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News Article | May 15, 2017
Site: globenewswire.com

SOLANA BEACH, Calif., May 15, 2017 (GLOBE NEWSWIRE) -- Evoke Pharma, Inc. (NASDAQ:EVOK), a specialty pharmaceutical company focused on treatments for gastrointestinal diseases, today announced its financial results for the first quarter ended March 31, 2017. Dave Gonyer, R.Ph., President and CEO, stated, “We started 2017 with a number of positive developments that bring us closer to filing the 505(b)(2) NDA for Gimoti™. This includes reaching agreement with FDA that a Human Factors (HF) Validation Study, a requirement for drug/device combinations, is not needed for Gimoti. Additionally, before the close of the quarter, we completed a positive Type A meeting in which FDA confirmed the acceptability of the design of our planned comparative exposure PK study for Gimoti, as well as certain other chemistry, manufacturing & controls (CMC) items associated with the proposed NDA. This PK trial in healthy volunteers, which is designed to establish comparative exposure of Gimoti to the listed drug, Reglan® Tablets, will serve in part as the basis for a 505(b)(2) NDA submission for Gimoti. We recently announced our partnership with Spaulding Clinical Research to conduct the PK trial and expect to initiate and complete the study in the second half of 2017. Finally, we believe that the pre-NDA agreements with FDA further reduce potential risks and save additional resources as we continue to prepare the NDA for submission in late 2017 or early 2018.” Mr. Gonyer continued, “From a financial perspective, Evoke completed a capital raise in March, which significantly enhanced our balance sheet and will allow us to complete the PK trial and focus on the NDA filing. We believe this capital infusion confirms our investors’ confidence in our strategy and intent to seek approval for Gimoti as rapidly and efficiently as possible. As we look forward to the rest of the year, we believe there is a clear path for an NDA submission and we are working hard to bring Gimoti to those patients suffering from diabetic gastroparesis.” For the first quarter of 2017, net loss was approximately $5.1 million, or $(0.37) per share, compared to a net loss of approximately $3.2 million, or $(0.45) per share, for the three-month period ended March 31, 2016. The year-over-year increase in net loss was primarily due to adjusting for the fair value of the warrant liability at March 31, 2017, which resulted in a significant non-cash expense. Research and development expenses totaled approximately $771,000 for the three months ended March 31, 2017, compared to approximately $2.0 million for the three months ended March 31, 2016. The decrease was due primarily to the expenses related to our Phase 3 clinical trial which was still being conducted during the three months ended March 31, 2016.  This trial was completed in the second quarter of 2016 and the analysis of the trial data occurred during the second half of 2016. For the first quarter of 2017, general and administrative expenses were approximately $1.2 million compared with approximately $1.1 million for the first quarter of 2016. Total operating expenses for the three months ended March 31, 2017 were approximately $2.0 million, compared to total operating expenses of approximately $3.2 million for the three months ended March 31, 2016. Included in net loss for the first quarter of 2017 was an increase of net loss due to the change in the fair value of the warrant liability of approximately $3.1 million.  The warrant liability is subject to remeasurement at each reporting period and we recognize any change in the fair value of the warrant liability in the statement of operations.  We anticipate that the value of the warrants could fluctuate from quarter to quarter and that such fluctuation could have a material impact on our financial statements from quarter to quarter and year to year. In March 2017, we completed a public offering of approximately 2.8 million shares of common stock at $2.90 per share, with gross proceeds of approximately $8.0 million, before underwriting discounts and commissions and estimated offering costs. As of March 31, 2017, our cash and cash equivalents were approximately $14.7 million. Evoke will hold a conference call on Monday, May 15, 2017, at 4:30 pm ET to discuss the results. Participants should dial 1-877-407-0789 (United States) or 1-201-689-8562 (International) and mention Evoke Pharma. A live webcast of the conference call will also be available on the investor relations page of the Company's corporate website at www.evokepharma.com. After the live webcast, the event will be archived on Evoke's website for one year. In addition, a telephonic replay of the call will be available until May 22, 2017. The replay can be accessed by dialing 1-844-512-2921 (United States) or 1-412-317-6671 (International) with confirmation code 13660963. Evoke is a specialty pharmaceutical company focused primarily on the development of drugs to treat GI disorders and diseases. The Company is developing Gimoti, a metoclopramide nasal spray for the relief of symptoms associated with acute and recurrent gastroparesis in women with diabetes mellitus. Diabetic gastroparesis is a GI disorder afflicting millions of sufferers worldwide, in which the stomach takes too long to empty its contents resulting in serious digestive system symptoms. Metoclopramide is the only product currently approved in the United States to treat gastroparesis, and is currently available only in oral and intravenous forms. Gimoti is a novel formulation of this drug, designed to provide systemic delivery of metoclopramide through nasal administration. Visit www.EvokePharma.com for more information. Evoke cautions you that statements included in this press release that are not a description of historical facts are forward-looking statements. In some cases, you can identify forward-looking statements by terms such as "may," "will," "should," "expect," "plan," "anticipate," "could," "intend," "target," "project," "contemplates," "believes," "estimates," "predicts," "potential" or "continue" or the negatives of these terms or other similar expressions. These statements are based on the Company's current beliefs and expectations. These forward-looking statements include statements regarding: the clear path forward with respect to submission of an 505(b) (2) NDA submission for Gimoti based on a comparative exposure PK trial; Evoke’s plans to initiate and complete the PK trial and submit the NDA and potentially receive regulatory approval of Gimoti; and the timing thereof, and Evoke’s expectation that it will not need to raise additional capital to complete the comparative exposure PK trial and submit the NDA for Gimoti. The inclusion of forward-looking statements should not be regarded as a representation by Evoke that any of its plans will be achieved. Actual results may differ from those set forth in this press release due to the risks and uncertainties inherent in Evoke's business, including, without limitation: risks associated with successfully commencing and receiving favorable results from the planned comparative exposure PK trial; later developments with the FDA that may be inconsistent with the already completed pre- NDA meetings, including inconsistent conclusions reflected in the official meeting minutes from the FDA; the inherent risks of clinical development of Gimoti; Evoke is entirely dependent on the success of Gimoti, and Evoke cannot be certain that it will be able to submit an NDA for Gimoti or obtain regulatory approval for or successfully commercialize Gimoti; risks associated with manufacturing new formulations of Gimoti for use in the comparative exposure PK trial; Evoke’s dependence on third parties for the manufacture of Gimoti as well as the conduct of the PK trial; Evoke may require additional funding to complete the PK trial and submit the NDA, and will require substantial additional funding to commercialize Gimoti, and may be unable to raise capital when needed, including to fund ongoing operations; Evoke may not be able to successfully commercialize Gimoti, if approved, as a result of risks associated with market acceptance, coverage and reimbursement and competing products; and other risks detailed in Evoke's prior press releases and in the periodic reports it files with the Securities and Exchange Commission. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and Evoke undertakes no obligation to revise or update this press release to reflect events or circumstances after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement. This caution is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995.


News Article | May 15, 2017
Site: globenewswire.com

SOLANA BEACH, Calif., May 15, 2017 (GLOBE NEWSWIRE) -- Evoke Pharma, Inc. (NASDAQ:EVOK), a specialty pharmaceutical company focused on treatments for gastrointestinal diseases, today announced its financial results for the first quarter ended March 31, 2017. Dave Gonyer, R.Ph., President and CEO, stated, “We started 2017 with a number of positive developments that bring us closer to filing the 505(b)(2) NDA for Gimoti™. This includes reaching agreement with FDA that a Human Factors (HF) Validation Study, a requirement for drug/device combinations, is not needed for Gimoti. Additionally, before the close of the quarter, we completed a positive Type A meeting in which FDA confirmed the acceptability of the design of our planned comparative exposure PK study for Gimoti, as well as certain other chemistry, manufacturing & controls (CMC) items associated with the proposed NDA. This PK trial in healthy volunteers, which is designed to establish comparative exposure of Gimoti to the listed drug, Reglan® Tablets, will serve in part as the basis for a 505(b)(2) NDA submission for Gimoti. We recently announced our partnership with Spaulding Clinical Research to conduct the PK trial and expect to initiate and complete the study in the second half of 2017. Finally, we believe that the pre-NDA agreements with FDA further reduce potential risks and save additional resources as we continue to prepare the NDA for submission in late 2017 or early 2018.” Mr. Gonyer continued, “From a financial perspective, Evoke completed a capital raise in March, which significantly enhanced our balance sheet and will allow us to complete the PK trial and focus on the NDA filing. We believe this capital infusion confirms our investors’ confidence in our strategy and intent to seek approval for Gimoti as rapidly and efficiently as possible. As we look forward to the rest of the year, we believe there is a clear path for an NDA submission and we are working hard to bring Gimoti to those patients suffering from diabetic gastroparesis.” For the first quarter of 2017, net loss was approximately $5.1 million, or $(0.37) per share, compared to a net loss of approximately $3.2 million, or $(0.45) per share, for the three-month period ended March 31, 2016. The year-over-year increase in net loss was primarily due to adjusting for the fair value of the warrant liability at March 31, 2017, which resulted in a significant non-cash expense. Research and development expenses totaled approximately $771,000 for the three months ended March 31, 2017, compared to approximately $2.0 million for the three months ended March 31, 2016. The decrease was due primarily to the expenses related to our Phase 3 clinical trial which was still being conducted during the three months ended March 31, 2016.  This trial was completed in the second quarter of 2016 and the analysis of the trial data occurred during the second half of 2016. For the first quarter of 2017, general and administrative expenses were approximately $1.2 million compared with approximately $1.1 million for the first quarter of 2016. Total operating expenses for the three months ended March 31, 2017 were approximately $2.0 million, compared to total operating expenses of approximately $3.2 million for the three months ended March 31, 2016. Included in net loss for the first quarter of 2017 was an increase of net loss due to the change in the fair value of the warrant liability of approximately $3.1 million.  The warrant liability is subject to remeasurement at each reporting period and we recognize any change in the fair value of the warrant liability in the statement of operations.  We anticipate that the value of the warrants could fluctuate from quarter to quarter and that such fluctuation could have a material impact on our financial statements from quarter to quarter and year to year. In March 2017, we completed a public offering of approximately 2.8 million shares of common stock at $2.90 per share, with gross proceeds of approximately $8.0 million, before underwriting discounts and commissions and estimated offering costs. As of March 31, 2017, our cash and cash equivalents were approximately $14.7 million. Evoke will hold a conference call on Monday, May 15, 2017, at 4:30 pm ET to discuss the results. Participants should dial 1-877-407-0789 (United States) or 1-201-689-8562 (International) and mention Evoke Pharma. A live webcast of the conference call will also be available on the investor relations page of the Company's corporate website at www.evokepharma.com. After the live webcast, the event will be archived on Evoke's website for one year. In addition, a telephonic replay of the call will be available until May 22, 2017. The replay can be accessed by dialing 1-844-512-2921 (United States) or 1-412-317-6671 (International) with confirmation code 13660963. Evoke is a specialty pharmaceutical company focused primarily on the development of drugs to treat GI disorders and diseases. The Company is developing Gimoti, a metoclopramide nasal spray for the relief of symptoms associated with acute and recurrent gastroparesis in women with diabetes mellitus. Diabetic gastroparesis is a GI disorder afflicting millions of sufferers worldwide, in which the stomach takes too long to empty its contents resulting in serious digestive system symptoms. Metoclopramide is the only product currently approved in the United States to treat gastroparesis, and is currently available only in oral and intravenous forms. Gimoti is a novel formulation of this drug, designed to provide systemic delivery of metoclopramide through nasal administration. Visit www.EvokePharma.com for more information. Evoke cautions you that statements included in this press release that are not a description of historical facts are forward-looking statements. In some cases, you can identify forward-looking statements by terms such as "may," "will," "should," "expect," "plan," "anticipate," "could," "intend," "target," "project," "contemplates," "believes," "estimates," "predicts," "potential" or "continue" or the negatives of these terms or other similar expressions. These statements are based on the Company's current beliefs and expectations. These forward-looking statements include statements regarding: the clear path forward with respect to submission of an 505(b) (2) NDA submission for Gimoti based on a comparative exposure PK trial; Evoke’s plans to initiate and complete the PK trial and submit the NDA and potentially receive regulatory approval of Gimoti; and the timing thereof, and Evoke’s expectation that it will not need to raise additional capital to complete the comparative exposure PK trial and submit the NDA for Gimoti. The inclusion of forward-looking statements should not be regarded as a representation by Evoke that any of its plans will be achieved. Actual results may differ from those set forth in this press release due to the risks and uncertainties inherent in Evoke's business, including, without limitation: risks associated with successfully commencing and receiving favorable results from the planned comparative exposure PK trial; later developments with the FDA that may be inconsistent with the already completed pre- NDA meetings, including inconsistent conclusions reflected in the official meeting minutes from the FDA; the inherent risks of clinical development of Gimoti; Evoke is entirely dependent on the success of Gimoti, and Evoke cannot be certain that it will be able to submit an NDA for Gimoti or obtain regulatory approval for or successfully commercialize Gimoti; risks associated with manufacturing new formulations of Gimoti for use in the comparative exposure PK trial; Evoke’s dependence on third parties for the manufacture of Gimoti as well as the conduct of the PK trial; Evoke may require additional funding to complete the PK trial and submit the NDA, and will require substantial additional funding to commercialize Gimoti, and may be unable to raise capital when needed, including to fund ongoing operations; Evoke may not be able to successfully commercialize Gimoti, if approved, as a result of risks associated with market acceptance, coverage and reimbursement and competing products; and other risks detailed in Evoke's prior press releases and in the periodic reports it files with the Securities and Exchange Commission. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and Evoke undertakes no obligation to revise or update this press release to reflect events or circumstances after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement. This caution is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995.


News Article | May 15, 2017
Site: globenewswire.com

SOLANA BEACH, Calif., May 15, 2017 (GLOBE NEWSWIRE) -- Evoke Pharma, Inc. (NASDAQ:EVOK), a specialty pharmaceutical company focused on treatments for gastrointestinal diseases, today announced its financial results for the first quarter ended March 31, 2017. Dave Gonyer, R.Ph., President and CEO, stated, “We started 2017 with a number of positive developments that bring us closer to filing the 505(b)(2) NDA for Gimoti™. This includes reaching agreement with FDA that a Human Factors (HF) Validation Study, a requirement for drug/device combinations, is not needed for Gimoti. Additionally, before the close of the quarter, we completed a positive Type A meeting in which FDA confirmed the acceptability of the design of our planned comparative exposure PK study for Gimoti, as well as certain other chemistry, manufacturing & controls (CMC) items associated with the proposed NDA. This PK trial in healthy volunteers, which is designed to establish comparative exposure of Gimoti to the listed drug, Reglan® Tablets, will serve in part as the basis for a 505(b)(2) NDA submission for Gimoti. We recently announced our partnership with Spaulding Clinical Research to conduct the PK trial and expect to initiate and complete the study in the second half of 2017. Finally, we believe that the pre-NDA agreements with FDA further reduce potential risks and save additional resources as we continue to prepare the NDA for submission in late 2017 or early 2018.” Mr. Gonyer continued, “From a financial perspective, Evoke completed a capital raise in March, which significantly enhanced our balance sheet and will allow us to complete the PK trial and focus on the NDA filing. We believe this capital infusion confirms our investors’ confidence in our strategy and intent to seek approval for Gimoti as rapidly and efficiently as possible. As we look forward to the rest of the year, we believe there is a clear path for an NDA submission and we are working hard to bring Gimoti to those patients suffering from diabetic gastroparesis.” For the first quarter of 2017, net loss was approximately $5.1 million, or $(0.37) per share, compared to a net loss of approximately $3.2 million, or $(0.45) per share, for the three-month period ended March 31, 2016. The year-over-year increase in net loss was primarily due to adjusting for the fair value of the warrant liability at March 31, 2017, which resulted in a significant non-cash expense. Research and development expenses totaled approximately $771,000 for the three months ended March 31, 2017, compared to approximately $2.0 million for the three months ended March 31, 2016. The decrease was due primarily to the expenses related to our Phase 3 clinical trial which was still being conducted during the three months ended March 31, 2016.  This trial was completed in the second quarter of 2016 and the analysis of the trial data occurred during the second half of 2016. For the first quarter of 2017, general and administrative expenses were approximately $1.2 million compared with approximately $1.1 million for the first quarter of 2016. Total operating expenses for the three months ended March 31, 2017 were approximately $2.0 million, compared to total operating expenses of approximately $3.2 million for the three months ended March 31, 2016. Included in net loss for the first quarter of 2017 was an increase of net loss due to the change in the fair value of the warrant liability of approximately $3.1 million.  The warrant liability is subject to remeasurement at each reporting period and we recognize any change in the fair value of the warrant liability in the statement of operations.  We anticipate that the value of the warrants could fluctuate from quarter to quarter and that such fluctuation could have a material impact on our financial statements from quarter to quarter and year to year. In March 2017, we completed a public offering of approximately 2.8 million shares of common stock at $2.90 per share, with gross proceeds of approximately $8.0 million, before underwriting discounts and commissions and estimated offering costs. As of March 31, 2017, our cash and cash equivalents were approximately $14.7 million. Evoke will hold a conference call on Monday, May 15, 2017, at 4:30 pm ET to discuss the results. Participants should dial 1-877-407-0789 (United States) or 1-201-689-8562 (International) and mention Evoke Pharma. A live webcast of the conference call will also be available on the investor relations page of the Company's corporate website at www.evokepharma.com. After the live webcast, the event will be archived on Evoke's website for one year. In addition, a telephonic replay of the call will be available until May 22, 2017. The replay can be accessed by dialing 1-844-512-2921 (United States) or 1-412-317-6671 (International) with confirmation code 13660963. Evoke is a specialty pharmaceutical company focused primarily on the development of drugs to treat GI disorders and diseases. The Company is developing Gimoti, a metoclopramide nasal spray for the relief of symptoms associated with acute and recurrent gastroparesis in women with diabetes mellitus. Diabetic gastroparesis is a GI disorder afflicting millions of sufferers worldwide, in which the stomach takes too long to empty its contents resulting in serious digestive system symptoms. Metoclopramide is the only product currently approved in the United States to treat gastroparesis, and is currently available only in oral and intravenous forms. Gimoti is a novel formulation of this drug, designed to provide systemic delivery of metoclopramide through nasal administration. Visit www.EvokePharma.com for more information. Evoke cautions you that statements included in this press release that are not a description of historical facts are forward-looking statements. In some cases, you can identify forward-looking statements by terms such as "may," "will," "should," "expect," "plan," "anticipate," "could," "intend," "target," "project," "contemplates," "believes," "estimates," "predicts," "potential" or "continue" or the negatives of these terms or other similar expressions. These statements are based on the Company's current beliefs and expectations. These forward-looking statements include statements regarding: the clear path forward with respect to submission of an 505(b) (2) NDA submission for Gimoti based on a comparative exposure PK trial; Evoke’s plans to initiate and complete the PK trial and submit the NDA and potentially receive regulatory approval of Gimoti; and the timing thereof, and Evoke’s expectation that it will not need to raise additional capital to complete the comparative exposure PK trial and submit the NDA for Gimoti. The inclusion of forward-looking statements should not be regarded as a representation by Evoke that any of its plans will be achieved. Actual results may differ from those set forth in this press release due to the risks and uncertainties inherent in Evoke's business, including, without limitation: risks associated with successfully commencing and receiving favorable results from the planned comparative exposure PK trial; later developments with the FDA that may be inconsistent with the already completed pre- NDA meetings, including inconsistent conclusions reflected in the official meeting minutes from the FDA; the inherent risks of clinical development of Gimoti; Evoke is entirely dependent on the success of Gimoti, and Evoke cannot be certain that it will be able to submit an NDA for Gimoti or obtain regulatory approval for or successfully commercialize Gimoti; risks associated with manufacturing new formulations of Gimoti for use in the comparative exposure PK trial; Evoke’s dependence on third parties for the manufacture of Gimoti as well as the conduct of the PK trial; Evoke may require additional funding to complete the PK trial and submit the NDA, and will require substantial additional funding to commercialize Gimoti, and may be unable to raise capital when needed, including to fund ongoing operations; Evoke may not be able to successfully commercialize Gimoti, if approved, as a result of risks associated with market acceptance, coverage and reimbursement and competing products; and other risks detailed in Evoke's prior press releases and in the periodic reports it files with the Securities and Exchange Commission. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and Evoke undertakes no obligation to revise or update this press release to reflect events or circumstances after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement. This caution is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995.


Mason J.W.,University of Utah | Mason J.W.,Spaulding Clinical Research | Florian Jr. J.A.,U.S. Food and Drug Administration | Garnett C.E.,U.S. Food and Drug Administration | And 3 more authors.
Journal of Clinical Pharmacology | Year: 2010

Moxifloxacin is used in thorough QT studies to assess sensitivity for detection of an increase in QTc. Moxifloxacin is usually over-encapsulated for blinding. However, there is concern that over-encapsulation alters its pharmacokinetics. In a 4-arm, randomized crossover study, 22 volunteers received over-encapsulated moxifloxacin, over-encapsulated placebo, bare moxifloxacin, and intravenous (IV) moxifloxacin. Placebo capsules and IV infusions were administered so that treatments in each arm, except for bare moxifloxacin, were indistinguishable. Pharmacokinetics of the oral treatments were found to be nearly identical and to meet Food and Drug Administration criteria for bioequivalency. Relative to the IV infusion administered over 1 hour, the tablet formulation was bioequivalent to total exposure but not peak exposure maximum plasma concentration, which was lower by 22%. Median time to maximum plasma concentration of the IV infusion was 1.00 hour. A 2-compartment model with oral absorption and linear elimination adequately described the observed moxifloxacin data. Changes in QTcF mirrored the pharmacokinetic changes, and there was a linear relationship between plasma concentration of moxifloxacin and change in QTcF. A 2-stage infusion scheme for IV moxifloxacin mimics the oral plasma concentration versus time curve. Over-encapsulation of moxifloxacin did not alter its peak or total systemic exposures or pharmacodynamics after oral administration. © The Author(s) 2010.


PubMed | Randstad Pharma, Covance, Spaulding Clinical Research, Basilea Pharmaceutica International Ltd and 2 more.
Type: Journal Article | Journal: Clinical pharmacology in drug development | Year: 2016

This report describes the phase 1 trials that evaluated the metabolism of the novel triazole antifungal isavuconazole by cytochrome P450 3A4 (CYP3A4) and isavuconazoles effects on CYP3A4-mediated metabolism in healthy adults. Coadministration of oral isavuconazole (100 mg once daily) with oral rifampin (600 mg once daily; CYP3A4 inducer) decreased isavuconazole area under the concentration-time curve (AUC


Mason J.W.,University of Utah | Mason J.W.,Spaulding Clinical Research | Selness D.S.,Spaulding Clinical Research | Moon T.E.,Spaulding Clinical Research | And 4 more authors.
Clinical Cancer Research | Year: 2012

Purpose: The need for greater clarity about the effects of 5-HT 3 receptor antagonists on cardiac repolarization is apparent in the changing product labeling across this therapeutic class. This study assessed the repolarization effects of granisetron, a 5-HT 3 receptor antagonist antiemetic, administered intravenously and by a granisetron transdermal system (GTDS). Experimental Design: In a parallel four-arm study, healthy subjects were randomized to receive intravenous granisetron, GTDS, placebo, or oral moxifloxacin (active control). The primary endpoint was difference in change from baseline in mean Fridericia-corrected QT interval (QTcF) between GTDS and placebo (ddQTcF) on days 3 and 5. Results: A total of 240 subjects were enrolled, 60 in each group. Adequate sensitivity for detection of QTc change was shown by a 5.75 ms lower bound of the 90% confidence interval (CI) for moxifloxacin versus placebo at 2 hours postdose on day 3. Day 3 ddQTcF values varied between 0.2 and 1.9 ms for GTDS (maximum upper bound of 90% CI, 6.88 ms), between -1.2 and 1.6 ms for i.v. granisetron (maximum upper bound of 90% CI, 5.86 ms), and between -3.4 and 4.7 ms for moxifloxacin (maximum upper bound of 90% CI, 13.45 ms). Day 5 findings were similar. Pharmacokinetic-ddQTcF modeling showed a minimally positive slope of 0.157 ms/(ng/mL), but a very low correlation (r = 0.090). Conclusion: GTDS was not associated with statistically or clinically significant effects on QTcF or other electrocardiographic variables. This study provides useful clarification on the effect of granisetron delivered by GTDS on cardiac repolarization. ©2012 AACR.


Zhang W.,Astellas Pharma Inc. | Smulders R.,Astellas Pharma Global Development | Abeyratne A.,Astellas Pharma Inc. | Dietz A.,Spaulding Clinical Research | And 3 more authors.
Clinical Therapeutics | Year: 2013

Ipragliflozin, a potent, selective sodium glucose cotransporter 2 inhibitor, is in development for the treatment of type 2 diabetes mellitus. The International Conference on Harmonisation recommends that the safety investigation of new drugs include characterization of each agent's effects on the QT/QTc interval. Objective: The goal of this study was to assess the effect on cardiac repolarization (QTc interval) of repeated oral dosing of ipragliflozin at therapeutic (100 mg/d) and supratherapeutic (600 mg/d) levels in healthy subjects. Methods: This was a double-blind, placebo- and active-controlled, 4-way crossover study. Subjects were randomized to 1 of 4 treatment sequences each including the following 4 treatments: placebo for 7 days; ipragliflozin 100 mg/d for 7 days; ipragliflozin 600 mg/d for 7 days; and active control moxifloxacin 400 mg on day 7 only. The primary assessment of QTc was based on Fridericia's correction for heart rate (QTcF). Continuous 12-lead ECG interval extraction assessments were conducted on day 7. The least squares mean treatment difference from placebo and corresponding 2-sided 90% CIs were calculated for QTcF up to 14 hours postdose on treatment day 7. Ipragliflozin was deemed unlikely to have a clinically relevant effect on QTcF if the upper bound of the maximum treatment difference from placebo for ipragliflozin across all time points was < 10 ms. Assay sensitivity for QTcF interval prolongation was confirmed if the lower bound of the 2-sided 90% CIs for the mean moxifloxacin QTcF difference from placebo, determined at sampling time closest to average Tmax, was > 5 ms. Results: A total of 88 subjects were randomized to treatment (n = 22 per sequence; 10 males and 12 females). The largest upper bounds of the 90% CIs of mean treatment differences from placebo were 4.44 and 3.39 ms for ipragliflozin 600 and 100 mg, respectively, in all subjects, indicating no clinically relevant effect on QTcF interval. No specific effects were observed when the data were analyzed according to sex. No subject showed outlier QTcF intervals > 480 ms or a time-matched change from baseline > 60 ms. Moxifloxacin confirmed assay sensitivity for QTcF interval prolongation; the lower bound of the 2-sided 90% CIs at 3 hours postdose was 11.7 ms (> 5 ms). Conclusions: No clinically meaningful QTc interval prolongation was observed in these healthy subjects who received ipragliflozin doses up to 600 mg/d for 7 days. ClinicalTrials.gov identifier: NCT01232413. © 2013 Elsevier HS Journals, Inc.


Dietz A.J.,Spaulding Clinical Research | Barnard J.C.,A GSK Company | van Rossem K.,Stiefel Inc.
Clinical Pharmacology in Drug Development | Year: 2014

Albaconazole is a triazole antifungal agent discovered at Palau Pharma SA (Barcelona, Spain) and currently being developed for the treatment of fungal infections of the nails. This randomized, double-blind, placebo-controlled, phase 1 study evaluated the safety, tolerability, pharmacokinetics, and effects on electrocardiogram parameters of albaconazole administered orally at escalating supratherapeutic doses. Healthy subjects received 400mg albaconazole every 24, 12, or 8hours for 5 days. Albaconazole was absorbed rapidly (2.5-22.5hours) after oral administration, reaching a maximal mean peak plasma concentration of 11,993.3ng/mL (standard deviation [SD], 2,413.85ng/mL) after 5 days of dosing every 8hours. Systemic exposure of albaconazole increased proportionally with dose frequency. Albaconazole was safe and well tolerated at all doses administered. No significant changes in ECG intervals or morphology were observed. In none of the three dosing groups was the slope of a study-specific correction for QT interval (QTcSS) on log plasma concentration statistically different from 0. The results of this study were to be used to inform the design of a thorough QT study using supratherapeutic doses. A dose regimen of 400mg, every 8hours for 5 days appears suitable for this purpose. © 2013, The American College of Clinical Pharmacology.


Mason J.W.,University of Utah | Moon T.E.,Tarizona eHealth Services Inc. | O'Boyle E.,AP Pharma | Dietz A.,Spaulding Clinical Research
Cancer Management and Research | Year: 2014

Background: Regulatory concern about potential QT-interval prolongation by serotonin-receptor antagonist antiemetics prompted product-label changes. The frst-generation serotonin-receptor antagonist granisetron is available in oral (PO), intravenous (IV), and transdermal formulations. APF530 is a formulation that provides sustained release of granisetron when administered as a single subcutaneous (SC) injection. The Phase I study reported here evaluated effects of APF530 on electrocardiographic intervals. Methods: This single-site, double-blind, placebo-controlled, four-period crossover trial randomized healthy men and women to receive varying sequences of APF530 1 g SC, granisetron 50 μg/kg IV, moxifoxacin 400 mg PO, and placebo. Subjects were assessed for 49 hours after each treatment. The primary objective was to evaluate differences between baseline-adjusted, heart rate-corrected QT-interval change using the Fridericia rate correction (dQTcF) for APF530 1 g SC and placebo. Electrocardiograms were performed at various times throughout the assessment period. Pharmacokinetics and safety were evaluated. Results: The upper one-sided 95% confdence interval (CI) for mean baseline-adjusted dQTcF at each post-dose time point between APF530 and placebo excluded 10 ms, indicating that APF530 1 g SC had no clinically signifcant effect on QTcF. Maximum observed QTcF change was 4.15 ms (90% CI, 0.94 to 7.36) at Hour 3. No clinically signifcant changes in other electrocardiogram intervals were observed. APF530 SC pharmacokinetics were as expected, with slow absorption (maximum plasma concentration 35.8 ng/mL, median time to maximum plasma concentration 11.1 hours) and slow elimination (mean half-life 18.6 hours; systemic clearance 20.2 L/hour) of granisetron versus the expected early peak concentration and elimination of granisetron I V. APF530 SC was well tolerated. Adverse events, most commonly constipation and SC injection-site reactions, were generally mild and quickly resolved. Conclusion: APF530 1 g SC did not induce clinically signifcant QTcF interval prolongation or changes in the other electrocardiogram intervals, and was well tolerated at twice the recommended dose. © 2014 Mason et al.


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