DURBAN, SOUTH AFRICA – Women who consistently used a monthly vaginal ring containing the antiretroviral drug dapivirine reduced their risk of acquiring HIV infection by 75%-91% in exploratory analyses of the phase III ASPIRE study, Elizabeth R. Brown, ScD, reported at the 21st International AIDS Conference.

ASPIRE (A Study to Prevent Infection with a Ring for Extended use), also known as the Microbicide Trials Network-020 trial, was a multicenter, randomized, double-blind, placebo-controlled, phase III trial of a silicone vaginal ring containing 25 mg of the non-nucleoside reverse transcriptase inhibitor dapivirine. ASPIRE involved 2,629 HIV-uninfected women aged 18-45 years from four Southern African countries with extremely high HIV infection rates: South Africa, Uganda, Malawi, and Zimbabwe. They were prospectively followed monthly for 12-33 months.

As reported at a conference earlier in 2016, seroconversion occurred in 71 women assigned to the dapivirine ring and 97 on a placebo ring during 4,280 person-years of follow-up. The resultant 27% relative risk reduction in an intent-to-treat analysis, while statistically significant, was less than hoped for by investigators.

However, the device only works if it’s used consistently, so the investigators decided to conduct exploratory analyses using an objective measure of adherence: the amount of dapivirine remaining in a ring after a month’s use. This was possible because the rings had been stored for analysis in a central laboratory.

The vaginal ring is self-inserted, then meant to be kept in place continuously for a month before being self-removed and replaced with a fresh ring. Dapivirine is released continuously while the ring is in place, so the less residual dapivirine contained in a used ring, the greater the adherence during that month, explained Dr. Brown, a biostatistician at the University of Washington, Seattle.

A dose-response effect was observed. In the most encouraging of the exploratory time-dependent use analyses, the rate of HIV acquisition was 4.7 cases per 100 person-years with placebo, 4.9/100 person-years in women defined as nonadherent based upon a residual dapivirine level of 23.5 mg or more, 3.1 with low use, 1.9 with moderate use, and 0.4 cases/100 person-years with consistent use as directed, meaning a patient left the device in place continuously for a month as reflected in a residual dapivirine rate below 22 mg.

This translates into a 91% reduction in risk, compared with placebo, in the most consistent users, a 58% relative risk reduction with moderate use, and a 29% reduction with low use, she continued.

The new results were hailed as a major advance in preventing HIV infection.

“We’re meeting here at AIDS 2016 in Durban, capital of the KwaZulu-Natal province of South Africa, which is one of the hardest-hit areas of the world for HIV. Over the course of their lifetime, women in Southern Africa have more than a 50% chance of HIV infection. So a new prevention tool that women can use on their own discretely to protect themselves against HIV would be a game changer,” Jared Baeten, MD, PhD, said in an interview.

Bruce Jancin/Frontline Medical News

“I see this as having an important potential role in the [United States] as well for women who face an increased risk of HIV. It’s extremely valuable for them to have a method of protection that they can control and feel good about and safely use for an extended period of time,” added Dr. Baeten, professor and vice chair of global health, as well as professor of allergy and infectious diseases at the University of Washington, Seattle.

The challenges involved in consistent use of the dapivirine ring are less formidable than are those posed by consistent use of a daily oral medication for preexposure prevention, he noted.

Dr. Baeten was a leader of ASPIRE and is codirector of the HOPE (HIV Open-label Prevention Extension) study, which is now underway. The expectation is that adherence to the dapivirine vaginal ring will be better in HOPE than in ASPIRE because participants can now be counseled that the ring works, it’s safe, and there is no chance of getting a placebo device, he said.

“There is an urgent unmet need to expand long-acting HIV prevention options for women and girls,” Zeda Rosenberg, ScD, founder and chief executive officer of the nonprofit International Partnership for Microbicides (IPM) in Silver Spring, Md., which is the sponsor and developer of the ring.

Toward that end, in the next several months the ASPIRE data will be combined with those from the IPM-sponsored Ring Study, another completed large phase III trial of the dapivirine ring conducted in Africa. The goals will be to try to identify potentially modifiable sociodemographic and behavioral correlates of adherence and to further strengthen the safety and efficacy findings. The plan is to submit the full data package to the Food and Drug Administration and regulat ory agencies in other countries in the spring of 2017.

“Hopefully, the product will receive marketing approval in 2018,” Dr. Rosenberg said.

In addition to sponsoring HOPE, IPM is also sponsoring the ongoing open-label DREAM (Dapivirine Ring Extended Access and Monitoring) study. IPM is also partnering with the Microbicides Trial Network to conduct a separate study of the vaginal ring in adolescents and young women in Africa.

A dapivirine vaginal ring that’s active for 3 months rather than 1 month will begin safety studies later in 2016. The potential advantages of this product are reduced annual cost and fewer clinic visits. Also, a 3-month version of the ring with an added contraceptive has been developed and will begin safety studies in the United States in fall 2016. The possibility that suboptimal adherence can be overcome by a ring containing a higher dose of dapivirine will also be explored, according to Dr. Rosenberg.

Dr. Brown, Dr. Baeten, and Dr. Rosenberg reported having no financial conflicts of interest.

[email protected]

DURBAN, SOUTH AFRICA – Women who consistently used a monthly vaginal ring containing the antiretroviral drug dapivirine reduced their risk of acquiring HIV infection by 75%-91% in exploratory analyses of the phase III ASPIRE study, Elizabeth R. Brown, ScD, reported at the 21st International AIDS Conference.

ASPIRE (A Study to Prevent Infection with a Ring for Extended use), also known as the Microbicide Trials Network-020 trial, was a multicenter, randomized, double-blind, placebo-controlled, phase III trial of a silicone vaginal ring containing 25 mg of the non-nucleoside reverse transcriptase inhibitor dapivirine. ASPIRE involved 2,629 HIV-uninfected women aged 18-45 years from four Southern African countries with extremely high HIV infection rates: South Africa, Uganda, Malawi, and Zimbabwe. They were prospectively followed monthly for 12-33 months.

As reported at a conference earlier in 2016, seroconversion occurred in 71 women assigned to the dapivirine ring and 97 on a placebo ring during 4,280 person-years of follow-up. The resultant 27% relative risk reduction in an intent-to-treat analysis, while statistically significant, was less than hoped for by investigators.

However, the device only works if it’s used consistently, so the investigators decided to conduct exploratory analyses using an objective measure of adherence: the amount of dapivirine remaining in a ring after a month’s use. This was possible because the rings had been stored for analysis in a central laboratory.

The vaginal ring is self-inserted, then meant to be kept in place continuously for a month before being self-removed and replaced with a fresh ring. Dapivirine is released continuously while the ring is in place, so the less residual dapivirine contained in a used ring, the greater the adherence during that month, explained Dr. Brown, a biostatistician at the University of Washington, Seattle.

A dose-response effect was observed. In the most encouraging of the exploratory time-dependent use analyses, the rate of HIV acquisition was 4.7 cases per 100 person-years with placebo, 4.9/100 person-years in women defined as nonadherent based upon a residual dapivirine level of 23.5 mg or more, 3.1 with low use, 1.9 with moderate use, and 0.4 cases/100 person-years with consistent use as directed, meaning a patient left the device in place continuously for a month as reflected in a residual dapivirine rate below 22 mg.

This translates into a 91% reduction in risk, compared with placebo, in the most consistent users, a 58% relative risk reduction with moderate use, and a 29% reduction with low use, she continued.

The new results were hailed as a major advance in preventing HIV infection.

“We’re meeting here at AIDS 2016 in Durban, capital of the KwaZulu-Natal province of South Africa, which is one of the hardest-hit areas of the world for HIV. Over the course of their lifetime, women in Southern Africa have more than a 50% chance of HIV infection. So a new prevention tool that women can use on their own discretely to protect themselves against HIV would be a game changer,” Jared Baeten, MD, PhD, said in an interview.

Bruce Jancin/Frontline Medical News

“I see this as having an important potential role in the [United States] as well for women who face an increased risk of HIV. It’s extremely valuable for them to have a method of protection that they can control and feel good about and safely use for an extended period of time,” added Dr. Baeten, professor and vice chair of global health, as well as professor of allergy and infectious diseases at the University of Washington, Seattle.

The challenges involved in consistent use of the dapivirine ring are less formidable than are those posed by consistent use of a daily oral medication for preexposure prevention, he noted.

Dr. Baeten was a leader of ASPIRE and is codirector of the HOPE (HIV Open-label Prevention Extension) study, which is now underway. The expectation is that adherence to the dapivirine vaginal ring will be better in HOPE than in ASPIRE because participants can now be counseled that the ring works, it’s safe, and there is no chance of getting a placebo device, he said.

“There is an urgent unmet need to expand long-acting HIV prevention options for women and girls,” Zeda Rosenberg, ScD, founder and chief executive officer of the nonprofit International Partnership for Microbicides (IPM) in Silver Spring, Md., which is the sponsor and developer of the ring.

Toward that end, in the next several months the ASPIRE data will be combined with those from the IPM-sponsored Ring Study, another completed large phase III trial of the dapivirine ring conducted in Africa. The goals will be to try to identify potentially modifiable sociodemographic and behavioral correlates of adherence and to further strengthen the safety and efficacy findings. The plan is to submit the full data package to the Food and Drug Administration and regulat ory agencies in other countries in the spring of 2017.

“Hopefully, the product will receive marketing approval in 2018,” Dr. Rosenberg said.

In addition to sponsoring HOPE, IPM is also sponsoring the ongoing open-label DREAM (Dapivirine Ring Extended Access and Monitoring) study. IPM is also partnering with the Microbicides Trial Network to conduct a separate study of the vaginal ring in adolescents and young women in Africa.

A dapivirine vaginal ring that’s active for 3 months rather than 1 month will begin safety studies later in 2016. The potential advantages of this product are reduced annual cost and fewer clinic visits. Also, a 3-month version of the ring with an added contraceptive has been developed and will begin safety studies in the United States in fall 2016. The possibility that suboptimal adherence can be overcome by a ring containing a higher dose of dapivirine will also be explored, according to Dr. Rosenberg.

Dr. Brown, Dr. Baeten, and Dr. Rosenberg reported having no financial conflicts of interest.

[email protected]

DURBAN, SOUTH AFRICA – Women who consistently used a monthly vaginal ring containing the antiretroviral drug dapivirine reduced their risk of acquiring HIV infection by 75%-91% in exploratory analyses of the phase III ASPIRE study, Elizabeth R. Brown, ScD, reported at the 21st International AIDS Conference.

ASPIRE (A Study to Prevent Infection with a Ring for Extended use), also known as the Microbicide Trials Network-020 trial, was a multicenter, randomized, double-blind, placebo-controlled, phase III trial of a silicone vaginal ring containing 25 mg of the non-nucleoside reverse transcriptase inhibitor dapivirine. ASPIRE involved 2,629 HIV-uninfected women aged 18-45 years from four Southern African countries with extremely high HIV infection rates: South Africa, Uganda, Malawi, and Zimbabwe. They were prospectively followed monthly for 12-33 months.

As reported at a conference earlier in 2016, seroconversion occurred in 71 women assigned to the dapivirine ring and 97 on a placebo ring during 4,280 person-years of follow-up. The resultant 27% relative risk reduction in an intent-to-treat analysis, while statistically significant, was less than hoped for by investigators.

However, the device only works if it’s used consistently, so the investigators decided to conduct exploratory analyses using an objective measure of adherence: the amount of dapivirine remaining in a ring after a month’s use. This was possible because the rings had been stored for analysis in a central laboratory.

The vaginal ring is self-inserted, then meant to be kept in place continuously for a month before being self-removed and replaced with a fresh ring. Dapivirine is released continuously while the ring is in place, so the less residual dapivirine contained in a used ring, the greater the adherence during that month, explained Dr. Brown, a biostatistician at the University of Washington, Seattle.

A dose-response effect was observed. In the most encouraging of the exploratory time-dependent use analyses, the rate of HIV acquisition was 4.7 cases per 100 person-years with placebo, 4.9/100 person-years in women defined as nonadherent based upon a residual dapivirine level of 23.5 mg or more, 3.1 with low use, 1.9 with moderate use, and 0.4 cases/100 person-years with consistent use as directed, meaning a patient left the device in place continuously for a month as reflected in a residual dapivirine rate below 22 mg.

This translates into a 91% reduction in risk, compared with placebo, in the most consistent users, a 58% relative risk reduction with moderate use, and a 29% reduction with low use, she continued.

The new results were hailed as a major advance in preventing HIV infection.

“We’re meeting here at AIDS 2016 in Durban, capital of the KwaZulu-Natal province of South Africa, which is one of the hardest-hit areas of the world for HIV. Over the course of their lifetime, women in Southern Africa have more than a 50% chance of HIV infection. So a new prevention tool that women can use on their own discretely to protect themselves against HIV would be a game changer,” Jared Baeten, MD, PhD, said in an interview.

Bruce Jancin/Frontline Medical News

“I see this as having an important potential role in the [United States] as well for women who face an increased risk of HIV. It’s extremely valuable for them to have a method of protection that they can control and feel good about and safely use for an extended period of time,” added Dr. Baeten, professor and vice chair of global health, as well as professor of allergy and infectious diseases at the University of Washington, Seattle.

The challenges involved in consistent use of the dapivirine ring are less formidable than are those posed by consistent use of a daily oral medication for preexposure prevention, he noted.

Dr. Baeten was a leader of ASPIRE and is codirector of the HOPE (HIV Open-label Prevention Extension) study, which is now underway. The expectation is that adherence to the dapivirine vaginal ring will be better in HOPE than in ASPIRE because participants can now be counseled that the ring works, it’s safe, and there is no chance of getting a placebo device, he said.

“There is an urgent unmet need to expand long-acting HIV prevention options for women and girls,” Zeda Rosenberg, ScD, founder and chief executive officer of the nonprofit International Partnership for Microbicides (IPM) in Silver Spring, Md., which is the sponsor and developer of the ring.

Toward that end, in the next several months the ASPIRE data will be combined with those from the IPM-sponsored Ring Study, another completed large phase III trial of the dapivirine ring conducted in Africa. The goals will be to try to identify potentially modifiable sociodemographic and behavioral correlates of adherence and to further strengthen the safety and efficacy findings. The plan is to submit the full data package to the Food and Drug Administration and regulat ory agencies in other countries in the spring of 2017.

“Hopefully, the product will receive marketing approval in 2018,” Dr. Rosenberg said.

In addition to sponsoring HOPE, IPM is also sponsoring the ongoing open-label DREAM (Dapivirine Ring Extended Access and Monitoring) study. IPM is also partnering with the Microbicides Trial Network to conduct a separate study of the vaginal ring in adolescents and young women in Africa.

A dapivirine vaginal ring that’s active for 3 months rather than 1 month will begin safety studies later in 2016. The potential advantages of this product are reduced annual cost and fewer clinic visits. Also, a 3-month version of the ring with an added contraceptive has been developed and will begin safety studies in the United States in fall 2016. The possibility that suboptimal adherence can be overcome by a ring containing a higher dose of dapivirine will also be explored, according to Dr. Rosenberg.

Dr. Brown, Dr. Baeten, and Dr. Rosenberg reported having no financial conflicts of interest.

[email protected]

The cognitive effects of estrogen were no different in women who started taking the hormone within 6 years of menopause, compared with those who began it 10 or more years after menopause, based on data from the double-blind randomized ELITE-Cog trial.

“Some hormone effects on cognition are postulated to vary by age or by timing in relation to the menopause,” wrote Victor W. Henderson, M.D., of Stanford (Calif.) University and his colleagues (Neurology. 2016 Jul 20. doi: 10.1212/WNL.0000000000002980).

©Highwaystarz-Photography/Thinkstock

To test whether the timing of estrogen therapy affected the primary cognitive endpoint of verbal episodic memory, the researchers conducted the ELITE (Early vs. Late Intervention Trial With Estradiol) trial in which they randomized 567 healthy women within 6 years of menopause or 10 or more years post menopause to 1 mg/day of oral 17-beta-estradiol or a placebo. Women with a uterus also received either 45 mg progesterone as a 4% vaginal gel or a matched placebo gel.

The main ELITE trial tested the effect of the timing of estradiol, compared with placebo, on the progression of subclinical atherosclerosis, whereas the ELITE-Cog trial assessed the effects of the timing of estradiol on a composite test of verbal episodic memory.

Overall, composite scores of verbal memory were not significantly different in women randomized to estrogen vs. placebo based on a mean standardized difference of –0.06 (95% confidence interval, –0.22 to 0.09) after an average of 57 months of treatment. The mean standardized difference was similar in the early and late treatment groups. In addition, the mean standardized differences in measures of executive functions (–0.04; 95% CI, –0.21 to 0.14) and global cognition (–0.025; 95% CI, –0.18 to 0.13) were not significantly different between women who started estrogen within 6 years of menopause and those who started estrogen 10 years or more after menopause. Safety profiles were similar between the groups.

“Results of this randomized, double-blind placebo-controlled trial fail to confirm the timing hypothesis for cognitive outcomes in healthy postmenopausal women,” the researchers wrote.

The results don’t generalize to other subgroups including women of reproductive age, those in transition to menopause, or those with premature menopause caused by surgery or chemotherapy, and the study “was not designed to assess short-term cognitive effects of estradiol or effects on risks of mild cognitive impairment or Alzheimer disease,” the researchers noted. However, the findings should be reassuring to healthy, younger postmenopausal women considering estrogen therapy, they said.

The study was supported by a grant from the National Institutes of Health, and the study drugs and placebo were supplied by Teva, Watson, and Abbott Laboratories. Dr. Henderson disclosed research support from the NIH, as well as travel expenses from the NIH, American Academy of Neurology, and International Menopause Society.

The cognitive effects of estrogen were no different in women who started taking the hormone within 6 years of menopause, compared with those who began it 10 or more years after menopause, based on data from the double-blind randomized ELITE-Cog trial.

“Some hormone effects on cognition are postulated to vary by age or by timing in relation to the menopause,” wrote Victor W. Henderson, M.D., of Stanford (Calif.) University and his colleagues (Neurology. 2016 Jul 20. doi: 10.1212/WNL.0000000000002980).

©Highwaystarz-Photography/Thinkstock

To test whether the timing of estrogen therapy affected the primary cognitive endpoint of verbal episodic memory, the researchers conducted the ELITE (Early vs. Late Intervention Trial With Estradiol) trial in which they randomized 567 healthy women within 6 years of menopause or 10 or more years post menopause to 1 mg/day of oral 17-beta-estradiol or a placebo. Women with a uterus also received either 45 mg progesterone as a 4% vaginal gel or a matched placebo gel.

The main ELITE trial tested the effect of the timing of estradiol, compared with placebo, on the progression of subclinical atherosclerosis, whereas the ELITE-Cog trial assessed the effects of the timing of estradiol on a composite test of verbal episodic memory.

Overall, composite scores of verbal memory were not significantly different in women randomized to estrogen vs. placebo based on a mean standardized difference of –0.06 (95% confidence interval, –0.22 to 0.09) after an average of 57 months of treatment. The mean standardized difference was similar in the early and late treatment groups. In addition, the mean standardized differences in measures of executive functions (–0.04; 95% CI, –0.21 to 0.14) and global cognition (–0.025; 95% CI, –0.18 to 0.13) were not significantly different between women who started estrogen within 6 years of menopause and those who started estrogen 10 years or more after menopause. Safety profiles were similar between the groups.

“Results of this randomized, double-blind placebo-controlled trial fail to confirm the timing hypothesis for cognitive outcomes in healthy postmenopausal women,” the researchers wrote.

The results don’t generalize to other subgroups including women of reproductive age, those in transition to menopause, or those with premature menopause caused by surgery or chemotherapy, and the study “was not designed to assess short-term cognitive effects of estradiol or effects on risks of mild cognitive impairment or Alzheimer disease,” the researchers noted. However, the findings should be reassuring to healthy, younger postmenopausal women considering estrogen therapy, they said.

The study was supported by a grant from the National Institutes of Health, and the study drugs and placebo were supplied by Teva, Watson, and Abbott Laboratories. Dr. Henderson disclosed research support from the NIH, as well as travel expenses from the NIH, American Academy of Neurology, and International Menopause Society.

The cognitive effects of estrogen were no different in women who started taking the hormone within 6 years of menopause, compared with those who began it 10 or more years after menopause, based on data from the double-blind randomized ELITE-Cog trial.

“Some hormone effects on cognition are postulated to vary by age or by timing in relation to the menopause,” wrote Victor W. Henderson, M.D., of Stanford (Calif.) University and his colleagues (Neurology. 2016 Jul 20. doi: 10.1212/WNL.0000000000002980).

©Highwaystarz-Photography/Thinkstock

To test whether the timing of estrogen therapy affected the primary cognitive endpoint of verbal episodic memory, the researchers conducted the ELITE (Early vs. Late Intervention Trial With Estradiol) trial in which they randomized 567 healthy women within 6 years of menopause or 10 or more years post menopause to 1 mg/day of oral 17-beta-estradiol or a placebo. Women with a uterus also received either 45 mg progesterone as a 4% vaginal gel or a matched placebo gel.

The main ELITE trial tested the effect of the timing of estradiol, compared with placebo, on the progression of subclinical atherosclerosis, whereas the ELITE-Cog trial assessed the effects of the timing of estradiol on a composite test of verbal episodic memory.

Overall, composite scores of verbal memory were not significantly different in women randomized to estrogen vs. placebo based on a mean standardized difference of –0.06 (95% confidence interval, –0.22 to 0.09) after an average of 57 months of treatment. The mean standardized difference was similar in the early and late treatment groups. In addition, the mean standardized differences in measures of executive functions (–0.04; 95% CI, –0.21 to 0.14) and global cognition (–0.025; 95% CI, –0.18 to 0.13) were not significantly different between women who started estrogen within 6 years of menopause and those who started estrogen 10 years or more after menopause. Safety profiles were similar between the groups.

“Results of this randomized, double-blind placebo-controlled trial fail to confirm the timing hypothesis for cognitive outcomes in healthy postmenopausal women,” the researchers wrote.

The results don’t generalize to other subgroups including women of reproductive age, those in transition to menopause, or those with premature menopause caused by surgery or chemotherapy, and the study “was not designed to assess short-term cognitive effects of estradiol or effects on risks of mild cognitive impairment or Alzheimer disease,” the researchers noted. However, the findings should be reassuring to healthy, younger postmenopausal women considering estrogen therapy, they said.

The study was supported by a grant from the National Institutes of Health, and the study drugs and placebo were supplied by Teva, Watson, and Abbott Laboratories. Dr. Henderson disclosed research support from the NIH, as well as travel expenses from the NIH, American Academy of Neurology, and International Menopause Society.

The Food and Drug Administration is currently accepting public comments on the agency’s proposed plans to implement a law that will restrict compounding of human drug products.

A statement issued by the FDA provides links to two draft guidances that describe how the agency “would implement provisions of federal law that restrict compounding human drug products that are essentially copies of commercially available or approved drug products.” One draft guidance and the legal restrictions referenced therein are relevant to physicians and pharmacists, as well as state-licensed pharmacies or federal facilities that compound drugs, according to the FDA. The other guidance applies to outsourcing facilities.

Although compounded drug products, such as a medication made without a dye for a patient allergic to that dye, or a medication made into liquid form for a patient who cannot swallow a pill, “may benefit certain patients whose medical needs cannot be met by a commercially available or an FDA-approved drug product,” the FDA statement said. “Taking compounded drug products that are essentially copies of a commercially available or approved drug needlessly exposes patients to drug products that FDA has not evaluated for safety, effectiveness, and quality. In addition, the compounded drugs may not have been produced according to appropriate quality standards. Such compounding would also undermine the new drug approval and over-the-counter drug monograph systems in the United States.”

The statement refers to serious adverse events, including infections and deaths that have resulted from “poor-quality” compounded drugs.

Written or electronic comments can be submitted until Oct. 11, and information on submitting comments is available at regulations.gov.

[email protected]

The Food and Drug Administration is currently accepting public comments on the agency’s proposed plans to implement a law that will restrict compounding of human drug products.

A statement issued by the FDA provides links to two draft guidances that describe how the agency “would implement provisions of federal law that restrict compounding human drug products that are essentially copies of commercially available or approved drug products.” One draft guidance and the legal restrictions referenced therein are relevant to physicians and pharmacists, as well as state-licensed pharmacies or federal facilities that compound drugs, according to the FDA. The other guidance applies to outsourcing facilities.

Although compounded drug products, such as a medication made without a dye for a patient allergic to that dye, or a medication made into liquid form for a patient who cannot swallow a pill, “may benefit certain patients whose medical needs cannot be met by a commercially available or an FDA-approved drug product,” the FDA statement said. “Taking compounded drug products that are essentially copies of a commercially available or approved drug needlessly exposes patients to drug products that FDA has not evaluated for safety, effectiveness, and quality. In addition, the compounded drugs may not have been produced according to appropriate quality standards. Such compounding would also undermine the new drug approval and over-the-counter drug monograph systems in the United States.”

The statement refers to serious adverse events, including infections and deaths that have resulted from “poor-quality” compounded drugs.

Written or electronic comments can be submitted until Oct. 11, and information on submitting comments is available at regulations.gov.

[email protected]

The Food and Drug Administration is currently accepting public comments on the agency’s proposed plans to implement a law that will restrict compounding of human drug products.

A statement issued by the FDA provides links to two draft guidances that describe how the agency “would implement provisions of federal law that restrict compounding human drug products that are essentially copies of commercially available or approved drug products.” One draft guidance and the legal restrictions referenced therein are relevant to physicians and pharmacists, as well as state-licensed pharmacies or federal facilities that compound drugs, according to the FDA. The other guidance applies to outsourcing facilities.

Although compounded drug products, such as a medication made without a dye for a patient allergic to that dye, or a medication made into liquid form for a patient who cannot swallow a pill, “may benefit certain patients whose medical needs cannot be met by a commercially available or an FDA-approved drug product,” the FDA statement said. “Taking compounded drug products that are essentially copies of a commercially available or approved drug needlessly exposes patients to drug products that FDA has not evaluated for safety, effectiveness, and quality. In addition, the compounded drugs may not have been produced according to appropriate quality standards. Such compounding would also undermine the new drug approval and over-the-counter drug monograph systems in the United States.”

The statement refers to serious adverse events, including infections and deaths that have resulted from “poor-quality” compounded drugs.

Written or electronic comments can be submitted until Oct. 11, and information on submitting comments is available at regulations.gov.

[email protected]

Using an implant device to administer buprenorphine for adult patients being treated for opioid addiction is a viable alternative to the standard sublingual buprenorphine, a randomized clinical trial published online July 19 suggests.

“An implantable buprenorphine delivery system reduces adherence issues and may improve efficacy,” wrote Richard N. Rosenthal, MD, of the Icahn School of Medicine at Mount Sinai, New York, and his coinvestigators. “Furthermore, buprenorphine implants may reduce the need for sublingual buprenorphine, decreasing its availability for diversion, misuse, and harms.”

Dr. Rosenthal and his coinvestigators enrolled 177 patients from June 2014 to May 2015. The participants were aged 18-65 years, had received a primary diagnosis of opioid addiction, and had been receiving daily 8-mg doses of sublingual buprenorphine at an outpatient clinic for at least 24 weeks. The average age of patients was 39 years, and 40.9% were female. All of the participants were recruited from 21 treatment sites across the United States (JAMA. 2016;316[3]:282-90).

The participants were randomized into one of two cohorts: 87 subjects received buprenorphine implants, and the remaining 90 received sublingual buprenorphine. Those in the former cohort received their implants on the day of randomization, with four subdermal devices implanted along the inner upper arm. The staff involved with implanting and removing the devices did not have anything to do with study evaluation, in order to maintain blinding. Ten urine samples were collected from subjects over the course of the study period, with follow-up visits at 1 week and 2 weeks post treatment.

“The primary efficacy endpoint was the difference in proportion of responders, defined as participants with at least 4 of 6 months without evidence of illicit opioid use (based on urine test and self-report composites) by treatment group” the authors clarified.

Ultimately, 84 of those who received implants and 89 of those receiving sublingual treatment completed the trial, and were included in the primary analysis. Of those, 81 of those receiving implants (96.4%) and 78 of those receiving sublingual buprenorphine (87.6%) responded to treatment.

Based on urine tests and self-reporting, 72 of those with implants (85.7%) maintained their opioid abstinence throughout the study period, compared with 64 of those in the sublingual treatment cohort (71.9%). Additionally, Dr. Rosenthal and his coinvestigators noted that sustained abstinence in months 3-6 was more prominent in the implant cohort. Adverse events not related to the implant site occurred in 42 of the implant subjects (48.3%) and 47 of the sublingual treatment subjects (52.8%).

“To our knowledge, this was the first comparative trial to evaluate efficacy and safety of 6-month buprenorphine implants relative to sublingual buprenorphine in this understudied population of patients clinically stable taking sublingual buprenorphine,” the authors stated. They added that “because there are limited data on patients stable on sublingual buprenorphine, it is important to study maintenance and improvement of stability in patients who achieve good clinical response to initial buprenorphine treatment” with regard to further study.

Dr. Rosenthal and his coinvestigators disclosed receiving grants and nonfinancial support from Braeburn Pharmaceuticals, which was the sole provider of funding for this study. The other investigators also reported financial relationships with other companies.

[email protected]

Using an implant device to administer buprenorphine for adult patients being treated for opioid addiction is a viable alternative to the standard sublingual buprenorphine, a randomized clinical trial published online July 19 suggests.

“An implantable buprenorphine delivery system reduces adherence issues and may improve efficacy,” wrote Richard N. Rosenthal, MD, of the Icahn School of Medicine at Mount Sinai, New York, and his coinvestigators. “Furthermore, buprenorphine implants may reduce the need for sublingual buprenorphine, decreasing its availability for diversion, misuse, and harms.”

Dr. Rosenthal and his coinvestigators enrolled 177 patients from June 2014 to May 2015. The participants were aged 18-65 years, had received a primary diagnosis of opioid addiction, and had been receiving daily 8-mg doses of sublingual buprenorphine at an outpatient clinic for at least 24 weeks. The average age of patients was 39 years, and 40.9% were female. All of the participants were recruited from 21 treatment sites across the United States (JAMA. 2016;316[3]:282-90).

The participants were randomized into one of two cohorts: 87 subjects received buprenorphine implants, and the remaining 90 received sublingual buprenorphine. Those in the former cohort received their implants on the day of randomization, with four subdermal devices implanted along the inner upper arm. The staff involved with implanting and removing the devices did not have anything to do with study evaluation, in order to maintain blinding. Ten urine samples were collected from subjects over the course of the study period, with follow-up visits at 1 week and 2 weeks post treatment.

“The primary efficacy endpoint was the difference in proportion of responders, defined as participants with at least 4 of 6 months without evidence of illicit opioid use (based on urine test and self-report composites) by treatment group” the authors clarified.

Ultimately, 84 of those who received implants and 89 of those receiving sublingual treatment completed the trial, and were included in the primary analysis. Of those, 81 of those receiving implants (96.4%) and 78 of those receiving sublingual buprenorphine (87.6%) responded to treatment.

Based on urine tests and self-reporting, 72 of those with implants (85.7%) maintained their opioid abstinence throughout the study period, compared with 64 of those in the sublingual treatment cohort (71.9%). Additionally, Dr. Rosenthal and his coinvestigators noted that sustained abstinence in months 3-6 was more prominent in the implant cohort. Adverse events not related to the implant site occurred in 42 of the implant subjects (48.3%) and 47 of the sublingual treatment subjects (52.8%).

“To our knowledge, this was the first comparative trial to evaluate efficacy and safety of 6-month buprenorphine implants relative to sublingual buprenorphine in this understudied population of patients clinically stable taking sublingual buprenorphine,” the authors stated. They added that “because there are limited data on patients stable on sublingual buprenorphine, it is important to study maintenance and improvement of stability in patients who achieve good clinical response to initial buprenorphine treatment” with regard to further study.

Dr. Rosenthal and his coinvestigators disclosed receiving grants and nonfinancial support from Braeburn Pharmaceuticals, which was the sole provider of funding for this study. The other investigators also reported financial relationships with other companies.

[email protected]

Using an implant device to administer buprenorphine for adult patients being treated for opioid addiction is a viable alternative to the standard sublingual buprenorphine, a randomized clinical trial published online July 19 suggests.

“An implantable buprenorphine delivery system reduces adherence issues and may improve efficacy,” wrote Richard N. Rosenthal, MD, of the Icahn School of Medicine at Mount Sinai, New York, and his coinvestigators. “Furthermore, buprenorphine implants may reduce the need for sublingual buprenorphine, decreasing its availability for diversion, misuse, and harms.”

Dr. Rosenthal and his coinvestigators enrolled 177 patients from June 2014 to May 2015. The participants were aged 18-65 years, had received a primary diagnosis of opioid addiction, and had been receiving daily 8-mg doses of sublingual buprenorphine at an outpatient clinic for at least 24 weeks. The average age of patients was 39 years, and 40.9% were female. All of the participants were recruited from 21 treatment sites across the United States (JAMA. 2016;316[3]:282-90).

The participants were randomized into one of two cohorts: 87 subjects received buprenorphine implants, and the remaining 90 received sublingual buprenorphine. Those in the former cohort received their implants on the day of randomization, with four subdermal devices implanted along the inner upper arm. The staff involved with implanting and removing the devices did not have anything to do with study evaluation, in order to maintain blinding. Ten urine samples were collected from subjects over the course of the study period, with follow-up visits at 1 week and 2 weeks post treatment.

“The primary efficacy endpoint was the difference in proportion of responders, defined as participants with at least 4 of 6 months without evidence of illicit opioid use (based on urine test and self-report composites) by treatment group” the authors clarified.

Ultimately, 84 of those who received implants and 89 of those receiving sublingual treatment completed the trial, and were included in the primary analysis. Of those, 81 of those receiving implants (96.4%) and 78 of those receiving sublingual buprenorphine (87.6%) responded to treatment.

Based on urine tests and self-reporting, 72 of those with implants (85.7%) maintained their opioid abstinence throughout the study period, compared with 64 of those in the sublingual treatment cohort (71.9%). Additionally, Dr. Rosenthal and his coinvestigators noted that sustained abstinence in months 3-6 was more prominent in the implant cohort. Adverse events not related to the implant site occurred in 42 of the implant subjects (48.3%) and 47 of the sublingual treatment subjects (52.8%).

“To our knowledge, this was the first comparative trial to evaluate efficacy and safety of 6-month buprenorphine implants relative to sublingual buprenorphine in this understudied population of patients clinically stable taking sublingual buprenorphine,” the authors stated. They added that “because there are limited data on patients stable on sublingual buprenorphine, it is important to study maintenance and improvement of stability in patients who achieve good clinical response to initial buprenorphine treatment” with regard to further study.

Dr. Rosenthal and his coinvestigators disclosed receiving grants and nonfinancial support from Braeburn Pharmaceuticals, which was the sole provider of funding for this study. The other investigators also reported financial relationships with other companies.

[email protected]

Lab mice

Photo by Aaron Logan

KOLOA, HAWAII—Preclinical research suggests that ARQ 531, a reversible Bruton’s tyrosine kinase (BTK) inhibitor, might prove effective against ibrutinib-resistant hematologic malignancies.

The study showed that ARQ 531 inhibits wild-type BTK and the ibrutinib-resistant BTK-C481S mutant with similar potency.

The compound also suppressed proliferation of hematologic cancer cells in vitro and inhibited tumor growth in a mouse model of B-cell lymphoma.

Researchers disclosed these results in a poster presentation at the 2016 Pan Pacific Lymphoma Conference. The research was supported by ArQule Inc., the company developing ARQ 531.

The researchers first demonstrated that ARQ 531 enacts biochemical inhibition of both wild-type and C481S-mutant BTK at sub-nanomolar levels and cellular inhibition in C481S-mutant BTK cells that are resistant to ibrutinib.

The team then tested ARQ 531 in a range of cell lines encompassing a variety of leukemias and lymphomas, as well as multiple myeloma.

They found that ARQ 531 can inhibit proliferation in many types of hematologic cancer cells, but it “potently inhibits” cell lines that are addicted to BCR, PI3K/AKT, and Notch signaling pathways.

The researchers also tested ARQ 531 in the BTK-driven TMD8 xenograft mouse model (B-cell lymphoma). They said the compound demonstrated strong target and pathway inhibition, with sustained tumor growth inhibition.

The team noted that ARQ 531 exhibits a distinct kinase selectivity profile, with strong inhibitory activity against several key oncogenic drivers from TEC, Trk, and Src family kinases. And the compound inhibits the RAF/MEK/ERK and PI3K/AKT/mTOR pathways.

The researchers said these results support further investigation of ARQ 531, particularly in the setting of ibrutinib resistance.

It is currently estimated that about 10% of patients treated with ibrutinib develop resistance, and more than 80% of these patients present with the C481S mutation.

“We are beginning to see increasing resistance to ibrutinib, which is creating the need for a BTK inhibitor, like ARQ 531, that targets the C481S mutation,” said Brian Schwartz, head of research and development and chief medical officer at ArQule.

“The preclinical profile of ARQ 531 as a potent and reversible inhibitor of wild-type and mutant BTK presents the potential for a first-in-class and best-in-class molecule. We are working toward completing GLP [good laboratory practice] toxicology studies and filing an IND [investigational new drug application] in early 2017.”

Lab mice

Photo by Aaron Logan

KOLOA, HAWAII—Preclinical research suggests that ARQ 531, a reversible Bruton’s tyrosine kinase (BTK) inhibitor, might prove effective against ibrutinib-resistant hematologic malignancies.

The study showed that ARQ 531 inhibits wild-type BTK and the ibrutinib-resistant BTK-C481S mutant with similar potency.

The compound also suppressed proliferation of hematologic cancer cells in vitro and inhibited tumor growth in a mouse model of B-cell lymphoma.

Researchers disclosed these results in a poster presentation at the 2016 Pan Pacific Lymphoma Conference. The research was supported by ArQule Inc., the company developing ARQ 531.

The researchers first demonstrated that ARQ 531 enacts biochemical inhibition of both wild-type and C481S-mutant BTK at sub-nanomolar levels and cellular inhibition in C481S-mutant BTK cells that are resistant to ibrutinib.

The team then tested ARQ 531 in a range of cell lines encompassing a variety of leukemias and lymphomas, as well as multiple myeloma.

They found that ARQ 531 can inhibit proliferation in many types of hematologic cancer cells, but it “potently inhibits” cell lines that are addicted to BCR, PI3K/AKT, and Notch signaling pathways.

The researchers also tested ARQ 531 in the BTK-driven TMD8 xenograft mouse model (B-cell lymphoma). They said the compound demonstrated strong target and pathway inhibition, with sustained tumor growth inhibition.

The team noted that ARQ 531 exhibits a distinct kinase selectivity profile, with strong inhibitory activity against several key oncogenic drivers from TEC, Trk, and Src family kinases. And the compound inhibits the RAF/MEK/ERK and PI3K/AKT/mTOR pathways.

The researchers said these results support further investigation of ARQ 531, particularly in the setting of ibrutinib resistance.

It is currently estimated that about 10% of patients treated with ibrutinib develop resistance, and more than 80% of these patients present with the C481S mutation.

“We are beginning to see increasing resistance to ibrutinib, which is creating the need for a BTK inhibitor, like ARQ 531, that targets the C481S mutation,” said Brian Schwartz, head of research and development and chief medical officer at ArQule.

“The preclinical profile of ARQ 531 as a potent and reversible inhibitor of wild-type and mutant BTK presents the potential for a first-in-class and best-in-class molecule. We are working toward completing GLP [good laboratory practice] toxicology studies and filing an IND [investigational new drug application] in early 2017.”

Lab mice

Photo by Aaron Logan

KOLOA, HAWAII—Preclinical research suggests that ARQ 531, a reversible Bruton’s tyrosine kinase (BTK) inhibitor, might prove effective against ibrutinib-resistant hematologic malignancies.

The study showed that ARQ 531 inhibits wild-type BTK and the ibrutinib-resistant BTK-C481S mutant with similar potency.

The compound also suppressed proliferation of hematologic cancer cells in vitro and inhibited tumor growth in a mouse model of B-cell lymphoma.

Researchers disclosed these results in a poster presentation at the 2016 Pan Pacific Lymphoma Conference. The research was supported by ArQule Inc., the company developing ARQ 531.

The researchers first demonstrated that ARQ 531 enacts biochemical inhibition of both wild-type and C481S-mutant BTK at sub-nanomolar levels and cellular inhibition in C481S-mutant BTK cells that are resistant to ibrutinib.

The team then tested ARQ 531 in a range of cell lines encompassing a variety of leukemias and lymphomas, as well as multiple myeloma.

They found that ARQ 531 can inhibit proliferation in many types of hematologic cancer cells, but it “potently inhibits” cell lines that are addicted to BCR, PI3K/AKT, and Notch signaling pathways.

The researchers also tested ARQ 531 in the BTK-driven TMD8 xenograft mouse model (B-cell lymphoma). They said the compound demonstrated strong target and pathway inhibition, with sustained tumor growth inhibition.

The team noted that ARQ 531 exhibits a distinct kinase selectivity profile, with strong inhibitory activity against several key oncogenic drivers from TEC, Trk, and Src family kinases. And the compound inhibits the RAF/MEK/ERK and PI3K/AKT/mTOR pathways.

The researchers said these results support further investigation of ARQ 531, particularly in the setting of ibrutinib resistance.

It is currently estimated that about 10% of patients treated with ibrutinib develop resistance, and more than 80% of these patients present with the C481S mutation.

“We are beginning to see increasing resistance to ibrutinib, which is creating the need for a BTK inhibitor, like ARQ 531, that targets the C481S mutation,” said Brian Schwartz, head of research and development and chief medical officer at ArQule.

“The preclinical profile of ARQ 531 as a potent and reversible inhibitor of wild-type and mutant BTK presents the potential for a first-in-class and best-in-class molecule. We are working toward completing GLP [good laboratory practice] toxicology studies and filing an IND [investigational new drug application] in early 2017.”

White blood cells

The US Food and Drug Administration (FDA) has decided not to approve Novartis’s application for a biosimilar of Amgen’s Neulasta, also known by the generic name pegfilgrastim.

The FDA issued a complete response letter for the pegfilgrastim biosimilar last month.

Novartis has not provided details about the agency’s decision or the contents of the letter, but the company said it is working with the FDA to answer its questions about the drug.

Novartis was seeking approval for its pegfilgrastim biosimilar for the same indication as Amgen’s Neulasta.

Neulasta is a leukocyte growth factor that is FDA-approved for the following indications:

• To decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.
• To increase survival in patients acutely exposed to myelosuppressive doses of radiation.

Neulasta is not FDA-approved for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

White blood cells

The US Food and Drug Administration (FDA) has decided not to approve Novartis’s application for a biosimilar of Amgen’s Neulasta, also known by the generic name pegfilgrastim.

The FDA issued a complete response letter for the pegfilgrastim biosimilar last month.

Novartis has not provided details about the agency’s decision or the contents of the letter, but the company said it is working with the FDA to answer its questions about the drug.

Novartis was seeking approval for its pegfilgrastim biosimilar for the same indication as Amgen’s Neulasta.

Neulasta is a leukocyte growth factor that is FDA-approved for the following indications:

• To decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.
• To increase survival in patients acutely exposed to myelosuppressive doses of radiation.

Neulasta is not FDA-approved for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

White blood cells

The US Food and Drug Administration (FDA) has decided not to approve Novartis’s application for a biosimilar of Amgen’s Neulasta, also known by the generic name pegfilgrastim.

The FDA issued a complete response letter for the pegfilgrastim biosimilar last month.

Novartis has not provided details about the agency’s decision or the contents of the letter, but the company said it is working with the FDA to answer its questions about the drug.

Novartis was seeking approval for its pegfilgrastim biosimilar for the same indication as Amgen’s Neulasta.

Neulasta is a leukocyte growth factor that is FDA-approved for the following indications:

• To decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.
• To increase survival in patients acutely exposed to myelosuppressive doses of radiation.

Neulasta is not FDA-approved for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

Natural killer cells

Agents that inhibit the protein kinase JAK3 could prove effective for treating natural killer/T-cell lymphoma (NKTL), according to research published in Blood.

Researchers investigated the role the cancer-promoting gene EZH2 plays in NKTL.

This revealed that EZH2 activity is regulated by JAK3, and a JAK3 inhibitor could significantly reduce the growth of NKTL cells.

Specifically, the team discovered that JAK3 activation leads to phosphorylation of EZH2.

This prompts the dissociation of EZH2 from the PRC2 complex and leads to decreased global H3K27me3 levels.

EZH2 then shifts from its normal function of suppressing gene expression to activating genes—specifically, upregulating a set of genes involved in DNA replication, cell cycle, biosynthesis, stemness, and invasiveness.

And this leads to the development of NKTL.

“As JAK3 is often mutated and activated in natural killer/T-cell lymphoma cells, this finding is particular intriguing, as it suggests a predominant non-catalytic function of EZH2 in JAK3-mutant natural killer/T-cell lymphoma,” said study author Wee-Joo Chng, MB ChB, PhD, of the National University of Singapore.

“Our study also suggests that various oncogenic mutations may modify the function of EZH2, explaining the complex roles of EZH2 in cancer.”

The researchers also found that a JAK3 inhibitor could significantly reduce the growth of NKTL cells, in an EZH2 phosphorylation-dependent manner.

However, compounds that have recently been developed to inhibit EZH2 methyltransferase activity did not have the same effect.

“Moving forward, a biomarker strategy might be needed to ensure appropriate application of EZH2 inhibitors,” Dr Chng said.

“This will help to identify tumors where EZH2 requires its catalytic activity or is actually acting through non-catalytic function. At the same time, we need to develop therapies that can target the non-catalytic function of EZH2.”

Natural killer cells

Agents that inhibit the protein kinase JAK3 could prove effective for treating natural killer/T-cell lymphoma (NKTL), according to research published in Blood.

Researchers investigated the role the cancer-promoting gene EZH2 plays in NKTL.

This revealed that EZH2 activity is regulated by JAK3, and a JAK3 inhibitor could significantly reduce the growth of NKTL cells.

Specifically, the team discovered that JAK3 activation leads to phosphorylation of EZH2.

This prompts the dissociation of EZH2 from the PRC2 complex and leads to decreased global H3K27me3 levels.

EZH2 then shifts from its normal function of suppressing gene expression to activating genes—specifically, upregulating a set of genes involved in DNA replication, cell cycle, biosynthesis, stemness, and invasiveness.

And this leads to the development of NKTL.

“As JAK3 is often mutated and activated in natural killer/T-cell lymphoma cells, this finding is particular intriguing, as it suggests a predominant non-catalytic function of EZH2 in JAK3-mutant natural killer/T-cell lymphoma,” said study author Wee-Joo Chng, MB ChB, PhD, of the National University of Singapore.

“Our study also suggests that various oncogenic mutations may modify the function of EZH2, explaining the complex roles of EZH2 in cancer.”

The researchers also found that a JAK3 inhibitor could significantly reduce the growth of NKTL cells, in an EZH2 phosphorylation-dependent manner.

However, compounds that have recently been developed to inhibit EZH2 methyltransferase activity did not have the same effect.

“Moving forward, a biomarker strategy might be needed to ensure appropriate application of EZH2 inhibitors,” Dr Chng said.

“This will help to identify tumors where EZH2 requires its catalytic activity or is actually acting through non-catalytic function. At the same time, we need to develop therapies that can target the non-catalytic function of EZH2.”

Natural killer cells

Agents that inhibit the protein kinase JAK3 could prove effective for treating natural killer/T-cell lymphoma (NKTL), according to research published in Blood.

Researchers investigated the role the cancer-promoting gene EZH2 plays in NKTL.

This revealed that EZH2 activity is regulated by JAK3, and a JAK3 inhibitor could significantly reduce the growth of NKTL cells.

Specifically, the team discovered that JAK3 activation leads to phosphorylation of EZH2.

This prompts the dissociation of EZH2 from the PRC2 complex and leads to decreased global H3K27me3 levels.

EZH2 then shifts from its normal function of suppressing gene expression to activating genes—specifically, upregulating a set of genes involved in DNA replication, cell cycle, biosynthesis, stemness, and invasiveness.

And this leads to the development of NKTL.

“As JAK3 is often mutated and activated in natural killer/T-cell lymphoma cells, this finding is particular intriguing, as it suggests a predominant non-catalytic function of EZH2 in JAK3-mutant natural killer/T-cell lymphoma,” said study author Wee-Joo Chng, MB ChB, PhD, of the National University of Singapore.

“Our study also suggests that various oncogenic mutations may modify the function of EZH2, explaining the complex roles of EZH2 in cancer.”

The researchers also found that a JAK3 inhibitor could significantly reduce the growth of NKTL cells, in an EZH2 phosphorylation-dependent manner.

However, compounds that have recently been developed to inhibit EZH2 methyltransferase activity did not have the same effect.

“Moving forward, a biomarker strategy might be needed to ensure appropriate application of EZH2 inhibitors,” Dr Chng said.

“This will help to identify tumors where EZH2 requires its catalytic activity or is actually acting through non-catalytic function. At the same time, we need to develop therapies that can target the non-catalytic function of EZH2.”

Apoptotic cells

A new study has shed light on the process leukemia cells use to evade apoptosis and revealed drugs that can fight this process.

Investigators found that leukemia cells expel a molecule that starts apoptosis, but antimalarial drugs and antifungal drugs can halt this process and force the leukemia cells to self-destruct.

Alexandre Chigaev, PhD, of the University of New Mexico in Albuquerque, and his colleagues described these discoveries in Oncotarget.

The investigators theorized that leukemia cells might evade death by regulating 3’-5’-cyclic adenosine monophosphate (cAMP), which is associated with pro-apoptotic signaling.

The team thought leukemic cells might possess mechanisms that efflux cAMP from the cytoplasm, thereby protecting them from apoptosis.

In studying VLA-4—an adhesion molecule that keeps each cell in its niche—the investigators discovered that cAMP reduces VLA-4’s adhesive properties, allowing cells to detach.

“That’s how we stumbled upon it,” Dr Chigaev said. “Cyclic AMP reduces cell adhesion, and maybe that’s one of the mechanisms by which [leukemic] cells leave bone marrow niches.”

The investigators then confirmed that cAMP starts apoptosis in leukemia cells. And they showed that leukemia cells could efflux cAMP, but normal blood cells could not.

The team substantiated their findings by testing several drugs that block cAMP efflux.

The drugs, which are all approved by the US Food and Drug Administration, are used to fight malaria or fungal infections. They include artesunate, dihydroartemisinin, clioquinol, cryptotanshinone, parthenolide, and patulin.

The investigators found these drugs successfully decreased cAMP efflux and induced apoptosis in a model of acute myeloid leukemia, in B-lineage acute lymphoblastic leukemia cell lines, and in samples from patients with B-lineage acute lymphoblastic leukemia.

On the other hand, the drugs did not affect peripheral blood mononuclear cells.

“This particular mechanism of action has not been reported for these drugs,” Dr Chigaev said. “And the idea that cells can have this apoptotic escape, or apoptotic evasion, through cyclic AMP pumping, that’s new. It’s never been reported previously.”

Dr Chigaev and his colleagues noted that repurposing already-approved drugs could greatly shorten the approval process to use them for leukemia.

Since the drugs were tested on cells from leukemia patients, the team hopes to continue seeing promising results. They have begun animal studies in preparation for clinical trials.

Apoptotic cells

A new study has shed light on the process leukemia cells use to evade apoptosis and revealed drugs that can fight this process.

Investigators found that leukemia cells expel a molecule that starts apoptosis, but antimalarial drugs and antifungal drugs can halt this process and force the leukemia cells to self-destruct.

Alexandre Chigaev, PhD, of the University of New Mexico in Albuquerque, and his colleagues described these discoveries in Oncotarget.

The investigators theorized that leukemia cells might evade death by regulating 3’-5’-cyclic adenosine monophosphate (cAMP), which is associated with pro-apoptotic signaling.

The team thought leukemic cells might possess mechanisms that efflux cAMP from the cytoplasm, thereby protecting them from apoptosis.

In studying VLA-4—an adhesion molecule that keeps each cell in its niche—the investigators discovered that cAMP reduces VLA-4’s adhesive properties, allowing cells to detach.

“That’s how we stumbled upon it,” Dr Chigaev said. “Cyclic AMP reduces cell adhesion, and maybe that’s one of the mechanisms by which [leukemic] cells leave bone marrow niches.”

The investigators then confirmed that cAMP starts apoptosis in leukemia cells. And they showed that leukemia cells could efflux cAMP, but normal blood cells could not.

The team substantiated their findings by testing several drugs that block cAMP efflux.

The drugs, which are all approved by the US Food and Drug Administration, are used to fight malaria or fungal infections. They include artesunate, dihydroartemisinin, clioquinol, cryptotanshinone, parthenolide, and patulin.

The investigators found these drugs successfully decreased cAMP efflux and induced apoptosis in a model of acute myeloid leukemia, in B-lineage acute lymphoblastic leukemia cell lines, and in samples from patients with B-lineage acute lymphoblastic leukemia.

On the other hand, the drugs did not affect peripheral blood mononuclear cells.

“This particular mechanism of action has not been reported for these drugs,” Dr Chigaev said. “And the idea that cells can have this apoptotic escape, or apoptotic evasion, through cyclic AMP pumping, that’s new. It’s never been reported previously.”

Dr Chigaev and his colleagues noted that repurposing already-approved drugs could greatly shorten the approval process to use them for leukemia.

Since the drugs were tested on cells from leukemia patients, the team hopes to continue seeing promising results. They have begun animal studies in preparation for clinical trials.

Apoptotic cells

A new study has shed light on the process leukemia cells use to evade apoptosis and revealed drugs that can fight this process.

Investigators found that leukemia cells expel a molecule that starts apoptosis, but antimalarial drugs and antifungal drugs can halt this process and force the leukemia cells to self-destruct.

Alexandre Chigaev, PhD, of the University of New Mexico in Albuquerque, and his colleagues described these discoveries in Oncotarget.

The investigators theorized that leukemia cells might evade death by regulating 3’-5’-cyclic adenosine monophosphate (cAMP), which is associated with pro-apoptotic signaling.

The team thought leukemic cells might possess mechanisms that efflux cAMP from the cytoplasm, thereby protecting them from apoptosis.

In studying VLA-4—an adhesion molecule that keeps each cell in its niche—the investigators discovered that cAMP reduces VLA-4’s adhesive properties, allowing cells to detach.

“That’s how we stumbled upon it,” Dr Chigaev said. “Cyclic AMP reduces cell adhesion, and maybe that’s one of the mechanisms by which [leukemic] cells leave bone marrow niches.”

The investigators then confirmed that cAMP starts apoptosis in leukemia cells. And they showed that leukemia cells could efflux cAMP, but normal blood cells could not.

The team substantiated their findings by testing several drugs that block cAMP efflux.

The drugs, which are all approved by the US Food and Drug Administration, are used to fight malaria or fungal infections. They include artesunate, dihydroartemisinin, clioquinol, cryptotanshinone, parthenolide, and patulin.

The investigators found these drugs successfully decreased cAMP efflux and induced apoptosis in a model of acute myeloid leukemia, in B-lineage acute lymphoblastic leukemia cell lines, and in samples from patients with B-lineage acute lymphoblastic leukemia.

On the other hand, the drugs did not affect peripheral blood mononuclear cells.

“This particular mechanism of action has not been reported for these drugs,” Dr Chigaev said. “And the idea that cells can have this apoptotic escape, or apoptotic evasion, through cyclic AMP pumping, that’s new. It’s never been reported previously.”

Dr Chigaev and his colleagues noted that repurposing already-approved drugs could greatly shorten the approval process to use them for leukemia.

Since the drugs were tested on cells from leukemia patients, the team hopes to continue seeing promising results. They have begun animal studies in preparation for clinical trials.

Increased awareness did not increase adolescent HPV vaccination rates in a high-risk population, according to Jessica Fishman, PhD, of the University of Pennsylvania, Philadelphia, and her associates.

The study sample included 211 low-income adolescents, aged 13-18 years, and 149 parents of different adolescents, aged 9-18 years, who had not been vaccinated for HPV. In the adolescent group, 3% received an HPV vaccination after 3 months, 9% received a vaccination after 6 months, and 15% received a vaccination after 1 year. In the parent group, 5% had their daughters vaccinated after 3 months, 10% had their daughters vaccinated after 6 months, and 13% had their daughters vaccinated after 1 year.

©jarun011/Thinkstock

Awareness was measured using a questionnaire asking about individual awareness of HPV, cervical cancer, HPV vaccination, and news or advertising about HPV vaccination. Both adolescents and parents were most aware of cervical cancer (73% and 94%, respectively) and least aware of news about HPV advertising (51% and 66%, respectively). A total of 14% of adolescents and 4% of parents had no awareness of any questionnaire item, while 32% of adolescents and 57% of parents had awareness of all items.

Probability of vaccination was less than 0.5 for all levels of awareness, and accuracy of HPV vaccination prediction models was poor, Dr. Fishman and her associates noted.

“For this high-risk population where vaccination is rare, evidence-based behavioral interventions are urgently needed. Ideally, interventions will target variables associated with vaccination. Interventions that do not target actual determinants can have no effect or even a ‘boomerang’ effect that increases unhealthy behavior,” the investigators concluded.

Find the full study in Pediatrics (doi: 10.1542/peds.2015-2048).

[email protected]

Increased awareness did not increase adolescent HPV vaccination rates in a high-risk population, according to Jessica Fishman, PhD, of the University of Pennsylvania, Philadelphia, and her associates.

The study sample included 211 low-income adolescents, aged 13-18 years, and 149 parents of different adolescents, aged 9-18 years, who had not been vaccinated for HPV. In the adolescent group, 3% received an HPV vaccination after 3 months, 9% received a vaccination after 6 months, and 15% received a vaccination after 1 year. In the parent group, 5% had their daughters vaccinated after 3 months, 10% had their daughters vaccinated after 6 months, and 13% had their daughters vaccinated after 1 year.

©jarun011/Thinkstock

Awareness was measured using a questionnaire asking about individual awareness of HPV, cervical cancer, HPV vaccination, and news or advertising about HPV vaccination. Both adolescents and parents were most aware of cervical cancer (73% and 94%, respectively) and least aware of news about HPV advertising (51% and 66%, respectively). A total of 14% of adolescents and 4% of parents had no awareness of any questionnaire item, while 32% of adolescents and 57% of parents had awareness of all items.

Probability of vaccination was less than 0.5 for all levels of awareness, and accuracy of HPV vaccination prediction models was poor, Dr. Fishman and her associates noted.

“For this high-risk population where vaccination is rare, evidence-based behavioral interventions are urgently needed. Ideally, interventions will target variables associated with vaccination. Interventions that do not target actual determinants can have no effect or even a ‘boomerang’ effect that increases unhealthy behavior,” the investigators concluded.

Find the full study in Pediatrics (doi: 10.1542/peds.2015-2048).

[email protected]

Increased awareness did not increase adolescent HPV vaccination rates in a high-risk population, according to Jessica Fishman, PhD, of the University of Pennsylvania, Philadelphia, and her associates.

The study sample included 211 low-income adolescents, aged 13-18 years, and 149 parents of different adolescents, aged 9-18 years, who had not been vaccinated for HPV. In the adolescent group, 3% received an HPV vaccination after 3 months, 9% received a vaccination after 6 months, and 15% received a vaccination after 1 year. In the parent group, 5% had their daughters vaccinated after 3 months, 10% had their daughters vaccinated after 6 months, and 13% had their daughters vaccinated after 1 year.

©jarun011/Thinkstock

Awareness was measured using a questionnaire asking about individual awareness of HPV, cervical cancer, HPV vaccination, and news or advertising about HPV vaccination. Both adolescents and parents were most aware of cervical cancer (73% and 94%, respectively) and least aware of news about HPV advertising (51% and 66%, respectively). A total of 14% of adolescents and 4% of parents had no awareness of any questionnaire item, while 32% of adolescents and 57% of parents had awareness of all items.

Probability of vaccination was less than 0.5 for all levels of awareness, and accuracy of HPV vaccination prediction models was poor, Dr. Fishman and her associates noted.

“For this high-risk population where vaccination is rare, evidence-based behavioral interventions are urgently needed. Ideally, interventions will target variables associated with vaccination. Interventions that do not target actual determinants can have no effect or even a ‘boomerang’ effect that increases unhealthy behavior,” the investigators concluded.

Find the full study in Pediatrics (doi: 10.1542/peds.2015-2048).

[email protected]

Penalties for health providers under the federal False Claims Act (FCA) are set to double under a proposed rule by the U.S. Department of Justice.

The interim final rule would increase minimum per-claim FCA fines from $5,500 to $10,781 and maximum per-claim penalties would rise from $11,000 to $21,563.

The adjusted civil penalty amounts would apply to civil penalties assessed after Aug. 1, 2016, whose associated violations occurred after Nov. 2, 2015. Violations on or before Nov. 2, 2015, and assessments made prior to Aug. 1, 2016, would continue to be subject to the lower penalties. The rise stems from the federal Civil Monetary Penalties Inflation Adjustment Act, which provides for the regular evaluation and adjustment for inflation of civil monetary penalties to ensure they maintain a deterrent effect, according to a summary of the rule.

The FCA penalizes any person who knowingly submits a false claim to the government or causes another to submit a false claim to the government or who knowingly makes a false record or statement to get a false claim paid by the government. In 2015, the DOJ recovered more than $3.5 billion in FCA settlements and judgments.

Health law experts say the higher penalties may encourage more whistleblowers to file FCA claims against doctors since the potential recoveries would be higher.

“The new maximums may make things still more enticing for relators with visions of increasingly large relators’ shares on the table,” said William W. Horton, a Birmingham, Ala.-based health law attorney and chair of the American Bar Association Health Law Section.

However, Mr. Horton does not believe the rates will have much practical effect in terms of strategy or settlement rates. Right now, the hypothetical penalties in such cases are so enormous they are almost not meaningful, he said in an interview.

“In reality, cases settle based on the amount of actual damages – overpayments, etc. – and not on the penalties, because the penalties are so high,” he said. “I don’t think making them higher is going to change that, because it doesn’t increase the amount of money available for defendants to settle with.”

The ultimate question is whether the higher penalties will help deter health fraud, adds Houston health law attorney Michael E. Clark.

“I don’t see it making a difference,” he said in an interview. “The FCA penalties are particularly ruinous in the health care field since so many claims get made and courts have accepted broad theories of liability.”

The DOJ is accepting comments on the interim final rule until Aug. 29.

[email protected]

On Twitter @legal_med

Penalties for health providers under the federal False Claims Act (FCA) are set to double under a proposed rule by the U.S. Department of Justice.

The interim final rule would increase minimum per-claim FCA fines from $5,500 to $10,781 and maximum per-claim penalties would rise from $11,000 to $21,563.

The adjusted civil penalty amounts would apply to civil penalties assessed after Aug. 1, 2016, whose associated violations occurred after Nov. 2, 2015. Violations on or before Nov. 2, 2015, and assessments made prior to Aug. 1, 2016, would continue to be subject to the lower penalties. The rise stems from the federal Civil Monetary Penalties Inflation Adjustment Act, which provides for the regular evaluation and adjustment for inflation of civil monetary penalties to ensure they maintain a deterrent effect, according to a summary of the rule.

The FCA penalizes any person who knowingly submits a false claim to the government or causes another to submit a false claim to the government or who knowingly makes a false record or statement to get a false claim paid by the government. In 2015, the DOJ recovered more than $3.5 billion in FCA settlements and judgments.

Health law experts say the higher penalties may encourage more whistleblowers to file FCA claims against doctors since the potential recoveries would be higher.

“The new maximums may make things still more enticing for relators with visions of increasingly large relators’ shares on the table,” said William W. Horton, a Birmingham, Ala.-based health law attorney and chair of the American Bar Association Health Law Section.

However, Mr. Horton does not believe the rates will have much practical effect in terms of strategy or settlement rates. Right now, the hypothetical penalties in such cases are so enormous they are almost not meaningful, he said in an interview.

“In reality, cases settle based on the amount of actual damages – overpayments, etc. – and not on the penalties, because the penalties are so high,” he said. “I don’t think making them higher is going to change that, because it doesn’t increase the amount of money available for defendants to settle with.”

The ultimate question is whether the higher penalties will help deter health fraud, adds Houston health law attorney Michael E. Clark.

“I don’t see it making a difference,” he said in an interview. “The FCA penalties are particularly ruinous in the health care field since so many claims get made and courts have accepted broad theories of liability.”

The DOJ is accepting comments on the interim final rule until Aug. 29.

[email protected]

On Twitter @legal_med

Penalties for health providers under the federal False Claims Act (FCA) are set to double under a proposed rule by the U.S. Department of Justice.

The interim final rule would increase minimum per-claim FCA fines from $5,500 to $10,781 and maximum per-claim penalties would rise from $11,000 to $21,563.

The adjusted civil penalty amounts would apply to civil penalties assessed after Aug. 1, 2016, whose associated violations occurred after Nov. 2, 2015. Violations on or before Nov. 2, 2015, and assessments made prior to Aug. 1, 2016, would continue to be subject to the lower penalties. The rise stems from the federal Civil Monetary Penalties Inflation Adjustment Act, which provides for the regular evaluation and adjustment for inflation of civil monetary penalties to ensure they maintain a deterrent effect, according to a summary of the rule.

The FCA penalizes any person who knowingly submits a false claim to the government or causes another to submit a false claim to the government or who knowingly makes a false record or statement to get a false claim paid by the government. In 2015, the DOJ recovered more than $3.5 billion in FCA settlements and judgments.

Health law experts say the higher penalties may encourage more whistleblowers to file FCA claims against doctors since the potential recoveries would be higher.

“The new maximums may make things still more enticing for relators with visions of increasingly large relators’ shares on the table,” said William W. Horton, a Birmingham, Ala.-based health law attorney and chair of the American Bar Association Health Law Section.

However, Mr. Horton does not believe the rates will have much practical effect in terms of strategy or settlement rates. Right now, the hypothetical penalties in such cases are so enormous they are almost not meaningful, he said in an interview.

“In reality, cases settle based on the amount of actual damages – overpayments, etc. – and not on the penalties, because the penalties are so high,” he said. “I don’t think making them higher is going to change that, because it doesn’t increase the amount of money available for defendants to settle with.”

The ultimate question is whether the higher penalties will help deter health fraud, adds Houston health law attorney Michael E. Clark.

“I don’t see it making a difference,” he said in an interview. “The FCA penalties are particularly ruinous in the health care field since so many claims get made and courts have accepted broad theories of liability.”

The DOJ is accepting comments on the interim final rule until Aug. 29.

[email protected]

On Twitter @legal_med