On November 4, 2019 AVEO Oncology (NASDAQ: AVEO) reported a regulatory update following a meeting with the U.S. Food and Drug Administration (FDA) to discuss results from the August 2019 overall survival (OS) analysis of the TIVO-3 trial and the Company’s proposal to proceed with a New Drug Application (NDA) for tivozanib (Press release, AVEO, NOV 4, 2019, View Source [SID1234550264]).

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TIVO-3 is the Company’s Phase 3 randomized, controlled, multi-center, open-label study to compare tivozanib, the Company’s vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI), to sorafenib in 350 subjects with highly refractory metastatic renal cell carcinoma (RCC). The TIVO-3 trial was designed to address the FDA’s concerns regarding the OS trend in the TIVO-1 trial. In the TIVO-1 trial, the Company’s initial RCC pivotal trial, the FDA found that the inconsistent progression free survival (PFS) and OS results and imbalance in post study treatments made the trial results uninterpretable and inconclusive when making a risk-benefit assessment necessary for drug approval.

The Company previously announced that the TIVO-3 trial met its primary endpoint of demonstrating a significant improvement in PFS. The study also demonstrated a significant improvement in the secondary endpoint of overall response rate. The August 2019 analysis of the secondary endpoint of OS was the second prespecified interim OS analysis of the TIVO-3 trial, and showed an updated OS hazard ratio (HR) of 0.99 at two years from the last patient enrolled in the study.

In the FDA’s preliminary feedback, based on its assessment of the totality of evidence presented to date, the FDA recommended that the Company not submit an NDA at this time. The FDA stated that it remained concerned about the results of TIVO-3 in the context of the overall development of tivozanib. The FDA noted that the Company’s current interim OS results do not abrogate the FDA’s concerns over detriment and that those results may worsen with final analysis at 263 events, and that the median OS for tivozanib is worse than that of sorafenib.

In view of the changing first-line treatment landscape as well as the FDA’s continued concerns, the Company informed the FDA that it intends to narrow its proposed indication to relapsed/refractory RCC. At the meeting, the FDA acknowledged AVEO’s responses and reiterated its concerns about the survival information and the totality of data. The FDA noted that the choice to submit the data is the Company’s, and that a discussion with the Oncologic Drug Advisory Committee will likely be required. The FDA said that if AVEO wishes to proceed with a revised OS analysis in June 2020, AVEO should submit an updated statistical analysis plan (SAP) with a planned OS update based on the projected number of events at that time.

AVEO intends to submit to the FDA an update to the SAP for the final OS analysis consistent with these discussions, followed by an NDA submission in the first quarter of 2020. AVEO expects to report the final OS analysis in June 2020 based on a May 1, 2020 cutoff, at which point the Company estimates that the study will have reached approximately 263 OS events, as discussed with the FDA. The FDA and the Company agreed that if the final analysis yields an OS HR above 1.00, the Company will withdraw its NDA application.

"During the meeting with the FDA, we believe that we established an appropriate path forward toward filing an NDA for tivozanib in the near term and a final analysis plan for OS," said Michael Bailey, president and chief executive officer of AVEO. "The continued separation of the PFS curves and the positive trend in OS HR observed from the first to the second interim analysis, together with tenfold more patients remaining progression free and on tivozanib vs. sorafenib therapy, make us believe that the final OS results will not worsen."

About TIVO-3

The TIVO-3 trial was designed to enroll patients with RCC who have failed at least two prior regimens, including VEGFR-TKI therapy. Eligible patients may also have received checkpoint inhibitor therapy in earlier lines of treatment. Patients were randomized 1:1 to receive either tivozanib or sorafenib, with no crossover between arms. The primary endpoint of the study is progression free survival (PFS). Secondary endpoints include overall survival (OS), overall response rate (ORR), and safety and tolerability. TIVO-3, together with the previously completed TIVO-1 trial of tivozanib in the first line treatment of RCC, is designed to support a regulatory submission of tivozanib in the U.S. as a treatment for RCC in multiple lines of therapy. TIVO-3 patients were exclusively enrolled in North America, Western Europe, and Central Europe.

About Tivozanib

Tivozanib (FOTIVDA) is an oral vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) discovered by Kyowa Kirin and approved for the treatment of adult patients with advanced renal cell carcinoma (RCC) in the European Union plus Norway, New Zealand and Iceland. It is a potent, selective and long half-life inhibitor of all three VEGF receptors and is designed to optimize VEGF blockade while minimizing off-target toxicities, potentially resulting in improved efficacy and minimal dose modifications.1,2 Tivozanib has been shown to significantly reduce regulatory T-cell production in preclinical models3 and has demonstrated synergy in combination with nivolumab (anti PD-1) in a Phase 2 study in RCC4. Tivozanib has been investigated in several tumor types, including renal cell, hepatocellular, colorectal, ovarian and breast cancers.

On November 4, 2019 ADC Therapeutics SA, a clinical-stage oncology-focused biotechnology company pioneering the development of highly potent and targeted antibody drug conjugates (ADCs) for patients suffering from hematological malignancies and solid tumors, reported that ADCT-402 (loncastuximab tesirine) data have been published in Clinical Cancer Research, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper), in a paper titled, "A Phase 1 study of ADCT-402 (Loncastuximab Tesirine), a Novel Pyrrolobenzodiazepine-Based Antibody Drug Conjugate, in Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma (Press release, ADC Therapeutics, NOV 4, 2019, View Source [SID1234596053])."

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The Phase 1 multi-center, open-label, single-arm, dose-escalation and dose-expansion clinical trial demonstrated the significant single-agent clinical activity and manageable tolerability profile of ADCT-402 in patients with CD19-positive relapsed or refractory B-cell non-Hodgkin lymphoma who had failed or were intolerant to established therapies. The published paper includes findings from the dose-escalation part of the trial. Notably, among the 61 patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who were evaluable for efficacy, a 55 percent response rate was observed at doses ≥120 µg/kg. Eighty-seven of the 88 patients enrolled in the trial experienced at least one treatment-emergent adverse event (TEAE). The most common TEAEs were low blood cell counts, fatigue, liver test abnormalities, nausea, rash, shortness of breath and tissue swelling.

Brad S. Kahl, MD, Professor of Medicine at Washington University School of Medicine and lead author of the paper, said, "The first-in-human study of ADCT-402 justified its continued evaluation and identified the initial 150 µg/kg dose for the Phase 2 clinical trial. The promising clinical activity and manageable toxicities observed thus far highlight the potential utility of ADCT-402 as an off-the-shelf therapy for heavily pre-treated patients with DLBCL, a population for which a significant unmet medical need remains."

Jay Feingold, MD, PhD, Senior Vice President, Chief Medical Officer and Head of Oncology Clinical Development at ADC Therapeutics, added, "The publication of early ADCT-402 data in a peer-reviewed journal further validates the potential of our lead product candidate to become an important part of the treatment paradigm for relapsed or refractory DLBCL. With enrollment in our pivotal 145-patient Phase 2 clinical trial of ADCT-402 complete, we plan to submit a Biologics License Application to the U.S. Food and Drug Administration for accelerated approval of ADCT-402 for the treatment of relapsed or refractory DLBCL in patients who have failed two or more treatment regimens in the second half of 2020."

ADCT-402 is also being evaluated in an ongoing Phase 1b clinical trial in combination with ibrutinib for the treatment of relapsed or refractory DLBCL or mantle cell lymphoma (MCL) and a Phase 1b clinical trial in combination with durvalumab for the treatment of relapsed or refractory DLBCL, MCL and follicular lymphoma.

About ADCT-402

ADCT-402 (loncastuximab tesirine) is an antibody drug conjugate (ADC) composed of a humanized monoclonal antibody directed against human CD19 and conjugated through a linker to a pyrrolobenzodiazepine (PBD) dimer cytotoxin. Once bound to a CD19-expressing cell, ADCT-402 is designed to be internalized by the cell, following which the warhead is released. The warhead is designed to bind irreversibly to DNA to create highly potent interstrand cross-links that block DNA strand separation, thus disrupting essential DNA metabolic processes such as replication and ultimately resulting in cell death. CD19 is a clinically validated target for the treatment of B-cell malignancies. ADCT-402 is being evaluated in a pivotal Phase 2 clinical trial in patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) (NCT03589469), a Phase 1b trial in combination with ibrutinib in patients with R/R DLBCL or mantle cell lymphoma (MCL) (NCT03684694) and a Phase 1b trial in combination with durvalumab in patients with R/R DLBCL, MCL or follicular lymphoma (NCT03685344). The U.S. Food and Drug Administration granted orphan drug designation to ADCT-402 for the treatment of relapsed or refractory DLBCL and MCL.

On November 4, 2019 Agenus Inc. (NASDAQ: AGEN), an immuno-oncology (I-O) company with a pipeline of immune checkpoint antibodies, adoptive cell therapies1, reported financial results for the third quarter of 2019 (Press release, Agenus, NOV 4, 2019, View Source [SID1234550212]).

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"We have made solid progress this year," said Garo H. Armen, Ph.D., Chairman and CEO of Agenus. "We expect clinical readouts from six separate antibody programs in 2020 as our robust pace continues. We expect to commence combo trials of our NexGen CTLA-4 with our own PD-1 this month. 2020 is expected to be an important year of data generation, substantial milestone payments and prudent collaborations for Agenus. We look forward to discussing these developments in more detail during our call and at our R&D day on November 15th."

Achievements
Delivered on partnership programs; received additional cash milestones
Received $22.5 million from Gilead as milestone payment for IND acceptances of AGEN1423 (now GS-1423), AGEN1223, & AGEN2373
CTLA-4 & PD-1 trials advance
2L cervical cancer trial designed to support BLA via accelerated pathway
Combination trial completes accrual and interim analysis
Monotherapy trial is on track to complete accrual and interim analysis by year-end
AGEN1181 (NexGen CTLA-4) trial advancing; combos with AGEN2034 (PD-1) to start
QS-21 Updates
Sales of Shingrix exceed $1Bn; eliminating HCR debt obligation and nearing milestone triggers of up to $40M
AgenTus Cell Therapy Business:
IND for AgenTus allogeneic cell therapy on track by year end; combos with Agenus check point antibodies planned in 2020
Partnership and private financing discussions are underway
Dr. Walter Flamenbaum appointed CEO of AgenTus
Third Quarter 2019 Financial Results

We ended the third quarter of 2019 with a cash balance of $93 million as compared to $53 million at December 31, 2018.

Cash used in operations for the quarter ended September 2019 was $28 million compared to $25 million for the same period in 2018. Cash provided by operations for the nine months ended September 2019 was $13 million as compared to cash used in operations of $95 million for the same period in 2018.

For the third quarter ended September 30, 2019, we reported net loss of $46 million or $0.33 per share compared to a net loss for same period in 2018 of $34 million, or $0.29 per share. For the nine months ended September 30, 2019, we reported a net loss of $81 million or $0.58 per share compared to a net loss for the same period in 2018 of $113 million or $1.04 per share.

During the nine months ended September 2019 we recognized revenue of $116 million which includes revenue from our transaction with Gilead and non-cash royalties earned. This compares to revenue of $30 for the nine months ended September 2018. Through the third quarter of 2019 we also recorded $30 million of non-cash interest expense due to our transaction with HCR related to the sale of future royalties.

Conference Call, Webcast and Prepared Statement Information

Date: Monday, November 4, 2019
Time: 8:30 a.m. ET
Domestic Dial-in Number: (844) 492-3727
International Dial-in Number: (412) 317-5118
Conference ID: Agenus

Live Webcast: accessible from the Company’s website at View Source or with this link View Source

A replay will be available on the Company’s website approximately two hours after the call and will remain available for 90 days.

On November 4, 2019 DURECT Corporation (Nasdaq: DRRX) reported financial results for the three months ended September 30, 2019 and provided a corporate update (Press release, DURECT, NOV 4, 2019, View Source [SID1234550232]).

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Total revenues were $10.8 million and net loss was $2.0 million for the three months ended September 30, 2019 as compared to total revenues of $8.0 million and net loss of $2.7 million for the three months ended September 30, 2018.

At September 30, 2019, cash and investments were $57.1 million, compared to cash and investments of $34.5 million at December 31, 2018. In September, DURECT earned a $10 million milestone under its agreement with Gilead; payment of the milestone was received in October and is therefore not reflected in the cash and investments figure as of September 30, 2019. Debt at September 30, 2019 was $21.0 million, which included partial accrual for the final payment of our term loan.

"Recent progress continues on both our proprietary and partnered clinical development programs, led by the completion of the DUR-928 Phase 2a alcoholic hepatitis study. The strength of the data from this study is underscored by its selection as an oral late-breaking presentation and for inclusion in the ‘Best of The Liver Meeting’ summary slide deck at the upcoming Liver Meeting 2019," stated James E. Brown, D.V.M., President and CEO of DURECT. "In addition, we completed enrollment in the DUR-928 psoriasis trial and passed the half way point for enrollment in the DUR-928 NASH trial. In September we earned a $10 million development milestone under our exclusive license agreement with Gilead for a long-acting injectable HIV investigational product utilizing DURECT’s SABER technology."

Update on Selected Programs and Transactions:

Epigenetic Regulator Program. DUR-928, the lead product candidate in the Company’s Epigenetic Regulator Program, is an endogenous, first-in-class small molecule, which may have broad applicability in acute organ injuries such as alcoholic hepatitis (AH) and acute kidney injury (AKI), in chronic liver diseases such as non-alcoholic steatohepatitis (NASH), and in inflammatory skin disorders such as psoriasis and atopic dermatitis.

Clinical Trials

Alcoholic Hepatitis (AH)

We completed the Phase 2a clinical trial of DUR-928 in patients with alcoholic hepatitis (AH). The final enrollment for the trial consists of 12 severe patients (Model for End-Stage Liver Disease (MELD) 21-30) and 7 moderate patients (MELD 11-20) for a total of 19 AH patients. After being discharged on day 2, one patient did not return for the scheduled day 7 and day 28 follow up visits; therefore Lille, bilirubin and MELD data reported below are based on 18 patients. Patients treated with DUR-928 had statistically significant reductions from baseline in bilirubin (day 7 and 28) and MELD (day 28), as well as statistically significantly lower Lille scores, compared with a historical control group (n=15) from a University of Louisville (UL) AH study1. All 19 patients treated with DUR-928 survived the 28-day follow-up period.

The study results have been selected for an oral presentation as part of the late-breaking session of The Liver Meeting 2019. Additionally, the results have been selected for inclusion in the ‘Best of The Liver Meeting’ summary slide deck in the alcohol-related liver disease category.

Our advisor, Dr. Craig McClain from the University of Louisville (UL), shared anonymized data from his study, in which 15 AH patients with initial MELD scores ranging from 15-30 received either supportive care alone (n=8) or supportive care with corticosteroids (n=7).

Tarek Hassanein, M.D., one of the trial’s principal investigators, will deliver the oral late-breaking presentation detailing trial results.

Oral Late-Breaking Presentation Details:

Title:

Safety and Efficacy of DUR-928: A Potential New Therapy for Acute Alcoholic Hepatitis

Date: Tuesday, November 12, 2019

Time: 8:30 a.m. Eastern Time

Location: Auditorium, Hynes Convention Center

Session Title: Late-Breaking Abstract Oral Session II

Presentation Type: Oral, Late-Breaking Session

Publication Number: LO9

In a separate poster presentation, Craig McClain, M.D., will present additional comparative data from the Phase 2a clinical trial of DUR-928 and a control group from a contemporaneous AH trial conducted at University of Louisville.

Poster Presentation Details:

Title: DUR-928 Therapy of Acute Alcoholic Hepatitis: A Pilot Study

Date: Sunday, November 10, 2019

Time: 12:00 – 2:00 p.m. Eastern Time

Presentation Type: Poster Presentation

Location: Hynes Convention Center, Hall B

Publication Number: 1376

Lille scores are used in clinical practice to help determine the prognosis and response for AH patients after 7 days of treatment. The lower the Lille score, the better the prognosis is for the AH patient. Patients with a Lille score below 0.45 have a 6-month survival rate of 85% vs. those with Lille scores of above 0.45, who have only a 25% 6-month survival rate (Louvet A et al. Hepatology 2007; 45: 1348-54). In our study, the median Lille score for the AH patients treated with DUR-928 was 0.10. 89% (16/18) had a Lille score below 0.45. The median Lille score among the UL cohort of 15 patients treated with either supportive care or supportive care with corticosteroids was 0.41, with 53% (8/15) having a Lille score below 0.45.

DUR-928 was well tolerated in all patients, with no drug-related serious adverse events reported at any dose level. Drug exposures were dose proportional and were not affected by the severity of the disease.

About the AH trial: Patients with moderate and severe AH were treated with intravenously administered DUR-928 in this open label, dose escalation multi-center U.S., Phase 2a clinical trial. Final enrollment was 19 patients comprised of: 8 patients (4 moderate and 4 severe) dosed at 30 mg, 7 patients (3 moderate and 4 severe) dosed at 90 mg and 4 patients (4 severe) dosed at 150 mg. The objectives of this study included assessment of safety, PK and pharmacodynamic (PD) signals, including liver biochemistry, biomarkers, and prognostic scores, including the Lille score, following DUR-928 treatment.

AH is an acute form of alcoholic liver disease (ALD), associated with long-term heavy intake of alcohol, and often occurs after a recent period of increased alcohol consumption. AH is typically characterized by recent onset jaundice and hepatic failure (Journal of Hepatology 2019, vol. 70; 314-318). An analysis of 77 studies published between 1971 and 2016, which included data from a total of 8,184 patients, showed the overall mortality from AH was 26% at 28 days (PLOS ONE | View Source, February 14, 2018). According to the most recent data provided by the Agency for Healthcare Research and Quality (AHRQ), a part of the US Department of Health and Human Services (HHS), there were over 117,000 hospitalizations for patients with alcoholic hepatitis in 2016. From a recent publication analyzing the mortality and costs associated with alcoholic hepatitis, the cost per patient is estimated at over $50,000 in the first year (Alcohol 2018:71:57-63). ALD is one of the leading causes of liver transplants in the US, each of which cost over $800,000.

Non-Alcoholic Steatohepatitis (NASH)

We have enrolled over half of the expected patients in a Phase 1b randomized and open-label clinical study being conducted in the U.S. to evaluate safety, pharmacokinetics and signals of biological activity of DUR-928 in NASH patients with stage 1-3 fibrosis. DUR-928 (at doses of 50 mg QD, 150 mg QD or 300 mg BID) is administered orally for 28 consecutive days with approximately 20 patients per dose group (targeting 15 evaluable) for a total of approximately 60 patients in the trial.

Key endpoints include safety, PK, and signals of biological activities, including clinical chemistry and biomarkers as well as liver fat content by imaging.

We expect to complete the study in the first half of 2020 and announce top-line study results following completion of the trial.

Psoriasis

We have completed enrollment in a Phase 2a, randomized, double-blind, vehicle-controlled proof-of-concept clinical trial, in which DUR-928 is applied topically once-daily for four weeks in patients with mild to moderate plaque psoriasis. The trial is being conducted at multiple clinical sites in the U.S. Over twenty patients have been enrolled with the goal of obtaining approximately 15 evaluable patients. Each patient serves as their own control, applying DUR-928 to the plaque on one arm and the vehicle (placebo) to a similar plaque on the other arm. After the treatment period, patients are followed for an additional four weeks. The primary efficacy endpoint is the change in local psoriasis scores from baseline in the DUR-928-treated plaques compared to the vehicle-treated plaques.

We expect to announce top line data from this study by the end of 2019.

POSIMIR (bupivacaine extended-release solution) Post-Operative Pain Relief Depot. POSIMIR is our investigational post-operative pain relief depot that utilizes our patented SABER technology and is designed to deliver bupivacaine to provide up to 3 days of pain relief after surgery.

In July 2019, the FDA agreed to file the submitted response to the Complete Response Letter (CRL) as a complete Class 2 Resubmission and initially assigned a user fee goal date of December 27, 2019. The FDA subsequently has tentatively scheduled an Advisory Committee meeting for January 16, 2020; a new user fee goal date has not been assigned.

The effort to evaluate the program, develop a strategy for filing the response, and preparing the response, has been under the direction of Dr. Lee Simon, who was formerly FDA’s Division Director of Analgesic, Anti-inflammatory and Ophthalmologic Drug Products. Dr. Simon is also leading our preparation efforts for the Advisory Committee meeting.

Gilead Agreement. In July 2019, we entered into an agreement with Gilead Sciences, Inc. (Gilead) granting Gilead the exclusive worldwide rights to develop and commercialize a long-acting injectable HIV investigational product utilizing our SABER technology. Gilead also received exclusive access to the SABER platform for HIV and Hepatitis B Virus (HBV) and the exclusive option to license additional SABER-based products directed to HIV and HBV. Under the terms of the agreement, Gilead made an upfront payment to us of $25 million, with the potential for up to an additional $75 million in development and regulatory milestones, up to an additional $70 million in sales-based milestones, as well as tiered royalties on product sales. In September 2019, we earned the first $10 million milestone payment under this program, which was received in the fourth quarter of 2019. Gilead has the exclusive option to license additional SABER-based products directed to HIV and HBV for an additional $150 million per product in upfront, development, regulatory and sales-based milestones as well as tiered royalties on sales. The parties will collaborate on specified development activities with Gilead controlling and funding the development programs.

Earnings Conference Call

We will host a conference call today at 4:30 p.m. Eastern Time/1:30 p.m. Pacific Time to discuss third quarter 2019 results and provide a corporate update:

Toll Free:877-407-0784

International:201-689-8560

Conference ID:13695661

Webcast:View Source

A live audio webcast of the presentation will also be available by accessing DURECT’s homepage at www.durect.com and clicking "Investors." If you are unable to participate during the live webcast, the call will be archived on DURECT’s website under "Event Calendar" in the "Investors" section.

On November 4, 2019 Endo International plc (NASDAQ: ENDP) reported third-quarter 2019 financial results, including (Press release, Endo Pharmaceuticals, NOV 4, 2019, View Source [SID1234550248]):

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Revenues of $729 million decreased 2% compared to third-quarter 2018 revenues of $745 million.
Branded Pharmaceuticals – Specialty Products revenues increased 18% to $132 million compared to third-quarter 2018 revenues of $112 million.
Sterile Injectables revenues increased 11% to $264 million compared to third-quarter 2018 revenues of $237 million.
Reported loss from continuing operations of $41 million compared to third-quarter 2018 reported loss from continuing operations of $146 million.
Reported diluted net loss per share from continuing operations of $0.18 compared to third-quarter 2018 reported diluted net loss per share from continuing operations of $0.65.
Adjusted income from continuing operations of $138 million compared to third-quarter 2018 adjusted income from continuing operations of $165 million.
Adjusted diluted net income per share from continuing operations of $0.60 compared to third-quarter 2018 adjusted diluted net income per share from continuing operations of $0.71.
Adjusted EBITDA of $321 million compared to third-quarter 2018 adjusted EBITDA of $328 million.
"Endo generated strong operating performance in the third quarter, which was led by continued year-over-year double-digit percentage revenue growth in our Sterile Injectables segment and in the Specialty Products portfolio of our Branded Pharmaceuticals segment, including 29% growth in our XIAFLEX franchise," said Paul Campanelli, President and Chief Executive Officer at Endo. "Additionally, during the quarter, we submitted a Biologics License Application for our CCH for Cellulite product with the FDA and settled the Track 1 opioid litigation cases. We believe that a balanced approach to executing our multi-year strategic plan while being responsive to the current external environment remains appropriate and that we are well-positioned to meet our 2019 financial guidance."

Reported Diluted Net Loss per Share from continuing operations is computed based on weighted average shares outstanding and, if there is income from continuing operations during the period, the dilutive impact of ordinary share equivalents outstanding during the period. In the case of Adjusted Diluted Weighted Average Shares, Adjusted Income from Continuing Operations is used in determining whether to include such dilutive impact.

CONSOLIDATED RESULTS

Total revenues were $729 million in third-quarter 2019 compared to $745 million during the same period in 2018. This decrease was primarily attributable to competitive pressures in the Generic Pharmaceuticals segment and the Established Products portfolio of the Branded Pharmaceuticals segment, partially offset by continued strong growth in the Sterile Injectables segment and the Specialty Products portfolio of the Branded Pharmaceuticals segment.

GAAP loss from continuing operations in third-quarter 2019 was $41 million compared to GAAP loss from continuing operations of $146 million during the same period in 2018. This result was primarily attributable to a decrease in asset impairment charges. GAAP diluted net loss per share from continuing operations in third-quarter 2019 was $0.18 compared to GAAP diluted net loss per share from continuing operations of $0.65 in third-quarter 2018.

Adjusted income from continuing operations in third-quarter 2019 was $138 million compared to $165 million in third-quarter 2018. This decrease was primarily attributable to lower adjusted gross margin in the Generic Pharmaceuticals segment due to a decline in revenue and an unfavorable change in product mix. Adjusted diluted net income per share from continuing operations in third-quarter 2019 was $0.60 compared to $0.71 in third-quarter 2018.

BRANDED PHARMACEUTICALS

Third-quarter 2019 Branded Pharmaceuticals revenues were $217 million compared to $220 million in third-quarter 2018. This decrease was primarily attributable to ongoing generic competition in the Established Products portfolio, offset by continued strong growth in the Specialty Products portfolio.

Specialty Products revenues increased 18% to $132 million in third-quarter 2019 compared to $112 million in third-quarter 2018, primarily driven by the continued strong performance of XIAFLEX. Sales of XIAFLEX increased 29% to $83 million compared to $64 million in third-quarter 2018, primarily attributable to demand growth in both the Peyronie’s Disease and Dupuytren’s Contracture indications driven by continued commercial execution and investment in promotional activities.

During third-quarter 2019, Endo also submitted a Biologics License Application to the U.S. Food and Drug Administration for its Collagenase Clostridium Histolyticum (CCH) product for the treatment of cellulite.

STERILE INJECTABLES

Third-quarter 2019 Sterile Injectables revenues were $264 million, an increase of 11% compared to $237 million in third-quarter 2018. This increase reflects the continued strong growth of VASOSTRICT and ADRENALIN, as well as strong growth of APLISOL, reflecting wholesalers’ restocking following a temporary supply shortage.

GENERIC PHARMACEUTICALS

Third-quarter 2019 Generic Pharmaceuticals revenues were $218 million, a decrease of 15% compared to $258 million in third-quarter 2018. This performance was primarily attributable to increased competitive pressure on certain generic products. Partially offsetting the decrease was the contribution of certain product launches including, among others, colchicine tablets, the authorized generic of Colcrys. During third-quarter 2019, the Generic Pharmaceuticals segment launched four products.

INTERNATIONAL PHARMACEUTICALS

Third-quarter 2019 International Pharmaceuticals revenues were $30 million, which was flat versus third-quarter 2018. This quarter benefited from delayed competition which Endo expects to materialize in the near-term.

2019 FINANCIAL GUIDANCE

Endo is updating its financial guidance for the 12 months ending December 31, 2019, narrowing the expected ranges regarding revenue, adjusted diluted net income per share from continuing operations, and Adjusted EBITDA. The Company now estimates:

Total revenues to be between $2.86 billion and $2.89 billion compared to previous guidance of $2.76 billion to $2.96 billion;
Adjusted diluted net income per share from continuing operations to be between $2.10 and $2.25 compared to previous guidance of $2.00 to $2.25; and
Adjusted EBITDA to be between $1.26 billion and $1.30 billion compared to previous guidance of $1.24 billion to $1.34 billion.
The Company’s 2019 non-GAAP financial guidance is based on the following assumptions:

Adjusted gross margin of approximately 64.7% to 65.7% compared to previous guidance of 65.0% to 66.0%;
Adjusted operating expenses as a percentage of revenue to be approximately 25.0% compared to 24.5% to 25.0%;
Adjusted interest expense of approximately $540 million compared to $550 million to $560 million;
Adjusted effective tax rate of approximately 16.5% compared to 17.5% to 18.5%; and
Adjusted diluted weighted average shares outstanding of approximately 234 million.
BALANCE SHEET, LIQUIDITY AND OTHER UPDATES

As of September 30, 2019, the Company had approximately $1.5 billion in unrestricted cash; debt of $8.4 billion; net debt of approximately $6.9 billion and a net debt to adjusted EBITDA ratio of 5.3.

Third-quarter 2019 cash provided by operating activities was $33 million, compared to $22 million of net cash used in operating activities during third-quarter 2018.

CONFERENCE CALL INFORMATION

Endo will conduct a conference call with financial analysts to discuss this press release on November 5, 2019 at 7:30 a.m. ET. The dial-in number to access the call is U.S./Canada (866) 497-0462, International (678) 509-7598, and the passcode is 1186004. Please dial in 10 minutes prior to the scheduled start time.

A replay of the call will be available from November 5, 2019 at 10:30 a.m. ET until 10:30 a.m. ET on November 8, 2019 by dialing U.S./Canada (855) 859-2056, International (404) 537-3406, and entering the passcode 1186004.

A simultaneous webcast of the call can be accessed by visiting View Source In addition, a replay of the webcast will be available on the Company website for one year following the event.

Products included within Other Specialty are NASCOBAL Nasal Spray and AVEED. Beginning with our first-quarter 2019 reporting, TESTOPEL, which was previously included in Other Specialty, has been reclassified and is now included in the Established Products portfolio for all periods presented.

Products included within Other Established include, but are not limited to, LIDODERM, VOLTAREN Gel, EDEX, FORTESTA Gel and TESTIM, including the authorized generics of FORTESTA Gel and TESTIM.

Individual products presented above represent the top two performing products in each product category for either the three or nine months ended September 30, 2019 and/or any product having revenues in excess of $25 million during any quarterly period in 2019 or 2018.

Products included within Other Sterile Injectables include ephedrine sulfate injection and others.

SUPPLEMENTAL FINANCIAL INFORMATION

To supplement the financial measures prepared in accordance with U.S. generally accepted accounting principles (GAAP), the Company uses certain non-GAAP financial measures. For additional information on the Company’s use of such non-GAAP financial measures, refer to Endo’s Current Report on Form 8-K furnished today to the U.S. Securities and Exchange Commission, which includes an explanation of the Company’s reasons for using non-GAAP measures.

The tables below provide reconciliations of certain of our non-GAAP financial measures to their most directly comparable GAAP amounts. Refer to the "Notes to the Reconciliations of GAAP and Non-GAAP Financial Measures" section below for additional details regarding the adjustments to the non-GAAP financial measures detailed throughout this Supplemental Financial Information section.

Reconciliation of Adjusted Income from Continuing Operations (non-GAAP)

The following table provides a reconciliation of our Loss from continuing operations (GAAP) to our Adjusted income from continuing operations (non-GAAP) for the three and nine months ended September 30, 2019 and 2018 (in thousands):

Reconciliation of Other Adjusted Income Statement Data (non-GAAP)

The following tables provide detailed reconciliations of various other income statement data between the GAAP and non-GAAP amounts for the three and nine months ended September 30, 2019 and 2018 (in thousands, except per share data):

Notes to the Reconciliations of GAAP and Non-GAAP Financial Measures

Notes to certain line items included in the reconciliations of the GAAP financial measures to the Non-GAAP financial measures for the three and nine months ended September 30, 2019 and 2018 are as follows:

Adjustments for amortization of commercial intangible assets included the following (in thousands):

To exclude adjustments for inventory step-up.

Adjustments for upfront and milestone-related payments to partners included the following (in thousands):

To exclude charges reflecting adjustments to excess inventory reserves related to our various restructuring initiatives.

Adjustments for retention and separation benefits and other restructuring included the following (in thousands):

To exclude adjustments to our accruals for litigation-related settlement charges and certain settlement proceeds related to suits filed by our subsidiaries.

Adjustments for acquisition and integration items primarily relate to various acquisitions.

To exclude the impact of changes in the fair value of contingent consideration liabilities resulting from changes to our estimates regarding the timing and amount of the future revenues of the underlying products and changes in other assumptions impacting the probability of incurring, and extent to which we could incur, related contingent obligations.

To exclude the gain on the extinguishment of debt associated with our March 2019 refinancing.

Other miscellaneous during the three and nine months ended September 30, 2019 includes $14.1 million in Operating expenses for a premium associated with an extended reporting period endorsement on an expiring insurance program and $17.5 million in Other non-operating expenses for contract termination costs incurred as a result of certain product discontinuation activities in our International Pharmaceuticals segment.

Adjusted income taxes are calculated by tax effecting adjusted pre-tax income and permanent book-tax differences at the applicable effective tax rate that will be determined by reference to statutory tax rates in the relevant jurisdictions in which the Company operates. Adjusted income taxes include current and deferred income tax expense commensurate with the non-GAAP measure of profitability.

To exclude the results of the businesses reported as discontinued operations, net of tax.

Calculated as Net (loss) income from continuing operations divided by the applicable weighted average share number. The applicable weighted average share numbers are as follows (in thousands):

Depreciation and amortization per the Adjusted EBITDA reconciliations do not include certain depreciation amounts reflected in other lines of the reconciliations,

including Acquisition-related and integration costs and Retention and separation benefits and other restructuring.

To exclude Other expense (income), net per the Condensed Consolidated Statements of Operations.

Reconciliation of Net Debt Leverage Ratio (non-GAAP)

The following table provides a reconciliation of our Net loss (GAAP) to our Adjusted EBITDA (non-GAAP) for the twelve months ended September 30, 2019 (in thousands) and the calculation of our Net Debt Leverage Ratio (non-GAAP):