CANbridge Receives Hong Kong Department of Health Market Approval for NERLYNX®

On November 5, 2019 CANbridge Pharmaceuticals Inc., a biopharmaceutical company developing innovative drug candidates to treat underserved medical conditions in China and other markets, reported that it received market approval from the Department of Health in Hong Kong for NERLYNX (neratinib) for the extended adjuvant treatment of adult patients with early‑stage hormone receptor positive HER2-overexpressed/amplified breast cancer, and who completed adjuvant trastuzumab-based therapy less than one year ago (Press release, CANbridge Life Sciences, NOV 5, 2019, View Source [SID1234550317]). This is the first targeted therapy approved in the CANbridge oncology platform and the first NERLYNX approval in greater China. CANbridge acquired the exclusive NERLYNX development and commercial rights for China, Taiwan, Hong Kong and Macao in 2018, and submitted the NDA for NERLYNX to the National Medical Products Administration (NMPA) in China for the extended adjuvant treatment of adult patients with early-stage HER2-positive breast cancer following adjuvant trastuzumab-based therapy, last year.

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"The rapid and smooth advancement of NERLYNX through the Hong Kong regulatory process to market approval is a testament to the quality of our regulatory expertise, and the CANbridge commitment to bring new treatments to underserved patient populations in greater China," said James Xue, PhD, Founder, Chairman and CEO, CANbridge Pharmaceuticals. "With this first targeted therapy approved in our oncology platform, CANbridge is able to provide women in Hong Kong, with HER2-positive breast cancer at risk of recurrence, a new and vital treatment option shortly after it was approved in the West."

About HER2-Positive Breast Cancer

Approximately 20 to 25 percent of breast cancer tumors over-express the HER2 protein. HER2-positive breast cancer is often more aggressive than other types of breast cancer, increasing the risk of disease progression and death. Research has shown that trastuzumab treatment can reduce the risk of early-stage HER2-positive breast cancer returning after surgery. However, up to 25% of patients treated with trastuzumab experience recurrence. There were 4,391 reported new cases of all types of breast cancer in Hong Kong in 2017, according to a report released by the Hong Kong Registry, Hospital Authority. Of these, it is reasonable to assume that 20-25% could be HER2-positive.

About Neratinib

Neratinib is a potent irreversible tyrosine kinase inhibitor that inhibits tumor growth and metastasis through the blocking of the pan-HER family (HER1, HER2 and HER4) and downstream signal transduction. Neratinib was approved by the U.S. Food and Drug Administration (FDA) in July 2017 for the extended adjuvant treatment of adult patients with early-stage HER2-positive breast cancer following adjuvant trastuzumab-based therapy, and is marketed in the United States as NERLYNX (neratinib) tablets. Neratinib was also approved by the European Medical Agency (EMA) in September, 2018.

OPKO Health Reports 2019 Third Quarter Business Highlights and Financial Results

On November 5, 2019 OPKO Health, Inc. (NASDAQ: OPK) reported business highlights and financial results for the three months ended September 30, 2019 (Press release, Opko Health, NOV 5, 2019, View Source [SID1234550333]).

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Business Highlights

Somatrogon meets primary and key secondary endpoints in global Phase 3 trial: On October 21, OPKO and Pfizer announced that the global Phase 3 trial evaluating somatrogon dosed once weekly in pre-pubertal children with growth hormone deficiency met its primary endpoint of non-inferiority to GENOTROPIN (somatropin) injected daily, as measured by annual height velocity at 12 months. Key secondary endpoints including change in height standard deviation scores at six and 12 months, and change in height velocity at six months, were also higher in the somatrogon group.

RAYALDEE total prescriptions reported by IQVIA increased 83% in 3Q 2019 compared with 3Q 2018: Total prescriptions for the three months ended September 30, 2019 increased to approximately 14,600, compared with approximately 8,000 during the comparable period of 2018.

BioReference Laboratories continued to establish new alliances: During the third quarter BioReference Laboratories formed a strategic collaboration with SOMOS, New York City’s largest multicultural physician-led network, and was named the preferred provider for the IPA Association of America in laboratory services and, also, to assist with data analytics for member patients. These wins build upon successes earlier in the year, including selection as part of the preferred lab network with UnitedHealthcare and new in-network status with Humana.

JAMA Oncology published data from a GeneDx study addressing cancer risk estimates for gastric cancers in patients with gene variants of CDH1: Results indicated that the lifetime risk of gastric cancer for individuals with pathogenic variants in the CDH1 gene is significantly lower than previously described; the lifetime risk of gastric cancer associated with pathogenic CDH1 variants was 42% in men and 33% in women, compared to published estimates of 40-70% in men and 56-83% in women. These results allow for a more personalized risk assessment and better informed decision making for patients at risk for hereditary gastric cancer.

Pharmaceutical pipeline continues to advance:

The open-label Phase 2 trial for RAYALDEE in hemodialysis patients is progressing and initial data are expected in 1Q 2020.

The somatrogon registration study in Japanese pediatric GHD patients to assess pharmacokinetics and compare efficacy of weekly somatrogon to daily GENOTROPIN is on track for data readout in 2020.

Financial Highlights

Consolidated revenues for the third quarter of 2019 were $228.8 million, compared with $249.8 million for the comparable period of 2018. Revenue from services in the third quarter was $181.1 million, revenue from products was $26.2 million, including RAYALDEE net revenue of $7.4 million, and revenue from licensing and intellectual property was $21.5 million.

Operating expenses for the third quarter of 2019 were $267.8 million. This included R&D expenses of $30.0 million, principally for the completion of the pediatric Phase 3 study for our long-acting human growth hormone product and other ongoing clinical trials.

Accounting rules require marking strategic investments to market at the end of each quarter, which had a negative impact on the net loss for the third quarter of 2019 of $13.6 million, or $0.02 per share. The net loss for the third quarter of 2019, after giving effect to the decrease in market value of our strategic investments, was $62.0 million, or $0.11 per share, compared with a net loss of $27.7 million, or $0.05 per share, for the comparable period of 2018. The 2018 period’s net loss benefited from an $11.6 million income tax benefit primarily resulting from a change in state income tax rates during that period.

Cash, cash equivalents and marketable securities were $64.7 million as of September 30, 2019. Subsequent to the close of the third quarter, the Company raised gross proceeds of $75.0 million from an underwritten public offering of common stock.

CONFERENCE CALL & WEBCAST INFORMATION

OPKO’s senior management will provide a business update and discuss results in greater detail in a conference call and live audio webcast at 4:30 p.m. Eastern time today, Tuesday, November 5, 2019. The conference call dial-in and webcast information is as follows:
DOMESTIC DIAL-IN:

866-634-2258
INTERNATIONAL DIAL-IN:

330-863-3454
PASSCODE:

7270239
WEBCAST:

OPKO 3Q19 Results Conference Call
For those unable to participate in the live conference call or webcast, a replay will be available beginning approximately two hours after the close of the conference call. To access the replay, dial 855-859-2056 or 404-537-3406. The replay passcode is 7270239. The replay can be accessed for a period of time on OPKO’s website at OPKO 3Q19 Results Conference Call.

Xencor Reports Third Quarter 2019 Financial Results

On November 5, 2019 Xencor, Inc. (NASDAQ: XNCR), a clinical-stage biopharmaceutical company developing engineered monoclonal antibodies for the treatment of cancer, autoimmune diseases, asthma and allergic diseases, reported financial results for the third quarter ended September 30, 2019 and provided a review of recent business and clinical highlights (Press release, Xencor, NOV 5, 2019, View Source [SID1234550349]).

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"The plug-and-play nature of Xencor’s XmAb technology has enabled the development of a broad and diversified portfolio of therapeutic bispecific antibodies and cytokines, including six programs currently being evaluated in Phase 1 studies. Our strong financial position will support expanded clinical development plans for these programs, as well as research into a growing set of opportunities," said Bassil Dahiyat, Ph.D., president and chief executive officer at Xencor. "Our technology’s inherent portability also allows us to provide partners with selective access, and our partners’ near-term plans to initiate Phase 1 studies evaluating XmAb bispecifics represent continued validation of our bispecific platform and Fc engineering capabilities."

Recent Business and Clinical Highlights and Anticipated Upcoming Milestones

CD3 Bispecific Antibodies: Xencor’s initial bispecific antibody programs are tumor-targeted antibodies that contain both a tumor antigen binding domain and a cytotoxic T-cell binding domain (CD3). These bispecific antibodies activate T cells for highly potent and targeted killing of malignant cells.

XmAb14045 (CD123 x CD3): A Phase 1 study in patients with relapsed or refractory acute myeloid leukemia is enrolling patients into dose-escalation cohorts. The Company is planning to initiate additional clinical studies evaluating XmAb14045 in 2020.
XmAb13676 (CD20 x CD3): A Phase 1 study in patients with B-cell malignancies is enrolling patients into dose-escalation cohorts. Initial data from the study will be presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December 2019.
XmAb18087 (SSTR2 x CD3): A Phase 1 study in patients with neuroendocrine tumors or gastrointestinal stromal tumors is enrolling patients into dose-escalation cohorts, and initial data are expected in the first half of 2020.
Tumor Microenvironment (TME) Activating Bispecific Antibodies: Xencor’s bispecific pipeline includes a suite of TME activators that engage multiple, different targets, such as T-cell checkpoint or agonist receptors. Xencor’s TME activators are designed to promote tumor-selective T-cell activation.

XmAb20717 (PD-1 x CTLA-4): A Phase 1 study in patients with advanced solid tumors is enrolling patients into dose-escalation cohorts, and initial data are expected in the first half of 2020.
XmAb22841 (CTLA-4 x LAG-3): A Phase 1 study evaluating XmAb22841 as a monotherapy and in combination with pembrolizumab in patients with select advanced solid tumors is enrolling patients into dose-escalation cohorts.
XmAb23104 (PD-1 x ICOS): A Phase 1 study in patients with select advanced solid tumors is enrolling patients into dose-escalation cohorts.
Cytokines: Xencor engineers cytokines to tune their potency and applies its bispecific Fc domain and Xtend technology for improved therapeutic index and longer half-life. Cytokines are immune signaling proteins that can be used to enhance immune responses against tumors.

XmAb24306 (IL15/IL15Rα-Fc fusion protein): The Company is supporting Genentech’s efforts to submit an investigational new drug (IND) application for this candidate, which is anticipated by the end of 2019.
Partnered XmAb Programs: Xencor has eight partnerships for its XmAb technology, which has resulted in one marketed product, four clinical-stage candidates and two candidates that have open INDs and are pending Phase 1 initiations.

The most advanced program using the Company’s licensed technology is Alexion’s Ultomiris, which uses the Xtend technology for longer half-life. Ultomiris has received marketing authorizations from regulatory agencies in the U.S., Europe and Japan for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH) and, in October 2019, also has received approval from the FDA for the treatment of patients with atypical hemolytic uremic syndrome (aHUS).
Investigational new drug (IND) applications have been allowed by the FDA for an undisclosed Novartis XmAb bispecific antibody and for Amgen’s AMG 509 (STEAP1 x CD3), an XmAb 2+1 bispecific antibody, which were developed in connection with the Company’s Novartis and Amgen collaborations, respectively. In the third quarter of 2019, the Company recognized milestone revenue of $10.0 million from Novartis and $5.0 million from Amgen.
Corporate: In September 2019, the Company appointed Celia Eckert as vice president, general counsel and corporate secretary. Ms. Eckert serves on the senior management team and is responsible for all legal matters, including transactions, corporate governance and employment law, as well as overseeing the Company’s intellectual property portfolio.

Ultomiris is a registered trademark of Alexion Pharmaceuticals, Inc.

Third Quarter Ended September 30, 2019 Financial Results

Cash, cash equivalents and marketable securities totaled $620.5 million as of September 30, 2019, compared to $530.5 million at December 31, 2018. The increase reflects upfront proceeds of $135 million received in 2019 from the Genentech and Astellas collaborations, offset by cash used to fund operating activities in the first nine months of 2019.

Total revenue for the third quarter ended September 30, 2019 was $21.8 million, which was primarily revenue recognized from milestones from the Company’s Novartis, Alexion and Amgen collaborations. Total revenue for the nine months ended September 30, 2019 was $153.2 million and includes revenue earned from the Genentech and Astellas collaborations and the milestone revenue recognized from the Company’s Novartis, Alexion and Amgen collaborations. Total revenue for the third quarter and nine months ended September 30, 2018 was $29.0 million and includes collaboration revenue earned from Novartis and milestone revenue earned from the Company’s Alexion collaboration.

Research and development expenses for the third quarter of 2019 were $29.8 million, compared to $21.0 million for the same period in 2018. Total research and development expenses for the nine months ended September 30, 2019 were $91.3 million, compared to $70.4 million for the same period in 2018. The increased research and development spending for the three and nine months ended September 30, 2019 reflects increased stock-based compensation expense and additional spending on Xencor’s CD3 bispecific antibody and cytokine development candidates and technologies.

General and administrative expenses for the third quarter of 2019 were $6.3 million, compared to $7.4 million for the same period in 2018. Total general and administrative expenses for the nine months ended September 30, 2019 were $17.5 million, compared to $17.0 million for the same period in 2018. The decreased general and administrative spending for the three months ended September 30, 2019 reflects decreased spending on expenses related to personnel. The increased spending for the nine months ended September 30, 2019 reflects additional spending on intellectual property including patents and licenses and expenses related to professional services.

Non-cash, stock-based compensation expense for the nine months ended September 30, 2019 was $24.7 million, compared to $15.5 million for the same period in 2018.

Net loss for the third quarter ended September 30, 2019 was $10.2 million, or $(0.18) on a fully diluted per share basis, compared to a net income of $3.2 million, or $0.05 on a fully diluted per share basis, for the same period in 2018. For the nine months ended September 30, 2019, net income was $53.8 million, or $0.92 on a fully diluted per share basis, compared to a net loss of $52.2 million, or $(0.98) on a fully diluted per share basis, for the same period in 2018. The net loss reported for the three months ended September 30, 2019 over the net income reported for the same period in 2018 is primarily due to lower collaboration revenue earned and higher research and development expenses. The net income reported for the nine months ended September 30, 2019 over the net loss reported for the same period in 2018 is primarily due to revenue recognized from the Genentech and Astellas collaborations and milestone revenue earned from the Novartis and Amgen collaborations.

The total shares outstanding were 56,714,788 as of September 30, 2019, compared to 56,212,449 as of September 30, 2018.

Financial Guidance

Based on current operating plans, Xencor expects to have cash to fund research and development programs and operations beyond 2024. Xencor expects to end 2019 with between $590 million and $625 million in cash, cash equivalents and marketable securities.

Conference Call and Webcast

Xencor will host a conference call today at 4:30 p.m. ET (1:30 p.m. PT) to discuss these third quarter 2019 financial results and provide a corporate update. The live call may be accessed by dialing (877) 359-9508 for domestic callers or (224) 357-2393 for international callers and referencing conference ID number 9415077. A live webcast of the conference call will be available under "Events & Presentations" in the Investors section of the Company’s website located at www.xencor.com. The webcast will be archived on the company website for 30 days.

Checkmate Pharmaceuticals Presents Positive Clinical Data with CMP-001 at The 34th Annual Meeting of The Society for Immunotherapy of Cancer (SITC)

On November 5, 2019 Checkmate Pharmaceuticals Inc. (Checkmate), a clinical stage biopharmaceutical company focused upon activation of innate immunity to treat cancer, reported the presentation of new data from two ongoing clinical trials evaluating CMP-001, Checkmate’s Toll-like receptor 9 (TLR9) agonist, in combination with the anti-PD-1 therapies pembrolizumab (KEYTRUDA) or nivolumab (OPDIVO), in patients with melanoma (Press release, Checkmate Pharmaceuticals, NOV 5, 2019, View Source [SID1234550365]).

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"CMP-001 is a differentiated TLR9 agonist that activates a tumor-specific T cell response. When combined with checkpoint inhibitors, CMP-001 can induce deep and durable systemic anti-tumor responses," said Dr. Art Krieg, Checkmate’s Founder and CSO. "These clinical data reaffirm the potential for CMP-001 to enhance responsiveness or overcome resistance to immune checkpoint inhibitors. We look forward to the next stages of development with this program, including evaluation in other cancers."

Durable responses in anti-PD-1 refractory melanoma following intra-tumoral injection of a Toll-like receptor 9 (TLR9) agonist, CMP-001, in combination with pembrolizumab (Abstract #: 11548/O87)

On Friday, November 8, 2019 at 12:15pm ET, Dr. John M. Kirkwood, Usher Professor of Medicine and Dermatology, University of Pittsburgh School of Medicine, and Co-Director, Melanoma and Skin Cancer Program, University of Pittsburgh Cancer Institute and UPMC Hillman Cancer Center, is presenting late-breaking data from a Checkmate-sponsored clinical trial of CMP-001, either in combination with pembrolizumab or as monotherapy (NCT02680184).

Updated data from the trial demonstrated that the combination of CMP-001 and pembrolizumab continued to be well tolerated, with an objective response rate (ORR) of 25% according to RECIST v1.1 criteria. The study treatment induced deep and durable systemic anti-tumor responses in patients with melanoma who previously progressed on anti-PD-1 treatments; with a current Kaplan Meier estimate of median duration of response of 16.9+ months for the 28 RECIST v1.1 responders.

"These current data suggest that CMP-001 might expand the patient population that benefits from anti-PD-1 therapies," said Dr. Kirkwood. "Most patients with cancer have non-inflamed tumor microenvironments that do not respond to checkpoint inhibitors. These trial data demonstrate that combining CMP-001 with pembrolizumab could induce an immune response against the cancer, forming a potentially effective treatment option for patients with advanced melanoma who are not responsive to anti-PD-1-based treatment regimens."

Data were presented on the intent to treat (ITT) population of 144 patients receiving combination therapy with CMP-001 and pembrolizumab. Two formulations of CMP-001 were evaluated, either 0.01% polysorbate 20 (PS20, N=83) or 0.00167% PS20 (N=61). The lower concentration of PS20 was found to be less effective. Data were also presented on 24 patients who received CMP-001 monotherapy.

Key highlights from these clinical data include:

CMP-001 in combination with pembrolizumab

The RECIST ORR in patients who received the 0.01% PS20 formulation was 25% (21/83; 95% confidence interval 16%-36%), including 6 complete responses and 15 partial responses.
Four additional patients who continued study therapy beyond initial disease progression achieved a partial or complete response.
The Kaplan Meier estimate for median duration of response is 16.9+ months [95% CI=5.8, not reached] in the 28 RECIST responders and 25.2+ months [95% CI=8.6, not reached] when including the additional 4 patients with post-progression responses. The median duration of response has not been reached.
Among responding patients, non-injected target lesions regressed by a similar magnitude to injected target lesions.
In the ITT population, the most common treatment-related adverse events were flu-like symptoms, including chills, fever, fatigue, nausea, vomiting and headache for patients receiving combination treatment. Six patients (4%) discontinued study therapy due to treatment-related adverse events.
CMP-001 monotherapy

Of the 24 patients treated with CMP-001 monotherapy, 5 patients achieved a partial response. Responses were less durable compared to those for patients receiving CMP-001 in combination with pembrolizumab.
Phase II Trial of neoadjuvant nivolumab (Nivo) and intra-tumoral (IT) CMP-001 in high risk resectable melanoma (MEL): Preliminary Results (Abstract #: 11648/O34)

On Saturday, November 9, 2019 at 6:15pm ET, Dr. Diwakar Davar, Assistant Professor of Medicine at the University of Pittsburgh School of Medicine, is presenting data from an investigator-sponsored trial evaluating neoadjuvant treatment with CMP-001 in combination with nivolumab in patients with Stage IIIB/C/D Melanoma (NCT03618641).

Preliminary data from the trial show that neoadjuvant IT CMP-001 in combination with nivolumab in PD-1 naïve patients was generally well tolerated with no dose limiting toxicities or delays in surgery related to the neoadjuvant treatment. A major pathologic response rate (MPR) of 71% (15/21) was reported in 21 evaluable patients to date. Of the 15 responding patients, 13 patients had a pathological complete response (pCR). These data suggest that the addition of IT CMP-001 may increase the clinical efficacy of PD-1 blockade. Furthermore, translational studies demonstrated that the combination augmented peripheral blood and intra-tumoral anti-melanoma CD8+ T cell immune responses.

"The preliminary results of our study show that a combination treatment with neoadjuvant nivolumab and CMP-001 is associated with high rates of major pathologic response, including a remarkable proportion of subjects with complete pathological response," said Dr. Davar. "Moreover, the combination treatment has a favorable toxicity profile. We look forward to evaluating the effect of the treatment upon post-surgical relapse as the data mature."

About Checkmate’s Phase 1b Study (CMP-001-001)

CMP-001-001 (NCT02680184) is an ongoing, multicenter two-part, open label Phase 1b clinical study in advanced melanoma. The study is being conducted at 13 sites in the USA.

The primary objective of Part 1 of the study is to determine the recommended phase 2 dose (RP2D) of CMP-001 when given in combination with pembrolizumab in PD-1 resistant patients. Secondary objectives are to assess the safety and efficacy of CMP-001 when given in combination with pembrolizumab, and to assess the pharmacodynamic effects of the addition of CMP-001 to pembrolizumab on serum concentrations of CXCL10 (IP-10).

Part 1 of the study utilized a dose escalation scheme to identify the RP2D and schedule. During dose escalation, patients were enrolled to cohorts of ≥ 3 patients at CMP-001 doses of 1, 3, 5, 7.5, and 10 mg CMP-001 in two dosing schedules (weekly for 7w, followed by q3w; or weekly for 2w, followed by q3w).

In the Part 1 dose expansion, two formulations of CMP-001 were evaluated, either with 0.01% polysorbate (PS20) or with 0.00167% PS20. The CMP-001 0.01% PS20 formulation, 10 mg dose, with a weekly dosing schedule for 7w, followed by q3w dosing, was selected for further development.

Part 2 of the study continues to enroll and is evaluating the safety and efficacy of CMP-001 administered as monotherapy at the same dose, schedule and formulation selected for further development in Part 1 of the study.

About CMP-001

CMP‐001 is a first‐in‐class CpG‐A Toll‐like receptor 9 (TLR9) agonist that is encapsulated in a virus‐like particle. CMP‐001 is designed to induce both innate and adaptive anti‐tumor immune responses, thereby converting immunologically "cold" tumors into immunologically "hot" tumors, with the potential to mediate tumor regression. It is the only CpG‐A class TLR9 agonist in clinical trials and differs from other CpG classes in clinical development by having a native DNA backbone that induces the highest levels of type I Interferon (IFN). Based on analyses of gene expression in human tumors showing that increased IFN and related immune gene expression is associated with better response to PD‐1 inhibition, it is believed that this mechanism of action may restore, enable or improve responses to anti‐PD‐1/PD‐L1 therapeutics. CMP‐001 is being evaluated in multiple tumor types to assess safety, activity, alternative routes of administration and combination with other immunotherapies and modalities. For information on CMP‐001 trials that are currently recruiting patients, please visit www.clinicaltrials.gov.

Mylan Reports Third Quarter 2019 Results and Updates 2019 Guidance

On November 5, 2019 Mylan N.V. (NASDAQ: MYL) reported its financial results for the three and nine months ended September 30, 2019 (Press release, Mylan, NOV 5, 2019, View Source [SID1234550381]).

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Third Quarter 2019 Financial Highlights

U.S. GAAP diluted earnings per ordinary share ("U.S. GAAP EPS") of $0.37, up 9% compared to U.S. GAAP EPS of $0.34 in the prior year period and adjusted diluted earnings per ordinary share ("adjusted EPS") of $1.17 compared to $1.25 in the prior year period.
Total revenues of $2.96 billion, up 3%, up 6% on a constant currency basis, compared to the prior year period.
Revenue Highlights:
North America segment net sales of $1.09 billion, up 8% on an actual and constant currency basis.
Europe segment net sales of $1.05 billion, up less than 1%, up 6% on a constant currency basis.
Rest of World segment net sales of $793.7 million, up 3%, up 4% on a constant currency basis.
U.S. GAAP net cash provided by operating activities for the three months ended September 30, 2019 of $487.8 million, compared to $653.6 million in the prior year period, and adjusted free cash flow for the three months ended September 30, 2019 of $542.1 million, compared to $698.4 million in the prior year period.
U.S. GAAP net cash provided by operating activities for the nine months ended September 30, 2019 of $1.12 billion, compared to $1.71 billion in the prior year period, and adjusted free cash flow for the nine months ended September 30, 2019 of $1.29 billion, compared to $2.02 billion in the prior year period, both driven primarily by the expected increased investment in working capital to support new product launches.
Mylan is not providing forward-looking guidance for U.S. GAAP reported financial measures or a quantitative reconciliation of forward-looking non-GAAP financial measures. Please see "Non-GAAP Financial Measures" for additional information.
Mylan CEO Heather Bresch commented, "Mylan achieved healthy revenue growth across all segments of our business during the third quarter, supporting solid year-to-date revenue growth as compared with last year on a constant currency basis. Also, this quarter, we continued the purposeful work of transforming our business by applying a highly disciplined financial lens to further maximize the value of our asset base. We will continue to execute and remain laser-focused as we now set our sights on year-end commitments, including the upcoming launch of our biosimilar to Herceptin, Ogivri, and as we continue to make progress toward a successful deal close with Pfizer’s Upjohn business, which we continue to expect will occur in mid-2020."

Mylan President Rajiv Malik continued, "During the third quarter, we benefited from continued momentum on key products, including Yupelri, Copaxone, Fulphila and Wixela Inhub. We also were pleased with the overall performance of our global key brands and anticipate continued growth across these areas of our portfolio as we head into the fourth quarter. We expect to finish the year from a position of strength as we have reached all of the product milestones necessary to meet our performance commitments, including approval on our Ogivri product, which we expect to launch in the coming weeks."

Mylan CFO Ken Parks added, "During the third quarter, we delivered adjusted free cash flow of $542 million, bringing total year-to-date adjusted free cash flow to approximately $1.3 billion, and are reaffirming our commitment to deliver $1.9 billion to $2.3 billion for the full year 2019. As of the end of the third quarter, we have repaid approximately $650 million of debt and remain committed to repay at least $1.1 billion of debt during 2019. Our commitment to delever and maintain our investment grade credit rating, while maintaining our financial flexibility to execute on our business strategies, is supported by our stable and durable cash flow profile. For the full year 2019, we also are narrowing certain of our financial guidance range metrics, and now expect total revenues to be in the range of $11.5 billion to $12.0 billion, and adjusted EPS to be in the range of $4.20 to $4.40."

(1) Amounts exclude intersegment revenue that eliminates on a consolidated basis.

(2) Third Quarter 2019 Financial Results

Total revenues for the three months ended September 30, 2019 were $2.96 billion, compared to $2.86 billion for the comparable prior year period, representing an increase of $99.3 million, or 3%. Total revenues include both net sales and other revenues from third parties. Net sales for the current quarter were $2.93 billion, compared to $2.83 billion for the comparable prior year period, representing an increase of $100.9 million, or 4%. Other revenues for the current quarter were $33.5 million, compared to $35.1 million for the comparable prior year period.

The increase in net sales included an increase in the North America segment of 8% and in the Rest of World segment of 3%. Net sales in the Europe segment increased less than 1% when compared to the prior year period. Mylan’s net sales were unfavorably impacted by the effect of foreign currency translation, primarily reflecting changes in the U.S. Dollar as compared to the currencies of Mylan’s subsidiaries in the European Union and Australia. The unfavorable impact of foreign currency translation on current period net sales was approximately $62.0 million, or 2%. On a constant currency basis, net sales increased by approximately $162.9 million, or 6%. This increase was primarily driven by new product sales, partially offset by a decrease in net sales from existing products as the impact of lower pricing exceeded the benefit of higher volumes. Below is a summary of net sales in each of our segments for the three months ended September 30, 2019:

Net sales from North America segment totaled $1.09 billion in the current quarter, an increase of $76.3 million or 8% when compared to the prior year period. This increase was primarily driven by new product sales partially offset by lower sales of existing products due to lower pricing and lower volumes. New product sales were primarily driven by sales of the Wixela Inhub and Yupelri. Lower sales of existing products was due to changes in the competitive environment, including the loss of exclusivity on tadalafil. The impact of foreign currency translation on current period net sales was insignificant within North America.
Net sales from Europe segment totaled $1.05 billion in the current quarter, an increase of $4.6 million, or less than 1%, when compared to the prior year period. Net sales in the current period were negatively affected by the unfavorable impact of foreign currency translation of approximately $53.3 million or 5%, and to a lesser extent, lower pricing on existing products. The unfavorable impact of these items was offset by new product sales, including Hulio, and higher volumes of existing products. Constant currency net sales increased by approximately $57.9 million, or 6%, when compared to the prior year period.
Net sales from Rest of World segment totaled $793.7 million in the current quarter, an increase of $20.0 million or 3% when compared to the prior year period. This increase was primarily driven by new product sales in Australia and emerging markets and higher volumes of existing products primarily driven by products sold in emerging markets. These increases were partially offset by lower pricing on existing products and, to a lesser extent, the unfavorable impact of foreign currency translation. Overall, net sales from Rest of World were unfavorably impacted by the effect of foreign currency translation by approximately $8.0 million, or 1%. Constant currency net sales increased by approximately $28.0 million, or 4% when compared to the prior year period.
U.S. GAAP gross profit was $1.07 billion and $1.04 billion for the third quarter of 2019 and 2018, respectively. U.S. GAAP gross margins were 36% in the third quarter of 2019 and 2018. U.S. GAAP gross margins were negatively impacted as a result of lower gross profit for sales of existing products, including higher sales of the authorized generic version of EpiPen, which has a lower than company average margin, as well as changes in the competitive environment on certain products. In addition, there were certain inventory write-offs, the largest of which is dated Wixela Inhub product resulting from the later than expected approval date. These decreases were offset by the impact from new product sales and lower site remediation expenses and restructuring charges related to activities at the Company’s Morgantown plant. Adjusted gross profit was $1.56 billion and adjusted gross margins were 53% for the third quarter of 2019 compared to adjusted gross profit of $1.58 billion and adjusted gross margins of 55% in the prior year period. Adjusted gross margins were also negatively impacted by EpiPen and the Wixela Inhub, partially offset by the impact from new product sales.

R&D expense for the three months ended September 30, 2019 was $167.9 million, compared to $144.1 million for the comparable prior year period, an increase of $23.8 million. This increase was primarily due to higher payments in the current year period related to licensing arrangements for products in development partially offset by lower expenditures related to the reprioritization of global programs.

SG&A expense for the three months ended September 30, 2019 was $632.7 million, compared to $577.3 million for the comparable prior year period, an increase of $55.4 million. The increase was due to continued investment in selling and marketing activities. Also contributing to the increase were higher consulting fees and other expenses primarily related to the pending Upjohn transaction totaling approximately $41.2 million in the current quarter. In addition, the increase included the impact of the reversal of cumulative expense in the prior year period related to the Company’s One-Time Special Performance-Based Five-Year Realizable Value Incentive Program that resulted in the Company recognizing a reduction in share-based compensation expense of approximately $47.1 million during the three months ended September 30, 2018. Partially offsetting these items was compensation expense of $20.0 million recognized in the prior year period for an additional discretionary bonus for a certain group of employees and lower restructuring expenses in the current quarter when compared to the prior year period. None of the employees who received the 2018 discretionary bonus were named executive officers.

During the third quarter of 2019, the Company recorded a net gain of $51.9 million in Litigation settlements and other contingencies, net compared to a net gain of $20.4 million in the comparable prior year period. The favorable litigation settlement for the three months ended September 30, 2019, consists primarily of a gain related to the Celgene Corporation settlement of $62.0 million partially offset by certain litigation related charges. The net gain recognized in the prior year period primarily relates to a gain of approximately $19.3 million for a contingent consideration fair value adjustment due to changes to assumptions relating to the timing of product launch along with other competitive and market factors related to the Wixela Inhub.

U.S. GAAP net earnings increased by $13.1 million to earnings of $189.8 million for the three months ended September 30, 2019, compared to earnings of $176.7 million for the prior year period and U.S. GAAP EPS increased from $0.34 in the prior year period to $0.37 in the current quarter. The Company recognized a U.S. GAAP income tax benefit of $4.0 million in the current year period, compared to a U.S. GAAP income tax provision of $15.5 million for the comparable prior year period, an increase of $19.5 million. During the current quarter, the Company recorded a $42.0 million benefit resulting from refinements to previous estimates in conjunction with the filing of the Company’s 2018 U.S. federal tax return, which revised the estimated impact of the Company’s valuation allowance on its interest limitation deductions and the estimate of available foreign tax credits. Also impacting the current year income tax benefit was the changing mix of income earned in jurisdictions with differing tax rates. Adjusted net earnings decreased to $604.4 million compared to $648.0 million for the prior year period. Adjusted EPS decreased to $1.17 from $1.25 in the prior year period.

EBITDA was $794.8 million for the current quarter and $841.6 million for the comparable prior year period. After adjusting for certain items as further detailed in the reconciliation below, adjusted EBITDA was $922.8 million for the current quarter and $935.9 million for the comparable prior year period.

Nine Months Ended September 30, 2019 Financial Results

Total revenues for the nine months ended September 30, 2019 were $8.31 billion, compared to $8.36 billion for the comparable prior year period, representing a decrease of $46.5 million, or 1%. Total revenues include both net sales and other revenues from third parties. Net sales for the nine months ended September 30, 2019 were $8.21 billion, compared to $8.23 billion for the comparable prior year period, representing a decrease of $26.2 million, or less than 1%. Other revenues for the nine months ended September 30, 2019 were $101.7 million, compared to $122.0 million for the comparable prior year period.

The decrease in net sales was primarily the result of a decrease in net sales in the Europe segment of 5%, partially offset by an increase in net sales in the Rest of World segment of 4% and an increase in net sales in the North America segment of 1%. Mylan’s net sales were unfavorably impacted by the effect of foreign currency translation, primarily reflecting changes in the U.S. Dollar as compared to the currencies of Mylan’s subsidiaries in India, Australia, and the European Union. The unfavorable impact of foreign currency translation on current year net sales was approximately $287.6 million, or 4%. On a constant currency basis, the increase in net sales was approximately $261.4 million, or 3% for the nine months ended September 30, 2019. This increase was primarily driven by new product sales, partially offset by a decrease in net sales from existing products as a result of lower pricing and volumes. Below is a summary of net sales in each of our segments for the nine months ended September 30, 2019:

Net sales from North America segment totaled $3.04 billion during the nine months ended September 30, 2019, an increase of $36.6 million or 1% when compared to the prior year period. This increase was due primarily to new product sales, including the Wixela Inhub and Fulphila (biosimilar to Neulasta). This increase was partially offset by lower pricing and volumes of existing products, driven by changes in the competitive environment and the impact of the Morgantown plant remediation activities. The impact of foreign currency translation on current period net sales was insignificant within North America.
Net sales from Europe segment totaled $2.93 billion during the nine months ended September 30, 2019, a decrease of $139.6 million or 5% when compared to the prior year period. This decrease was primarily the result of the unfavorable impact of foreign currency translation of approximately $190.4 million or 6%. Sales of existing products were also negatively impacted by lower pricing. This decrease was partially offset by new product sales and higher volumes. Constant currency net sales increased by approximately $50.8 million or 2% when compared to the prior year period.
Net sales from Rest of World segment totaled $2.24 billion during the nine months ended September 30, 2019, an increase of $76.8 million or 4% when compared to the prior year period. This increase was primarily the result of new product sales, primarily in Australia and emerging markets, and higher volumes of existing products. Increased volumes of existing products were primarily driven by the Company’s anti-retroviral therapy franchise. This increase was partially offset by the unfavorable impact of foreign currency translation and, to a lesser extent, by lower pricing on existing products. Overall, net sales from Rest of World were unfavorably impacted by the effect of foreign currency translation of approximately $91.7 million, or 4%. Constant currency net sales increased by approximately $168.5 million or 8% when compared to the prior year period.
U.S. GAAP gross profit was $2.81 billion and $2.99 billion for the nine months ended September 30, 2019 and 2018, respectively. U.S. GAAP gross margins were 34% and 36% for the nine months ended September 30, 2019 and 2018, respectively. U.S. GAAP gross margins were negatively impacted by lower gross profit for sales of existing products. In addition, gross margins were negatively impacted by approximately 65 basis points for higher site remediation expenses related to activities at the Company’s Morgantown plant, by approximately 10 basis points related to the incremental amortization from product acquisitions and by approximately 40 basis points for recall related costs, including inventory write-offs. These items were partially offset by the impact of new product sales. Adjusted gross profit was $4.44 billion and adjusted gross margins were 53% for the nine months ended September 30, 2019 compared to adjusted gross profit of $4.50 billion and adjusted gross margins of 54% in the prior year period.

R&D expense for the nine months ended September 30, 2019 was $488.1 million, compared to $555.7 million for the comparable prior year period, a decrease of $67.6 million. This decrease was primarily due to lower expenditures related to the reprioritization of global programs and lower restructuring related costs.

SG&A expense for the nine months ended September 30, 2019 was $1.91 billion, compared to $1.81 billion for the comparable prior year period, an increase of $101.1 million. The increase was due to continued investment in selling and marketing activities. Also contributing to the increase were higher consulting fees and other expenses primarily related to the pending Upjohn transaction totaling approximately $45.3 million in the current year period. In addition, the current year period was impacted by higher share-based compensation expense due to a reduction of approximately $70.6 million during the nine months ended September 30, 2018 related to certain performance-based awards. Partially offsetting these increases was a decrease in bad debt expense of approximately $23.0 million related to a special business interruption event for one customer in the prior year period and $20.0 million of compensation expense for an additional discretionary bonus for a certain group of employees in the prior year period. None of the employees who received the 2018 discretionary bonus were named executive officers.

During the nine months ended September 30, 2019 the Company recorded a net gain of $30.3 million in Litigation settlements and other contingencies, net compared to a net gain of $50.6 million in the comparable prior year period. During the nine months ended September 30, 2019, the Company recognized a net gain of approximately $1.4 million primarily related to a favorable litigation settlement related to the Celgene matter of $62.0 million recognized during the nine months ended September 30, 2019 offset by litigation related charges for settlements reached related to the modafinil antitrust matter of $18.0 million and the settlement with the SEC in connection with the SEC staff’s investigation of the Company’s public disclosures regarding its 2016 settlement with the Department of Justice concerning the EpiPen Medicaid Drug Rebate Program of $30.0 million. In addition, a $28.9 million gain was recognized for the reduction of contingent consideration related to the respiratory delivery platform. Litigation settlements for the nine months ended September 30, 2018, consisted primarily of a gain of approximately $14.7 million related to a favorable litigation settlement, which was partially offset by litigation related charges of approximately $13.3 million related to an antitrust and a patent infringement matter. In addition, a $49.3 million gain was recognized for the reduction of contingent consideration related to the respiratory delivery platform.

U.S. GAAP net (loss) earnings decreased by $305.0 million to a loss of $3.7 million for the nine months ended September 30, 2019, compared to earnings of $301.3 million for the prior year period and U.S. GAAP EPS decreased from $0.58 in the prior year period to $(0.01) for the nine months ended September 30, 2019. The Company recognized a U.S. GAAP income tax provision of $22.9 million, compared to a U.S. GAAP income tax benefit of $79.9 million for the comparable prior year period, an increase of $102.8 million. During the nine months ended September 30, 2019, primarily due to the settlement reached with the U.S. Internal Revenue Service, partially offset by the expiration of federal and foreign statutes of limitations, the Company increased its net liability for unrecognized tax benefits by approximately $50.9 million. Additionally, during the nine months ended September 30, 2019, the Company recorded a $42.0 million benefit resulting from refinements to previous estimates in conjunction with the filing of the Company’s 2018 U.S. federal tax return, which revised the estimated impact of the Company’s valuation allowance on its interest limitation deductions and the estimate of available foreign tax credits. In the prior year period, as a result of federal and state audits and settlements and expirations of certain state, federal, and foreign statutes of limitations, the Company reduced its liability for unrecognized tax benefits by approximately $86.0 million, which resulted in a net benefit to the income tax provision of approximately $53.0 million. Partially offsetting this benefit was an increase in the reserve for uncertain tax benefits of approximately $18.0 million for certain other matters. Additionally, during the nine months ended September 30, 2018, income tax benefits of approximately $30.0 million were recognized upon revaluations of certain deferred tax items upon statutory rate changes in certain non-U.S. jurisdictions, $6.9 million of valuation allowance releases in certain jurisdictions, and a benefit of approximately $6.2 million related to the finalization of previously recorded 2017 tax estimates upon the filing of tax returns. Also impacting the current year income tax expense was the changing mix of income earned in jurisdictions with differing tax rates. Adjusted net earnings decreased to $1.56 billion compared to $1.70 billion for the prior year period. Adjusted EPS decreased to $3.02 from $3.28 in the prior year period.

EBITDA was $1.93 billion for the nine months ended September 30, 2019, and $2.19 billion for the comparable prior year period. After adjusting for certain items as further detailed in the reconciliation below, adjusted EBITDA was $2.48 billion for the nine months ended September 30, 2019 and $2.62 billion for the comparable prior year period.

Cash Flow

U.S. GAAP net cash provided by operating activities for the three and nine months ended September 30, 2019 was $487.8 million and $1.12 billion, compared to $653.6 million and $1.71 billion in the comparable prior year periods. Capital expenditures were approximately $42.3 million and $139.6 million for the three and nine months ended September 30, 2019 compared to approximately $61.5 million and $137.4 million for the comparable prior year periods.

Adjusted net cash provided by operating activities for the three and nine months ended September 30, 2019 was $584.4 million and $1.43 billion compared to adjusted net cash provided by operating activities of $759.9 million and $2.16 billion for the comparable prior year periods. Adjusted free cash flow, defined as adjusted net cash provided by operating activities less capital expenditures, was $542.1 million and $1.29 billion for the three and nine months ended September 30, 2019, compared to $698.4 million and $2.02 billion in comparable the prior year periods.

Updated Full Year 2019 Financial Guidance

Mylan is updating certain of its previous full year 2019 guidance by narrowing certain guidance metric’s ranges. As discussed in the "Non-GAAP Financial Measures" section below, Mylan is not providing forward looking guidance for U.S. GAAP reported financial measures or a quantitative reconciliation of forward-looking non-GAAP financial measures to the most directly comparable U.S. GAAP measure. For 2019, Mylan continues to expect to generate $1.9 billion to $2.3 billion of adjusted free cash flow. Adjusted EPS for 2019 is now expected to be in the range of $4.20 to $4.40. Mylan now expects 2019 total revenues in the range of $11.50 billion to $12.00 billion.

Conference Call and Earnings Materials

Mylan N.V. will host a conference call and live webcast, today at 10:00 a.m. ET, to review the Company’s financial results for the third quarter ended September 30, 2019. The earnings call can be accessed live by calling 855.493.3607 or 346.354.0950 for international callers (ID#: 1519969) or at the following address on the Company’s website: investor.mylan.com. The Q3 2019 "Earnings Call Presentation", which will be referenced during the call can be found at investor.mylan.com. A replay of the webcast will also be available on the website.

Non-GAAP Financial Measures

This press release includes the presentation and discussion of certain financial information that differs from what is reported under accounting principles generally accepted in the United States ("U.S. GAAP"). These non-GAAP financial measures, including, but not limited to, adjusted EPS, adjusted gross profit, adjusted gross margins, adjusted net earnings, EBITDA, adjusted EBITDA, adjusted R&D and as a % of total revenues, adjusted SG&A and as a % of total revenues, adjusted earnings from operations, adjusted interest expense, adjusted other income, adjusted effective tax rate, notional debt to Credit Agreement Adjusted EBITDA leverage ratio, long term average debt to Credit Agreement Adjusted EBITDA leverage ratio target, adjusted net cash provided by operating activities, adjusted free cash flow, constant currency total revenues and constant currency net sales are presented in order to supplement investors’ and other readers’ understanding and assessment of the financial performance of Mylan N.V. ("Mylan" or the "Company"). Management uses these measures internally for forecasting, budgeting, measuring its operating performance, and incentive-based awards. Primarily due to acquisitions and other significant events which may impact comparability of our periodic operating results, Mylan believes that an evaluation of its ongoing operations (and comparisons of its current operations with historical and future operations) would be difficult if the disclosure of its financial results was limited to financial measures prepared only in accordance with U.S. GAAP. We believe that non-GAAP financial measures are useful supplemental information for our investors and when considered together with our U.S. GAAP financial measures and the reconciliation to the most directly comparable U.S. GAAP financial measure, provide a more complete understanding of the factors and trends affecting our operations. The financial performance of the Company is measured by senior management, in part, using adjusted metrics included herein, along with other performance metrics. Management’s annual incentive compensation is derived, in part, based on the adjusted EPS metric and the adjusted free cash flow metric. In addition, the Company believes that including EBITDA and supplemental adjustments applied in presenting adjusted EBITDA and Credit Agreement Adjusted EBITDA (as defined below) pursuant to our Credit Agreement is appropriate to provide additional information to investors to demonstrate the Company’s ability to comply with financial debt covenants and assess the Company’s ability to incur additional indebtedness. We also report sales performance using the non-GAAP financial measures of "constant currency" total revenues and net sales. These measures provide information on the change in total revenues and net sales assuming that foreign currency exchange rates had not changed between the prior and current period. The comparisons presented at constant currency rates reflect comparative local currency sales at the prior year’s foreign exchange rates. We routinely evaluate our net sales and total revenues performance at constant currency so that sales results can be viewed without the impact of foreign currency exchange rates, thereby facilitating a period-to-period comparison of our operational activities, and believe that this presentation also provides useful information to investors for the same reason. The "Summary of Total Revenues by Segment" table below compares net sales on an actual and constant currency basis for each reportable segment for the quarters and year to date periods ended September 30, 2019 and 2018 as well as for total revenues. Also, set forth below, Mylan has provided reconciliations of such non-GAAP financial measures to the most directly comparable U.S. GAAP financial measures. Investors and other readers are encouraged to review the related U.S. GAAP financial measures and the reconciliations of the non-GAAP measures to their most directly comparable U.S. GAAP measures set forth below, and investors and other readers should consider non-GAAP measures only as supplements to, not as substitutes for or as superior measures to, the measures of financial performance prepared in accordance with U.S. GAAP.

For additional information regarding the components and uses of Non-GAAP financial measures refer to Management’s Discussion and Analysis of Financial Condition and Results of Operations–Use of Non-GAAP Financial Measures section of Mylan’s Quarterly Report on Form 10-Q for the three months ended September 30, 2019 (the "Form 10-Q").

Mylan is not providing forward looking guidance for U.S. GAAP reported financial measures or a quantitative reconciliation of forward-looking non-GAAP financial measures to the most directly comparable U.S. GAAP measure because it is unable to predict with reasonable certainty the ultimate outcome of certain significant items without unreasonable effort. These items include, but are not limited to, acquisition-related expenses, including integration, restructuring expenses, asset impairments, litigation settlements and other contingencies, including changes to contingent consideration and certain other gains or losses. These items are uncertain, depend on various factors, and could have a material impact on U.S. GAAP reported results for the guidance period.

Reconciliation of U.S. GAAP Net Earnings to Adjusted Net Earnings and U.S. GAAP EPS to Adjusted EPS

Below is a reconciliation of U.S. GAAP net earnings (loss) and U.S. GAAP EPS to adjusted net earnings and adjusted EPS for the three and nine months ended September 30, 2019 compared to the prior year period:

Significant items for the three and nine months ended September 30, 2019 include the following:

Acquisition related costs consist primarily of transaction costs including legal and consulting fees and integration activities. The increase for the three and nine months ended September 30, 2019 relates to transaction costs for the pending Upjohn transaction.

For the three months ended September 30, 2019, charges of approximately $11.4 million are included in cost of sales and a net gain of $10.5 million is included in SG&A. For the nine months ended September 30, 2019, charges of approximately $72.2 million are included in cost of sales and net charges of approximately $6.1 million are included in SG&A. Refer to Note 17 Restructuring included in Part I, Item 1 of the Form 10-Q for additional information.

Beginning in 2019, share-based compensation expense is excluded from adjusted net earnings and adjusted EPS. The full year impact for the year ended December 31, 2018 was insignificant. As such, the three and nine months ended September 30, 2018 amounts were not added back to U.S. GAAP net earnings.

Costs incurred during the three months ended September 30, 2019 primarily relate to incremental manufacturing variances and site remediation activities as a result of the activities at the Company’s Morgantown plant of approximately $50.0 million. The nine months ended September 30, 2019 increased $128.7 million primarily due to $54.4 million for certain incremental manufacturing variances and site remediation activities as a result of the activities at the Company’s Morgantown plant, approximately $35.1 million for product recall costs, including inventory write-offs, and charges related to the cancellation of a contract, each of which were higher during the nine months ended September 30, 2019 compared to the prior year period.

R&D expense for the three months ended September 30, 2019 consists primarily of expenses for product development arrangements of approximately $39.8 million. Refer to Note 4 Acquisitions and Other Transactions included in Part I, Item 1 of the Form 10-Q for additional information. R&D expense for the three months ended September 30, 2018 includes expenses relating to on-going collaboration agreements, including Momenta Pharmaceuticals, Inc.

The 2018 amount primarily related to mark-to-market losses of investments in equity securities historically accounted for as available-for-sale securities and the cumulative realized gains on such investments.

The impact of changes related to uncertain tax positions is excluded from adjusted earnings.