%. The majority of this decrease was related to a $10.0 million milestone owed to PharmaEngine in the second quarter of 2016;
Restructuring expenses were $0.8 million for the third quarter of 2016 and were related to Merrimack implementing a 22% reduction in headcount as part of a major corporate restructuring with the objective of prioritizing its research and development on a focused set of systems biology-derived oncology products and strengthening its financing runway;
Interest expense was $6.9 million for the third quarter of 2016, compared to $21.1 million for the second quarter of 2016. This $14.2 million decrease was primarily due to a $14.6 million one-time, non-cash loss related to the conversion of an aggregate principal amount of $64.2 million of Merrimack’s convertible notes in April 2016; and
Net loss attributable to Merrimack for the third quarter of 2016 was $30.1 million, or $0.23 per share, compared to a net loss attributable to Merrimack of $50.8 million, or $0.40 per share, for the second quarter of 2016.
Financial Outlook

In an effort to provide further insight into the expected timing of upcoming research and development and regulatory milestones, Merrimack provides the following schedule:



Milestone Trigger

Cash Inflows
from Shire plc
(in millions)


Cash Outflows to
PharmaEngine, Inc.
(in millions)


Expected Timing

Milestone Accounting Treatment
Sale1 of ONIVYDE in first major European country

$
30.0


$
25.5


Q4 2016

Substantive
Sale1 of ONIVYDE in two additional major
European countries


30.0



3.0


First half of 2017

Substantive
First patient dosed in small cell lung cancer trial


10.0



—


First half of 2017

Non-Substantive
Sale1 of ONIVYDE in first major non-European,
non-Asian country


5.0



—


First half of 2017

Substantive
Sale1 of ONIVYDE in first Asian country


25.0



25.0


Second half of 2017

Substantive
Total expected cash flows from upcoming
milestones

$
100.0


$
53.5


1 Sale means the earlier of first commercial sale or receipt of pricing/reimbursement approval.

In addition to the above milestones, future potential research and development and regulatory milestone obligations from Shire are $427.5 million and are offset by $35.0 million of future potential commitments to PharmaEngine related to these milestones.
With respect to its fiscal 2016 guidance, Merrimack:

Lowers and narrows its previously provided expense guidance range, such that Merrimack now anticipates aggregate research and development and selling, general and administrative expenses for 2016, when calculated in accordance with GAAP, to be in the range of $235.5 million to $245.5 million. Excluding anticipated milestone obligations to PharmaEngine of $35.5 million, this corresponds to a range of $200.0 million to $210.0 million of anticipated aggregate research and development and selling, general and administrative expenses for 2016, which is a non-GAAP financial measure.
With respect to its fiscal 2017 guidance:

Merrimack had previously provided guidance as to the achievement of $46.5 million of net milestones related to ONIVYDE in 2016. Merrimack is revising this guidance to reflect that Merrimack now anticipates that only $4.5 million of these net milestones are expected to be achieved in 2016. Merrimack now anticipates that the achievement of the remaining $42.0 million of net milestones related to ONIVYDE will occur in the first half of 2017. This remaining amount is made up of $32.0 million of net substantive milestones, which are expected to increase net income in 2017, and $10.0 million of net non-substantive milestones, which are expected to increase deferred revenues on Merrimack’s balance sheet, as they are included in the Shire proportional performance revenue recognition model;

Merrimack anticipates that aggregate research and development and selling, general and administrative expenses for 2017, when calculated in accordance with GAAP, will be approximately $193.0 million, which includes the anticipated achievement of $28.0 million of milestone obligations to PharmaEngine. This corresponds to aggregate research and development and selling, general and administrative expenses, excluding anticipated milestone obligations to PharmaEngine, a non-GAAP financial measure, of approximately $165.0 million for 2017; and

Merrimack expects that at its currently forecasted spending rates, its existing financial resources, together with anticipated net product revenues and net royalty payments from sales of ONIVYDE, the net milestone payments and reimbursements it expects to receive under its Shire collaboration and access to its $25.0 million credit facility, will be sufficient to fund its operations into 2018.
A table reconciling guidance for aggregate research and development and selling, general and administrative expenses, excluding anticipated milestone obligations to PharmaEngine, a non-GAAP financial measure, to aggregate research and development and selling, general and administrative expenses calculated in accordance with GAAP is included at the end of this press release.

On November 9, 2016 Infinity Pharmaceuticals, Inc. (NASDAQ: INFI) reported the publication of new findings by research collaborators at Memorial Sloan Kettering Cancer Center (MSK) and Infinity scientists in the November 9 online issue of Nature (Press release, Infinity Pharmaceuticals, NOV 9, 2016, View Source [SID1234516466]).

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The paper, entitled "Overcoming resistance to checkpoint blockade by targeting PI3K-gamma in tumor-infiltrating myeloid cells,"[1] describes research showing that the presence of suppressive myeloid cells play a critical role in tumor resistance to checkpoint inhibitors. IPI-549, an oral immuno-oncology development candidate that selectively inhibits PI3K-gamma, is able to help recover sensitivity to checkpoint inhibition in this setting by remodeling the immune-suppressive tumor microenvironment primarily through its effects on myeloid cells. Infinity is conducting a Phase 1 clinical study of IPI-549, which is the only PI3K-gamma inhibitor in clinical development.

The tumor microenvironment, or TME, refers to the non-cancerous cells present in the tumor. Cells within the TME, including immune-suppressive myeloid cells, can provide growth signals to tumor cells, as well as signals that inhibit an anti-tumor immune response. The presence of the supportive TME is thought to be one reason why some cancer therapies do not provide durable or effective results. Targeting the immune-suppressive myeloid cells represents an emerging approach within the field of cancer immunotherapy. Inhibition of PI3K-gamma represents a novel approach to targeting the immune-suppressive microenvironment.

"While new immunotherapies, such as T cell checkpoint inhibitors, are showing great promise in the treatment of various cancers, multiple mechanisms of immune resistance exist in tumors and additional treatments are needed that can further improve outcomes for patients," stated Jedd Wolchok, M.D., Ph.D., Chief of the Melanoma and Immunotherapeutics Service at MSK, as well as Associate Director of the Ludwig Center for Cancer Immunotherapy and Director of the Parker Institute for Cancer Immunotherapy, both at MSK. Dr. Wolchok is also a co-senior author on the Nature publication and lead investigator for the Phase 1 clinical study. "Our research suggests that targeting PI3K-gamma by IPI-549 within the immune-suppressive myeloid cells could offer a unique way to both enhance the activity of checkpoint inhibition in sensitive tumors, as well as to overcome tumor resistance to checkpoint inhibition."

"The preclinical findings published today further reinforce the therapeutic potential of IPI-549 to alter the immune-suppressive microenvironment, promoting an anti-tumor immune response that leads to tumor growth inhibition. These data, coupled with other data published earlier this year on the role of PI3K-gamma in tumor-associated myeloid cells, provide a strong rationale for the ongoing Phase 1 study," stated Jeffery Kutok, M.D., Ph.D., vice president of biology and translational science at Infinity Pharmaceuticals and a co-author of the paper. "Infinity is excited to be developing a potentially first-in-class therapy that could offer a new and possibly complementary approach to existing immunotherapies, including checkpoint inhibitors."

Details of Today’s Nature Publication
In the Nature paper, researchers demonstrate that resistance to immune checkpoint blockade is directly mediated by the suppressive activity of tumor-infiltrating myeloid cells in a number of preclinical tumor models and confirm that immune-suppressive myeloid cells play a critical role in resistance to checkpoint inhibitors. Furthermore, they also showed that inhibition of PI3K-gamma by IPI-549 switched the activation of myeloid cells from an immune-suppressive state to a pro-inflammatory state, leading to enhanced anti-tumor cytotoxic T cell activity, particularly when combined with checkpoint inhibitors. Thus, in preclinical models, IPI-549 treatment is able to reverse the lack of response in tumor models that are resistant to checkpoint inhibitors. These findings provide further rationale for studying IPI-549 in combination with checkpoint inhibitors in the clinic.

PI3K-Gamma Research Also Published in September 19 Online Edition of Nature
In September, Infinity announced the first Nature publication on PI3K-gamma by research collaborators at University of California San Diego School of Medicine and Moores Cancer Center and Infinity scientists in the September 19 online issue of Nature. The paper, entitled "PI3K-gamma is a molecular switch that controls immune suppression,"[2] described preclinical data which showed that macrophage PI3K-gamma signaling promotes immune suppression by inhibiting activation of anti-tumor T cells. Additionally, blocking PI3K-gamma activated the immune response and significantly suppressed growth of implanted tumors in animal models. Inhibiting PI3K-gamma also boosted sensitivity of some tumors to existing anti-cancer drugs and showed synergy with existing immunotherapies.

The September publication, along with today’s publication, will appear back-to-back in the November 17, 2016, issue of Nature.

Phase 1 Study of IPI-549 Ongoing
Earlier this year, Infinity initiated its first clinical study of IPI-549 designed to explore safety, tolerability, pharmacokinetics and pharmacodynamics of IPI-549 both as a monotherapy and in combination with Opdivo (nivolumab), a PD-1 immune checkpoint inhibitor, in approximately 175 patients with advanced solid tumors, including non-small cell lung cancer, melanoma and squamous cell carcinoma of the head and neck.[3] In September, initial clinical data were reported from nine patients who received monotherapy treatment with IPI-549. The data reported showed that the safety, pharmacokinetics and pharmacodynamics of IPI-549 monotherapy treatment appeared favorable. These data were presented in a poster session at the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference (CIMT) (Free CIMT Whitepaper): Translating Science into Survival.[4]

About IPI-549
IPI-549 is an orally administered immuno-oncology development candidate that selectively inhibits PI3K-gamma. In preclinical studies, IPI-549 inhibits immune-suppressive macrophages within the tumor microenvironment, whereas other immunotherapies such as checkpoint modulators more directly target immune effector cell function. As such, IPI-549 may have the potential to treat a broad range of solid tumors and represents a potentially complementary approach to restoring anti-tumor immunity in combination with other immunotherapies such as checkpoint inhibitors.

IPI-549 is an investigational compound and its safety and efficacy has not been evaluated by the U.S. Food and Drug Administration or any other health authority.

On November 9, 2016 Curis, Inc. (Nasdaq:CRIS), a biotechnology company focused on the development and commercialization of innovative and effective drug candidates for the treatment of cancer, reported preliminary clinical pharmacokinetic (PK) and early biomarker data from the ongoing dose escalation stage of CA-170’s Phase 1 trial at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 31st Annual Meeting & Associated Programs in National Harbor, MD. CA-170 is a potent and selective, orally available small molecule antagonist of the programmed death ligand-1 (PDL1) and V-domain Ig suppressor of T cell activation (VISTA) immune checkpoints (Press release, Curis, NOV 9, 2016, View Source [SID1234516455]).

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CA-170 is the first orally available small molecule immune checkpoint antagonist to be investigated in cancer patients. Preclinical data presented previously demonstrated dose-dependent oral exposure in multiple non-clinical models, as well as immune modulation and anti-tumor activity with CA-170 in multiple syngeneic mouse tumor models. Clinical data from a limited number of patients in the Phase 1 trial presented at the SITC (Free SITC Whitepaper) conference, demonstrate that similar to the preclinical findings, CA-170 has a dose proportional and predictable PK profile in patients treated orally at various doses in the ongoing dose escalation stage of the study. Further, evaluation of patient blood samples demonstrate that CA-170 appears to be biologically active in modulating the immune system, with a several-fold increase in percentage of circulating CD8+ T cells expressing activation markers within 24 hours of oral dosing.

The clinical findings were presented in an oral session at SITC (Free SITC Whitepaper) by David Tuck, MD, Chief Medical Officer of Curis. Additional details will be presented during the conference at a poster session on Friday, November 11 at 12:15pm. In addition to the CA-170 data, Curis’s collaborator, Aurigene will also present pre-clinical data from the PDL1/ T-cell immunoglobulin and mucin domain containing protein-3 (TIM-3) program at a poster session on Saturday, November 12 at 11:45am.

"We are pleased with these early PK and biomarker data demonstrating that CA-170 performs in a predictable manner in patients, and very similar to what we observed in the preclinical setting. It is encouraging to observe significant drug exposure at the starting clinical dose, as well as increasing drug exposure with ascending doses. Based on the increase in the proportion of activated CD8+ T cells in blood samples of treated patients, we believe that CA-170 is biologically active in immune modulation by functioning as a checkpoint antagonist at these exposure levels using once daily oral dosing," said Ali Fattaey, Ph.D., Curis’s President and CEO. "These initial patient data also affirm our belief in this innovative small molecule checkpoint targeting strategy invented by our partner Aurigene, and we plan to continue to advance and expand this technology. We look forward to CA-170’s continued clinical development, as well as bringing our second small molecule, oral checkpoint inhibitor in this collaboration, CA-327, which targets PDL1 and TIM3 into clinical studies next year."

Figure 1: Preliminary Patient PK data from CA-170 Phase 1 trial


Patient Plasma
Cycle 1 Day 1
Dose (mg) 50 100 200 400
T1/2 (hours) 8.7 9.6 5.3 12.9
Cmax (ng/mL) 412 1107 1998 4100
AUClast (hr*ng/mL) 5197 11019 27488 66664
T1/2: half life; Cmax: maximum concentration; AUC: Area under the curve

Figure 2: Preliminary Biomarker Data (Activated CD8+ T cells)

A graphic accompanying this release is available at View Source

About CA-170
CA-170 is a first-in-class, orally available, small molecule that was rationally designed to target and inhibit the immune checkpoints, Programmed Death Ligand-1 (PDL1) and V-domain Immunoglobulin Suppressor of T-cell Activation (VISTA). CA-170 is currently being evaluated in a Phase 1 study to assess safety, tolerability and pharmacokinetics of ascending doses of CA-170 in patients with advanced solid tumors or lymphoma (clinicaltrials.gov identifier: NCT02812875).

About CA-327
CA-327 is an orally available, small molecule that was rationally designed to target and inhibit the immune checkpoints, Programmed Death Ligand-1 (PDL1) and T-cell immunoglobulin and mucin domain containing protein-3 (TIM3). CA-327 is currently undergoing IND-enabling studies.

On November 9, 2016 Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in T-cell therapy to treat cancer, reported that the U.S. Food and Drug Administration has removed the partial clinical hold on the planned study of its NY‑ESO SPEAR (Specific Peptide Enhanced Affinity Receptor) T-cell therapy in MRCLS (Press release, Adaptimmune, NOV 9, 2016, View Source [SID1234516452]).

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Under a revised protocol, Adaptimmune will initiate a study in up to 15 MRCLS patients. Patient screening is expected to begin in 4Q 2016. Results from this study will inform a potential future registration trial.

The Company will provide an overview of the removal of the partial clinical hold during its conference call to discuss the third quarter ended September 30, 2016, scheduled for 8:00 a.m. EST (1:00 p.m. GMT) on Thursday November 10, 2016. The live webcast of the conference call will be available via the events page of Adaptimmune’s corporate website at www.adaptimmune.com. An archive will be available after the call at the same address. To participate in the live conference call, if preferred, please dial (877) 280-2296 (U.S.) or +44(0)20 3427 1906 or 0800 279 4977 (United Kingdom). After placing the call, please ask to be joined into the Adaptimmune conference call and provide the confirmation code (3960227).

On November 9, 2016 Array BioPharma (Nasdaq: ARRY) and Pierre Fabre jointly reported new results from the pivotal Phase 3 COLUMBUS trial of binimetinib plus encorafenib (bini/enco) treatment in BRAF-mutant melanoma patients at the Society for Melanoma Research Annual Congress (Press release, Array BioPharma, NOV 9, 2016, View Source [SID1234516442]). The study met its primary endpoint, with the combination of bini/enco significantly improving progression free survival (PFS) compared with vemurafenib, a BRAF inhibitor, alone. The combination of bini/enco was generally well-tolerated and reported adverse events (AEs) were overall consistent with previous published clinical trial results for the bini/enco combination in BRAF-mutant melanoma patients.

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"The results presented today from the COLUMBUS trial, including estimated progression free survival, objective response rate, dose intensity and tolerability of the combination, provide a strong and consistent theme across multiple endpoints, underscoring the promise of binimetinib plus encorafenib as a potential, attractive treatment option for patients diagnosed with BRAF-mutant melanoma," said Keith T. Flaherty, M.D., Director of the Termeer Center for Targeted Therapy, Massachusetts General Hospital and Professor of Medicine, Harvard Medical School.

In the analysis of the primary endpoint, the median PFS (mPFS) for patients treated with the combination of bini/enco was 14.9 months versus 7.3 months for patients treated with vemurafenib; hazard ratio (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 (BICR) of patient scans, while results by local review at the investigative site were also analyzed. The chart below outlines the mPFS results, as determined by both assessments, for the combination of bini/enco versus vemurafenib, bini/enco versus encorafenib, and encorafenib versus vemurafenib:



mPFS BICR

mPFS Local Review
Bini/Enco vs.
Vemurafenib

Bini/Enco
Vemurafenib

Bini/Enco
Vemurafenib

14.9 months
7.3 months

14.8 months
7.3 months

HR (95% CI): 0.54 (0.41-0.71); P<0.001

HR (95% CI): 0.49 (0.37-0.64); P<0.001

Bini/Enco vs.
Encorafenib

Bini/Enco
Encorafenib

Bini/Enco
Encorafenib

14.9 months
9.6 months

14.8 months
9.2 months

HR (95% CI): 0.75 (0.56-1.00); P=0.051

HR (95% CI): 0.68 (0.52-0.90); P=0.006

Encorafenib vs.
Vemurafenib

Encorafenib
Vemurafenib

Encorafenib
Vemurafenib

9.6 months
7.3 months

9.2 months
7.3 months

HR (95% CI): 0.68 (0.52-0.90); P=0.007

HR (95% CI): 0.70 (0.54-0.91); P=0.008


The combination of bini/enco also demonstrated an improvement in confirmed overall response rate (ORR; complete response plus partial response), as well as favorable median duration of exposure, high median dose intensity and consistent activity in patients with prior immunotherapy treatment as well as an advantage in terms of maintaining quality of life for patients.


Confirmed ORR BICR
Confirmed ORR Local Review
Bini/Enco
63% (95% CI: 56-70%)
75% (95% CI: 68-81%)
Vemurafenib
40% (95% CI: 33-48%)
49% (95% CI: 42-57%)
Encorafenib
51% (95% CI: 43-58%)
58% (95% CI: 50-65%)


Median duration of exposure was approximately 51 weeks for patients receiving bini/enco, versus 31 weeks and 27 weeks for the encorafenib and vemurafenib monotherapy arms, respectively
Median dose intensity for patients treated with bini/enco was 100% (encorafenib) and 99.6% (binimetinib)
5% of bini/enco patients had received prior treatment with check-point inhibitors, including ipilimumab, anti-PD-1 and/or anti-PD-L1 therapies, and the observed clinical activity for these patients was consistent with that of bini/enco patients who had not received prior immunotherapy
The Quality of Life (QoL) measures were consistent between two scales and showed an advantage in terms of maintaining quality of life for patients receiving bini/enco compared to patients treated with either encorafenib or vemurafenib single agent therapy. The QoL scales used were the EORTC Quality of Life Questionnaire Core 30 and FACT-Melanoma Scale Score (Functional Assessment of Cancer Therapy).
The combination of bini/enco was generally well-tolerated and reported AEs were overall consistent with previous bini/enco combination clinical trial results in BRAF-mutant melanoma patients.

Grade 3/4 AEs which occurred in more than 5% of patients receiving bini/enco included increased gamma-glutamyltransferase (GGT), increased blood creatine phosphokinase (CK), and hypertension
The incidence of AEs of special interest (toxicities commonly associated with commercially available MEK+BRAF-inhibitor treatments), for patients receiving bini/enco included (% of patients): rash (23%), pyrexia (18%), retinal pigment epithelial detachment (13%) and photosensitivity (5%)
"The robust PFS benefit and tolerability observed with binimetinib plus encorafenib in COLUMBUS suggest the combination represents a potential important addition to the MEK/BRAF treatment landscape for patients with BRAF-mutant melanoma," said Victor Sandor, Chief Medical Officer, Array BioPharma. "We are preparing these data for regulatory submission in 2017."

Frédéric Duchesne, Chief Executive Officer Pharmaceutical Division, Pierre Fabre remarked, "We are very pleased with the promising results and look forward to the possibility that, if approved, the combination of encorafenib plus binimetinib could offer a new treatment option for patients suffering from this devastating disease."

About the Phase 3 COLUMBUS Study
The COLUMBUS trial, (NCT01909453), is a two-part, international, randomized, open label Phase 3 study evaluating the efficacy and safety of the combination of binimetinib plus encorafenib to vemurafenib and encorafenib monotherapy in 921 patients with locally advanced, unresectable or metastatic melanoma with BRAF V600 mutation. Prior immunotherapy treatment was allowed. Over 200 sites across North America, Europe, South America, Africa, Asia and Australia participated in the study. Patients were randomized into two parts:

In Part 1, 577 patients were randomized 1:1:1 to receive bini/enco of 45mg binimetinib plus 450mg encorafenib, 300mg encorafenib alone, or 960mg vemurafenib alone. The primary endpoint for the COLUMBUS trial was a PFS comparison of bini/enco versus vemurafenib. PFS is determined based on tumor assessment (RECIST version 1.1 criteria) by a Blinded Independent Central Review. Secondary endpoints include a comparison of the PFS of encorafenib monotherapy to that of bini/enco and a comparison of overall survival (OS) for bini/enco to that of vemurafenib alone.
In Part 2, 344 patients were randomized 3:1 to receive 45mg binimetinib plus 300mg encorafenib or 300mg encorafenib alone. Part 2 is designed to provide additional data to help evaluate the contribution of binimetinib to the combination of bini/enco. While formal statistical analysis of Part 2 is only planned if both the comparison of PFS between bini/enco versus vemurafenib and bini/enco versus encorafenib achieve statistical significance in Part 1, data from Part 2 are anticipated in mid 2017 and will be provided to global health authorities as part of planned regulatory submissions in 2017.
Binimetinib and encorafenib are investigational medicines and are not currently approved in any country.

About BRAF-Mutant Melanoma
Melanoma is the fifth most common cancer among men and the seventh most common cancer among women in the United States, with more than 76,000 new cases and over 10,000 deaths from the disease expected in 2016. Novel therapies that target the RAS-RAF-MEK-ERK pathway have a strong scientific rationale for activity in this disease, as up to 50% of patients with metastatic melanoma have activating BRAF mutations, the most common gene mutation in this patient population. Current marketed MEK/BRAF combination agents have a run rate forecasted to approach $1 billion in annual worldwide sales.

About Binimetinib & Encorafenib
MEK and BRAF are key protein kinases in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Research has shown this pathway regulates several key cellular activities including proliferation, differentiation, survival and angiogenesis. Inappropriate activation of proteins in this pathway has been shown to occur in many cancers, such as melanoma, colorectal and thyroid cancers. Binimetinib is a late-stage small molecule MEK inhibitor and encorafenib is a late-stage small molecule BRAF inhibitor, both of which target key enzymes in this pathway.

Binimetinib and encorafenib are being studied in clinical trials in advanced cancer patients, including the recently initiated Phase 3 BEACON CRC trial that will study encorafenib in combination with cetuximab with or without binimetinib in patients with BRAF V600E-mutant colorectal cancer. In September 2016, the FDA accepted the New Drug Application (NDA) for binimetinib in NRAS-mutant melanoma with a target action date under the Prescription Drug User Fee Act (PDUFA) of June 30, 2017. Also, the binimetinib Marketing Authorization Application (MAA) submitted by Pierre Fabre was validated and is currently under evaluation by the Committee for Medicinal Products for Human Use (CHMP).

Array BioPharma retains exclusive rights to binimetinib and encorafenib in key markets including the U.S., Japan, Canada, Korea and Israel. Pierre Fabre will have exclusive rights to commercialize both products in all other countries, including Europe, Asia and Latin America.