EXECUTIVE INTERVIEW - Array BioPharma: Steadily Moving to Late-Stage Development, Preparing for Commercialization

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. Seven Phase 3 or pivotal studies are already in progress, or are planned to begin within the coming months. These programs include Array’s wholly-owned hematology drug, filanesib (ARRY-520) for multiple myeloma (MM), and two cancer drugs, selumetinib partnered with AstraZeneca and binimetinib (MEK162) partnered with Novartis.

First, Array is developing filanesib in combination with the novel proteasome inhibitor Kyprolis (carfilzomib). To support this, Array is already advancing a Phase 2 trial of Kyprolis plus filanesib. This study will be followed later this year with a Phase 3 registration trial with this same combination. Array is also investigating the activity of single-agent filanesib in a global Phase 2 trial, which should start enrolling patients over the next couple of months.

Second, Array’s binimetinib team continues to enroll patients in a Phase 3 trial in low-grade serous ovarian cancer. Array is also supporting Novartis with its two Phase 3 trials in NRAS-mutant melanoma and BRAF-mutant melanoma. NRAS-mutant melanoma represents the first potential marketed indication for binimetinib, with a projected regulatory filing from the NRAS-mutant melanoma study estimated by Novartis to be in 2015. And AstraZeneca is rapidly advancing three pivotal trials with selumetinib in KRAS-mutant non-small cell lung cancer, differentiated thyroid cancer and metastatic uveal melanoma. Uveal melanoma represents the first potential marketed indication for selumetinib, with an estimated primary completion date for the trial of mid-2015.

Finally, Array and its partners continue to develop a rich pipeline of earlier-stage assets across therapeutic areas, including most notably, ARRY-614, a Phase 1 p38/Tie2 inhibitor designed to treat myelodysplastic syndrome (MDS) patients, and ARRY-797, a Phase 2 p38 inhibitor advancing in a small study  in patients with LMNA-related dilated cardiomyopathy (DCM), a serious, genetic cardiovascular disease, believed to be caused by a mutation of the lamin A/C gene which leads to cardiovascular death, heart transplant or major cardiac event. Array anticipates having preliminary results from this study by the end of 2014.

With a deep pipeline of clinical and preclinical candidates, Array is focused on two strategic objectives: First, Array will selectively develop and commercialize drugs that address an unmet medical need for patients fighting cancer. As filanesib advances into pivotal studies, Array will begin to build a hematology-focused sales and marketing organization to prepare for product launch and commercialization. Second, Array will identify best-in-class development and commercialization partners for its non-core assets to fully maximize the potential of those drugs. As evidenced by its existing collaborations with AstraZeneca, Celgene, Genentech, InterMune/Roche, and Novartis, among others, Array’s drugs draw interest from the most successful pharmaceutical companies in the world. Drug Development & Delivery recently interviewed Chief Executive Officer Ron Squarer about the company’s pipeline and evolution into a fully integrated, commercial-stage biopharmaceutical company.

Q: What makes Array’s business model unique? How have you been able to be so successful in the drug development arena?

A: Array was founded in 1998 as a discovery phase, small molecule-focused company. Its platform was designed to accelerate the discovery of novel chemical entities by integrating protein structure-based design, target-driven combinatorial chemistry and using proprietary software to predict drug properties that would decrease attrition rates in drug development.

Array’s business model emphasized the design and creation of proprietary screening libraries and other uniquely designed collections of compounds that would speed the drug discovery process. Collaborative and wholly-owned discovery programs focused on novel therapeutic targets. These targets were chosen based on the linkage to human clinical data (i.e., genetic mutations) that drive certain disease conditions and novel targets within signaling pathways that have been validated by injectable protein therapeutics.

Funding from partners, proprietary tools, and expertise gained through multiple discovery programs allowed Array to build a fully integrated pharmaceutical company over time. This approach has proven successful. In Array’s 15-year history, 18 molecules have advanced into human testing and development. Of these, 15 remain in development, ten are currently in Phase 2 or 3 trials, having stood the test of early clinical evaluations. Most importantly, the non-dilutive fundraising from our strategic partnerships has allowed Array to retain full global ownership of important clinical-stage assets we believe show great promise in addressing significant unmet medical need in diseases like MM and MDS.

Q: Which of Array’s drugs are advancing in Phase 3 and pivotal trials?

A: Three programs are advancing in Phase 3 trials: our wholly-owned hematology drug, filanesib for multiple myeloma, and two partnered cancer drugs, selumetinib and binimetinib. Filanesib is a highly selective, targeted KSP inhibitor with a mechanism of action distinct from currently available drugs to treat MM such as immunomodulatory drugs (IMiDs) and proteasome inhibitors. Across multiple studies, filanesib has demonstrated activity in heavily pre-treated MM patients, with a consistent safety profile including no drug-induced peripheral neuropathy and limited non-hematologic toxicity. Adverse events are generally limited to transient, non-cumulative and predominantly asymptomatic myelosuppression (decreases in blood counts) when supportive measures are used. We have further shown that alpha-1 acid glycoprotein (AAG) is a potential patient selection marker for filanesib. AAG is being further investigated in our pivotal trials, and could represent the first patient selection marker for a drug in myeloma.

Based on the strength of data from ongoing or completed clinical trials, and recent discussions with the Food and Drug Administration (FDA), Array is developing filanesib in combination with the novel proteasome inhibitor Kyprolis. To support the potential approval of filanesib, our development plan includes three current or future trials:

1. The FACTOR trial, which is expected to initiate in mid-2014, will be a global Phase 3 study comparing Kyprolis plus filanesib to Kyprolis alone in several hundred patients with relapsed and refractory multiple myeloma (RRMM). The primary endpoint of this trial is Progression Free Survival (PFS). There are more than 70,000 patients with RRMM in developed countries, and if successful, this would represent the first new drug to be combined with Kyprolis in patients who have previously been treated with Revlimid (lenalidomide) and Velcade (bortezomib).

2. A randomized Phase 2 trial comparing Kyprolis plus filanesib versus Kyprolis alone in 75 RRMM patients with PFS as the primary endpoint. This trial, which initiated in November 2013, is designed to confirm the dose and schedule of the combination of Kyprolis and filanesib observed in the Phase 1 Kyprolis plus filanesib trial at MD Anderson. This trial will further provide important safety and activity data to support the Phase 3 trial, including data to support AAG as a marker for patient selection in the combination of Kyprolis plus filanesib. In addition, published results from this trial should support Phase 3 enrollment.

3. The AFFIRM trial, a global Phase 2 study with single agent filanesib in 160 patients with RRMM, including both low- and high-AAG patients. Trial initiation is planned for mid-2014. The primary endpoint will be ORR in patients with low levels of AAG. This trial is also designed to support future regulatory submissions, will include important safety and pharmacology data, and will also validate the use of AAG.

Binimetinib, our MEK inhibitor partnered with Novartis, is advancing in three Phase 3 trials: NRAS-mutant melanoma, low-grade serous ovarian cancer and BRAF-mutant melanoma. NRAS-mutant melanoma represents the first potential indication for binimetinib, with a projected regulatory filing from the NRAS-mutant melanoma study estimated to be in 2015. The Novartis partnership is particularly important for Array, given the economics of the agreement, which includes double-digit royalties and co-detailing opportunities.

Selumetinib, our MEK inhibitor partnered with AstraZeneca, is advancing in three pivotal trials: KRAS-mutant advanced or metastatic NSCLC, differentiated thyroid cancer and metastatic uveal melanoma. Patients with KRAS NSCLC, which is approximately 25% of the NSCLC population, or 400,000 patients globally, represent the most significant area with unmet medical need. Uveal melanoma represents the first indication for selumetinib, and the estimated primary completion date for the trial is mid-2015.

Q: Why do you believe these drugs represent significant revenue opportunities?

A: For every drug in our development pipeline, we believe we have identified an unmet need in healthcare: either a patient population that has few or no additional alternative options to current treatments, or an entirely new mechanism of action that represents a significant benefit over current therapies.

Our proprietary pipeline is focused on targeted drugs that treat cancer. We believe there is a substantial opportunity in creating drugs for these diseases to meet demand from the medical community for targeted therapies that not only treat the underlying disease and control symptoms, but do so more effectively and/or more safely than drugs that are currently available. We believe future patient care will improve with the use of screening to select targeted therapies for more effective disease treatment. Also, clinical trials aimed at well-defined patient populations may show improved response rates and may thereby increase the chances for approval with regulatory agencies, such as the FDA. This approach may result in a greater number of marketed drugs each aimed at a smaller subset of patients.

Filanesib, a highly selective, targeted KSP inhibitor with a mechanism of action distinct from existing therapies, is being developed to treat patients with multiple myeloma.   Multiple myeloma is a cancer of the plasma cells in the bone marrow.  For patients with multiple myeloma, as the number of malignant plasma cells increases and dominates the bone marrow, normal blood cell production is disrupted. The growth of malignant plasma cells also destroys normal bone tissue and causes pain and weakness in the bones. Frequently, multiple myeloma cells also produce a monoclonal antibody also called “paraprotein” or “M-protein” which can cause kidney problems and weaken the immune system.

Multiple myeloma is the second most common hematology malignancy in the US with over 24,000 newly diagnosed patients annually, and over 125,000 patients living with the disease in the US, EU, and Japan.  Despite advancements with new treatments, the vast majority of patients progress and die from multiple myeloma leaving an unmet need for novel agents which can provide benefit in combination with, and after existing therapies have failed.

Our partnered programs likewise target high-potential markets, such as lung cancer, melanoma, and thyroid cancer.

Q: What other drugs in your longer term pipeline are you excited about?

A: ARRY-797 is an exciting compound with the potential to be an effective treatment for patients with a serious cardiovascular disease called LMNA-related dilated cardiomyopathy (DCM). Currently, there are no effective specific treatment options to alter the course of this rare degenerative genetic disease. By age 45, patients with LMNA-related DCM have an event free survival of only 31% despite conventional heart failure therapies (events defined as cardiovascular death, transplant or major cardiac event). In vivo studies of ARRY-797 in models of LMNA-related DCM demonstrated significant improvements in heart function, reversal of cardiac remodeling, general well-being and survival. Under a physician-sponsored, single-patient IND, a patient has been receiving ARRY-797 for one year. The patient has had echocardiographic improvements and the drug has been well-tolerated. Based on these encouraging data and discussions with the FDA, Array is enrolling a 12-patient Phase 2 study to explore the effectiveness and safety of ARRY-797 in patients with LMNA-related DCM. The primary endpoint is the change from baseline in a 6-minute walk test at 12 weeks. We anticipate having preliminary results from this study by the end of 2014.

Q: What is your vision for the company?

A: All of Array’s resources are focused right now on bringing our current development programs to commercialization. We believe our wholly-owned programs could represent significant revenue opportunities, as filanesib addresses a patient population struggling with significant unmet medical need and no good alternative treatments. Likewise, for the partnered portfolio, we have favorable economic agreements that will provide additional milestone payments over the coming years, as well as royalties once commercialization is achieved. With all of that, we can build a self-sustaining pharmaceutical development company once key drugs in our pipeline come to market.

Q: How will you build a sales force to bring your wholly owned portfolio to market?

A: Our internal resources are focused on hematology indications, which is a very discrete market opportunity that can be served without the need to build a big pharma-sized sales force.  Additionally, we feel confident about the benefit our drugs will provide to patients and physicians, so there will be compelling reasons to use our products. For these reasons, we believe strongly that we have the ability to quickly build out our team to successfully commercialize our drugs. The other drugs in our portfolio would be partnered with a company that has a sales force in place, so that would enable us to conserve resources.

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