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 Takeda Pharmaceutical Company Limited (TSE:4502) ("Takeda") and ARIAD Pharmaceuticals, Inc. (NASDAQ:ARIA) ("ARIAD") reported that they have entered into a definitive agreement under which Takeda will acquire all of the outstanding shares in ARIAD for $24.00 per share in cash, or an enterprise value of approximately $5.2 billion (Press release, Ariad, JAN 9, 2017, View Source;p=RssLanding&cat=news&id=2234958 [SID1234517324]). The transaction has been approved unanimously by the boards of directors of both companies, and is expected to close by the end of February 2017, subject to required regulatory approvals and other customary closing conditions. Sarissa Capital, the holder of 6.6% of ARIAD’s common shares, as well as each of the members of ARIAD’s Board of Directors have agreed to tender their shares to Takeda pursuant to the offer.

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"The acquisition of ARIAD is a unique opportunity that will enable us to positively impact the lives of more patients worldwide, advance our strategic priorities and generate attractive returns for our shareholders," said Christophe Weber, president and chief executive officer of Takeda. "This is a very exciting time for Takeda as we will broaden our hematology portfolio and transform our global solid tumor franchise through the addition of two innovative targeted therapies. Opportunities to acquire such high-quality, complementary targeted therapies do not come often, and we are very excited about the potential for this transaction to benefit patients, our shareholders and other stakeholders."

Paris Panayiotopoulos, president and chief executive officer of ARIAD, said, "We are very pleased to combine with Takeda, which will allow us to not only accelerate our mission to discover, develop and deliver precision therapies to patients with rare cancers, but also deliver immediate and meaningful value to our shareholders through a substantial cash premium. This exciting transaction is a testament to the hard work and dedication of ARIAD’s talented team of employees. We have tremendous respect for Takeda, and I believe our shared commitment to innovation and research-driven cultures will provide for a smooth transition."

"This transaction is a great outcome for shareholders of ARIAD and Takeda. Both ARIAD and Takeda are passionate about helping cancer patients, and I believe the talent and resources of Takeda coupled with ARIAD’s pipeline and people will accelerate the development of cancer treatments. I would like to extend my deepest gratitude to the management team and everyone at ARIAD for their unrelenting dedication," said Alexander J. Denner, Ph.D., Chairman of the Board of ARIAD.

Highly strategic deal which transforms global oncology portfolio and pipeline by expanding into solid tumors and reinforcing existing strength in hematology

The acquisition of ARIAD brings two innovative targeted therapies that will expand and enhance Takeda’s existing oncology portfolio. Brigatinib, an investigational drug product, has the potential to add a differentiated, global therapy in a genetically-defined subpopulation of non-small cell lung cancer (NSCLC). The addition of Iclusig will broaden Takeda’s strong hematology franchise to include chronic myeloid leukemia (CML) and a subset of acute lymphoblastic leukemia (ALL). Together, these two innovative targeted therapies will position Takeda for sustainable long-term growth in oncology.

Takeda’s track record of successful oncology product launches [ADCETRIS (Brentuximab Vedotin), NINLAROTM (ixazomib) and VELCADE (bortezomib)] means it has the experience and expertise required to deliver the successful launch of brigatinib and to ensure that it achieves global reach and share of voice thereafter.

Accretive to Takeda’s Underlying Core Earnings by FY2018 and generates immediate and long-term revenue growth

The transaction is a compelling opportunity for Takeda shareholders. It will provide immediate revenue, bring considerable long-term revenue potential and deliver synergy savings.

ARIAD provided calendar year 2016 revenue guidance for Iclusig of $170-180 million, and Takeda expects significant long-term revenue potential from the two lead assets.

Takeda projects the acquisition of ARIAD to be accretive to Underlying Core Earnings by FY2018 and broadly neutral in FY2017. Strong revenue growth and synergy savings will offset increased sales and marketing costs for the brigatinib launch.

Attractive value drivers include two very innovative medicines, Iclusig and brigatinib, an exciting early stage pipeline and cost synergies

Iclusig, a commercialized therapy with continued strong sales growth potential, delivers immediate value. Brigatinib, an investigational drug product with peak annual sales potential of over $1 billion, will generate significant long-term value for Takeda. U.S. approval is expected in the first half of 2017 with global filing thereafter. Beyond Iclusig and brigatinib, ARIAD’s commitment and expertise in targeted kinase inhibition linked to strong translational science generated further pipeline opportunities which provide additional long-term upside potential.

Takeda will leverage ARIAD’s R&D capabilities and platform, and largely absorb its R&D costs within Takeda’s existing R&D budget. G&A cost synergies will be fully captured by FY2018.

Takeda retains financial flexibility with no impact on dividend policy

The transaction will be funded by up to $4.0 billion of new debt and the remainder from existing cash. FY2017 Net Debt/EBITDA is estimated at approximately 2.6x, which is expected to remain investment grade. The transaction has no impact on Takeda’s dividend policy.

Transaction terms

The acquisition is structured as an all cash tender offer by a subsidiary of Takeda for all of the outstanding shares of ARIAD common stock, followed by a merger in which remaining shares of ARIAD would be converted into the right to receive the same $24.00 cash per share price paid in the tender offer and ARIAD will become an indirect wholly owned subsidiary of Takeda.

The transaction is subject to the tender of a majority of the outstanding shares of ARIAD common stock as well as other customary closing conditions, including expiration of the applicable waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976 and the antitrust laws of applicable foreign jurisdictions. The transaction is expected to close by the end of February 2017.

Takeda Pharmaceuticals U.S.A, a wholly owned subsidiary of Takeda, has established Kiku Merger Co., Inc. to effect the transaction.

(1) Tender offeror Kiku Merger Co., Inc.
(2) Target company ARIAD Pharmaceuticals, Inc.
(3) Class of shares to be acquired Common stock
(4) Tender offer price $24.00 per share
(5) Acquisition amount
(Aggregate tender offer price)
Approximately $5.4 billion (estimate)
* The amount is an estimated amount calculated by multiplying the number of the target company’s shares (fully diluted basis) by the tender offer price per share. It does not include advisory fees.
(6) Payment Cash
* Funded by up to $4.0 billion of new debt and the remainder from existing cash.
(7) Period of tender offer From January, 2017 to February, 2017
** The initial period of the tender offer will commence within 10 business days following execution of the merger agreement with ARIAD [January 8, 2017 (U.S.)], and will close 20 business days after commencement. If the situation arises whereby the conditions of the tender offer are not satisfied, the period of the tender offer will be extended, but the extension period will not exceed May 2017 (or August 2017 if antitrust clearance not received).
(8) Minimum number of shares to be purchased Consummation of the tender offer will occur once the majority of shares outstanding of the company have been tendered and other customary closing conditions have been satisfied.
(9) Financial advisor to Takeda Evercore Partners
(10) Legal counsel to Takeda Cleary Gottlieb Steen & Hamilton LLP
(11) Financial advisor to ARIAD J.P. Morgan Securities LLC, Goldman, Sachs & Co., Lazard
(12) Legal counsel to ARIAD Paul, Weiss, Rifkind, Wharton & Garrison LLP

Overview of ARIAD

(1) Company name ARIAD Pharmaceuticals, Inc.
(2) Headquarters 125 Binney Street, Cambridge, Massachusetts 02142, USA
(3) Representative Paris Panayiotopoulos, President and Chief Executive Officer
(4) Business description ARIAD Pharmaceuticals, Inc., headquartered in Cambridge, Massachusetts is focused on discovering, developing and commercializing precision therapies for patients with rare cancers. ARIAD is working on new medicines to advance the treatment of rare forms of chronic and acute leukemia, lung cancer and other rare cancers. ARIAD utilizes computational and structural approaches to design small-molecule drugs that overcome resistance to existing cancer medicines.
(5) Capital US$1,339 million (Additional paid-in capital as of December 31, 2015)
(6) Date of establishment April, 1991
(7) Major shareholders
and percentage of
shares held*
Wellington Management Group LLP 8.8%
FMR LLC 7.8%
Vanguard Group Inc. 6.8%
Others
(8) Relationships between Takeda Capital relationship Not applicable
Personnel relationship Not applicable
Transactional relationship Not applicable
(9) Operating result and financial conditions for the last three years (consolidated)
Accounting period Fiscal year ended December 31, 2013 Fiscal year ended December 31, 2014 Fiscal year ended December 31, 2015
Net assets
(US$ in thousands)
185,517 80,801 (103,141)
Total assets
(US$ in thousands)
370,894 603,116 546,692
Net assets per share
(US$)
1.01 0.43 (0.55)
Revenue
(US$ in thousands)
45,561 105,412 118,804
Operating profit
(US$ in thousands)
(273,566) (160,195) (217,276)
Net loss
(US$ in thousands)
(274,158) (162,602) (231,156)
Net loss per share
(US$)
(1.49) (0.87) (1.23)

* As reported in the 13F filings. Percentage of shares is calculated by dividing the number of shareholdings (as of the end of September 2016) by the number of total shares outstanding of the target company.

Change in ownership before and after acquisition

(1) Number of shares already acquired 0 shares
Percentage of voting rights: 0%
(2) Number of shares to be acquired 194,389,661 shares*
Percentage of voting rights: 100% (planned)
* Total shares outstanding

Schedule

(1) Board meeting resolution January 6, 2017
(2) Signing date January 8, 2017
(3) Commencement date and settlement date of the tender offer From January, 2017 to February, 2017
**The initial period of the tender offer will commence within 10 business days following execution of the merger agreement with ARIAD [January 8, 2017 (U.S.)], and will close 20 business days after commencement. If the conditions of the tender offer are not satisfied, the period of the tender offer will be extended, but the extension period will not exceed May 2017 (or August 2017 if antitrust clearance not received).
(4) Completion of acquisition By the end of February, 2017 (planned)*
* Fulfillment of the terms and conditions of the U.S. Antitrust Law and the satisfaction of certain other customary conditions are required to complete the acquisition.

Outlook

FY2016

At this stage we expect minimal impact on Underlying Revenue and Underlying Core Earnings. We do expect to incur transition and integration expenses, however, these expenses are not material to the current year result. We will incorporate the financial impact in our FY2016 consolidated earnings forecast and announce at the third quarter earnings conference in February 2017.

FY2017 and beyond

It is expected that the acquisition of ARIAD will be accretive to Takeda’s Underlying Core Earnings by FY2018 and broadly neutral in FY2017. Strong revenue growth and synergy savings will offset increased sales and marketing costs for the brigatinib launch. Takeda’s financial guidance, including EPS, for FY2017 will be announced when Takeda reports earnings for FY2016 in May 2017.

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.