On January 9, 2017 Advaxis, Inc. (NASDAQ:ADXS), a clinical-stage biotechnology company developing cancer immunotherapies, reported its 2017 business outlook to provide an overview of anticipated events and key milestones for the coming year, as well as a look back at clinical and business highlights from 2016 (Press release, Advaxis, JAN 9, 2017, View Source [SID1234517383]).

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Advaxis made significant strides in its clinical development programs and expanded its pipeline with additional preclinical assets in 2016. The company’s lead product candidate, axalimogene filolisbac, received Fast Track designation and a Special Protocol Assessment (SPA) for the global Phase 3 AIM2CERV study, a randomized study of axalimogene filolisbac following chemoradiation in patients with high-risk, locally advanced cervical cancer (HRLACC). Also in 2016, axalimogene filolisbac was classified as an advanced therapy medicinal product (ATMP) for the treatment of cervical cancer by the European Medicines Agency’s (EMA) Committee for Advanced Therapies (CAT). Late in 2016, the company initiated AIM2CERV and announced positive, final data from the GOG-0265 Phase 2 trial that supports pursuing a second global Phase 3 study in a metastatic recurrent cervical cancer. Also in 2016, Advaxis entered into a collaboration with Amgen Inc. (Amgen) for the global development and commercialization of Advaxis’ preclinical neoantigen technology, ADXS-NEO, to create a personalized approach to cancer treatment.

In 2016, Advaxis expanded its capabilities and added significant resources to support execution of two global registrational clinical trials and future commercialization of its immuno-oncology products. The company added close to $100 million in capital from proceeds from the Amgen collaboration, a direct placement and a state grant. Advaxis expanded its management team in 2016 with the appointment of Chris Duke as Chief Operating Officer, and added approximately 30 more employees in key areas, as the company grew its headcount to 80 over the course of the year. In September, the company completed the buildout of its clinical manufacturing facility to produce clinical trial supplies and expanded its research laboratory facility. Also, the company began construction of its commercial manufacturing facility, all at its Princeton headquarters.

2017 OPERATIONAL MILESTONES

Advaxis anticipates the following development milestones in 2017:

Clinical Operations

Axalimogene Filolisbac

Present a detailed data analysis of the completed Phase 2 GOG-0265 trial, which was conducted by the GOG Foundation, Inc. (GOG, now part of NRG Oncology), evaluating patients with persistent or recurrent metastatic (squamous or non-squamous cell) carcinoma of the cervix (PRmCC), at a medical meeting in the first half of 2017. Top-line data released in 2016 showed a 12-month overall survival rate of 38 percent observed in 50 patients in the trial. This is a 52 percent improvement over the 12-month overall survival rate that was expected in the trial’s patient population based on prognostic factors.
Attend an end-of-Phase-2 meeting with respect to PRmCC with the U.S. Food and Drug Administration (FDA) to discuss the results of GOG-0265.
Submit a marketing authorization application to the EMA for approval of axalimogene filolisbac to treat patients with metastatic cervical cancer in the second half of 2017.
Open approximately 150 clinical sites for the global, 450-patient Phase 3 AIM2CERV trial in patients with HRLACC, with a trial enrollment update to be issued at a medical meeting in the first half of 2017. There are 10 active trial sites in the United States as of this week.
Initiate a second global, registrational Phase 3 study in patients with metastatic cervical cancer in the second half of 2017.
Present updated clinical data from the Phase 1/2 combination trial with AstraZeneca’s investigational anti-PD-L1 inhibitor, durvalumab, in patients with recurrent, persistent or metastatic cervical cancer or HPV+ squamous cell cancer of the head and neck (HNSCC) at a medical meeting in the second half of 2017.
Present additional data from the Phase 2 BrUOG trial in high-risk, locally advanced anal cancer, conducted in collaboration with Brown University’s Oncology Research Group, at a medical meeting in the first half of 2017.
Present additional data from the Phase 2 window of opportunity trial in HPV-positive head and neck cancers at a medical meeting in the first half of 2017.
With full enrollment achieved in Stage 1 of the FAWCETT Phase 2 trial in patients with persistent or recurrent metastatic anal cancer, the company plans to present a preliminary trial update at a medical meeting in the second half of 2017.
ADXS-PSA

Complete initial dosing of Part B of the Phase 1/2 trial evaluating ADXS-PSA in combination with KEYTRUDA (pembrolizumab) in advanced, metastatic castration-resistant prostate cancer (mCRPC) and present preliminary data at a medical meeting in 2017.
Initiate and complete enrollment of the expansion cohort by year-end 2017.
ADXS-HER2

Initiate a study in pediatric osteosarcoma in collaboration with the Children’s Oncology Group in 2017.
Expanding Pipeline

ADXS-NEO Collaboration with Amgen

Submit an Investigational New Drug (IND) application to the FDA in early 2017.
Initiate the first-in-human ADXS-NEO clinical trial.
Accelerate the discovery of personalized cancer immunotherapies derived from neoantigens as part of the TESLA (Tumor neoantigEn SeLection Alliance) with the Parker Institute for Cancer Immunotherapy and the Cancer Research Institute.
ADXS-HOT

Prepare and file an IND with the FDA for ADXS-HOT constructs that target tumor driver genes, so-called hotspot mutations or public mutations, found in various cancer types in the second half of 2017.
Enhanced Manufacturing and Research Capabilities

Increase capacity to include in-house clinical and commercial manufacturing capabilities, initially to manufacture clinical supplies for the ADXS-NEO program in 2017.
Reduce lead times and improve overall supply chain by operationalizing several technology transfers with its partners and by installing new innovative technologies.
Corporate Development

Pursue research, clinical and commercial partnerships to optimize the cancer immunotherapy portfolio, including to enable development of lead asset, axalimogene filolisbac, in combination with other novel cancer therapies and to support its registration and potential commercialization in the EU.
Explore the application of detoxified Listeriolysin O (dtLLO) technology and optimize the research and development as an adjuvant molecule in the development of vaccines.
2016 REVIEW

Advaxis achieved several regulatory, clinical, business and operational milestones in 2016:

Clinical Milestones

Axalimogene Filolisbac

June: Presented preliminary data at American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) from stage 1 of the Phase 2 GOG-0265 clinical study showing a 6-month survival rate of 38.5 percent in 26 patients, which exceeds prior historical GOG trials in this patient population. Of particular note, a patient from this stage experienced a complete response following three doses which remains ongoing.
June: Dosed the first patient in the first stage of the Phase 2 FAWCETT trial in patients with persistent or recurrent metastatic anal cancer.
July: Reached an agreement with the FDA under the SPA process for the Phase 3 AIM2CERV trial.
July: Received classification as an ATMP for the treatment of cervical cancer by the EMA’s CAT and received Fast Track Designation from the FDA for high-risk, locally advanced cervical cancer.
October: Entered Phase 3 with initiation of AIM2CERV evaluating axalimogene filolisbac as an adjuvant therapy following chemotherapy and radiation.
October: Announced updated data from the Phase 2 GOG-0265 clinical study which showed a patient with recurrent cervical cancer achieved a durable complete response, as well as a 12-month overall survival rate of 38 percent across all study subjects (n=50), surpassing historical 12-month survival rates in GOG studies which have never exceeded 30 percent.
November: As presented at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) annual meeting, a patient with cervical cancer participating in the combination trial with AstraZeneca’s durvalumab achieved a complete response, and two patients with HNSCC achieved stable disease.
April: The window of opportunity trial, as presented as American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting, showed increased systemic HPV-reactive T-cell responses in patients with late-stage HPV-positive oropharyngeal cancer, allowing for the trial to advance to the second stage, being conducted at the Icahn School of Medicine at Mount Sinai.
ADXS-PSA

April: Finalized the part A dose-escalation cohort of the Phase 1/2 KEYNOTE-046 combination trial with Merck, which evaluated maximum tolerability of ADXS-PSA in patients with previously treated mCRPC.
October: Initiated the combination portion evaluating ADXS-PSA in combination with KEYTRUDA.
ADXS-HER2

May: As published in Clinical Cancer Research, in a dose-escalation study of ADXS-HER2 in canine osteosarcoma, antigen-specific T-cell responses were seen within 6 months of immunotherapy administration.
April: FDA granted Fast Track designation for ADXS-HER2 for patients with newly diagnosed, non-metastatic, surgically-resectable osteosarcoma.
Expanding Pipeline

ADXS-NEO

January: Established a five-year exclusive supply agreement with Synthetic Genomics, Inc. to manufacture the synthetic DNA used in ADXS-NEO.
August: Advaxis entered into a global collaboration with Amgen to develop and commercialize ADXS-NEO. Under the collaboration agreement, Advaxis will lead the clinical development of ADXS-NEO through proof-of-concept, retain manufacturing responsibilities, and receive development, regulatory and sales milestone payments of up to $475 million. Amgen received worldwide rights to develop and commercialize ADXS-NEO.
December: Advaxis joined the TESLA (Tumor neoantigEn SeLection Alliance) collaboration with the Parker Institute for Cancer Immunotherapy and the Cancer Research Institute, along with 30 leading academia and industry partners, to further cancer neoantigen research.
Business & Operations

Advaxis achieved the following operational milestones in 2016:

Over the course of 2016, Advaxis expanded its leadership team, deepening its clinical operations, manufacturing and business development functions:
Christopher Duke, Senior Vice President and Chief Operating Officer.
Ranya Dajani, Vice President, Corporate Development
January: Established a Scientific Advisory Board, including Antoni Ribas, M.D., Ph.D., Jedd Wolchok, M.D., Ph.D., Nancy Freitag, Ph.D., Marc Lecuit, M.D., Ph.D.
January: Added two more patents to its growing patent portfolio; European Patent No. 1804831 expands the composition of matter claims covering HER-2 tumor antigens, and U.S. Patent No. 9,226,958 expands the use of the Company’s Lm Technology beyond oncology, specifically to induce an immune response in parasitically infected patients.
February: Bradley Monk, co-primary investigator of the GOG-0265 Phase 2 study, joined Advaxis as the company’s Lead Cervical Cancer Advisor to head the development of Advaxis’ Lm Technology platform and lead the AIM2CERV program.
February: Agreement established with Especificos Stendhal SA de CV ("Stendhal") to co-develop and commercialize axalimogene filolisbac in Latin America.
February: Daniel O’Connor, president and chief executive officer of Advaxis, was appointed to the Board of Trustees of BioNJ.
April: Advaxis became the first biotechnology company to receive the Vision of Hope Award from the Sarcoma Foundation of America for its ADXS-HER2 osteosarcoma immunotherapy platform.
August: Advaxis secured $30 million in direct placement financing from healthcare institutional specialist investors.
September: Advaxis unveiled its state-of-the-art laboratory and manufacturing facility to develop immuno-oncology therapeutics in Princeton N.J. where Governor Chris Christie led the ribbon-cutting event.
October: Advaxis received $2.5M through the New Jersey Economic Development Authority’s (NJEDA) New Jersey Technology Business Tax Certificate Transfer (NOL) program.

On January 9, 2017 Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the fields of cancer metabolism and rare genetic metabolic diseases, reported key 2017 milestones in conjunction with its presentation at the 35th Annual J.P. Morgan Healthcare Conference in San Francisco (Press release, Agios Pharmaceuticals, JAN 9, 2017, View Source;p=RssLanding&cat=news&id=2234926 [SID1234517384]). The presentation will outline important milestones as Agios evolves into a commercial stage company, including potential launches for enasidenib and AG-120 in R/R AML, pivotal development for its second wholly owned asset, AG-348 in pyruvate kinase (PK) deficiency, and an investigational new drug (IND) application submission for the company’s next development candidate, focused on MTAP deleted cancers. The company will webcast its presentation on Monday, January 9, 2017 at 10:00 a.m. PT (1:00 p.m. ET) at www.agios.com.

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"This is the year Agios will evolve into a commercial-stage organization with the anticipated launch of enasidenib for patients with R/R AML, followed by the NDA submission of AG-120 and AG-348 preparing to enter a pivotal trial in PK deficiency," said David Schenkein, M.D., chief executive officer of Agios. "We believe these milestones will enable us to achieve our vision of delivering important medicines with the potential to transform patients’ lives. Additionally, our robust research engine continues to be highly productive with an IND submission for the company’s sixth development candidate in eight years anticipated by the end of 2017."

The company expects to achieve the following key milestones by the end of 2017:

Potential approval of enasidenib in the United States for IDH2m positive R/R AML in collaboration with Celgene.
Submit a new drug application (NDA) to the U.S. FDA for AG-120 by the end of 2017. AG-120 is a wholly owned, first-in-class, oral, selective, potent inhibitor of IDH1m, in IDH1m positive R/R AML.
Initiate a global, registration-enabling Phase 3 study combining AG-120 and VIDAZA in frontline AML patients with an IDH1 mutation ineligible for intensive chemotherapy in the first half of 2017.
Finalize design and operational activities for a global pivotal trial of AG-348 to initiate in the first half of 2018. AG-348 is a wholly owned, first-in-class, oral activator of both wild-type (normal) and mutated pyruvate kinase-R (PKR) enzymes, in PK deficiency.
File an IND application for the MTAP pathway development candidate by the end of 2017.
The company also provided an update on the following 2016 milestones achieved in December:

Supported Celgene’s submission of an NDA for enasidenib in IDH2m positive R/R AML.
Initiated a global, registration-enabling randomized Phase 3 trial for AG-120 in IDH1m positive cholangiocarcinoma. The FDA also granted AG-120 Fast Track Designation for the treatment of patients with previously treated, unresectable or metastatic cholangiocarcinoma with an IDH1 mutation.
Selected a development candidate focused on the MTAP pathway to enter IND-enabling studies.
2016 Year-End Cash and Guidance

Agios ended 2016 with approximately $574 million of cash, cash equivalents and marketable securities. Based on its current operating plans, the company expects that its existing cash, cash equivalents and marketable securities as of December 31, 2016, together with anticipated interest income, and anticipated expense reimbursements under its collaboration agreements with Celgene, but excluding any additional program-specific milestone payments from Celgene, will enable the company to fund its anticipated operating expenses and capital expenditure requirements through at least the end of 2018.

On January 9, 2017 Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) reported an update on its business performance, including preliminary financial results for 2016 and a financial outlook for 2017, and an update on its ongoing research and development programs (Filing, 8-K, Vertex Pharmaceuticals, JAN 9, 2017, View Source [SID1234517404]). Jeffrey Leiden, M.D., Ph.D., Chairman, President and Chief Executive Officer of Vertex, will discuss these updates as part of a webcast presentation at the 35th Annual J.P. Morgan Healthcare Conference in San Francisco on Monday, January 9 at 9:30 a.m. PT (12:30 p.m. ET). The presentation will be available on Vertex’s website, www.vrtx.com.
"In 2016, the number of people with cystic fibrosis treated with ORKAMBI and KALYDECO increased significantly and we advanced our broad pipeline of medicines in development for CF," said Dr. Leiden. "Entering 2017, we expect to continue to increase the number of people treated with our medicines and to generate important data from multiple medicines across our CF pipeline. Our progress has positioned us well to reach our long-term goal of treating all patients with CF with medicines that treat the underlying cause of the disease."

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2016 Financial Highlights and 2017 Financial Outlook

"We have seen total CF product revenues grow from $983 million in 2015 to $1.68 billion in 2016, and we anticipate revenue growth in 2017 and beyond," said Ian Smith, Executive Vice President, Chief Operating Officer and Chief Financial Officer. "A key driver of continued revenue growth in 2017 will be to treat more patients with ORKAMBI by completing multiple reimbursement agreements in Europe and treating children ages 6 to 11 in the U.S."

The company will announce its complete fourth quarter and full-year 2016 financial results on January 25, 2017 and today provided preliminary 2016 selected financial results, as summarized below:

Preliminary 2016 Selected Financial Results*

Fourth-Quarter 2016

Full-year
2016
ORKAMBI **

$276M

$979M
KALYDECO

$177M

$703M
TOTAL CF PRODUCT REVENUES

$453M

$1.68B

For the full year 2016, Vertex expects to report combined GAAP R&D and SG&A expenses of approximately $1.48 billion and non-GAAP R&D and SG&A expenses of approximately $1.21 billion.

* The above preliminary financial results are unaudited and are provided as approximations in advance of the company’s complete financial results announcement on January 25, 2017.
** 2016 ORKAMBI revenues do not include any revenues from France. In France, approximately 1,000 of the 1,500 eligible patients have initiated therapy as of the end of 2016. Approximately €70 million was collected through early access programs in France during 2016, and approximately €30 million of these funds was collected in the fourth quarter of 2016. Vertex expects that revenues from these early access programs will be recognized in the period that a formal reimbursement agreement in France is reached based on the terms of such agreement.

The company entered 2017 with approximately $1.43 billion in cash, cash equivalents and marketable securities. As of December 31, 2016, Vertex had $300 million outstanding from a credit agreement.

Vertex today provided full-year 2017 net product revenue guidance for KALYDECO and ORKAMBI, and guidance for combined non-GAAP R&D and SG&A expenses, as summarized below:

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•
KALYDECO: Vertex anticipates full-year 2017 global KALYDECO net product revenues of $690 to $710 million.

•
ORKAMBI: The company anticipates full-year 2017 ORKAMBI net product revenues of $1.1 to $1.3 billion. This range includes an estimate of potential additional European revenues in 2017 that is largely dependent on which European countries complete reimbursement agreements in 2017 and when these agreements become effective. The company expects first-quarter 2017 ORKAMBI net product revenues to be similar to fourth-quarter 2016 ORKAMBI net product revenues.

•
Combined Non-GAAP R&D and SG&A Expenses: Vertex expects that its combined non-GAAP R&D and SG&A expenses in 2017 will be in the range of $1.25 to $1.30 billion. The increase as compared to 2016 primarily reflects increased costs related to ongoing and planned CF development efforts and global commercial support for ORKAMBI and KALYDECO.

Approved Medicines for CF
ORKAMBI
Planned submission for approval to treat children ages 6 to 11 in the EU: On November 7, 2016, Vertex announced that a Phase 3 study evaluating ORKAMBI in children ages 6 through 11 who have two copies of the F508del mutation met its primary endpoint of absolute change in lung clearance index (LCI2.5) through 24 weeks of treatment. Based on these data, Vertex plans to submit a Marketing Authorization Application (MAA) line extension to the European Medicines Agency (EMA) in the first half of 2017 for approval of ORKAMBI in children ages 6 through 11. There are approximately 3,400 children ages 6 through 11 who have two copies of the F508del mutation in Europe.
Phase 3 study in children ages 2 to 5: Vertex is currently conducting a Phase 3 study of ORKAMBI in children ages 2 through 5 who have two copies of the F508del mutation. Enrollment of the study is expected to be complete in mid-2017.

KALYDECO
Phase 3 study in children under two years of age: Vertex is currently conducting a Phase 3 study evaluating the safety of KALYDECO in children under 2 years of age. The study is enrolling infants with one of the 10 mutations for which KALYDECO is currently approved and will evaluate the effect

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of KALYDECO on markers of CF in young children. The study will utilize a weight-based dose of KALYDECO granules that can be mixed in soft foods or liquids.

Medicines in Development for CF
Tezacaftor (VX-661)
In the first half of 2017, Vertex expects to obtain data from Phase 3 studies of tezacaftor to support the planned submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) in the second half of 2017 for tezacaftor in combination with ivacaftor. The Phase 3 studies include:
Two Copies of the F508del Mutation: Enrollment is complete in a study evaluating 24 weeks of treatment with tezacaftor in combination with ivacaftor in approximately 500 people with CF who have two copies of the F508del mutation.
One Copy of the F508del Mutation and a Second Mutation that Results in Residual CFTR Function: Enrollment is complete in a study evaluating tezacaftor in combination with ivacaftor in approximately 200 people with residual function mutations. This crossover study includes two 8-week dosing periods, separated by an 8-week washout period. The study includes an arm of ivacaftor monotherapy, in addition to an arm evaluating tezacaftor in combination with ivacaftor and a placebo arm.
One Copy of the F508del Mutation and One Copy of a Mutation that Results in Minimal CFTR Protein Function: The planned NDA submission will include safety data from a Phase 3 study of tezacaftor and ivacaftor in people with one copy of the F508del mutation and one copy of a mutation that results in minimal CFTR protein function. As previously announced, this study was discontinued in mid-2016 based on a planned interim futility analysis that showed the combination of tezacaftor and ivacaftor did not result in a pre-specified improvement in lung function.
One Copy of the F508del Mutation and a Second Mutation that Results in a Gating Defect in the CFTR Protein: In the first half of 2017, Vertex expects to complete enrollment in a study evaluating tezacaftor in combination with ivacaftor in people with one copy of the F508del mutation and a second mutation that results in a gating defect in the CFTR protein that has been shown to be responsive to ivacaftor alone. The study is evaluating 8 weeks of treatment with tezacaftor in combination with ivacaftor. Data from this study are not expected to be part of the initial regulatory submissions planned for tezacaftor/ivacaftor.

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Phase 3 study in children ages 6 to 11: Vertex is currently conducting a Phase 3 open-label study evaluating the safety and tolerability of tezacaftor in combination with ivacaftor in children ages 6 through 11 with two copies of the F508del mutation, and in children ages 6 through 11 with one copy of the F508del mutation and one copy of a mutation that has been clinically demonstrated to be ivacaftor responsive, including gating and residual function mutations.

Next-Generation Correctors
Vertex expects to have four different triple-combination regimens in Phase 1 or 2 clinical development during the first quarter of 2017. Clinical data in CF patients for three of these regimens are expected in the second half of 2017.
Dosing is underway in two Phase 2 studies evaluating the next-generation correctors VX-440 and VX-152 in triple combination regimens with tezacaftor and ivacaftor in people with CF. The Phase 2 study of VX-440 is designed to evaluate the safety and efficacy of 4-week dosing of VX-440 in combination with tezacaftor and ivacaftor in approximately 40 people with CF who have one F508del mutation and one minimal function mutation and approximately 25 people with two copies of the F508del mutation. The Phase 2 study of VX-152 will evaluate 2 weeks of triple combination dosing in approximately 35 people with CF who have one F508del mutation and one minimal function mutation and approximately 25 people with two copies of the F508del mutation. Both VX-440 and VX-152 have received Fast Track designation from the FDA.
The first data from these studies are expected in the second half of 2017. These data are intended to support the initiation of Phase 3 development for VX-440 and of a longer-duration Phase 2b or registrational program for VX-152.
As part of the company’s strategy to develop multiple next-generation correctors, Vertex is also developing the additional next-generation correctors VX-659 and VX-445. Dosing is now underway for a Phase 1 study of VX-659 in healthy volunteers, and dosing in CF patients is planned in the first half of 2017. The Phase 1 study of VX-659 will evaluate single ascending doses, multiple ascending doses and triple combination dosing in healthy volunteers, and includes an arm to evaluate triple combination dosing in CF patients who have one F508del mutation and one minimal function mutation. Dosing of a fourth next generation corrector, VX-445, is expected to begin in the first quarter of 2017. Pending data from both Phase 1 studies, Vertex plans to begin Phase 2 development for one or both of these next-generation correctors in the second half of 2017.

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VX-371 (ENaC inhibitor)
Phase 2 study of VX-371 in combination with ORKAMBI ongoing: Enrollment is ongoing in a study evaluating VX-371 in combination with ORKAMBI, both with and without the addition of hypertonic saline, in patients with CF ages 12 and older who have two copies of the F508del mutation. The primary endpoints of this study are safety and mean absolute change from baseline in FEV1 at day 28 compared to placebo. Data are expected in the second half of 2017.

Ongoing Research and Development Programs in Other Diseases

In addition to clinical development programs focused on CF, Vertex has ongoing development programs for potential medicines aimed at other serious and life-threatening diseases, including VX-371 for the treatment of primary ciliary dyskinesia (PCD), VX-210 for the treatment of acute cervical spinal cord injury and VX-150 for the treatment of pain. Additionally, Vertex is evaluating three compounds designed to inhibit DNA repair pathways that are fundamental to the survival and proliferation of certain cancers, including the lead compound, VX-970, an ATR inhibitor being evaluated in 10 ongoing Phase 1 and 2 studies, VX-803, a second ATR inhibitor, and VX-984, an inhibitor of DNA-dependent protein kinase that also targets the DNA damage repair system.

Non-GAAP Financial Measures

In this press release, Vertex’s financial results and financial guidance are provided in accordance with accounting principles generally accepted in the United States (GAAP) and using certain non-GAAP financial measures. In particular, the combined non-GAAP R&D and SG&A expenses and guidance exclude stock-based compensation expense, expenses related to variable interest entities and certain payments related to business development activities included in research expenses. This information is provided as a complement to results provided in accordance with GAAP because management believes these non-GAAP financial measures help indicate underlying trends in the company’s business, are important in comparing current results with prior period results and provide additional information regarding the company’s financial position. Management also uses these non-GAAP financial measures to establish budgets and operational goals that are communicated internally and externally and to manage the company’s business and to evaluate its performance. The company is not providing guidance regarding 2017 GAAP R&D and SG&A expenses

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because of the difficulty of estimating stock-based compensation expenses, costs associated with variable interest entities and predicting whether or not there will be additional expense items for which adjustments are appropriate, including for example adjustments with respect to business development activities. A reconciliation of the 2016 GAAP financial results to 2016 non-GAAP financial results is included below:

Preliminary Reconciliation of Non-GAAP Information

Twelve Months Ended
December 31, 2016
Combined GAAP R&D and SG&A expenses
$1.48B
Adjustments*
($0.27B)
Combined non-GAAP R&D and SG&A expenses*
$1.21B

* Adjustments include stock-based compensation expense, expenses related to variable interest entities and certain payments related to business development activities included in research expenses, and other adjustments.

INDICATION AND IMPORTANT SAFETY INFORMATION FOR KALYDECO (ivacaftor)

KALYDECO (ivacaftor) is a prescription medicine used for the treatment of cystic fibrosis (CF) in patients age 2 years and older who have one of the following mutations in their CF gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, or R117H. KALYDECO is not for use in people with CF due to other mutations in the CF gene. KALYDECO is not effective in patients with CF with two copies of the F508del mutation (F508del/F508del) in the CF gene. It is not known if KALYDECO is safe and effective in children under 2 years of age.

Patients should not take KALYDECO if they are taking certain medicines or herbal supplements such as: the antibiotics rifampin or rifabutin; seizure medications such as phenobarbital, carbamazepine, or phenytoin; or St. John’s wort.

Before taking KALYDECO, patients should tell their doctor if they: have liver or kidney problems; drink grapefruit juice, or eat grapefruit or Seville oranges; are pregnant or plan to become pregnant because it is not known if KALYDECO will harm an unborn baby; and are breastfeeding or planning to breastfeed because is not known if KALYDECO passes into breast milk.

Vertex Pharmaceuticals Incorporated

KALYDECO may affect the way other medicines work, and other medicines may affect how KALYDECO works. Therefore the dose of KALYDECO may need to be adjusted when taken with certain medications. Patients should especially tell their doctor if they take antifungal medications such as ketoconazole, itraconazole, posaconazole, voriconazole, or fluconazole; or antibiotics such as telithromycin, clarithromycin, or erythromycin.

KALYDECO can cause dizziness in some people who take it. Patients should not drive a car, use
machinery, or do anything that needs them to be alert until they know how KALYDECO affects them.
Patients should avoid food containing grapefruit or Seville oranges while taking KALYDECO.

KALYDECO can cause serious side effects including:

High liver enzymes in the blood have been reported in patients receiving KALYDECO. The patient’s doctor will do blood tests to check their liver before starting KALYDECO, every 3 months during the first year of taking KALYDECO, and every year while taking KALYDECO. For patients who have had high liver enzymes in the past, the doctor may do blood tests to check the liver more often. Patients should call their doctor right away if they have any of the following symptoms of liver problems: pain or discomfort in the upper right stomach (abdominal) area; yellowing of their skin or the white part of their eyes; loss of appetite; nausea or vomiting; or dark, amber-colored urine.

Abnormality of the eye lens (cataract) has been noted in some children and adolescents receiving
KALYDECO. The patient’s doctor should perform eye examinations prior to and during treatment with KALYDECO to look for cataracts. The most common side effects include headache; upper respiratory tract infection (common cold), which includes sore throat, nasal or sinus congestion, and runny nose; stomach (abdominal) pain; diarrhea; rash; nausea; and dizziness.

These are not all the possible side effects of KALYDECO.

Please click here to see the full Prescribing Information for KALYDECO (ivacaftor).

Vertex Pharmaceuticals Incorporated

INDICATION AND IMPORTANT SAFETY INFORMATION FOR ORKAMBI (lumacaftor/ivacaftor) TABLETS

ORKAMBI is a prescription medicine used for the treatment of cystic fibrosis (CF) in patients age 6 years and older who have two copies of the F508del mutation (F508del/F508del) in their CFTR gene. ORKAMBI should only be used in these patients. It is not known if ORKAMBI is safe and effective in children under 6 years of age.

Patients should not take ORKAMBI if they are taking certain medicines or herbal supplements, such as: the antibiotics rifampin or rifabutin; the seizure medicines phenobarbital, carbamazepine, or phenytoin; the sedatives/anti-anxiety medicines triazolam or midazolam; the immunosuppressant medicines everolimus, sirolimus, or tacrolimus; or St. John’s wort.

Before taking ORKAMBI, patients should tell their doctor if they: have or have had liver problems; have kidney problems; have had an organ transplant; are using birth control (hormonal contraceptives, including oral, injectable, transdermal or implantable forms). Hormonal contraceptives should not be used as a method of birth control when taking ORKAMBI. Patients should tell their doctor if they are pregnant or plan to become pregnant (it is unknown if ORKAMBI will harm the unborn baby) or if they are breastfeeding or planning to breastfeed (it is unknown if ORKAMBI passes into breast milk).

ORKAMBI may affect the way other medicines work and other medicines may affect how ORKAMBI works. Therefore, the dose of ORKAMBI or other medicines may need to be adjusted when taken together. Patients should especially tell their doctor if they take: antifungal medicines such as ketoconazole, itraconazole, posaconazole, or voriconazole; or antibiotics such as telithromycin, clarithromycin, or erythromycin.

When taking ORKAMBI, patients should tell their doctor if they stop ORKAMBI for more than 1 week as the doctor may need to change the dose of ORKAMBI or other medicines the patient is taking. It is unknown if ORKAMBI causes dizziness. Patients should not drive a car, use machinery, or do anything requiring alertness until the patient knows how ORKAMBI affects them.

ORKAMBI can cause serious side effects including:

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High liver enzymes in the blood, which can be a sign of liver injury, have been reported in patients receiving ORKAMBI. The patient’s doctor will do blood tests to check their liver before they start ORKAMBI, every three months during the first year of taking ORKAMBI, and annually thereafter. The patient should call the doctor right away if they have any of the following symptoms of liver problems: pain or discomfort in the upper right stomach (abdominal) area; yellowing of the skin or the white part of the eyes; loss of appetite; nausea or vomiting; dark, amber-colored urine; or confusion.

Respiratory events such as shortness of breath or chest tightness were observed in patients when starting ORKAMBI. If a patient has poor lung function, their doctor may monitor them more closely when starting ORKAMBI.

An increase in blood pressure has been seen in some patients treated with ORKAMBI. The patient’s doctor should monitor their blood pressure during treatment with ORKAMBI.

Abnormality of the eye lens (cataract) has been noted in some children and adolescents receiving ORKAMBI and ivacaftor, a component of ORKAMBI. For children and adolescents, the patient’s doctor should perform eye examinations prior to and during treatment with ORKAMBI to look for cataracts.

The most common side effects of ORKAMBI include: shortness of breath and/or chest tightness; upper respiratory tract infection (common cold), including sore throat, stuffy or runny nose; gastrointestinal symptoms including nausea, diarrhea, or gas; rash; fatigue; flu or flu-like symptoms; increase in muscle enzyme levels; and irregular, missed, or abnormal menstrual periods and heavier bleeding.

Please click here to see the full Prescribing Information for ORKAMBI.

On January 9, 2017 RXi Pharmaceuticals Corporation (NASDAQ: RXII), a clinical-stage RNAi company developing innovative therapeutics that address significant unmet medical needs, reported the closing of its acquisition of all of the outstanding capital stock of MirImmune Inc., a privately-held company focused on the development of next generation immunotherapies for the treatment of cancer, pursuant to that previously disclosed exclusive option agreement (Press release, RXi Pharmaceuticals, JAN 9, 2017, View Source [SID1234517343]).

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Under the terms of the stock purchase agreement, MirImmune shareholders will initially receive a total of approximately 2.75 million shares of the Company’s common stock and an additional 1.1 million shares of Series C Preferred Stock, which is convertible 1:1 into common stock, subject to receipt of stockholder approval. MirImmune’s shareholders will also be entitled to potential additional consideration contingent upon the achievement of certain milestones set forth in the stock purchase agreement.

To date, MirImmune’s data using RXi’s propriety self-delivering RNAi (sd-rxRNA) platform have demonstrated the unique applicability of sd-rxRNA for immune checkpoint modulation in cellular immuno-oncology therapies. The advantages of the sd-rxRNA technology include excellent transfection efficiency with little to no loss in cell viability and allows for the potential to silence multiple check points at once including both extracellular and intracellular targets.

"This is an exciting and promising start of 2017 for RXi Pharmaceuticals," said Dr. Geert Cauwenbergh, President and CEO of RXi Pharmaceuticals. He further added that, "The outstanding work done by MirImmune using RXi’s proprietary self-delivering RNAi technology has clearly established the unique competitive advantages of the sd-rxRNA platform for cell therapy and immuno-oncology. We anticipate that evaluating our RNAi platform in the immuno-oncology space will open up novel and better therapeutic approaches for treatment of some of the more difficult to treat cancers, including hematological malignancies as well as solid tumors. Finally, the addition of this immuno-oncology program strengthens and diversifies RXi’s existing clinical pipeline providing significant value to our shareholders."

To lead the Company in this effort, Alexey Eliseev, PhD has been appointed as RXi’s Chief Business Officer. In this new role, Dr. Eliseev will spearhead the business development initiatives for the Company’s immunotherapy program. Dr. Eliseev is a highly accomplished leader with over 20 years of experience in academia, biotechnology industry and venture capital and most recently was the founder and CEO of MirImmune Inc. He also co-founded Therascope, later Alantos Pharmaceuticals, with a number of prominent founders including French Nobel Laureate Jean-Marie Lehn, where he later became CTO of the company and President of its US division. Alantos was acquired by Amgen in 2007. Dr. Eliseev was also among the founders of AC Immune (Switzerland) and Boston BioCom LLC. Over recent years, he has worked with Maxwell Biotech Venture Fund as its Managing Director and ran the investment activity of the fund in the United States. Dr. Eliseev earned his PhD in Bioorganic Chemistry from Moscow State University and MBA from the MIT Sloan School of Management. Following postdoctoral research in Germany and in the US, he joined the faculty at SUNY Buffalo in 1995 where he was awarded tenure in 2000.

Dr. Eliseev said, "I look forward to joining the team at RXi and applying its unique self-delivering RNAi platform to the development of cell-based cancer immunotherapies." James D. Griffin, MD, Chairman, Department of Medical Oncology, Dana-Farber Cancer Institute further added that, "The formation of one entity through the merger of RXi Pharmaceuticals and MirImmune Inc. is exciting news for the immuno-oncology and cell therapy space."

About RXi’s Proprietary Self-delivering RNAi (sd-rxRNA) Technology Platform

RXi’s proprietary sd-rxRNA technology has many advantages over its competitors in the RNAi space. Scientists at RXi have designed chemically-modified RNAi compounds with improved drug-like properties that are potent, stable and specific. These proprietary compounds have built-in delivery properties and therefore do not require a delivery vehicle for local therapeutic applications. The enhanced properties of sd-rxRNA include: efficient spontaneous cellular uptake, stability, reduced potential for immune stimulation, and potent, long-lasting intracellular activity. All cell types tested (primary, neuronal and non-adherent) internalize sd-rxRNA compounds uniformly and efficiently, resulting in potent and long lasting silencing. sd‑rxRNA compounds have the ability to selectively block the expression of any target in the genome providing applicability to a broad spectrum of therapeutic areas.

On January 9, 2017 Celgene Corporation (NASDAQ: CELG) reported a business update as well as its preliminary 2016 unaudited results and financial guidance for 2017 at the 35 th Annual J.P. Morgan Healthcare Conference (Press release, Celgene, JAN 9, 2017, View Source [SID1234517385]). In 2017, total revenue is expected to be approximately $13.0 billion to $13.4 billion, an 18 percent increase year-over-year, based on the mid-point of the range. The negative impact of foreign exchange on total revenue is expected to be approximately $170 million in 2017. For the full-year 2017, REVLIMID net sales are expected to be in the range of $8.0 billion to $8.3 billion.

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Based on U.S. Generally Accepted Accounting Principles (GAAP), diluted earnings per share (EPS) for the full-year 2017 is expected to be in the range of $5.85 to $6.21, excluding the impact of any strategic transactions, impairments and loss contingencies that have not yet occurred. For the full-year 2017, adjusted diluted EPS is expected to be in the range of $7.10 to $7.25, a 21 percent increase year-overyear, based on the mid-point of the range.

"In 2016, we made exceptional progress strengthening and growing our franchises while accelerating and adding to our robust pipeline; our significant business momentum supports raising our 2017 guidance," said Mark J. Alles, Chief Executive Officer of Celgene. "We are entering a pivotal two-year period with multiple catalysts increasing our confidence in our ability to achieve or exceed our 2020 targets and sustain our growth from 2020 to 2030."

Preliminary 2016 Financial Results Year-Over-Year (Unaudited)
Total net product sales are expected to be approximately $11,187 million, up 22 percent year-overyear.
REVLIMID: $6,976 million, 20 percent year-over-year increase
POMALYST/IMNOVID: $1,311 million, 33 percent year-over-year increase
OTEZLA: $1,017 million, 116 percent year-over-year increase
ABRAXANE: $973 million, 1 percent year-over-year increase 2

GAAP operating margin is expected to be approximately 28 percent, an increase from 24 percent in the prior year, primarily due to increased product sales. Full-year 2016 GAAP diluted EPS is expected to be in the range of $2.43 to $2.51, a 27 percent year-over-year increase.

Adjusted operating margin is expected to be approximately 55 percent for the full year, an increase of 290 basis points (bps) year-over-year. Adjusted diluted EPS is expected to be approximately $5.94, a 26 percent year-over-year increase.
Certain activities involved in determining the audited results for the fiscal year ended December 31, 2016 are in-process and could result in the final reported audited results being different from the unaudited results noted in this press release. Additionally, please see the attached Use of Non-GAAP Financial Measures and Reconciliation of Estimated/Projected GAAP to Adjusted (Non-GAAP) Measures for further information relevant to the interpretation of adjusted financial measures and reconciliations of these adjusted financial measures to the most comparable GAAP measures, respectively, for each of 2016 and 2017.
Celgene Expects Strong Product Sales and Earnings Growth in 2017 Year-over-Year Change* Total Revenue Approximately $13.0B to $13.4B 18% REVLIMID Net Sales Approximately $8.0B to $8.3B 17% POMALYST/ IMNOVID Net Sales Approximately $1.6B 22% OTEZLA Net Sales Approximately $1.5B to $1.7B 57% ABRAXANE Net Sales Approximately $1.0B 3% GAAP diluted EPS $5.85 to $6.21 N/M** Adjusted diluted EPS $7.10 to $7.25 21% GAAP operating margin Approximately 45.5% N/M** Adjusted operating margin 56.4% +150bps Weighted average diluted shares ~815M +12M
*Year-over-year percentage change based on mid-point in range.
**Not meaningful as the 2017 measures exclude the impact of any strategic transactions, impairments and loss contingencies that have not yet occurred.

Reaffirming Expected 2020 Long-term financial Targets
2020 Total Revenue to exceed $21 billion
Adjusted Diluted EPS to exceed $13.00

2017 Expected Operational Milestones
Hematology/Oncology
Regulatory Submissions/Decisions
Decision by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) 3 on REVLIMID as maintenance treatment for patients with multiple myeloma following autologous stem cell transplant
Submission of a supplemental New Drug Authorization (sNDA) to the U.S. FDA for REVLIMID in combination with bortezomib and dexamethasone (RVd) in patients with newly diagnosed multiple myeloma (NDMM)
Approval by the U.S. FDA for enasidenib (AG-221) for the treatment of patients with relapsed and/or refractory acute myeloid leukemia (AML) with isocitrate dehydrogenase-2 (IDH2) mutation

Clinical Data
Data from the phase III RELEVANCE trial with REVLIMID in combination with rituximab in patients with newly diagnosed follicular lymphoma (FL)
Data from the phase III AUGMENT trial with REVLIMID in combination with rituximab in patients with relapsed and/or refractory FL
Data from the phase III apact (PANC-003) trial with ABRAXANE as adjuvant therapy in patients with surgically resected pancreatic cancer
Data from the phase IV abound.70+ trial with ABRAXANE in combination with carboplatin as a first-line treatment in patients with advanced non-small cell lung cancer (NSCLC)
Data from the phase II abound.PS2 trial with ABRAXANE in combination with carboplatin as a first-line treatment in patients with advanced NSCLC and an Eastern Cooperative Group (ECOG) performance status of 2 (PS2)
Data from the phase II abound.2L+ trial with ABRAXANE alone or in combination with CC-486 or durvalumab as a second or third-line treatment in patients with advanced non-small cell lung cancer
Data from the phase II trial with CC-486 in combination with fulvestrant in patients with ER+, HER2 breast cancer
Data from phase I/II trials with CC-122 and CC-220 in patients with relapsed and/or refractory multiple myeloma
Data from the phase I/II FUSION trial evaluating durvalumab as a single agent or in combination with novel agents in patients with relapsed and/or refractory multiple myeloma (RRMM), myelodysplastic syndromes and AML in collaboration with AstraZeneca, plc.
Data from the phase II YOSEMITE trial with demcizumab in combination with ABRAXANE in patients with first-line metastatic pancreatic cancer in collaboration with OncoMed Pharmaceuticals, Inc.
Data from the phase II DENALI trial with demcizumab in patients with first-line advanced stage NSCLC in collaboration with OncoMed Pharmaceuticals, Inc.
Trial Enrollment
Complete enrollment in the phase III OPTIMISMM trial with POMALYST/IMNOVID in second-line RRMM
Complete enrollment in the phase III ROBUST trial with REVLIMID in newly diagnosed diffuse large B-cell lymphoma (DLBCL)
Complete enrollment in the phase III QUAZAR trial with CC-486 in post-induction AML maintenance
Complete enrollment in the phase III MEDALIST trial with luspatercept in patients with low and INT-1 myelodysplastic syndrome with ring sideroblasts who require red blood cell (RBC) transfusions
Complete enrollment in the phase III BELIEVE trial with luspatercept in patients with beta- 4 thalassemia who have regular RBC transfusions
Trial Initiations
Initiate enrollment in a phase III trial with CC-122 in relapsed and/or refractory non-Hodgkin lymphoma (NHL)
Initiate enrollment in a pivotal program with marizomib in glioblastoma
Initiate enrollment in a phase II trial with luspatercept in myelofibrosis in collaboration with Acceleron Pharma, Inc.
Initiate enrollment in a phase II trial with bb2121, a B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy, in RRMM in collaboration with bluebird bio, Inc.
Initiate enrollment in a pivotal program with JCAR017 in relapsed and/or refractory non-Hodgkin lymphoma in collaboration with Juno Therapeutics, Inc.

Inflammation and Immunology (I&I)
Regulatory Submissions/Decisions
Submission of an sNDA for OTEZLA once-daily formulation
Submission of an NDA for ozanimod in patients with multiple sclerosis

Clinical Data
Data from the phase III SUNBEAM and RADIANCE trials with ozanimod in multiple sclerosis
Data from the phase II STEPSTONE trial with ozanimod in Crohn’s disease
Data from a phase II trial with GED-0301 in ulcerative colitis
Data from a phase II trial with OTEZLA in ulcerative colitis

Trial Enrollment
Complete enrollment in the phase III TRUE NORTH trial with ozanimod in ulcerative colitis
Complete enrollment in the phase III REVOLVE trial (CD-002) with GED-0301 in Crohn’s disease
Complete enrollment in the phase III RELIEF trial with OTEZLA in Behçet’s disease
Complete enrollment in a phase II trial (UC-001) with OTEZLA in ulcerative colitis
Complete enrollment in a pediatric phase II trial (PPSO-001) with OTEZLA in psoriasis

Trial Initiations
Initiate enrollment in a phase III trial with RPC-4046 in eosinophilic esophagitis Initiate enrollment in a phase III trial with OTEZLA in scalp psoriasis
Initiate enrollment in a phase III trial with OTEZLA in ankylosing spondylitis
Initiate enrollment in a phase IIb trial with CC-220 in systemic lupus erythematosus
Initiate enrollment in a phase IIa trial with CC-90001 in idiopathic pulmonary fibrosis

Research and Early Development
File at least 8 Investigational New Drug (IND) or Clinical Trial Applications (CTA)
Submission of an IND for a new CELMoD compound in patients with multiple myeloma
Submission of an IND for EM901, a T-cell bi-specific antibody targeting BCMA in patients with multiple myeloma