10-Q – Quarterly report [Sections 13 or 15(d)]

(Filing, 10-Q, PTC Therapeutics, JUL 31, 2015, View Source [SID:1234506781])

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!


ZAI Lab announces a global licensing agreement with Sanofi for a novel
compound to potentially treat NSCLC

On July 31, 2015 ZAI Lab Limited (ZAI Lab), an innovative biotech company based in China reported that it has entered into a global licensing agreement with Sanofi for a novel multi-kinase inhibitor for the potential treatment of non-small cell lung cancer and other oncology indications (Press release, Zai Laboratory, JUL 31, 2015, View Source [SID:SID1234515698]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Under the terms of the agreement, ZAI Lab will be responsible for global development, manufacturing and commercialization of this novel product. Sanofi will potentially receive development and regulatory approval milestones and tiered royalties from the global net sales of the licensed product. Additional terms of the agreement were not disclosed.

Dr. Samantha Du, founder and CEO of ZAI Lab said: "NSCLC is a serious disease with large patient population and unmet medical needs in the world, especially in China. We are very excited to partner with Sanofi on this innovative program that may significantly improve patients’ survival outlook and quality of life."

ImmunoGen, Inc. Reports Fourth Quarter and Fiscal Year 2015 Financial Results

On July 31, 2015 ImmunoGen, Inc. (Nasdaq: IMGN), a biotechnology company that develops novel anticancer therapeutics using its antibody-drug conjugate (ADC) technology, reported financial results for the Company’s 2015 fiscal year ended June 30, 2015 (Press release, ImmunoGen, JUL 31, 2015, View Source [SID:1234506779]). ImmunoGen also provided an update on product programs and guidance for its 2016 fiscal year.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"This is clearly a transformational year for ImmunoGen," commented Daniel Junius, President and CEO. "Our lead product candidate, mirvetuximab soravtansine, has demonstrated impressive single-agent activity against platinum-resistant ovarian cancer in early clinical testing, and we are on track to initiate a trial later this year that could potentially support an accelerated registration pathway. We are also preparing to start a separate trial by year end to assess mirvetuximab soravtansine used in combination with other anticancer agents to potentially help more patients benefit from this promising agent, including women with earlier-stage disease. We plan to start the clinical assessment of our IMGN529 ADC in combination with rituximab shortly, with combination assessment of our other promising ADC for B-cell malignancies, coltuximab ravtansine, expected to start in 2016. And we are on track to submit an IND this fall for our next novel anticancer agent, IMGN779, which utilizes one of our potent new IGN payload agents."

Mr. Junius continued, "In the coming months, we also expect the progress being made by ImmunoGen partners to become more visible, with several programs on track to advance into potential registration trials in 2016, and other programs moving toward IND filing and the start of clinical testing. We believe our product pipeline will look markedly different – in stage and breadth – a year from now."

Updates on Product Programs

Mirvetuximab soravtansine (IMGN853), a potential new therapy for many cases of ovarian cancer as well as for other solid tumors that highly express folate receptor α (FRα); wholly owned by ImmunoGen.

Data presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting in May showed that treatment with mirvetuximab soravtansine monotherapy achieved marked tumor shrinkage in 53% of patients with FRα-positive platinum-resistant ovarian cancer in the expansion cohort of a Phase I trial. The enrollment of patients into this expansion cohort is expected to complete by year end, with presentation of the findings for the full 40-patient cohort anticipated in mid-2016.

ImmunoGen plans to initiate a Phase 2 trial assessing mirvetuximab soravtansine as a single agent for FRα-positive pre-treated ovarian cancer in late 2015; this trial potentially could support an accelerated registration pathway.

The Company also is preparing to start by year end a Phase 1b/2 trial assessing this ADC in combination regimens for FRα-positive ovarian cancer.

FRα is highly expressed on cases of many different types of solid tumors, including endometrial, breast, and lung cancers. Mirvetuximab soravtansine currently is being evaluated in a Phase 1 expansion cohort for the treatment of relapsed/refractory endometrial cancer, with other potential uses being assessed preclinically.

The Company recently established a collaboration with the National Comprehensive Cancer Network’s Oncology Research Program to facilitate assessment of mirvetuximab soravtansine in a variety of preclinical and clinical settings.

IMGN529 and coltuximab ravtansine (SAR3419), CD37- and CD19-targeting ADCs, respectively, are potential treatments for diffuse large B-cell lymphoma (DLBCL) and other B-cell malignancies; both are wholly owned by ImmunoGen.

The Company plans to begin assessment of IMGN529 for DLBCL in combination with rituximab later this year. Preclinical findings with this combination were presented in June, with additional data planned for submission to a medical conference in December. ImmunoGen also expects to begin assessment of IMGN529, used as a single agent, for the treatment of chronic lymphocytic leukemia in 2H2015.

For coltuximab ravtansine, ImmunoGen is assessing alternative combination strategies and expects to initiate combination clinical testing in 2016.

IMGN779, a CD33-targeting ADC utilizing one of ImmunoGen’s DNA-acting payload agents; a potential treatment for acute myeloid leukemia and myelodysplastic syndrome; wholly owned by ImmunoGen.

Remains on track for IND submission in 2H2015.
Anticipated events for partner product programs include:

Kadcyla (ado-trastuzumab emtansine) – Roche expects to apply for marketing approval in 2016 for second-line treatment of HER2-positive advanced gastric cancer using the results from its GATSBY trial, if positive;
ImmunoGen expects up to three partner compounds to advance into potentially pivotal Phase 2 or Phase 3 testing in 2016;
The Company anticipates several of its partners will have clinical data presentations in the next 12 months; and
ImmunoGen expects 2 to 4 additional partner compounds to advance into clinical testing by mid-2016.

Fiscal Year 2015 Financial Results

For the Company’s fiscal year ended June 30, 2015 (FY2015), ImmunoGen reported a net loss of $60.7 million, or $0.71 per basic and diluted share, compared to a net loss of $71.4 million, or $0.83 per basic and diluted share, for its fiscal year ended June 30, 2014 (FY2014). For the quarter ending June 30, 2015, ImmunoGen reported a net loss of $30.5 million, or $0.35 per basic and diluted share, compared to a net loss of $26.5 million, or $0.31 per basic and diluted share, for the same quarter in FY2014.

Revenues in FY2015 were $85.5 million, compared to $59.9 million in FY2014. FY2015 revenues include $57.8 million of license and milestone fees compared to $39.5 million in FY2014, with the increase primarily due to more development and commercialization licenses being taken by Novartis and Lilly in FY2015 and the associated amortization of upfront license fees, as well as increased revenue from milestone payments. FY2015 revenues also include $2.8 million of research and development support fees, compared to $7.2 million in such fees for FY2014, and $5.5 million of clinical materials revenue, compared to $2.9 million for FY2014. The level of research support and the number of batches of clinical materials produced and released to partners varies on a year-to-year basis.

FY2015 revenues also include $13.9 million of cash royalty revenues and $5.5 million of non-cash royalty revenues on Roche sales of Kadcyla for the nine-months ended December 31, 2014 and three months ended March 31, 2015, respectively. The latter reflects that royalties on Kadcyla sales occurring after January 1, 2015 are covered by the royalty purchase agreement announced in March 2015, and thus the associated cash is remitted to Immunity Royalty Holdings L.P. In FY2014, royalty payments received on sales of Kadcyla during the twelve months ended March 31, 2014 totaled $10.3 million.

Operating expenses in FY2015 were $140.0 million, compared to $131.4 million in FY2014. FY2015 operating expenses include research and development expenses of $111.8 million, compared to $107.0 million in FY2014 (inclusive of a $12.8 million non-cash charge related to a collaboration established with CytomX). The increase in FY2015 is primarily due to greater third-party costs related to the advancement of ImmunoGen product candidates, increased costs associated with the manufacturing of clinical materials on behalf of our partners, and higher personnel expenses, principally due to recent hiring. Operating expenses also include general and administrative expenses of $28.2 million in FY2015, compared to $24.5 million in FY2014. This increase is primarily due to greater personnel expenses, patent expenses and third-party service fees.

FY2015 expenses also include $5.4 million in imputed non-cash interest expense related to the sale of future Kadcyla royalties, which is treated as a liability for accounting purposes. ImmunoGen will be recording non-cash interest expense related to this transaction on an on-going basis.

ImmunoGen had approximately $278.1 million in cash and cash equivalents as of June 30, 2015, compared with $142.3 million as of June 30, 2014 and had no debt outstanding in either period. Cash used in operations was $55.3 million in FY2015, compared with $53.7 million in FY2014. Capital expenditures were $7.4 million and $8.2 million for FY2015 and FY2014, respectively.

Financial Guidance for 2016 Fiscal Year

For its fiscal year ending June 30, 2016, ImmunoGen expects: its revenues to be between $70 million and $80 million; its operating expenses to be between $175 million and $180 million; its net loss to be between $120 million and $125 million; its cash used in operations to be between $100 million and $105 million; and its capital expenditures to be between $13 million and $15 million. Cash and marketable securities at June 30, 2016 are anticipated to be between $165 million and $170 million.

Conference Call Information

ImmunoGen is holding a conference call today at 8:00 am ET to discuss these results. To access the live call by phone, dial 913-312-0951; the conference ID is 2265897. The call also may be accessed through the Investors section of the Company’s website, www.immunogen.com. Following the live webcast, a replay of the call will be available at the same location through August 14, 2015.

NewLink Genetics Corporation Provides Operational Update and Reports Second Quarter 2015 Financial Results

On July 31, 2015 NewLink Genetics Corporation (NASDAQ:NLNK), a biopharmaceutical company at the forefront of developing and commercializing novel immuno-oncology product candidates to improve the lives of patients with cancer, reported consolidated financial results for the second quarter of 2015 and progress in its clinical and business development programs (Press release, NewLink Genetics, JUL 31, 2015, View Source [SID:1234506780]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"NewLink Genetics continues to drive forward, and to execute on, its strategy of developing treatment options for patients with cancer using targeted immune response and disruptive checkpoint blockade," said Dr. Charles Link, Chairman and Chief Executive Officer. "We have seven product candidates across multiple cancer types in clinical development from Phase 1 to Phase 3. Our combined platform of product candidates positions us well to execute on our vision of combining cancer vaccines and checkpoint blockade inhibitors through our HyperAcute Immunotherapy and indoleamine 2,3-dioxygenase (IDO) pathway inhibitor platforms."

"During the second quarter, we continued our planned hiring and pre-commercial activities relating to our HyperAcute Immunotherapy algenpantucel-L, which is being studied for adjuvant treatment of patients with surgically resected pancreatic cancer," said Dr. Nicholas Vahanian, President and Chief Medical Officer.

The Company continued to build its presence with key opinion leaders by having a booth and poster presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. The poster (#2070) highlighted encouraging results of the Phase 1b portion of a study showing that the combination of indoximod and temozolomide in temozolomide-refractory patients with progressive or refractory glioblastoma was well tolerated, with preliminary evidence of efficacy. Enrollment of the Phase 2 portion of the study is underway.

In addition, the Company hosted its first-ever analyst day on July 14, outlining its vision and execution plans surrounding its clinical programs. A webcast of the Company’s presentations can be found at View Source

Program Updates:

HyperAcute Immunotherapy Cancer Programs
NewLink Genetics’ proprietary HyperAcute Immunotherapy programs may prove to have broad potential for patients across a spectrum of cancer indications, including use in combination with checkpoint inhibitors. NewLink Genetics has multiple HyperAcute Immunotherapy programs in various stages of clinical development, including for pancreatic cancer, lung cancer, melanoma, renal cell cancer and prostate cancer.

Algenpantucel-L is NewLink Genetics’ HyperAcute Immunotherapy pancreatic cancer candidate in a Phase 3 clinical trial called IMPRESS, or IMmunotherapy for Pancreatic RESsectable Cancer Study. During the second quarter, following the second interim analysis of the study, the Company announced the recommendation of the data safety monitoring committee to proceed without modification to final analysis. The Company has announced that at the time of the second interim analysis, the estimated blended median overall survival in the trial from the time of randomization was 28.5 months for all patients. Median time from surgery to randomization was approximately 1.5 months. Therefore median survival from surgery was estimated to be approximately 30 months for all patients in our study. We believe that the median months of overall survival from randomization in the control arm is in the low twenties. The study is powered to show an improvement in overall survival after 442 events.

PILLAR, or Pancreatic Immunotherapy with Algenpantucel-L for Locally Advanced Non-Resectable Disease, is our Phase 3 clinical trial studying the efficacy of algenpantucel-L in patients with borderline resectable or locally advanced pancreatic cancer. We expect to complete enrollment in this study during 2015.

NewLink Genetics’ HyperAcute Immunotherapy product candidate tergenpumatucel-L is being tested versus docetaxel in a randomized Phase 2b study in patients with advanced lung cancer. We are currently enrolling patients in this study.

HyperAcute Immunotherapy product candidate dorgenmeltucel-L for patients with melanoma is being evaluated in a randomized Phase 2 study in combination with the checkpoint inhibitors ipilimumab, nivolumab, and pembrolizumab versus these checkpoint inhibitors alone.

IDO Pathway Inhibitor Programs

NewLink Genetics’ proprietary IDO pathway inhibitor, indoximod, is in multiple Phase 1 and Phase 2 clinical trials for the treatment of patients with breast, prostate, pancreatic and brain cancers as well as melanoma. We expect to complete enrollment of the following studies with indoximod within the next 12-15 months.

NLG2101, a global randomized Phase 2 trial testing indoximod in combination with docetaxel or paclitaxel in patients with metastatic breast cancer, is expected to fully enroll by the end of 2015. NewLink Genetics intends to present preliminary data from this study at an upcoming medical meeting in 2015.

NLG2102 is a Phase 2 trial of the combination of indoximod and temozolomide in refractory or relapsed glioblastoma multiforme patients.

NLG2103 is a Phase 2 trial testing indoximod in combination with the checkpoint inhibitors ipilimumab, nivolumab or pembrolizumab in patients with advanced melanoma. We expect to report top-line Phase 1b results at the Immunotherapy in Cancer Poster Session of the ESMO (Free ESMO Whitepaper)/ECC meeting in Vienna on Saturday, September 26 (#248, abstract 514).

NLG2104 is in a Phase 1b/2 trial testing indoximod in combination with gemcitabine plus nab-paclitaxel in patients with metastatic pancreatic cancer. Top-line Phase 1b results are expected in 2016.

NewLink Genetics has also entered into an exclusive worldwide license and collaboration agreement with Genentech, a member of the Roche Group, for the development of the IDO inhibitor GDC-0919. Based on pre-clinical data presented at ASCO (Free ASCO Whitepaper) by our partner, GDC-0919 demonstrated decreases in plasma kynurenine levels and regulatory T-cells as well as an anti-tumor efficacy when combined with anti-PD-L1 and anti-CTLA4. This product candidate is currently in Phase 1 clinical development in patients with advanced solid tumors, and Phase 1 data on GDC-0919 is expected to be presented in a poster presentation at the ESMO (Free ESMO Whitepaper)/ECC meeting in Vienna on Sunday, September 27 (#157, abstract 346). In addition, a Phase 1 clinical trial, with a planned enrollment target of 224 patients, will study GDC-0919 in combination with Genentech’s PD-L1 inhibitor MPDL3280A for patients with locally advanced or metastatic solid tumors. An additional study is planned for GDC-0919 in combination with an OX40 inhibitor.

Financial Results for the Three-Month Period Ended June 30, 2015

Cash Position: NewLink Genetics ended the quarter on June 30, 2015, with cash and equivalents totaling $207.6 million, compared to $202.8 million for the year ending December 31, 2014.

R&D Expenses: Research and development expenses in the second quarter of 2015 were $16.1 million, compared to $6.5 million during the comparable period in 2014. The increase is primarily due to clinical trial expenses related to NewLink Genetics’ broad pipeline of product candidates, as well as expenses for manufacturing and research related to the Ebola vaccine candidate. Most of the Ebola-related expenses are subject to reimbursement under government contracts.

Net Income/Loss: NewLink Genetics reported a net loss of $14.1 million, or ($0.49) per diluted share, for the second quarter of 2015, compared to a net loss of $9.2 million, or ($0.33) per diluted share, for the comparable period in 2014.

NewLink Genetics ended the quarter with 28,661,588 shares outstanding.

Financial Guidance

NewLink Genetics expects to have more than $160 million in cash and equivalents on December 31, 2015.

"Our research and development expenses and capital expenditures continue to reflect our commitment to developing a broad pipeline of drug candidates and to ensure that we have the infrastructure in place to support the commercialization and manufacturing of algenpantucel-L," said Jack Henneman, Executive Vice President and Chief Financial Officer. "We will continue to make significant investments for the remainder of 2015 to support these efforts."

Takeda Announces Completion of the Pioglitazone Post-Marketing Commitment and Submission of Results to the EMA, the FDA and the PMDA

On July 31, 2015 Takeda Pharmaceutical Company Limited ("Takeda") reported the completion of the study to fulfill the post-marketing commitment and submissions of data to regulatory authorities from the Pan European Multi-Database Bladder Cancer Risk Characterization Study, a large (n= 112,674), multi-database retrospective matched cohort study, conducted in four European countries, for pioglitazone containing medicines, including ACTOS (pioglitazone HCI) with up to 10 years of follow-up (Press release, Takeda, JUL 30, 2015, View Source [SID:1234506785]). Findings demonstrate that there is no association between the use of pioglitazone and the risk of bladder cancer, (hazard ratio [HR] 0.99 [95% CI: 0.75, 1.30]). These results are consistent with those of a 10-year, prospective cohort study, conducted by the University of Pennsylvania (U. of Penn.) and Division of Research at Kaiser Permanente Northern California (KPNC), which demonstrated no increased risk of bladder cancer among patients ever exposed to pioglitazone ([HR] 1.06 [95% CI 0.89-1.26]).1 Additionally, both studies found no association between the risk of bladder cancer and cumulative dose of pioglitazone, or duration of pioglitazone exposure.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"ACTOS is an important treatment option for patients with Type 2 diabetes. These data further reinforce the positive benefit/risk profile for ACTOS," said Alfonso Perez, MD, vice president, clinical research, Takeda. "These long-term studies underscore Takeda’s commitment to ensuring physicians have the best available information to make treatment decisions."

The data from the Pan European Multi-Database Bladder Cancer Risk Characterization Study also shows a mortality decrease with ever use of pioglitazone (adjusted HR 0.67 [95% CI: 0.64, 0.70]).This study was completed as part of the post-marketing request from the Committee for Medicinal Products for Human Use (CHMP). In addition to the European Medicines Agency (EMA), the results from the Pan European study were also submitted to the U.S. Food and Drug Administration (FDA) and the Japanese Ministry of Health, Labour and Welfare (MHLW)/Pharmaceuticals and Medical Devices Agency (PMDA). The data will be shared with additional regulatory authorities in accordance with local requirements around the world.

"Patient safety remains a top priority for Takeda," said Perez. "Throughout a product’s lifecycle we continue to monitor and conduct additional research to further our knowledge. This milestone is an important example of Takeda’s commitment to conducting further research and sharing the outcomes with regulatory agencies, physicians, and others."

About the Study
The retrospective cohort study of the European Union (EU) medical record databases was conducted using six medical records databases across four countries, including Finland, The Netherlands, Sweden, and the United Kingdom. Type 2 diabetes patients treated with pioglitazone were matched equally with patients with similar characteristics who were not treated with pioglitazone. Patients were matched based on diabetes duration, diabetes complications, cardiovascular complications, and previous antidiabetic drug use. This study design was developed to minimize treatment allocation bias, an issue seen in some previous epidemiological studies of pioglitazone.

About Pioglitazone
Pioglitazone is a thiazolidinedione for the treatment of Type 2 diabetes in adults as an adjunct to diet and exercise.

Unlike many oral antidiabetic drugs, pioglitazone is not an insulin secretagogue. Pioglitazone is an agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism. Therefore, pioglitazone is a medication that depends on the presence of insulin for its mechanism of action, and it decreases insulin resistance in muscle and the liver, resulting in increased insulin-dependent glucose disposal as well as decreased hepatic glucose output.

Clinical studies demonstrate that pioglitazone improves insulin sensitivity in insulin-resistant patients. Pioglitazone enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal and improves hepatic sensitivity to insulin. In patients with Type 2 diabetes, the decreased insulin resistance produced by pioglitazone results in lower plasma glucose concentrations, lower plasma insulin concentrations, and lower HbA1c values. In controlled clinical trials, pioglitazone had an additive effect on glycemic control when used in combination with sulfonylurea, metformin, or insulin.

Important Safety Information
Contraindications
Initiation of ACTOS is contraindicated in patients with NYHA Class III or IV heart failure.

ACTOS is contraindicated in patients with known hypersensitivity to pioglitazone or any of its excipients so as to avoid inducing a potentially serious hypersensitivity reaction.

Warnings and Precautions
Fluid retention and cardiac failure: Thiazolidinediones, including ACTOS, can cause dose-dependent fluid retention, which may exacerbate or precipitate heart failure. After initiation of ACTOS, and after dose increases, monitor patients carefully for signs and symptoms of heart failure (e.g., excessive, rapid weight gain, dyspnea, and/or edema). If heart failure develops, discontinuation of ACTOS must be considered. ACTOS should be used with caution in patients with cardiac dysfunction whose physical activity is markedly limited. Combination use with insulin may increase risk.

Hepatic effects: Post-marketing reports of hepatitis and hepatic dysfunction have been received. Very rarely these reports have involved hepatic failure, with and without a fatal outcome, although causality has not been established. Obtain liver tests before starting ACTOS and periodically thereafter. Pioglitazone therapy should not be initiated in patients with increased liver enzyme levels (ALT> 2.5x upper limit of normal) or with any other evidence of liver disease. Existing pioglitazone therapy should be discontinued if ALT levels are persistently higher than 3x the upper limit of normal, and symptoms suggesting hepatic dysfunction should cause the liver enzymes to be checked. Pending the results of laboratory investigations, the decision as to whether pioglitazone therapy should continue must be based on clinical judgment; in the presence of jaundice, drug therapy should be discontinued.

Weight gain: Weight gain was observed in clinical trials and has been seen in post-marketing experience with pioglitazone, so patient weight should be closely monitored.

Fractures: An increased incidence of bone fracture has been noted in female patients.

Bladder cancer: Some data suggest there may be an increased risk of bladder cancer in ACTOS users and also that the risk increases with duration of use. Do not use ACTOS in patients with active bladder cancer. Use caution when using in patients with a prior history of bladder cancer. Tell patients to promptly report any sign of macroscopic hematuria or other symptoms such as dysuria or urinary urgency that develop or increase during treatment as these may be due to bladder cancer.

Hypoglycemia: When ACTOS is used with insulin, a sulfonylurea or other oral hypoglycemic agents, hypoglycemia may occur.

Ovulation: Ovulation in premenopausal anovulatory women or women with polycystic ovarian syndrome may occur with ACTOS.

Macular edema: Post-marketing reports of new-onset or worsening diabetic macular edema with decreased visual acuity have been reported with thiazolidinediones, including pioglitazone. Physicians should consider the possibility of macular edema if a patient reports decreased visual activity.

Drug interactions: Use of ACTOS with CYP2C8 inducers or strong inhibitors may require dose adjustment.
Please refer to the Summary of Product Characteristics (SmPC) for ACTOS before prescribing.

ACTOS should be used according to the indication, posology and method of administration described in the SmPC.

Please consult with your local regulatory agency for approved labeling in your country.