User login
Ask, listen, help: Pearls to treat sexual dysfunction in menopause
LAS VEGAS – The first step is to ask. A menopausal woman may be struggling with a female sexual disorder (FSD), but unless her clinician asks, the patient may never volunteer information about her sexual health.
Susan Kellogg Spadt, Ph.D., offered that advice, along with a toolkit of tips, treatments, and pearls for physicians and others caring for the menopausal woman’s sexual health.
Dr. Kellogg Spadt, a certified sexual counselor and professor of obstetrics and gynecology at Drexel University, Philadelphia, addressed FSD in the context of the complicated psychosocial landscape of midlife.
Women at this stage of life may be experiencing life stress as children move out, retirement looms, and aging parents require time and attention. Also, as women age, they are more likely to require medications that can negatively affect sexual health. Body image issues, depression, anxiety, and discrepancy with partner desire levels can all be prevalent in women aged 45-64 years, the group most likely to experience distress from sexual problems, she said at the NAMS 2015 annual meeting.
This is important in the context of a relationship, said Dr. Kellogg Spadt. She pointed out that “when sex is good, it adds a little bit – like icing on the cupcake – to a good relationship.” But when sex is bad or nonexistent, she said, it plays an inordinately negative role, reducing the quality of the relationship by 50%-70% in some studies.
Dr. Kellogg Spadt said a good opening approach should confirm the ubiquity of sexual problems in midlife and normalize concerns. Clinicians can ask: “With menopause, many women have changes in their sexual response. These concerns are very common. Tell me – are you feeling well and complete in your sex life?”
If questioning reveals unsatisfying or nonexistent sex, many problems can be addressed in the office. First, careful questioning and an exam can tease out the extent to which dyspareunia and vaginal dryness may be limiting sexual pleasure. In that case, lubricants, moisturizers, and topical estrogen can be considered.
Office sessions with physical therapists certified in pelvic issues, combined with home use of dilators, can help overcome physical contributors to an uncomfortable sexual experience, she said.
Clinicians can also provide brief office-based counseling using the “PLISSIT” model, which. gives permission for the patient to speak openly about sexual issues; provides limited information to educate the patient about her anatomy and resources available; offers specific suggestions, for example, positioning tips or moisturizer recommendations; and offers intensive therapy, when indicated, such as referring for adjunctive psychotherapy.
Dr. Kellogg Stadt concluded with her top clinical pearls for sexual health in menopausal women:
• Add moisture daily. Using a water-based, bioadhesive lubricant several times a week regardless of sexual frequency can significantly ease comfort and satisfaction with sex and make it easier to have an orgasm.
• Nourish. A Mediterranean diet has been shown to promote sexual function, and regular exercise improves mood and overall health.
• Talk. Partners can use “I” language to talk about sex honestly and in a nonaccusatory way. Clinicians can help provide the vocabulary and communication tips to facilitate this.
• Prioritize pleasure. Intimate time together won’t just happen; even a 20-minute block of time, scheduled weekly, for touching and intimate conversation can clear the way to better sex.
• Think. Reading or watching erotica, being mindful of erotic thoughts as they occur, and focusing on sensation rather than distractions during arousal are all important.
• Stimulate. After menopause, some women need more intense stimulation to reach orgasm, so vibrators can be incorporated into sex play. Women who are uncomfortable with this can use the “doctor’s orders” approach with their partners.
• Try. Just opening up and talking about sex problems shows that a woman is committed to her partner, and taking action shows her level of care and concern for the relationship.
Dr. Kellogg Stadt reported being a consultant or on the advisory board of Neogyn and Nuelle, and on the speakers bureau of Novo Nordisk and Shionogi.
On Twitter @karioakes
LAS VEGAS – The first step is to ask. A menopausal woman may be struggling with a female sexual disorder (FSD), but unless her clinician asks, the patient may never volunteer information about her sexual health.
Susan Kellogg Spadt, Ph.D., offered that advice, along with a toolkit of tips, treatments, and pearls for physicians and others caring for the menopausal woman’s sexual health.
Dr. Kellogg Spadt, a certified sexual counselor and professor of obstetrics and gynecology at Drexel University, Philadelphia, addressed FSD in the context of the complicated psychosocial landscape of midlife.
Women at this stage of life may be experiencing life stress as children move out, retirement looms, and aging parents require time and attention. Also, as women age, they are more likely to require medications that can negatively affect sexual health. Body image issues, depression, anxiety, and discrepancy with partner desire levels can all be prevalent in women aged 45-64 years, the group most likely to experience distress from sexual problems, she said at the NAMS 2015 annual meeting.
This is important in the context of a relationship, said Dr. Kellogg Spadt. She pointed out that “when sex is good, it adds a little bit – like icing on the cupcake – to a good relationship.” But when sex is bad or nonexistent, she said, it plays an inordinately negative role, reducing the quality of the relationship by 50%-70% in some studies.
Dr. Kellogg Spadt said a good opening approach should confirm the ubiquity of sexual problems in midlife and normalize concerns. Clinicians can ask: “With menopause, many women have changes in their sexual response. These concerns are very common. Tell me – are you feeling well and complete in your sex life?”
If questioning reveals unsatisfying or nonexistent sex, many problems can be addressed in the office. First, careful questioning and an exam can tease out the extent to which dyspareunia and vaginal dryness may be limiting sexual pleasure. In that case, lubricants, moisturizers, and topical estrogen can be considered.
Office sessions with physical therapists certified in pelvic issues, combined with home use of dilators, can help overcome physical contributors to an uncomfortable sexual experience, she said.
Clinicians can also provide brief office-based counseling using the “PLISSIT” model, which. gives permission for the patient to speak openly about sexual issues; provides limited information to educate the patient about her anatomy and resources available; offers specific suggestions, for example, positioning tips or moisturizer recommendations; and offers intensive therapy, when indicated, such as referring for adjunctive psychotherapy.
Dr. Kellogg Stadt concluded with her top clinical pearls for sexual health in menopausal women:
• Add moisture daily. Using a water-based, bioadhesive lubricant several times a week regardless of sexual frequency can significantly ease comfort and satisfaction with sex and make it easier to have an orgasm.
• Nourish. A Mediterranean diet has been shown to promote sexual function, and regular exercise improves mood and overall health.
• Talk. Partners can use “I” language to talk about sex honestly and in a nonaccusatory way. Clinicians can help provide the vocabulary and communication tips to facilitate this.
• Prioritize pleasure. Intimate time together won’t just happen; even a 20-minute block of time, scheduled weekly, for touching and intimate conversation can clear the way to better sex.
• Think. Reading or watching erotica, being mindful of erotic thoughts as they occur, and focusing on sensation rather than distractions during arousal are all important.
• Stimulate. After menopause, some women need more intense stimulation to reach orgasm, so vibrators can be incorporated into sex play. Women who are uncomfortable with this can use the “doctor’s orders” approach with their partners.
• Try. Just opening up and talking about sex problems shows that a woman is committed to her partner, and taking action shows her level of care and concern for the relationship.
Dr. Kellogg Stadt reported being a consultant or on the advisory board of Neogyn and Nuelle, and on the speakers bureau of Novo Nordisk and Shionogi.
On Twitter @karioakes
LAS VEGAS – The first step is to ask. A menopausal woman may be struggling with a female sexual disorder (FSD), but unless her clinician asks, the patient may never volunteer information about her sexual health.
Susan Kellogg Spadt, Ph.D., offered that advice, along with a toolkit of tips, treatments, and pearls for physicians and others caring for the menopausal woman’s sexual health.
Dr. Kellogg Spadt, a certified sexual counselor and professor of obstetrics and gynecology at Drexel University, Philadelphia, addressed FSD in the context of the complicated psychosocial landscape of midlife.
Women at this stage of life may be experiencing life stress as children move out, retirement looms, and aging parents require time and attention. Also, as women age, they are more likely to require medications that can negatively affect sexual health. Body image issues, depression, anxiety, and discrepancy with partner desire levels can all be prevalent in women aged 45-64 years, the group most likely to experience distress from sexual problems, she said at the NAMS 2015 annual meeting.
This is important in the context of a relationship, said Dr. Kellogg Spadt. She pointed out that “when sex is good, it adds a little bit – like icing on the cupcake – to a good relationship.” But when sex is bad or nonexistent, she said, it plays an inordinately negative role, reducing the quality of the relationship by 50%-70% in some studies.
Dr. Kellogg Spadt said a good opening approach should confirm the ubiquity of sexual problems in midlife and normalize concerns. Clinicians can ask: “With menopause, many women have changes in their sexual response. These concerns are very common. Tell me – are you feeling well and complete in your sex life?”
If questioning reveals unsatisfying or nonexistent sex, many problems can be addressed in the office. First, careful questioning and an exam can tease out the extent to which dyspareunia and vaginal dryness may be limiting sexual pleasure. In that case, lubricants, moisturizers, and topical estrogen can be considered.
Office sessions with physical therapists certified in pelvic issues, combined with home use of dilators, can help overcome physical contributors to an uncomfortable sexual experience, she said.
Clinicians can also provide brief office-based counseling using the “PLISSIT” model, which. gives permission for the patient to speak openly about sexual issues; provides limited information to educate the patient about her anatomy and resources available; offers specific suggestions, for example, positioning tips or moisturizer recommendations; and offers intensive therapy, when indicated, such as referring for adjunctive psychotherapy.
Dr. Kellogg Stadt concluded with her top clinical pearls for sexual health in menopausal women:
• Add moisture daily. Using a water-based, bioadhesive lubricant several times a week regardless of sexual frequency can significantly ease comfort and satisfaction with sex and make it easier to have an orgasm.
• Nourish. A Mediterranean diet has been shown to promote sexual function, and regular exercise improves mood and overall health.
• Talk. Partners can use “I” language to talk about sex honestly and in a nonaccusatory way. Clinicians can help provide the vocabulary and communication tips to facilitate this.
• Prioritize pleasure. Intimate time together won’t just happen; even a 20-minute block of time, scheduled weekly, for touching and intimate conversation can clear the way to better sex.
• Think. Reading or watching erotica, being mindful of erotic thoughts as they occur, and focusing on sensation rather than distractions during arousal are all important.
• Stimulate. After menopause, some women need more intense stimulation to reach orgasm, so vibrators can be incorporated into sex play. Women who are uncomfortable with this can use the “doctor’s orders” approach with their partners.
• Try. Just opening up and talking about sex problems shows that a woman is committed to her partner, and taking action shows her level of care and concern for the relationship.
Dr. Kellogg Stadt reported being a consultant or on the advisory board of Neogyn and Nuelle, and on the speakers bureau of Novo Nordisk and Shionogi.
On Twitter @karioakes
EXPERT ANALYSIS FROM THE NAMS 2015 ANNUAL MEETING
Inflammation points the way to new target in solid tumors
NEW YORK – Inflammation is a hallmark of solid tumors, and chronic inflammation is a key regulator of T cell biology and therapeutic response in cancer. Bruton’s tyrosine kinase (BTK), a target in blood cancers for BTK inhibitors such as ibrutinib (Imbruvica), also poses a promising means to modulate humoral immunity and quiet a tumorigenic environment in solid tumors.
At the first International Cancer Immunotherapy Conference, Lisa Coussens, Ph.D., professor and chair of the department of cell, developmental, and cancer biology at Oregon Health Sciences University and associate director of basic research at Knight Cancer Institute, Portland (Ore.), provided a background and summarized how she and collaborators are working to limit B cell activity through inhibiting BTK.
BTK is an enzyme that plays a role both in B cell maturation and mast cell activation. Dr. Coussens, noting the importance of humoral immunity in many cancers, cited the work of Karin de Visser, Ph.D., among other researchers, who has found that circulating immune complexes can be angiogenic and tumorigenic.
In particular, the T helper-2 pathway (Th2), to a much greater extent than the Th1 pathway, can be proangiogenic, profibrotic, and immune suppressive. In cancer, when this pathway is unregulated, it “lets a tumor grow and be bad,” said Dr. Coussens.
Dr. Coussens said that Dr. de Visser’s work asks the key question: “If we depleted B cells, could we abate this pathway?”
The mechanism by which T cells are suppressed, she said, is tissue specific rather than oncogene specific. Mouse models of mammary adenocarcinoma, squamous cell carcinoma, and non–small cell lung adenocarcinoma have helped elaborate the importance of blocking the Th2 phenotype or promoting the Th1 pathway, resulting in CD8+ T cell mobilization. When the balance shifts to a Th1-predominant milieu, said Dr. Coussens, the host environment becomes angiostatic, immunostimulatory, and ultimately antitumorigenic.
In humans with chronic lymphocytic leukemia, the BTK pathway is activated in B cells and in the myeloid compartment. BTK inhibitors such as ibrutinib are currently in use for lymphomas and chronic lymphocytic leukemia.
Though BTK positive cells are also seen in pancreatic cancer. Dr. Coussens said that pancreatic cancer had been considered largely immunologically inert until recently, when researchers have begun to pay more attention to humoral immunity in the disease. However, asked Dr. Coussens, “Does the humorally mediated signature appear as a tractable target?”
To help answer the question, Dr. Coussens and her collaborators have recently shown that BTK inhibition improves response to gemcitabine in pancreatic cancer in a mouse model. Mice with an induced pancreatic tumor received the BTK inhibitor (BTKi) termed ACP-196 alone, gemcitabine alone, both, or neither. After 28 days, the combination group had significantly smaller tumor size than any other group.
Decreased desmoplasia was seen in tumor pathology when gemcitabine was combined with another BTKi, ibrutinib, said Dr. Coussens. An early dosing strategy, she said, shows that BTKi can also be effective as monotherapy when begun early enough in both tumor models studied.
Current clinical trials are underway investigating BTK inhibition in combination with conventional chemotherapy for pancreatic duct adenocarcinoma, as well as for head and neck squamous cell carcinoma.
Potential mechanisms for the promising efficacy of BTK inhibition in solid tumors include regulation of macrophage adhesion to the extracellular matrix, with suppressed adhesion to VCAM-1, and suppressed integrin activation. “Tumors are quite likely dying as a consequence of failure to adhere outside of the tumor environment,” said Dr. Coussens.
Dr. Coussens reported being on the advisory boards of Pharmacyclics Inc (the manufacturer of ibrutinib); AstraZeneca; Cellgene; and Five Prime. She receives research support from multiple pharmaceutical companies.
On Twitter @karioakes
NEW YORK – Inflammation is a hallmark of solid tumors, and chronic inflammation is a key regulator of T cell biology and therapeutic response in cancer. Bruton’s tyrosine kinase (BTK), a target in blood cancers for BTK inhibitors such as ibrutinib (Imbruvica), also poses a promising means to modulate humoral immunity and quiet a tumorigenic environment in solid tumors.
At the first International Cancer Immunotherapy Conference, Lisa Coussens, Ph.D., professor and chair of the department of cell, developmental, and cancer biology at Oregon Health Sciences University and associate director of basic research at Knight Cancer Institute, Portland (Ore.), provided a background and summarized how she and collaborators are working to limit B cell activity through inhibiting BTK.
BTK is an enzyme that plays a role both in B cell maturation and mast cell activation. Dr. Coussens, noting the importance of humoral immunity in many cancers, cited the work of Karin de Visser, Ph.D., among other researchers, who has found that circulating immune complexes can be angiogenic and tumorigenic.
In particular, the T helper-2 pathway (Th2), to a much greater extent than the Th1 pathway, can be proangiogenic, profibrotic, and immune suppressive. In cancer, when this pathway is unregulated, it “lets a tumor grow and be bad,” said Dr. Coussens.
Dr. Coussens said that Dr. de Visser’s work asks the key question: “If we depleted B cells, could we abate this pathway?”
The mechanism by which T cells are suppressed, she said, is tissue specific rather than oncogene specific. Mouse models of mammary adenocarcinoma, squamous cell carcinoma, and non–small cell lung adenocarcinoma have helped elaborate the importance of blocking the Th2 phenotype or promoting the Th1 pathway, resulting in CD8+ T cell mobilization. When the balance shifts to a Th1-predominant milieu, said Dr. Coussens, the host environment becomes angiostatic, immunostimulatory, and ultimately antitumorigenic.
In humans with chronic lymphocytic leukemia, the BTK pathway is activated in B cells and in the myeloid compartment. BTK inhibitors such as ibrutinib are currently in use for lymphomas and chronic lymphocytic leukemia.
Though BTK positive cells are also seen in pancreatic cancer. Dr. Coussens said that pancreatic cancer had been considered largely immunologically inert until recently, when researchers have begun to pay more attention to humoral immunity in the disease. However, asked Dr. Coussens, “Does the humorally mediated signature appear as a tractable target?”
To help answer the question, Dr. Coussens and her collaborators have recently shown that BTK inhibition improves response to gemcitabine in pancreatic cancer in a mouse model. Mice with an induced pancreatic tumor received the BTK inhibitor (BTKi) termed ACP-196 alone, gemcitabine alone, both, or neither. After 28 days, the combination group had significantly smaller tumor size than any other group.
Decreased desmoplasia was seen in tumor pathology when gemcitabine was combined with another BTKi, ibrutinib, said Dr. Coussens. An early dosing strategy, she said, shows that BTKi can also be effective as monotherapy when begun early enough in both tumor models studied.
Current clinical trials are underway investigating BTK inhibition in combination with conventional chemotherapy for pancreatic duct adenocarcinoma, as well as for head and neck squamous cell carcinoma.
Potential mechanisms for the promising efficacy of BTK inhibition in solid tumors include regulation of macrophage adhesion to the extracellular matrix, with suppressed adhesion to VCAM-1, and suppressed integrin activation. “Tumors are quite likely dying as a consequence of failure to adhere outside of the tumor environment,” said Dr. Coussens.
Dr. Coussens reported being on the advisory boards of Pharmacyclics Inc (the manufacturer of ibrutinib); AstraZeneca; Cellgene; and Five Prime. She receives research support from multiple pharmaceutical companies.
On Twitter @karioakes
NEW YORK – Inflammation is a hallmark of solid tumors, and chronic inflammation is a key regulator of T cell biology and therapeutic response in cancer. Bruton’s tyrosine kinase (BTK), a target in blood cancers for BTK inhibitors such as ibrutinib (Imbruvica), also poses a promising means to modulate humoral immunity and quiet a tumorigenic environment in solid tumors.
At the first International Cancer Immunotherapy Conference, Lisa Coussens, Ph.D., professor and chair of the department of cell, developmental, and cancer biology at Oregon Health Sciences University and associate director of basic research at Knight Cancer Institute, Portland (Ore.), provided a background and summarized how she and collaborators are working to limit B cell activity through inhibiting BTK.
BTK is an enzyme that plays a role both in B cell maturation and mast cell activation. Dr. Coussens, noting the importance of humoral immunity in many cancers, cited the work of Karin de Visser, Ph.D., among other researchers, who has found that circulating immune complexes can be angiogenic and tumorigenic.
In particular, the T helper-2 pathway (Th2), to a much greater extent than the Th1 pathway, can be proangiogenic, profibrotic, and immune suppressive. In cancer, when this pathway is unregulated, it “lets a tumor grow and be bad,” said Dr. Coussens.
Dr. Coussens said that Dr. de Visser’s work asks the key question: “If we depleted B cells, could we abate this pathway?”
The mechanism by which T cells are suppressed, she said, is tissue specific rather than oncogene specific. Mouse models of mammary adenocarcinoma, squamous cell carcinoma, and non–small cell lung adenocarcinoma have helped elaborate the importance of blocking the Th2 phenotype or promoting the Th1 pathway, resulting in CD8+ T cell mobilization. When the balance shifts to a Th1-predominant milieu, said Dr. Coussens, the host environment becomes angiostatic, immunostimulatory, and ultimately antitumorigenic.
In humans with chronic lymphocytic leukemia, the BTK pathway is activated in B cells and in the myeloid compartment. BTK inhibitors such as ibrutinib are currently in use for lymphomas and chronic lymphocytic leukemia.
Though BTK positive cells are also seen in pancreatic cancer. Dr. Coussens said that pancreatic cancer had been considered largely immunologically inert until recently, when researchers have begun to pay more attention to humoral immunity in the disease. However, asked Dr. Coussens, “Does the humorally mediated signature appear as a tractable target?”
To help answer the question, Dr. Coussens and her collaborators have recently shown that BTK inhibition improves response to gemcitabine in pancreatic cancer in a mouse model. Mice with an induced pancreatic tumor received the BTK inhibitor (BTKi) termed ACP-196 alone, gemcitabine alone, both, or neither. After 28 days, the combination group had significantly smaller tumor size than any other group.
Decreased desmoplasia was seen in tumor pathology when gemcitabine was combined with another BTKi, ibrutinib, said Dr. Coussens. An early dosing strategy, she said, shows that BTKi can also be effective as monotherapy when begun early enough in both tumor models studied.
Current clinical trials are underway investigating BTK inhibition in combination with conventional chemotherapy for pancreatic duct adenocarcinoma, as well as for head and neck squamous cell carcinoma.
Potential mechanisms for the promising efficacy of BTK inhibition in solid tumors include regulation of macrophage adhesion to the extracellular matrix, with suppressed adhesion to VCAM-1, and suppressed integrin activation. “Tumors are quite likely dying as a consequence of failure to adhere outside of the tumor environment,” said Dr. Coussens.
Dr. Coussens reported being on the advisory boards of Pharmacyclics Inc (the manufacturer of ibrutinib); AstraZeneca; Cellgene; and Five Prime. She receives research support from multiple pharmaceutical companies.
On Twitter @karioakes
EXPERT ANALYSIS FROM THE FIRST INTERNATIONAL CANCER IMMUNOTHERAPY CONFERENCE
Immunotherapy: Inject locally, treat globally?
NEW YORK – “Inject locally, treat globally” may become a new mantra for cancer immunotherapy. Dr. Ronald Levy, professor and chief of the department of oncology at Stanford (Calif.) University, discussed impressive and durable systemic results from local treatment of tumors, reviewing his group’s recent work and discussing ongoing early stage clinical trials.
In the hope of triggering an immune response that induces a systemic CD8 T-cell response, Dr. Levy and other investigators began experimenting with intralesional injections of immunotherapies, with and without adjunctive radiation or chemotherapy. The principle has been evaluated in a mouse model, in which up to 80% of mice receiving intratumoral immunotherapy were cured. Now, human trials are underway for solid tumors as well as lymphoma.
An early clinical trial involving 15 patients with recurrent low-grade B-cell lymphoma combined targeted low-dose radiation of a single tumor site with injection of CpG, immune-boosting snippets of DNA, into the same site. Looking for partial or complete regression, investigators saw promising results, though some patients who were responders didn’t see full effect until 24 weeks after injection (J Clin Oncol. 2010 Oct 1;28[28]:4324-32). The overall objective response rate was 27%, although 80% of patients (12 of 15) had stable disease or partial or complete response through a median follow-up of 33.7 months. Some individual patients had marked regression or disappearance of bulky tumors at distant sites.
CpG – motifs of cytosines and guanines – were strung together, said Dr. Levy, with a sulfur rather than a phosphate backbone to make them more stable for injection. These bits of DNA, which are present in both bacteria and vertebrates, are an agonist for toll-like receptor 9, activating B cells and dendritic cells, and then tumor-specific T-cells.
Dr. Levy and his collaborators used a two-tumor mouse model to track intralesional injection effectiveness for a variety of immunotherapies. Mice seeded with tumor cells bilaterally over the abdomen were injected with CpG and two other immune therapies at a single abdominal tumor site, and bilateral regression, if any, was tracked in comparison to systemic immunotherapy (J Clin Invest. 2013;123[6]:2447-63).
Though both treatment arms had good initial response, 70% of the systemically treated mice relapsed by 150 days after injection, compared with just 10% of those receiving intratumoral therapy (P = .002).
Of the 23 mice whose therapy consisted of intratumoral administration of CpG together with anti-CTLA4 and anti-OX40 antibodies (aCTLA4 and aOX40), 21 (91%) were alive 50 days after treatment. These mice fared better than did those receiving any other intratumoral treatment combination (P = .004, compared with CpG+aOX40; P = .03, compared with aCTLA4), suggesting a synergistic benefit to the triple combination.
Somewhat surprisingly, even murine models that also had tumor seeding into brain tissue saw marked reduction or even resolution of brain tumors, showing that the blood-brain barrier does not impede the effect within the CNS.
What didn’t work? PD-1 inhibitors were not particularly effective at provoking a systemic effect when injected into tumors. Peritumoral injection, though theoretically taking advantage of some aspects of the tumor microenvironment, also did not show global effect.
Based on the human CpG + radiation trials and the mouse experiments, the research group is proceeding with phase I and II clinical trials of CpG in combinations with aCTLA4 and aOX40. These, Dr. Levy said, were more likely to be available clinically, and human intratumoral T regulatory cells are known to express both CTLA4 and OX40.
All agents and combinations had an enhancing effect, said Dr. Levy. “We like this treatment and trial design,” he said, noting that everyone sees benefit at the local injection site, and some see global results.
Dr. Levy discussed multiple studies, and he disclosed receiving grant support from Pfizer, Dynavax, and Bristol-Myers Squibb. He also has served as a consultant to Five Prime, Kite, BeiGene, Innate Pharma, Bullet Biotech, and Immune Design.
NEW YORK – “Inject locally, treat globally” may become a new mantra for cancer immunotherapy. Dr. Ronald Levy, professor and chief of the department of oncology at Stanford (Calif.) University, discussed impressive and durable systemic results from local treatment of tumors, reviewing his group’s recent work and discussing ongoing early stage clinical trials.
In the hope of triggering an immune response that induces a systemic CD8 T-cell response, Dr. Levy and other investigators began experimenting with intralesional injections of immunotherapies, with and without adjunctive radiation or chemotherapy. The principle has been evaluated in a mouse model, in which up to 80% of mice receiving intratumoral immunotherapy were cured. Now, human trials are underway for solid tumors as well as lymphoma.
An early clinical trial involving 15 patients with recurrent low-grade B-cell lymphoma combined targeted low-dose radiation of a single tumor site with injection of CpG, immune-boosting snippets of DNA, into the same site. Looking for partial or complete regression, investigators saw promising results, though some patients who were responders didn’t see full effect until 24 weeks after injection (J Clin Oncol. 2010 Oct 1;28[28]:4324-32). The overall objective response rate was 27%, although 80% of patients (12 of 15) had stable disease or partial or complete response through a median follow-up of 33.7 months. Some individual patients had marked regression or disappearance of bulky tumors at distant sites.
CpG – motifs of cytosines and guanines – were strung together, said Dr. Levy, with a sulfur rather than a phosphate backbone to make them more stable for injection. These bits of DNA, which are present in both bacteria and vertebrates, are an agonist for toll-like receptor 9, activating B cells and dendritic cells, and then tumor-specific T-cells.
Dr. Levy and his collaborators used a two-tumor mouse model to track intralesional injection effectiveness for a variety of immunotherapies. Mice seeded with tumor cells bilaterally over the abdomen were injected with CpG and two other immune therapies at a single abdominal tumor site, and bilateral regression, if any, was tracked in comparison to systemic immunotherapy (J Clin Invest. 2013;123[6]:2447-63).
Though both treatment arms had good initial response, 70% of the systemically treated mice relapsed by 150 days after injection, compared with just 10% of those receiving intratumoral therapy (P = .002).
Of the 23 mice whose therapy consisted of intratumoral administration of CpG together with anti-CTLA4 and anti-OX40 antibodies (aCTLA4 and aOX40), 21 (91%) were alive 50 days after treatment. These mice fared better than did those receiving any other intratumoral treatment combination (P = .004, compared with CpG+aOX40; P = .03, compared with aCTLA4), suggesting a synergistic benefit to the triple combination.
Somewhat surprisingly, even murine models that also had tumor seeding into brain tissue saw marked reduction or even resolution of brain tumors, showing that the blood-brain barrier does not impede the effect within the CNS.
What didn’t work? PD-1 inhibitors were not particularly effective at provoking a systemic effect when injected into tumors. Peritumoral injection, though theoretically taking advantage of some aspects of the tumor microenvironment, also did not show global effect.
Based on the human CpG + radiation trials and the mouse experiments, the research group is proceeding with phase I and II clinical trials of CpG in combinations with aCTLA4 and aOX40. These, Dr. Levy said, were more likely to be available clinically, and human intratumoral T regulatory cells are known to express both CTLA4 and OX40.
All agents and combinations had an enhancing effect, said Dr. Levy. “We like this treatment and trial design,” he said, noting that everyone sees benefit at the local injection site, and some see global results.
Dr. Levy discussed multiple studies, and he disclosed receiving grant support from Pfizer, Dynavax, and Bristol-Myers Squibb. He also has served as a consultant to Five Prime, Kite, BeiGene, Innate Pharma, Bullet Biotech, and Immune Design.
NEW YORK – “Inject locally, treat globally” may become a new mantra for cancer immunotherapy. Dr. Ronald Levy, professor and chief of the department of oncology at Stanford (Calif.) University, discussed impressive and durable systemic results from local treatment of tumors, reviewing his group’s recent work and discussing ongoing early stage clinical trials.
In the hope of triggering an immune response that induces a systemic CD8 T-cell response, Dr. Levy and other investigators began experimenting with intralesional injections of immunotherapies, with and without adjunctive radiation or chemotherapy. The principle has been evaluated in a mouse model, in which up to 80% of mice receiving intratumoral immunotherapy were cured. Now, human trials are underway for solid tumors as well as lymphoma.
An early clinical trial involving 15 patients with recurrent low-grade B-cell lymphoma combined targeted low-dose radiation of a single tumor site with injection of CpG, immune-boosting snippets of DNA, into the same site. Looking for partial or complete regression, investigators saw promising results, though some patients who were responders didn’t see full effect until 24 weeks after injection (J Clin Oncol. 2010 Oct 1;28[28]:4324-32). The overall objective response rate was 27%, although 80% of patients (12 of 15) had stable disease or partial or complete response through a median follow-up of 33.7 months. Some individual patients had marked regression or disappearance of bulky tumors at distant sites.
CpG – motifs of cytosines and guanines – were strung together, said Dr. Levy, with a sulfur rather than a phosphate backbone to make them more stable for injection. These bits of DNA, which are present in both bacteria and vertebrates, are an agonist for toll-like receptor 9, activating B cells and dendritic cells, and then tumor-specific T-cells.
Dr. Levy and his collaborators used a two-tumor mouse model to track intralesional injection effectiveness for a variety of immunotherapies. Mice seeded with tumor cells bilaterally over the abdomen were injected with CpG and two other immune therapies at a single abdominal tumor site, and bilateral regression, if any, was tracked in comparison to systemic immunotherapy (J Clin Invest. 2013;123[6]:2447-63).
Though both treatment arms had good initial response, 70% of the systemically treated mice relapsed by 150 days after injection, compared with just 10% of those receiving intratumoral therapy (P = .002).
Of the 23 mice whose therapy consisted of intratumoral administration of CpG together with anti-CTLA4 and anti-OX40 antibodies (aCTLA4 and aOX40), 21 (91%) were alive 50 days after treatment. These mice fared better than did those receiving any other intratumoral treatment combination (P = .004, compared with CpG+aOX40; P = .03, compared with aCTLA4), suggesting a synergistic benefit to the triple combination.
Somewhat surprisingly, even murine models that also had tumor seeding into brain tissue saw marked reduction or even resolution of brain tumors, showing that the blood-brain barrier does not impede the effect within the CNS.
What didn’t work? PD-1 inhibitors were not particularly effective at provoking a systemic effect when injected into tumors. Peritumoral injection, though theoretically taking advantage of some aspects of the tumor microenvironment, also did not show global effect.
Based on the human CpG + radiation trials and the mouse experiments, the research group is proceeding with phase I and II clinical trials of CpG in combinations with aCTLA4 and aOX40. These, Dr. Levy said, were more likely to be available clinically, and human intratumoral T regulatory cells are known to express both CTLA4 and OX40.
All agents and combinations had an enhancing effect, said Dr. Levy. “We like this treatment and trial design,” he said, noting that everyone sees benefit at the local injection site, and some see global results.
Dr. Levy discussed multiple studies, and he disclosed receiving grant support from Pfizer, Dynavax, and Bristol-Myers Squibb. He also has served as a consultant to Five Prime, Kite, BeiGene, Innate Pharma, Bullet Biotech, and Immune Design.
EXPERT ANALYSIS FROM THE FIRST INTERNATIONAL CANCER IMMUNOTHERAPY CONFERENCE
Mandatory prescriber training now available for flibanserin
Physicians can now complete the training and paperwork required to prescribe flibanserin (Addyi, Sprout Pharmaceuticals), a new centrally acting, nonhormonal daily medication that treats female hypoactive sexual desire disorder.
The Food and Drug Administration’s August 2015 approval of flibanserin came with a required REMS(Risk Evaluation and Mitigation Strategy ) to address safety concerns.
Flibanserin, which the FDA had twice previously declined to approve, has an increased risk for syncope and hypotension with alcohol and moderate or strong CYP3A4 inhibitors, such as proton pump inhibitors, selective serotonin reuptake inhibitors, benzodiazepines, and antifungals. Flibanserin taken alone also caused hypotension and syncope in a few patients during clinical trials.
The REMS addresses these risks by requiring all prescribers to complete training and a knowledge assessment about flibanserin’s risks and to enroll in a REMS certification program for the drug. Prescribers must also review a patient-provider agreement form with patients and have both parties sign before prescribing flibanserin.
Outpatient pharmacies must designate a representative to complete training and knowledge assessment, train their staff, and counsel every patient receiving flibanserin to abstain from alcohol. Inpatient pharmacies have similar training requirements and may not dispense flibanserin for outpatient use.
Flibanserin is approved for treatment of acquired, generalized hypoactive sexual desire disorder in premenopausal women only. It is a medication that is meant to be taken on a chronic basis, acting as a mixed agonist/antagonist for dopamine and serotonin receptors. In clinical trials, it showed a statistically significant, but modest improvement in reported sexual desire and the number of sexually satisfying events per month.
The certification materials are available online at www.Addyi.com. To complete the certification process, prescribers and pharmacists should fax the completed knowledge assessment and enrollment forms to 844-694-3373 or email scanned copies to [email protected].
On Twitter @karioakes
Physicians can now complete the training and paperwork required to prescribe flibanserin (Addyi, Sprout Pharmaceuticals), a new centrally acting, nonhormonal daily medication that treats female hypoactive sexual desire disorder.
The Food and Drug Administration’s August 2015 approval of flibanserin came with a required REMS(Risk Evaluation and Mitigation Strategy ) to address safety concerns.
Flibanserin, which the FDA had twice previously declined to approve, has an increased risk for syncope and hypotension with alcohol and moderate or strong CYP3A4 inhibitors, such as proton pump inhibitors, selective serotonin reuptake inhibitors, benzodiazepines, and antifungals. Flibanserin taken alone also caused hypotension and syncope in a few patients during clinical trials.
The REMS addresses these risks by requiring all prescribers to complete training and a knowledge assessment about flibanserin’s risks and to enroll in a REMS certification program for the drug. Prescribers must also review a patient-provider agreement form with patients and have both parties sign before prescribing flibanserin.
Outpatient pharmacies must designate a representative to complete training and knowledge assessment, train their staff, and counsel every patient receiving flibanserin to abstain from alcohol. Inpatient pharmacies have similar training requirements and may not dispense flibanserin for outpatient use.
Flibanserin is approved for treatment of acquired, generalized hypoactive sexual desire disorder in premenopausal women only. It is a medication that is meant to be taken on a chronic basis, acting as a mixed agonist/antagonist for dopamine and serotonin receptors. In clinical trials, it showed a statistically significant, but modest improvement in reported sexual desire and the number of sexually satisfying events per month.
The certification materials are available online at www.Addyi.com. To complete the certification process, prescribers and pharmacists should fax the completed knowledge assessment and enrollment forms to 844-694-3373 or email scanned copies to [email protected].
On Twitter @karioakes
Physicians can now complete the training and paperwork required to prescribe flibanserin (Addyi, Sprout Pharmaceuticals), a new centrally acting, nonhormonal daily medication that treats female hypoactive sexual desire disorder.
The Food and Drug Administration’s August 2015 approval of flibanserin came with a required REMS(Risk Evaluation and Mitigation Strategy ) to address safety concerns.
Flibanserin, which the FDA had twice previously declined to approve, has an increased risk for syncope and hypotension with alcohol and moderate or strong CYP3A4 inhibitors, such as proton pump inhibitors, selective serotonin reuptake inhibitors, benzodiazepines, and antifungals. Flibanserin taken alone also caused hypotension and syncope in a few patients during clinical trials.
The REMS addresses these risks by requiring all prescribers to complete training and a knowledge assessment about flibanserin’s risks and to enroll in a REMS certification program for the drug. Prescribers must also review a patient-provider agreement form with patients and have both parties sign before prescribing flibanserin.
Outpatient pharmacies must designate a representative to complete training and knowledge assessment, train their staff, and counsel every patient receiving flibanserin to abstain from alcohol. Inpatient pharmacies have similar training requirements and may not dispense flibanserin for outpatient use.
Flibanserin is approved for treatment of acquired, generalized hypoactive sexual desire disorder in premenopausal women only. It is a medication that is meant to be taken on a chronic basis, acting as a mixed agonist/antagonist for dopamine and serotonin receptors. In clinical trials, it showed a statistically significant, but modest improvement in reported sexual desire and the number of sexually satisfying events per month.
The certification materials are available online at www.Addyi.com. To complete the certification process, prescribers and pharmacists should fax the completed knowledge assessment and enrollment forms to 844-694-3373 or email scanned copies to [email protected].
On Twitter @karioakes
Lives saved with lower systolic BP: SPRINT trial
Deaths were reduced by nearly one-quarter when systolic blood pressure was treated to a target of 120 rather than 140 mm Hg, according to a large NIH-sponsored study comparing standard blood pressure treatment with more-intensive lowering of systolic blood pressure. The lower blood pressure group also saw a 30% reduction in the composite primary composite endpoint of cardiovascular events, stroke, and cardiovascular death.
The magnitude of the effect of the lower blood pressure target prompted the study’s data safety monitoring board to end the study early, said officials from several National Institutes of Health agencies at a telebriefing. The study was unblinded in August 2015, and a full report of the primary outcome measures will come in a paper due out by the end of the year, they said.
The Systolic Blood Pressure Intervention Trial, or SPRINT, is a 100-site trial that enrolled more than 9,300 people in the United States and Puerto Rico aged at least 50 years with high blood pressure and at risk for cardiovascular disease; those with diabetes were excluded. Patients were randomized to a standard treatment target of 140 mm Hg or less, or to a more intensive 120 mm Hg.
SPRINT participants received evidence-based treatment with a variety of antihypertensives, with the intervention arm requiring an average of almost three medications, compared with just under two for the less-intensive treatment arm.
Against a backdrop of uncertainty in the literature about what the target systolic blood pressure should be for those with hypertension and at risk for cardiovascular events or kidney disease, the study provides compelling evidence that more-aggressive blood pressure lowering is important. “More-intensive management of blood pressure can save lives,” said Dr. Gary Gibbons, director of the National Heart, Lung, and Blood Institute. This is good news, he said, since about one in three Americans has high blood pressure, and only about half of those 70 million currently have their blood pressure under control.
Dr. Jackson T. Wright Jr., SPRINT study lead and director of the clinical hypertension program at Case Western Reserve University in Cleveland, also emphasized that intensive blood pressure management can prevent the cardiovascular complications of hypertension. Though subgroup analysis is ongoing, the effect seems robust and consistent across age groups, sex, and ethnicity, he said. SPRINT, he said, also “offers an excellent opportunity to examine the tolerability and safety of the lower target.” The first look at the safety data shows that the more-intensive treatment is well tolerated, though data analysis is ongoing, he said.
Dr. Suzanne Oparil, director of the vascular biology and hypertension program at the University of Alabama-Birmingham, said, “This is a time of enlightenment.” The previous absence of compelling data played a part in the debate surrounding blood pressure levels that should be used in guidance documents, and Dr. Gibbons and Dr. Wright both emphasized that they would expect the forthcoming primary outcomes paper to have an impact on guideline-writing bodies. Dr. Wright said, however, “We are not providing guidance for providers or patients right now. The study was just unblinded a little less than 3 weeks ago.”
In 2014, the group of experts who had constituted the JNC 8 panel, a team assembled in 2008 by NHLBI to update official U.S. hypertension management guidelines, set the target blood pressure for the general population aged 60 years or older to less than 150/90 mm Hg, a major break from long-standing practice to treat such patients to a target systolic pressure of less than 140 mm Hg (JAMA. 2014;311[5]:507-20). These guidelines, released after SPRINT began, remain controversial.
The SPRINT MIND trial, tracking the relationship between systolic blood pressure and cognitive impairment or dementia, is ongoing. The study is also still collecting data about kidney function in study participants.
The study was funded by the National Institutes of Health. Two drug companies, Takeda and Arbor, provided some medication for the trial.
On Twitter @karioakes
Deaths were reduced by nearly one-quarter when systolic blood pressure was treated to a target of 120 rather than 140 mm Hg, according to a large NIH-sponsored study comparing standard blood pressure treatment with more-intensive lowering of systolic blood pressure. The lower blood pressure group also saw a 30% reduction in the composite primary composite endpoint of cardiovascular events, stroke, and cardiovascular death.
The magnitude of the effect of the lower blood pressure target prompted the study’s data safety monitoring board to end the study early, said officials from several National Institutes of Health agencies at a telebriefing. The study was unblinded in August 2015, and a full report of the primary outcome measures will come in a paper due out by the end of the year, they said.
The Systolic Blood Pressure Intervention Trial, or SPRINT, is a 100-site trial that enrolled more than 9,300 people in the United States and Puerto Rico aged at least 50 years with high blood pressure and at risk for cardiovascular disease; those with diabetes were excluded. Patients were randomized to a standard treatment target of 140 mm Hg or less, or to a more intensive 120 mm Hg.
SPRINT participants received evidence-based treatment with a variety of antihypertensives, with the intervention arm requiring an average of almost three medications, compared with just under two for the less-intensive treatment arm.
Against a backdrop of uncertainty in the literature about what the target systolic blood pressure should be for those with hypertension and at risk for cardiovascular events or kidney disease, the study provides compelling evidence that more-aggressive blood pressure lowering is important. “More-intensive management of blood pressure can save lives,” said Dr. Gary Gibbons, director of the National Heart, Lung, and Blood Institute. This is good news, he said, since about one in three Americans has high blood pressure, and only about half of those 70 million currently have their blood pressure under control.
Dr. Jackson T. Wright Jr., SPRINT study lead and director of the clinical hypertension program at Case Western Reserve University in Cleveland, also emphasized that intensive blood pressure management can prevent the cardiovascular complications of hypertension. Though subgroup analysis is ongoing, the effect seems robust and consistent across age groups, sex, and ethnicity, he said. SPRINT, he said, also “offers an excellent opportunity to examine the tolerability and safety of the lower target.” The first look at the safety data shows that the more-intensive treatment is well tolerated, though data analysis is ongoing, he said.
Dr. Suzanne Oparil, director of the vascular biology and hypertension program at the University of Alabama-Birmingham, said, “This is a time of enlightenment.” The previous absence of compelling data played a part in the debate surrounding blood pressure levels that should be used in guidance documents, and Dr. Gibbons and Dr. Wright both emphasized that they would expect the forthcoming primary outcomes paper to have an impact on guideline-writing bodies. Dr. Wright said, however, “We are not providing guidance for providers or patients right now. The study was just unblinded a little less than 3 weeks ago.”
In 2014, the group of experts who had constituted the JNC 8 panel, a team assembled in 2008 by NHLBI to update official U.S. hypertension management guidelines, set the target blood pressure for the general population aged 60 years or older to less than 150/90 mm Hg, a major break from long-standing practice to treat such patients to a target systolic pressure of less than 140 mm Hg (JAMA. 2014;311[5]:507-20). These guidelines, released after SPRINT began, remain controversial.
The SPRINT MIND trial, tracking the relationship between systolic blood pressure and cognitive impairment or dementia, is ongoing. The study is also still collecting data about kidney function in study participants.
The study was funded by the National Institutes of Health. Two drug companies, Takeda and Arbor, provided some medication for the trial.
On Twitter @karioakes
Deaths were reduced by nearly one-quarter when systolic blood pressure was treated to a target of 120 rather than 140 mm Hg, according to a large NIH-sponsored study comparing standard blood pressure treatment with more-intensive lowering of systolic blood pressure. The lower blood pressure group also saw a 30% reduction in the composite primary composite endpoint of cardiovascular events, stroke, and cardiovascular death.
The magnitude of the effect of the lower blood pressure target prompted the study’s data safety monitoring board to end the study early, said officials from several National Institutes of Health agencies at a telebriefing. The study was unblinded in August 2015, and a full report of the primary outcome measures will come in a paper due out by the end of the year, they said.
The Systolic Blood Pressure Intervention Trial, or SPRINT, is a 100-site trial that enrolled more than 9,300 people in the United States and Puerto Rico aged at least 50 years with high blood pressure and at risk for cardiovascular disease; those with diabetes were excluded. Patients were randomized to a standard treatment target of 140 mm Hg or less, or to a more intensive 120 mm Hg.
SPRINT participants received evidence-based treatment with a variety of antihypertensives, with the intervention arm requiring an average of almost three medications, compared with just under two for the less-intensive treatment arm.
Against a backdrop of uncertainty in the literature about what the target systolic blood pressure should be for those with hypertension and at risk for cardiovascular events or kidney disease, the study provides compelling evidence that more-aggressive blood pressure lowering is important. “More-intensive management of blood pressure can save lives,” said Dr. Gary Gibbons, director of the National Heart, Lung, and Blood Institute. This is good news, he said, since about one in three Americans has high blood pressure, and only about half of those 70 million currently have their blood pressure under control.
Dr. Jackson T. Wright Jr., SPRINT study lead and director of the clinical hypertension program at Case Western Reserve University in Cleveland, also emphasized that intensive blood pressure management can prevent the cardiovascular complications of hypertension. Though subgroup analysis is ongoing, the effect seems robust and consistent across age groups, sex, and ethnicity, he said. SPRINT, he said, also “offers an excellent opportunity to examine the tolerability and safety of the lower target.” The first look at the safety data shows that the more-intensive treatment is well tolerated, though data analysis is ongoing, he said.
Dr. Suzanne Oparil, director of the vascular biology and hypertension program at the University of Alabama-Birmingham, said, “This is a time of enlightenment.” The previous absence of compelling data played a part in the debate surrounding blood pressure levels that should be used in guidance documents, and Dr. Gibbons and Dr. Wright both emphasized that they would expect the forthcoming primary outcomes paper to have an impact on guideline-writing bodies. Dr. Wright said, however, “We are not providing guidance for providers or patients right now. The study was just unblinded a little less than 3 weeks ago.”
In 2014, the group of experts who had constituted the JNC 8 panel, a team assembled in 2008 by NHLBI to update official U.S. hypertension management guidelines, set the target blood pressure for the general population aged 60 years or older to less than 150/90 mm Hg, a major break from long-standing practice to treat such patients to a target systolic pressure of less than 140 mm Hg (JAMA. 2014;311[5]:507-20). These guidelines, released after SPRINT began, remain controversial.
The SPRINT MIND trial, tracking the relationship between systolic blood pressure and cognitive impairment or dementia, is ongoing. The study is also still collecting data about kidney function in study participants.
The study was funded by the National Institutes of Health. Two drug companies, Takeda and Arbor, provided some medication for the trial.
On Twitter @karioakes
FROM AN NHLBI TELEBRIEFING
Extremes of sleep linked with early signs of CVD
Extremely short or extremely long sleep was associated with increased incidence of preclinical signs of cardiovascular disease in a large cross-sectional study of healthy and relatively young adults. Poor subjective sleep quality was also associated with early signs of CVD.
Dr. Chan-Won Kim of the Sungkyunkwan University in Seoul, South Korea, and his coinvestigators gathered self-reports of sleep quality and sleep duration from 47,309 healthy adults who underwent regularly scheduled physical examinations. Of those, 29,203 adults, 81% of whom were male, had measurement of coronary artery calcification (CAC); while 18,106 patients, 69% of whom were male, underwent brachial-ankle pulse wave velocity (baPWV) measurement. The patients were relatively young, with a mean age of 42 years for the CAC cohort and 46 for the baPWV cohort.
Coronary artery calcification and distal arterial stiffness are considered to be markers for preclinical CVD; by measuring these markers in a relatively young cohort, the investigators sought to avoid the many confounders that complicate the association between CVD and sleep in older patients with more comorbidities.
The study used multivariable analysis to control for factors such as smoking and alcohol use, marital status and education attainment, and physiologic variables including blood pressure, body mass index, and cholesterol.
Overall, more than 80% of subjects reported good subjective sleep quality, regardless of duration. However, women who reported poor sleep had a higher incidence of CAC, and men with poor sleep had a higher mean baPWV.
For sleep duration, Dr. Kim, Dr. Chang, and their colleagues found a U-shaped association between sleep duration and CAC and baPWV. Compared with individuals who slept 7 hours per night, individuals who reported sleeping less than 5 hours nightly had a CAC score ratio of 1.50, and an increase in baPWV of 6.7 cm/sec. At the other extreme, those who slept 9 or more hours per night had a CAC score ratio of 1.72 and an increase in baPWV of 9.6cm/sec. All these differences were statistically significant (Arterioscler Thromb Vasc Biol. 2015 Sept 10; doi: 10.1161/ATVBAHA.115.306110.).
The results help clarify that the previously known associations between sleep duration, quality, and CVD risk are not fully attributable to the comorbidities that can affect both sleep and heart health, said Dr. Kim and associates. Though they encourage further study to delineate sleep’s contribution to CVD, their results “underscore the importance of adequate sleep quantity and quality, and support the need for considering subjects with extreme duration or poor subjective quality of sleep at high risk for CVD,” they said.
On Twitter @karioakes
Extremely short or extremely long sleep was associated with increased incidence of preclinical signs of cardiovascular disease in a large cross-sectional study of healthy and relatively young adults. Poor subjective sleep quality was also associated with early signs of CVD.
Dr. Chan-Won Kim of the Sungkyunkwan University in Seoul, South Korea, and his coinvestigators gathered self-reports of sleep quality and sleep duration from 47,309 healthy adults who underwent regularly scheduled physical examinations. Of those, 29,203 adults, 81% of whom were male, had measurement of coronary artery calcification (CAC); while 18,106 patients, 69% of whom were male, underwent brachial-ankle pulse wave velocity (baPWV) measurement. The patients were relatively young, with a mean age of 42 years for the CAC cohort and 46 for the baPWV cohort.
Coronary artery calcification and distal arterial stiffness are considered to be markers for preclinical CVD; by measuring these markers in a relatively young cohort, the investigators sought to avoid the many confounders that complicate the association between CVD and sleep in older patients with more comorbidities.
The study used multivariable analysis to control for factors such as smoking and alcohol use, marital status and education attainment, and physiologic variables including blood pressure, body mass index, and cholesterol.
Overall, more than 80% of subjects reported good subjective sleep quality, regardless of duration. However, women who reported poor sleep had a higher incidence of CAC, and men with poor sleep had a higher mean baPWV.
For sleep duration, Dr. Kim, Dr. Chang, and their colleagues found a U-shaped association between sleep duration and CAC and baPWV. Compared with individuals who slept 7 hours per night, individuals who reported sleeping less than 5 hours nightly had a CAC score ratio of 1.50, and an increase in baPWV of 6.7 cm/sec. At the other extreme, those who slept 9 or more hours per night had a CAC score ratio of 1.72 and an increase in baPWV of 9.6cm/sec. All these differences were statistically significant (Arterioscler Thromb Vasc Biol. 2015 Sept 10; doi: 10.1161/ATVBAHA.115.306110.).
The results help clarify that the previously known associations between sleep duration, quality, and CVD risk are not fully attributable to the comorbidities that can affect both sleep and heart health, said Dr. Kim and associates. Though they encourage further study to delineate sleep’s contribution to CVD, their results “underscore the importance of adequate sleep quantity and quality, and support the need for considering subjects with extreme duration or poor subjective quality of sleep at high risk for CVD,” they said.
On Twitter @karioakes
Extremely short or extremely long sleep was associated with increased incidence of preclinical signs of cardiovascular disease in a large cross-sectional study of healthy and relatively young adults. Poor subjective sleep quality was also associated with early signs of CVD.
Dr. Chan-Won Kim of the Sungkyunkwan University in Seoul, South Korea, and his coinvestigators gathered self-reports of sleep quality and sleep duration from 47,309 healthy adults who underwent regularly scheduled physical examinations. Of those, 29,203 adults, 81% of whom were male, had measurement of coronary artery calcification (CAC); while 18,106 patients, 69% of whom were male, underwent brachial-ankle pulse wave velocity (baPWV) measurement. The patients were relatively young, with a mean age of 42 years for the CAC cohort and 46 for the baPWV cohort.
Coronary artery calcification and distal arterial stiffness are considered to be markers for preclinical CVD; by measuring these markers in a relatively young cohort, the investigators sought to avoid the many confounders that complicate the association between CVD and sleep in older patients with more comorbidities.
The study used multivariable analysis to control for factors such as smoking and alcohol use, marital status and education attainment, and physiologic variables including blood pressure, body mass index, and cholesterol.
Overall, more than 80% of subjects reported good subjective sleep quality, regardless of duration. However, women who reported poor sleep had a higher incidence of CAC, and men with poor sleep had a higher mean baPWV.
For sleep duration, Dr. Kim, Dr. Chang, and their colleagues found a U-shaped association between sleep duration and CAC and baPWV. Compared with individuals who slept 7 hours per night, individuals who reported sleeping less than 5 hours nightly had a CAC score ratio of 1.50, and an increase in baPWV of 6.7 cm/sec. At the other extreme, those who slept 9 or more hours per night had a CAC score ratio of 1.72 and an increase in baPWV of 9.6cm/sec. All these differences were statistically significant (Arterioscler Thromb Vasc Biol. 2015 Sept 10; doi: 10.1161/ATVBAHA.115.306110.).
The results help clarify that the previously known associations between sleep duration, quality, and CVD risk are not fully attributable to the comorbidities that can affect both sleep and heart health, said Dr. Kim and associates. Though they encourage further study to delineate sleep’s contribution to CVD, their results “underscore the importance of adequate sleep quantity and quality, and support the need for considering subjects with extreme duration or poor subjective quality of sleep at high risk for CVD,” they said.
On Twitter @karioakes
FROM ARTERIOSCLEROSIS, THROMBOSIS, AND VASCULAR BIOLOGY
Key clinical point: Individuals with very long or short sleep, or poor sleep quality, showed signs of early cardiovascular disease.
Major finding: Extremely short and extremely long sleep duration were associated with significantly increased levels of coronary artery calcification (CAC) and increased brachial-ankle pulse wave velocity (baPWV).
Data source: Cross-sectional study of more than 47,000 healthy adult men and women who reported sleep duration and quality, and underwent either measurement of CAC.
Disclosures: The funding source was not reported. The authors reported no disclosures.
Consider finer needle for some facial onabotulinumtoxinA patients
Some patients may benefit from using finer needles for facial onabotulinumtoxinA injections, although the procedure is well tolerated by most. Results of a small randomized, double-blinded split-face study of 30- vs. 32-gauge needles found that the patient experience was improved for some when the smaller needle diameter was used.
Dr. Murad Alam of Northwestern University, Chicago, and his colleagues used a split-face design to assign 20 female patients to receive onabotulinumtoxinA with a 30-gauge needle on one side of the face and a 32-gauge needle on the left side. Injections were performed for moderate dynamic forehead and glabellar wrinkles (JAMA Dermatol. 2015 Sep 9. doi: 10.1001/jamadermatol.2015.2232).
Patients were randomized according to which needle bore was used first, and according to which size bore was used on which side of the face. The 20 patients also received injections of saline on the inner upper arm with needles of each diameter. This study design, together with masking the needle hub size to ensure operator blinding, “significantly mitigated inadvertent bias” that may have been present in previous needle size studies, according to Dr. Alam.
Primary outcome measures included patient-reported pain using an 10-point visual analog scale (VAS), as well as the proportion of patients whose pain was identified as being clinically significant (set by study parameters as more than 5.4 on the VAS scale). The secondary outcome measure of patient-reported pain characteristics was assessed by use of the Short-Form McGill Pain Questionnaire.
The injections were tolerated well by most patients, regardless of needle size, so statistical adjustments were made for the large proportion of patients who reported no pain with either needle bore. Overall, needle bore did not make a statistically significant difference in mean pain levels for either the face or arm injection sites.
However, the likelihood of clinically significant pain during facial injection (pain reported as over 5.4 on the VAS) was significantly higher with the larger needle. Eight of 20 (40%) patients reported clinically significant pain from the 30-gauge needles, compared with just three reports (15%) of clinically significant pain from the 32-gauge needles (odds ratio, 3.80; P = 0.04). The difference was not seen for arm injections, and the character of the pain did not differ between the two needle types.
Noting that 32-gauge needles are about 25% smaller in external diameter than 30-gauge needles, but that they are more expensive, Dr. Alam and his colleagues suggested that use of the finer needles could be “restricted to the subset of patients who have in earlier treatments encountered clinically significant pain with large-bore needles.”
On Twitter @karioakes
Some patients may benefit from using finer needles for facial onabotulinumtoxinA injections, although the procedure is well tolerated by most. Results of a small randomized, double-blinded split-face study of 30- vs. 32-gauge needles found that the patient experience was improved for some when the smaller needle diameter was used.
Dr. Murad Alam of Northwestern University, Chicago, and his colleagues used a split-face design to assign 20 female patients to receive onabotulinumtoxinA with a 30-gauge needle on one side of the face and a 32-gauge needle on the left side. Injections were performed for moderate dynamic forehead and glabellar wrinkles (JAMA Dermatol. 2015 Sep 9. doi: 10.1001/jamadermatol.2015.2232).
Patients were randomized according to which needle bore was used first, and according to which size bore was used on which side of the face. The 20 patients also received injections of saline on the inner upper arm with needles of each diameter. This study design, together with masking the needle hub size to ensure operator blinding, “significantly mitigated inadvertent bias” that may have been present in previous needle size studies, according to Dr. Alam.
Primary outcome measures included patient-reported pain using an 10-point visual analog scale (VAS), as well as the proportion of patients whose pain was identified as being clinically significant (set by study parameters as more than 5.4 on the VAS scale). The secondary outcome measure of patient-reported pain characteristics was assessed by use of the Short-Form McGill Pain Questionnaire.
The injections were tolerated well by most patients, regardless of needle size, so statistical adjustments were made for the large proportion of patients who reported no pain with either needle bore. Overall, needle bore did not make a statistically significant difference in mean pain levels for either the face or arm injection sites.
However, the likelihood of clinically significant pain during facial injection (pain reported as over 5.4 on the VAS) was significantly higher with the larger needle. Eight of 20 (40%) patients reported clinically significant pain from the 30-gauge needles, compared with just three reports (15%) of clinically significant pain from the 32-gauge needles (odds ratio, 3.80; P = 0.04). The difference was not seen for arm injections, and the character of the pain did not differ between the two needle types.
Noting that 32-gauge needles are about 25% smaller in external diameter than 30-gauge needles, but that they are more expensive, Dr. Alam and his colleagues suggested that use of the finer needles could be “restricted to the subset of patients who have in earlier treatments encountered clinically significant pain with large-bore needles.”
On Twitter @karioakes
Some patients may benefit from using finer needles for facial onabotulinumtoxinA injections, although the procedure is well tolerated by most. Results of a small randomized, double-blinded split-face study of 30- vs. 32-gauge needles found that the patient experience was improved for some when the smaller needle diameter was used.
Dr. Murad Alam of Northwestern University, Chicago, and his colleagues used a split-face design to assign 20 female patients to receive onabotulinumtoxinA with a 30-gauge needle on one side of the face and a 32-gauge needle on the left side. Injections were performed for moderate dynamic forehead and glabellar wrinkles (JAMA Dermatol. 2015 Sep 9. doi: 10.1001/jamadermatol.2015.2232).
Patients were randomized according to which needle bore was used first, and according to which size bore was used on which side of the face. The 20 patients also received injections of saline on the inner upper arm with needles of each diameter. This study design, together with masking the needle hub size to ensure operator blinding, “significantly mitigated inadvertent bias” that may have been present in previous needle size studies, according to Dr. Alam.
Primary outcome measures included patient-reported pain using an 10-point visual analog scale (VAS), as well as the proportion of patients whose pain was identified as being clinically significant (set by study parameters as more than 5.4 on the VAS scale). The secondary outcome measure of patient-reported pain characteristics was assessed by use of the Short-Form McGill Pain Questionnaire.
The injections were tolerated well by most patients, regardless of needle size, so statistical adjustments were made for the large proportion of patients who reported no pain with either needle bore. Overall, needle bore did not make a statistically significant difference in mean pain levels for either the face or arm injection sites.
However, the likelihood of clinically significant pain during facial injection (pain reported as over 5.4 on the VAS) was significantly higher with the larger needle. Eight of 20 (40%) patients reported clinically significant pain from the 30-gauge needles, compared with just three reports (15%) of clinically significant pain from the 32-gauge needles (odds ratio, 3.80; P = 0.04). The difference was not seen for arm injections, and the character of the pain did not differ between the two needle types.
Noting that 32-gauge needles are about 25% smaller in external diameter than 30-gauge needles, but that they are more expensive, Dr. Alam and his colleagues suggested that use of the finer needles could be “restricted to the subset of patients who have in earlier treatments encountered clinically significant pain with large-bore needles.”
On Twitter @karioakes
FROM JAMA DERMATOLOGY
Key clinical point: Fewer patients had clinically significant pain when receiving facial onabotulinumtoxinA via a finer-gauge needle.
Major finding: Eight of 20 patients (40%) receiving facial onabotulinumtoxinA via 30-gauge needle had clinically significant pain in a split-face study, compared with 3 of 20 (15%) whose onabotulinumtoxinA was administered via 32-gauge needle (P = 0.04).
Data source: Randomized, double-blinded, split-face study of 20 women receiving facial botulinum toxin type A injections for forehead wrinkles.
Disclosures: The study was supported by the department of dermatology at Northwestern University. Dr. Alam has received research support and has been a consultant to several cosmetic and pharmaceutical companies unrelated to this study. No other disclosures were reported.
Tabalumab development for lupus stops because of mixed phase III results
The injectable investigational biologic tabalumab met its primary endpoint only at higher doses, and failed to meet secondary endpoints in phase III clinical trials for moderate to severe systemic lupus erythematosus. A heterogeneous patient population, intensity of background therapy, and endpoints that set a relatively high bar for efficacy all contributed to the mixed results of the ILLUMINATE-1 and ILLUMINATE-2 trials, according one of the study’s lead authors.
“This is a complex set of data,” Dr. Joan T. Merrill, professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, said in an interview. “Clinical trials are very hard to conduct,” she said, especially in an era where the standard of care already promotes aggressive treatment of patients with systemic lupus erythematosus (SLE). The fact that SLE is such a heterogeneous disease entity and the range of severity is so broad further complicates study design and data analysis, she said.
Tabalumab is a fully human monoclonal antibody that targets B-cell activating factor (BAFF), a ligand in the tumor necrosis factor (TNF) family that is necessary for B-cell development and survival. The elevated BAFF levels seen in SLE are associated with increased disease activity. Tabalumab binds to and neutralizes both soluble and membrane BAFF.
For ILLUMINATE-2, a tabalumab phase III clinical trial, 1,124 patients with moderate-to-severe SLE who were maintained on standard of care therapy were randomized 1:1:1 to receive tabalumab 120 mg subcutaneously every 2 weeks, the same dose every 4 weeks, or to receive placebo. At the start of the trial, each group received either a 240-mg loading dose of the study drug or placebo. Patients were stratified according to anti-dsDNA status and according to African ancestry (Ann Rheum Dis. 2015 Aug 20. doi: 10.1136/annrheumdis-2015-207654).
Patient characteristics were balanced across study arms, and 872 patients completed the study period of 52 weeks.
The composite SLE Responder Index 5 (SRI-5) was used to identify the primary outcome measure, the proportion of patients who attained an SRI-5 response at week 52. This threshold was achieved by improvement of at least five points in the Safety of Estrogens in Lupus Erythematosus National Assessment–SLE Disease Activity Index (SELENA-SLEDAI) score; no scores of A and not more than one B score on the British Isles Lupus Assessment Group 2004 index (BILAG); no worsening on the Physician’s Global Assessment (PGA); no added or increased antimalarial or immunosuppressant treatment; adherence to corticosteroid-dosing requirements; and enrollment in the study through week 52.
The study identified multiple secondary endpoints, including the time to the first severe SLE flare, reduction of at least 25% in corticosteroid dosing (to an equivalent of 7.5 mg or less of prednisone per day) for at least 3 consecutive months during the second half of the study period, and the increase or decrease from baseline score on the Brief Fatigue Index (BFI) at week 52.
For the group of patients receiving tabalumab every 2 weeks, the primary endpoint was met by 38.4%, compared with 27.7% of the placebo group (P = .0002). Of the group on the 4-week injection schedule, 34.8% met SRI-5, but the difference from placebo was not significant (P = .051).
Although the tabalumab treatment arms did not meet secondary endpoints, “active treatment had better outcomes than placebo on some measures,” including the corticosteroid-sparing endpoint, Dr. Merrill and her colleagues wrote.
Depression and suicidal ideation, though rare, were reported more frequently in the treatment arms than in the placebo arm: A total of 32 of 745 patients receiving tabalumab reported depression, compared with 3 of 376 receiving placebo. Furthermore, 19 tabalumab patients reported suicidal thoughts, compared with 1 receiving placebo. Injection site reactions were more common among those on tabalumab. Other adverse events were similar between treatment arms, or more common with placebo.
In discussion, Dr. Merrill and her coauthors wrote that the effect of the background standard of care therapy on BAFF signals is not known, and the large corticosteroid-dosing adjustments that were permitted may also have had an impact on BAFF levels. “Whether forced steroid tapering or withdrawal of background treatments would increase tabalumab treatment effect remains unknown,” the investigators wrote.
In ILLUMINATE-1, a similar phase III trial of tabalumab, investigators found that neither dosing regimen of the investigational drug yielded better SRI-5 response rates (31.8% for dosing every 2 weeks and 35.2% for every 4 weeks) than did placebo (29.3%). Depression and suicidal ideation also did not appear more frequently with tabalumab treatment than with placebo in ILLUMINATE-1 (Ann Rheum Dis. 2015 Sep 3. doi: 10.1136/annrheumdis-2015-207653).
However, Dr. Merrill and her coauthors noted that “ILLUMINATE-1 stipulated that new, increased or decreased standard of care medications would define a patient as nonresponsive, whereas only new or increased medications in [ILLUMINATE-2] determined nonresponse.” Analyses that did not consider patients who decreased antimalarials or immunosuppressants to be nonresponders found a significantly higher SRI-5 response rate for patients who took tabalumab every 4 weeks (37% vs. 29.8% with placebo), but not for biweekly dosing (34.1%).
In an interview, Dr. Merrill put forward the idea that rethinking study design for SLE drugs might make sense. Going forward, she said, investigators should consider breaking the population into two subgroups. For the sicker patients, background medication would have to be maintained, but the data would be more interpretable if this subgroup were analyzed separately. Patients who are less ill, she said, could be moved to homogeneous background drugs, easing data analysis and minimizing the effect of complicated and largely unknown biochemical interactions.
Regarding the rare events of depression and suicidal ideation seen in the treatment arms but not the control arm of the study, Dr. Merrill said, “You can never rule out a biochemical cause, even for a rare finding, and suicidal ideation and depression are serious events which were also numerically greater in the phase III trials of ... belimumab, but also quite rare in those studies, too.” She said that she would be interested in tracking the clinical course of those patients who became depressed and learning more about immune signaling in those individuals. “There is a lot to be learned about these treatments,” she said.
Eli Lilly and Company, tabalumab’s manufacturer, elected not to proceed with the drug development and approval process. Noting that more therapies are needed for SLE, Dr. Merrill said, “I’m very sad that Lilly decided not to develop this drug further. I understand it, but as a doctor, I’m still very sad.”
On Twitter @karioakes
The injectable investigational biologic tabalumab met its primary endpoint only at higher doses, and failed to meet secondary endpoints in phase III clinical trials for moderate to severe systemic lupus erythematosus. A heterogeneous patient population, intensity of background therapy, and endpoints that set a relatively high bar for efficacy all contributed to the mixed results of the ILLUMINATE-1 and ILLUMINATE-2 trials, according one of the study’s lead authors.
“This is a complex set of data,” Dr. Joan T. Merrill, professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, said in an interview. “Clinical trials are very hard to conduct,” she said, especially in an era where the standard of care already promotes aggressive treatment of patients with systemic lupus erythematosus (SLE). The fact that SLE is such a heterogeneous disease entity and the range of severity is so broad further complicates study design and data analysis, she said.
Tabalumab is a fully human monoclonal antibody that targets B-cell activating factor (BAFF), a ligand in the tumor necrosis factor (TNF) family that is necessary for B-cell development and survival. The elevated BAFF levels seen in SLE are associated with increased disease activity. Tabalumab binds to and neutralizes both soluble and membrane BAFF.
For ILLUMINATE-2, a tabalumab phase III clinical trial, 1,124 patients with moderate-to-severe SLE who were maintained on standard of care therapy were randomized 1:1:1 to receive tabalumab 120 mg subcutaneously every 2 weeks, the same dose every 4 weeks, or to receive placebo. At the start of the trial, each group received either a 240-mg loading dose of the study drug or placebo. Patients were stratified according to anti-dsDNA status and according to African ancestry (Ann Rheum Dis. 2015 Aug 20. doi: 10.1136/annrheumdis-2015-207654).
Patient characteristics were balanced across study arms, and 872 patients completed the study period of 52 weeks.
The composite SLE Responder Index 5 (SRI-5) was used to identify the primary outcome measure, the proportion of patients who attained an SRI-5 response at week 52. This threshold was achieved by improvement of at least five points in the Safety of Estrogens in Lupus Erythematosus National Assessment–SLE Disease Activity Index (SELENA-SLEDAI) score; no scores of A and not more than one B score on the British Isles Lupus Assessment Group 2004 index (BILAG); no worsening on the Physician’s Global Assessment (PGA); no added or increased antimalarial or immunosuppressant treatment; adherence to corticosteroid-dosing requirements; and enrollment in the study through week 52.
The study identified multiple secondary endpoints, including the time to the first severe SLE flare, reduction of at least 25% in corticosteroid dosing (to an equivalent of 7.5 mg or less of prednisone per day) for at least 3 consecutive months during the second half of the study period, and the increase or decrease from baseline score on the Brief Fatigue Index (BFI) at week 52.
For the group of patients receiving tabalumab every 2 weeks, the primary endpoint was met by 38.4%, compared with 27.7% of the placebo group (P = .0002). Of the group on the 4-week injection schedule, 34.8% met SRI-5, but the difference from placebo was not significant (P = .051).
Although the tabalumab treatment arms did not meet secondary endpoints, “active treatment had better outcomes than placebo on some measures,” including the corticosteroid-sparing endpoint, Dr. Merrill and her colleagues wrote.
Depression and suicidal ideation, though rare, were reported more frequently in the treatment arms than in the placebo arm: A total of 32 of 745 patients receiving tabalumab reported depression, compared with 3 of 376 receiving placebo. Furthermore, 19 tabalumab patients reported suicidal thoughts, compared with 1 receiving placebo. Injection site reactions were more common among those on tabalumab. Other adverse events were similar between treatment arms, or more common with placebo.
In discussion, Dr. Merrill and her coauthors wrote that the effect of the background standard of care therapy on BAFF signals is not known, and the large corticosteroid-dosing adjustments that were permitted may also have had an impact on BAFF levels. “Whether forced steroid tapering or withdrawal of background treatments would increase tabalumab treatment effect remains unknown,” the investigators wrote.
In ILLUMINATE-1, a similar phase III trial of tabalumab, investigators found that neither dosing regimen of the investigational drug yielded better SRI-5 response rates (31.8% for dosing every 2 weeks and 35.2% for every 4 weeks) than did placebo (29.3%). Depression and suicidal ideation also did not appear more frequently with tabalumab treatment than with placebo in ILLUMINATE-1 (Ann Rheum Dis. 2015 Sep 3. doi: 10.1136/annrheumdis-2015-207653).
However, Dr. Merrill and her coauthors noted that “ILLUMINATE-1 stipulated that new, increased or decreased standard of care medications would define a patient as nonresponsive, whereas only new or increased medications in [ILLUMINATE-2] determined nonresponse.” Analyses that did not consider patients who decreased antimalarials or immunosuppressants to be nonresponders found a significantly higher SRI-5 response rate for patients who took tabalumab every 4 weeks (37% vs. 29.8% with placebo), but not for biweekly dosing (34.1%).
In an interview, Dr. Merrill put forward the idea that rethinking study design for SLE drugs might make sense. Going forward, she said, investigators should consider breaking the population into two subgroups. For the sicker patients, background medication would have to be maintained, but the data would be more interpretable if this subgroup were analyzed separately. Patients who are less ill, she said, could be moved to homogeneous background drugs, easing data analysis and minimizing the effect of complicated and largely unknown biochemical interactions.
Regarding the rare events of depression and suicidal ideation seen in the treatment arms but not the control arm of the study, Dr. Merrill said, “You can never rule out a biochemical cause, even for a rare finding, and suicidal ideation and depression are serious events which were also numerically greater in the phase III trials of ... belimumab, but also quite rare in those studies, too.” She said that she would be interested in tracking the clinical course of those patients who became depressed and learning more about immune signaling in those individuals. “There is a lot to be learned about these treatments,” she said.
Eli Lilly and Company, tabalumab’s manufacturer, elected not to proceed with the drug development and approval process. Noting that more therapies are needed for SLE, Dr. Merrill said, “I’m very sad that Lilly decided not to develop this drug further. I understand it, but as a doctor, I’m still very sad.”
On Twitter @karioakes
The injectable investigational biologic tabalumab met its primary endpoint only at higher doses, and failed to meet secondary endpoints in phase III clinical trials for moderate to severe systemic lupus erythematosus. A heterogeneous patient population, intensity of background therapy, and endpoints that set a relatively high bar for efficacy all contributed to the mixed results of the ILLUMINATE-1 and ILLUMINATE-2 trials, according one of the study’s lead authors.
“This is a complex set of data,” Dr. Joan T. Merrill, professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, said in an interview. “Clinical trials are very hard to conduct,” she said, especially in an era where the standard of care already promotes aggressive treatment of patients with systemic lupus erythematosus (SLE). The fact that SLE is such a heterogeneous disease entity and the range of severity is so broad further complicates study design and data analysis, she said.
Tabalumab is a fully human monoclonal antibody that targets B-cell activating factor (BAFF), a ligand in the tumor necrosis factor (TNF) family that is necessary for B-cell development and survival. The elevated BAFF levels seen in SLE are associated with increased disease activity. Tabalumab binds to and neutralizes both soluble and membrane BAFF.
For ILLUMINATE-2, a tabalumab phase III clinical trial, 1,124 patients with moderate-to-severe SLE who were maintained on standard of care therapy were randomized 1:1:1 to receive tabalumab 120 mg subcutaneously every 2 weeks, the same dose every 4 weeks, or to receive placebo. At the start of the trial, each group received either a 240-mg loading dose of the study drug or placebo. Patients were stratified according to anti-dsDNA status and according to African ancestry (Ann Rheum Dis. 2015 Aug 20. doi: 10.1136/annrheumdis-2015-207654).
Patient characteristics were balanced across study arms, and 872 patients completed the study period of 52 weeks.
The composite SLE Responder Index 5 (SRI-5) was used to identify the primary outcome measure, the proportion of patients who attained an SRI-5 response at week 52. This threshold was achieved by improvement of at least five points in the Safety of Estrogens in Lupus Erythematosus National Assessment–SLE Disease Activity Index (SELENA-SLEDAI) score; no scores of A and not more than one B score on the British Isles Lupus Assessment Group 2004 index (BILAG); no worsening on the Physician’s Global Assessment (PGA); no added or increased antimalarial or immunosuppressant treatment; adherence to corticosteroid-dosing requirements; and enrollment in the study through week 52.
The study identified multiple secondary endpoints, including the time to the first severe SLE flare, reduction of at least 25% in corticosteroid dosing (to an equivalent of 7.5 mg or less of prednisone per day) for at least 3 consecutive months during the second half of the study period, and the increase or decrease from baseline score on the Brief Fatigue Index (BFI) at week 52.
For the group of patients receiving tabalumab every 2 weeks, the primary endpoint was met by 38.4%, compared with 27.7% of the placebo group (P = .0002). Of the group on the 4-week injection schedule, 34.8% met SRI-5, but the difference from placebo was not significant (P = .051).
Although the tabalumab treatment arms did not meet secondary endpoints, “active treatment had better outcomes than placebo on some measures,” including the corticosteroid-sparing endpoint, Dr. Merrill and her colleagues wrote.
Depression and suicidal ideation, though rare, were reported more frequently in the treatment arms than in the placebo arm: A total of 32 of 745 patients receiving tabalumab reported depression, compared with 3 of 376 receiving placebo. Furthermore, 19 tabalumab patients reported suicidal thoughts, compared with 1 receiving placebo. Injection site reactions were more common among those on tabalumab. Other adverse events were similar between treatment arms, or more common with placebo.
In discussion, Dr. Merrill and her coauthors wrote that the effect of the background standard of care therapy on BAFF signals is not known, and the large corticosteroid-dosing adjustments that were permitted may also have had an impact on BAFF levels. “Whether forced steroid tapering or withdrawal of background treatments would increase tabalumab treatment effect remains unknown,” the investigators wrote.
In ILLUMINATE-1, a similar phase III trial of tabalumab, investigators found that neither dosing regimen of the investigational drug yielded better SRI-5 response rates (31.8% for dosing every 2 weeks and 35.2% for every 4 weeks) than did placebo (29.3%). Depression and suicidal ideation also did not appear more frequently with tabalumab treatment than with placebo in ILLUMINATE-1 (Ann Rheum Dis. 2015 Sep 3. doi: 10.1136/annrheumdis-2015-207653).
However, Dr. Merrill and her coauthors noted that “ILLUMINATE-1 stipulated that new, increased or decreased standard of care medications would define a patient as nonresponsive, whereas only new or increased medications in [ILLUMINATE-2] determined nonresponse.” Analyses that did not consider patients who decreased antimalarials or immunosuppressants to be nonresponders found a significantly higher SRI-5 response rate for patients who took tabalumab every 4 weeks (37% vs. 29.8% with placebo), but not for biweekly dosing (34.1%).
In an interview, Dr. Merrill put forward the idea that rethinking study design for SLE drugs might make sense. Going forward, she said, investigators should consider breaking the population into two subgroups. For the sicker patients, background medication would have to be maintained, but the data would be more interpretable if this subgroup were analyzed separately. Patients who are less ill, she said, could be moved to homogeneous background drugs, easing data analysis and minimizing the effect of complicated and largely unknown biochemical interactions.
Regarding the rare events of depression and suicidal ideation seen in the treatment arms but not the control arm of the study, Dr. Merrill said, “You can never rule out a biochemical cause, even for a rare finding, and suicidal ideation and depression are serious events which were also numerically greater in the phase III trials of ... belimumab, but also quite rare in those studies, too.” She said that she would be interested in tracking the clinical course of those patients who became depressed and learning more about immune signaling in those individuals. “There is a lot to be learned about these treatments,” she said.
Eli Lilly and Company, tabalumab’s manufacturer, elected not to proceed with the drug development and approval process. Noting that more therapies are needed for SLE, Dr. Merrill said, “I’m very sad that Lilly decided not to develop this drug further. I understand it, but as a doctor, I’m still very sad.”
On Twitter @karioakes
FROM ANNALS OF THE RHEUMATIC DISEASES
Key clinical point: Phase III trials for tabalumab in systemic lupus erythematosus yielded mixed results for efficacy and safety. Eli Lilly discontinued the drug development process for tabalumab.
Major finding: In ILLUMINATE-2, tabalumab, when dosed at 120 mg every 2 weeks, resulted in significantly more patients who achieved a treatment response according to the SLE Responder Index 5 (SRI-5) than did placebo, when added to standard of care (P = .0002).
Data source: Two 52-week, double-blind, placebo-controlled trials of patients with moderate to severe SLE on standard of care therapy, randomized 1:1:1 to receive tabalumab 120 mg subcutaneously every 2 weeks or every 4 weeks, or to receive placebo.
Disclosures: The studies were funded by Eli Lilly and Company. Dr. Merrill has consulted for Eli Lilly and has multiple other relationships with pharmaceutical companies. Each coauthor disclosed a relationship with Eli Lilly (several are employees and stockholders), and several coauthors have extensive additional disclosures for pharmaceutical companies.
FDA warns of disabling joint pain from DPP-4 inhibitors
Multiple reports of severe and disabling joint pain in some patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes have prompted the Food and Drug Administration to add a new warning and precaution for this class of drugs. Some cases were severe enough to require hospitalization, though symptoms eventually resolved after patients stopped taking the medication.
In a MedWatch Bulletin, the FDA advises that physicians should be alert for DPP-4 inhibitors as a causative factor for patients who present with severe, persistent joint pain, even for those who have been on the medication for some time.
Most patients developed symptoms within a month of beginning treatment; however, some patients had been on a DPP-4 inhibitor for as long as a year before the onset of joint pain. When the medication was stopped, arthralgia resolved within a month in all reported cases.
Of the 33 cases of severe arthralgia found in the FDA adverse events reporting database, 28 were associated with the use of sitagliptin (Januvia), with some cases also reported with saxagliptin (Onglyza), linagliptin (Tradjenta), alogliptin (Nesina), and vildagliptin (Galvus). Ten patients’ symptoms were severe enough to require hospitalization; eight experienced recurrent arthralgia when rechallenged.
A literature search conducted by FDA officials revealed seven reports of DPP-4 inhibitor–associated arthralgia, two of which also were in their reporting database.
Patients taking DPP-4 inhibitors should continue taking their medication but consult their health care providers if they experience severe, persistent joint pain, according to the FDA advisory.
On Twitter @karioakes
Multiple reports of severe and disabling joint pain in some patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes have prompted the Food and Drug Administration to add a new warning and precaution for this class of drugs. Some cases were severe enough to require hospitalization, though symptoms eventually resolved after patients stopped taking the medication.
In a MedWatch Bulletin, the FDA advises that physicians should be alert for DPP-4 inhibitors as a causative factor for patients who present with severe, persistent joint pain, even for those who have been on the medication for some time.
Most patients developed symptoms within a month of beginning treatment; however, some patients had been on a DPP-4 inhibitor for as long as a year before the onset of joint pain. When the medication was stopped, arthralgia resolved within a month in all reported cases.
Of the 33 cases of severe arthralgia found in the FDA adverse events reporting database, 28 were associated with the use of sitagliptin (Januvia), with some cases also reported with saxagliptin (Onglyza), linagliptin (Tradjenta), alogliptin (Nesina), and vildagliptin (Galvus). Ten patients’ symptoms were severe enough to require hospitalization; eight experienced recurrent arthralgia when rechallenged.
A literature search conducted by FDA officials revealed seven reports of DPP-4 inhibitor–associated arthralgia, two of which also were in their reporting database.
Patients taking DPP-4 inhibitors should continue taking their medication but consult their health care providers if they experience severe, persistent joint pain, according to the FDA advisory.
On Twitter @karioakes
Multiple reports of severe and disabling joint pain in some patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes have prompted the Food and Drug Administration to add a new warning and precaution for this class of drugs. Some cases were severe enough to require hospitalization, though symptoms eventually resolved after patients stopped taking the medication.
In a MedWatch Bulletin, the FDA advises that physicians should be alert for DPP-4 inhibitors as a causative factor for patients who present with severe, persistent joint pain, even for those who have been on the medication for some time.
Most patients developed symptoms within a month of beginning treatment; however, some patients had been on a DPP-4 inhibitor for as long as a year before the onset of joint pain. When the medication was stopped, arthralgia resolved within a month in all reported cases.
Of the 33 cases of severe arthralgia found in the FDA adverse events reporting database, 28 were associated with the use of sitagliptin (Januvia), with some cases also reported with saxagliptin (Onglyza), linagliptin (Tradjenta), alogliptin (Nesina), and vildagliptin (Galvus). Ten patients’ symptoms were severe enough to require hospitalization; eight experienced recurrent arthralgia when rechallenged.
A literature search conducted by FDA officials revealed seven reports of DPP-4 inhibitor–associated arthralgia, two of which also were in their reporting database.
Patients taking DPP-4 inhibitors should continue taking their medication but consult their health care providers if they experience severe, persistent joint pain, according to the FDA advisory.
On Twitter @karioakes
Evolocumab is second PCSK9 inhibitor approved to lower LDL in high-risk patients
The Food and Drug Administration has approved evolocumab for lowering LDL cholesterol in some high-risk populations, making this the second biologic lipid-lowering therapy to be approved in the United States.
Evolocumab, a PCSK9 inhibitor, is self-injected subcutaneously once or twice a month, and will be marketed as Repatha by Amgen. It is approved for use in addition to diet and maximally tolerated statin therapy in adults with heterozygous familial hypercholesterolemia (HeFH), homozygous familial hypercholesterolemia (HoFH), or clinical atherosclerotic cardiovascular disease, “who require additional lowering of LDL cholesterol,” according to the FDA statement announcing approval.
“Repatha provides another treatment option in this new class of drugs for patients with familial hypercholesterolemia or with known cardiovascular disease who have not been able to lower their LDL cholesterol enough with statins,” Dr. John Jenkins, director of the office of new drugs, in the FDA’s Center for Drug Evaluation and Research, said in the statement.
In studies, evolocumab lowered low-density lipoprotein cholesterol (LDL-C) by approximately 55%-75%, compared with placebo, and by 35%-45%, compared with ezetimibe after 10-12 weeks, in patients with primary hyperlipidemia and those with mixed dyslipidemia. In a phase III study of 49 patients with HoFH, evolocumab reduced LDL-C by about 31%, compared with placebo.
Nasopharyngitis, upper respiratory tract infection, flu, back pain, and reactions such as redness, pain, or bruising at the injection site are among the adverse events associated with evolocumab, according to the FDA. Allergic reactions, such as rash and hives, have been reported in patients treated with evolocumab, who should “stop using Repatha and get medical help if they experience symptoms of a serious allergic reaction,” the statement said.
In July, the FDA approved the first PCSK9 inhibitor, alirocumab (Praluent), as an “adjunct to diet and maximally tolerated statin therapy” for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease, “who require additional lowering” of LDL-C. Alirocumab was not approved for HoFH.
Evolocumab and alirocumab are human monoclonal antibodies that lower LDL-C by binding to and inactivating proprotein convertase subtilisin kexin type 9 (PCSK9), which regulates the LDL receptor. When PCSK9 is inhibited, more LDL receptors are available to remove LDL-C from the bloodstream.
The prescribing information for alirocumab includes a “Limitations of Use” statement that says the effects of treatment on cardiovascular morbidity and mortality has not been determined, an issue discussed at the FDA advisory panel meetings held in June where the drugs were reviewed. Cardiovascular outcomes trials for both alirocumab and evolocumab are underway. The FDA statement notes that many clinical trials “have demonstrated that statins lower the risk of having a heart attack or stroke,” and refers to the ongoing study that is evaluating the effect of adding evolocumab to statins for reducing cardiovascular risk.
That study, the CV outcomes trial for evolocumab – FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) – is fully enrolled and is expected to be completed by 2017, according to Amgen.
Although long-term outcome data about the drug’s impact on cardiovascular events, CVD-related mortality, and all-cause mortality are still being collected, an FDA advisory panel voted unanimously in June to approve evolocumab to treat patients aged 12 years and older with HoFH. The panel also voted 11-4 to approve the drug for other high-risk populations, including HeFH and other groups at high risk for CVD with elevated LDL-C.
At the hearing, the panel chair, Dr. Robert Smith, professor of medicine at Brown University, Providence, R.I., said that evolocumab “is addressing an unmet need in a very-severe clinical situation with a new class of drugs that has promise.” Evolocumab, he said, “is worth the risks that accompany uncertainty about its ultimate effects on outcome.” Another panelist, Dr. Michael Blaha, director of clinical research at the Ciccarone Center for Prevention of Heart Disease, Johns Hopkins University, Baltimore, said at the hearing that he strongly supported approval for patients with well-documented HeFH, for whom lowering LDL-C is a “valid surrogate for expected cardiovascular benefit.”
In an interview, Dr. Stephen L. Kopecky of the Mayo Clinic, Rochester, Minn., agreed. Although those taking evolocumab may experience some of the same side effects seen with statins, “no one believes the outcomes won’t be good,” he said.
Dr. Seth S. Martin, a cardiologist at Johns Hopkins Hospital, said that as a clinician and a public health researcher, he is optimistic about the data. Although longterm clinical trials are needed to detect safety signals, evolocumab represents “a triumph of translational medicine,” he said in an interview.
Large clinical trials assessing efficacy and safety are ongoing, but early results from the OSLER-1 (Open-Label Study of Long-Term Evaluation Against LDL Cholesterol) and OSLER-2 studies show an overall reduction in the rate of cardiovascular events, lead study author Dr. Marc S. Sabatine, senior physician in cardiovascular medicine at Brigham and Women’s Hospital, said in an interview. Dr. Sabatine, chairman of the TIMI (Thrombolysis in Myocardial Infarction Study Group), spoke on behalf of Amgen at the FDA panel meeting on evolocumab.
Asked about the appropriate target population for evolocumab, Dr. Sabatine said, “it comes down to one simple principle: This medicine should be used for those at risk of cardiovascular events, but whose LDL is not well controlled.” Whether the elevated LDL cholesterol is caused by one genetic factor, as in familial hypercholesterolemia, or whether a host of genetic or environmental factors contribute, the effect for the patient is the same, he noted, “the LDL is still too high.”
For most patients, said Dr. Sabatine,“reach for statins first, to the maximally tolerated dose.”
The cost of the two PCKS9 inhibitors are a concern, said Dr. Martin and Dr. Sabatine, although Dr. Martin pointed out that these medications may prove to be cost-effective if used as part of rigorous and evidence-based stepwise therapy for dyslipidemia.
At the time of approval, Regeneron and Sanofi said that the cost of alirocumab would be about $14,000 yearly, based on its average wholesale price. At press time, the price of evolocumab was not available.
The timing of FDA approval for the two PCSK9 inhibitors may help pricing, according to David Whitrap, director of corporate communications for the pharmacy benefits management company Express Scripts. “These back-to-back approvals should allow natural market competition to influence the ultimate cost for the PCSK9 inhibitors....[W]e plan to leverage this competition to achieve the best possible price for the patients and payers we represent,” he wrote in an email interview. Express Scripts hopes to be able to offer both PCSK9 inhibitors in formularies for its clients, he added.
After the alirocumab decision in July, CVS Caremark said that it would wait until the FDA had ruled on both drugs before making formulary decisions. Investors have been speculating about whether the close timing of the drugs’ arrival on the market could spark a price war.
Recommended dosing for evolocumab is 140 mg subcutaneously every 2 weeks or 420 mg once a month; dosing for patients with HoFH is 420 mg every 2 or 4 weeks.
Dr. Martin reported being a co-inventor on a pending patent through Johns Hopkins University for a method of LDL-C determination. Dr. Sabatine reported relationships with multiple pharmaceutical companies, and testified on behalf of Amgen, which funded Osler-1 and -2, before the FDA advisory committee. Dr. Kopecky has received research support from Genzyme, Regeneron, and Amgen, and reported multiple additional relationships.
On Twitter @karioakes
This article was updated 8/30/15.
The Food and Drug Administration has approved evolocumab for lowering LDL cholesterol in some high-risk populations, making this the second biologic lipid-lowering therapy to be approved in the United States.
Evolocumab, a PCSK9 inhibitor, is self-injected subcutaneously once or twice a month, and will be marketed as Repatha by Amgen. It is approved for use in addition to diet and maximally tolerated statin therapy in adults with heterozygous familial hypercholesterolemia (HeFH), homozygous familial hypercholesterolemia (HoFH), or clinical atherosclerotic cardiovascular disease, “who require additional lowering of LDL cholesterol,” according to the FDA statement announcing approval.
“Repatha provides another treatment option in this new class of drugs for patients with familial hypercholesterolemia or with known cardiovascular disease who have not been able to lower their LDL cholesterol enough with statins,” Dr. John Jenkins, director of the office of new drugs, in the FDA’s Center for Drug Evaluation and Research, said in the statement.
In studies, evolocumab lowered low-density lipoprotein cholesterol (LDL-C) by approximately 55%-75%, compared with placebo, and by 35%-45%, compared with ezetimibe after 10-12 weeks, in patients with primary hyperlipidemia and those with mixed dyslipidemia. In a phase III study of 49 patients with HoFH, evolocumab reduced LDL-C by about 31%, compared with placebo.
Nasopharyngitis, upper respiratory tract infection, flu, back pain, and reactions such as redness, pain, or bruising at the injection site are among the adverse events associated with evolocumab, according to the FDA. Allergic reactions, such as rash and hives, have been reported in patients treated with evolocumab, who should “stop using Repatha and get medical help if they experience symptoms of a serious allergic reaction,” the statement said.
In July, the FDA approved the first PCSK9 inhibitor, alirocumab (Praluent), as an “adjunct to diet and maximally tolerated statin therapy” for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease, “who require additional lowering” of LDL-C. Alirocumab was not approved for HoFH.
Evolocumab and alirocumab are human monoclonal antibodies that lower LDL-C by binding to and inactivating proprotein convertase subtilisin kexin type 9 (PCSK9), which regulates the LDL receptor. When PCSK9 is inhibited, more LDL receptors are available to remove LDL-C from the bloodstream.
The prescribing information for alirocumab includes a “Limitations of Use” statement that says the effects of treatment on cardiovascular morbidity and mortality has not been determined, an issue discussed at the FDA advisory panel meetings held in June where the drugs were reviewed. Cardiovascular outcomes trials for both alirocumab and evolocumab are underway. The FDA statement notes that many clinical trials “have demonstrated that statins lower the risk of having a heart attack or stroke,” and refers to the ongoing study that is evaluating the effect of adding evolocumab to statins for reducing cardiovascular risk.
That study, the CV outcomes trial for evolocumab – FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) – is fully enrolled and is expected to be completed by 2017, according to Amgen.
Although long-term outcome data about the drug’s impact on cardiovascular events, CVD-related mortality, and all-cause mortality are still being collected, an FDA advisory panel voted unanimously in June to approve evolocumab to treat patients aged 12 years and older with HoFH. The panel also voted 11-4 to approve the drug for other high-risk populations, including HeFH and other groups at high risk for CVD with elevated LDL-C.
At the hearing, the panel chair, Dr. Robert Smith, professor of medicine at Brown University, Providence, R.I., said that evolocumab “is addressing an unmet need in a very-severe clinical situation with a new class of drugs that has promise.” Evolocumab, he said, “is worth the risks that accompany uncertainty about its ultimate effects on outcome.” Another panelist, Dr. Michael Blaha, director of clinical research at the Ciccarone Center for Prevention of Heart Disease, Johns Hopkins University, Baltimore, said at the hearing that he strongly supported approval for patients with well-documented HeFH, for whom lowering LDL-C is a “valid surrogate for expected cardiovascular benefit.”
In an interview, Dr. Stephen L. Kopecky of the Mayo Clinic, Rochester, Minn., agreed. Although those taking evolocumab may experience some of the same side effects seen with statins, “no one believes the outcomes won’t be good,” he said.
Dr. Seth S. Martin, a cardiologist at Johns Hopkins Hospital, said that as a clinician and a public health researcher, he is optimistic about the data. Although longterm clinical trials are needed to detect safety signals, evolocumab represents “a triumph of translational medicine,” he said in an interview.
Large clinical trials assessing efficacy and safety are ongoing, but early results from the OSLER-1 (Open-Label Study of Long-Term Evaluation Against LDL Cholesterol) and OSLER-2 studies show an overall reduction in the rate of cardiovascular events, lead study author Dr. Marc S. Sabatine, senior physician in cardiovascular medicine at Brigham and Women’s Hospital, said in an interview. Dr. Sabatine, chairman of the TIMI (Thrombolysis in Myocardial Infarction Study Group), spoke on behalf of Amgen at the FDA panel meeting on evolocumab.
Asked about the appropriate target population for evolocumab, Dr. Sabatine said, “it comes down to one simple principle: This medicine should be used for those at risk of cardiovascular events, but whose LDL is not well controlled.” Whether the elevated LDL cholesterol is caused by one genetic factor, as in familial hypercholesterolemia, or whether a host of genetic or environmental factors contribute, the effect for the patient is the same, he noted, “the LDL is still too high.”
For most patients, said Dr. Sabatine,“reach for statins first, to the maximally tolerated dose.”
The cost of the two PCKS9 inhibitors are a concern, said Dr. Martin and Dr. Sabatine, although Dr. Martin pointed out that these medications may prove to be cost-effective if used as part of rigorous and evidence-based stepwise therapy for dyslipidemia.
At the time of approval, Regeneron and Sanofi said that the cost of alirocumab would be about $14,000 yearly, based on its average wholesale price. At press time, the price of evolocumab was not available.
The timing of FDA approval for the two PCSK9 inhibitors may help pricing, according to David Whitrap, director of corporate communications for the pharmacy benefits management company Express Scripts. “These back-to-back approvals should allow natural market competition to influence the ultimate cost for the PCSK9 inhibitors....[W]e plan to leverage this competition to achieve the best possible price for the patients and payers we represent,” he wrote in an email interview. Express Scripts hopes to be able to offer both PCSK9 inhibitors in formularies for its clients, he added.
After the alirocumab decision in July, CVS Caremark said that it would wait until the FDA had ruled on both drugs before making formulary decisions. Investors have been speculating about whether the close timing of the drugs’ arrival on the market could spark a price war.
Recommended dosing for evolocumab is 140 mg subcutaneously every 2 weeks or 420 mg once a month; dosing for patients with HoFH is 420 mg every 2 or 4 weeks.
Dr. Martin reported being a co-inventor on a pending patent through Johns Hopkins University for a method of LDL-C determination. Dr. Sabatine reported relationships with multiple pharmaceutical companies, and testified on behalf of Amgen, which funded Osler-1 and -2, before the FDA advisory committee. Dr. Kopecky has received research support from Genzyme, Regeneron, and Amgen, and reported multiple additional relationships.
On Twitter @karioakes
This article was updated 8/30/15.
The Food and Drug Administration has approved evolocumab for lowering LDL cholesterol in some high-risk populations, making this the second biologic lipid-lowering therapy to be approved in the United States.
Evolocumab, a PCSK9 inhibitor, is self-injected subcutaneously once or twice a month, and will be marketed as Repatha by Amgen. It is approved for use in addition to diet and maximally tolerated statin therapy in adults with heterozygous familial hypercholesterolemia (HeFH), homozygous familial hypercholesterolemia (HoFH), or clinical atherosclerotic cardiovascular disease, “who require additional lowering of LDL cholesterol,” according to the FDA statement announcing approval.
“Repatha provides another treatment option in this new class of drugs for patients with familial hypercholesterolemia or with known cardiovascular disease who have not been able to lower their LDL cholesterol enough with statins,” Dr. John Jenkins, director of the office of new drugs, in the FDA’s Center for Drug Evaluation and Research, said in the statement.
In studies, evolocumab lowered low-density lipoprotein cholesterol (LDL-C) by approximately 55%-75%, compared with placebo, and by 35%-45%, compared with ezetimibe after 10-12 weeks, in patients with primary hyperlipidemia and those with mixed dyslipidemia. In a phase III study of 49 patients with HoFH, evolocumab reduced LDL-C by about 31%, compared with placebo.
Nasopharyngitis, upper respiratory tract infection, flu, back pain, and reactions such as redness, pain, or bruising at the injection site are among the adverse events associated with evolocumab, according to the FDA. Allergic reactions, such as rash and hives, have been reported in patients treated with evolocumab, who should “stop using Repatha and get medical help if they experience symptoms of a serious allergic reaction,” the statement said.
In July, the FDA approved the first PCSK9 inhibitor, alirocumab (Praluent), as an “adjunct to diet and maximally tolerated statin therapy” for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease, “who require additional lowering” of LDL-C. Alirocumab was not approved for HoFH.
Evolocumab and alirocumab are human monoclonal antibodies that lower LDL-C by binding to and inactivating proprotein convertase subtilisin kexin type 9 (PCSK9), which regulates the LDL receptor. When PCSK9 is inhibited, more LDL receptors are available to remove LDL-C from the bloodstream.
The prescribing information for alirocumab includes a “Limitations of Use” statement that says the effects of treatment on cardiovascular morbidity and mortality has not been determined, an issue discussed at the FDA advisory panel meetings held in June where the drugs were reviewed. Cardiovascular outcomes trials for both alirocumab and evolocumab are underway. The FDA statement notes that many clinical trials “have demonstrated that statins lower the risk of having a heart attack or stroke,” and refers to the ongoing study that is evaluating the effect of adding evolocumab to statins for reducing cardiovascular risk.
That study, the CV outcomes trial for evolocumab – FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) – is fully enrolled and is expected to be completed by 2017, according to Amgen.
Although long-term outcome data about the drug’s impact on cardiovascular events, CVD-related mortality, and all-cause mortality are still being collected, an FDA advisory panel voted unanimously in June to approve evolocumab to treat patients aged 12 years and older with HoFH. The panel also voted 11-4 to approve the drug for other high-risk populations, including HeFH and other groups at high risk for CVD with elevated LDL-C.
At the hearing, the panel chair, Dr. Robert Smith, professor of medicine at Brown University, Providence, R.I., said that evolocumab “is addressing an unmet need in a very-severe clinical situation with a new class of drugs that has promise.” Evolocumab, he said, “is worth the risks that accompany uncertainty about its ultimate effects on outcome.” Another panelist, Dr. Michael Blaha, director of clinical research at the Ciccarone Center for Prevention of Heart Disease, Johns Hopkins University, Baltimore, said at the hearing that he strongly supported approval for patients with well-documented HeFH, for whom lowering LDL-C is a “valid surrogate for expected cardiovascular benefit.”
In an interview, Dr. Stephen L. Kopecky of the Mayo Clinic, Rochester, Minn., agreed. Although those taking evolocumab may experience some of the same side effects seen with statins, “no one believes the outcomes won’t be good,” he said.
Dr. Seth S. Martin, a cardiologist at Johns Hopkins Hospital, said that as a clinician and a public health researcher, he is optimistic about the data. Although longterm clinical trials are needed to detect safety signals, evolocumab represents “a triumph of translational medicine,” he said in an interview.
Large clinical trials assessing efficacy and safety are ongoing, but early results from the OSLER-1 (Open-Label Study of Long-Term Evaluation Against LDL Cholesterol) and OSLER-2 studies show an overall reduction in the rate of cardiovascular events, lead study author Dr. Marc S. Sabatine, senior physician in cardiovascular medicine at Brigham and Women’s Hospital, said in an interview. Dr. Sabatine, chairman of the TIMI (Thrombolysis in Myocardial Infarction Study Group), spoke on behalf of Amgen at the FDA panel meeting on evolocumab.
Asked about the appropriate target population for evolocumab, Dr. Sabatine said, “it comes down to one simple principle: This medicine should be used for those at risk of cardiovascular events, but whose LDL is not well controlled.” Whether the elevated LDL cholesterol is caused by one genetic factor, as in familial hypercholesterolemia, or whether a host of genetic or environmental factors contribute, the effect for the patient is the same, he noted, “the LDL is still too high.”
For most patients, said Dr. Sabatine,“reach for statins first, to the maximally tolerated dose.”
The cost of the two PCKS9 inhibitors are a concern, said Dr. Martin and Dr. Sabatine, although Dr. Martin pointed out that these medications may prove to be cost-effective if used as part of rigorous and evidence-based stepwise therapy for dyslipidemia.
At the time of approval, Regeneron and Sanofi said that the cost of alirocumab would be about $14,000 yearly, based on its average wholesale price. At press time, the price of evolocumab was not available.
The timing of FDA approval for the two PCSK9 inhibitors may help pricing, according to David Whitrap, director of corporate communications for the pharmacy benefits management company Express Scripts. “These back-to-back approvals should allow natural market competition to influence the ultimate cost for the PCSK9 inhibitors....[W]e plan to leverage this competition to achieve the best possible price for the patients and payers we represent,” he wrote in an email interview. Express Scripts hopes to be able to offer both PCSK9 inhibitors in formularies for its clients, he added.
After the alirocumab decision in July, CVS Caremark said that it would wait until the FDA had ruled on both drugs before making formulary decisions. Investors have been speculating about whether the close timing of the drugs’ arrival on the market could spark a price war.
Recommended dosing for evolocumab is 140 mg subcutaneously every 2 weeks or 420 mg once a month; dosing for patients with HoFH is 420 mg every 2 or 4 weeks.
Dr. Martin reported being a co-inventor on a pending patent through Johns Hopkins University for a method of LDL-C determination. Dr. Sabatine reported relationships with multiple pharmaceutical companies, and testified on behalf of Amgen, which funded Osler-1 and -2, before the FDA advisory committee. Dr. Kopecky has received research support from Genzyme, Regeneron, and Amgen, and reported multiple additional relationships.
On Twitter @karioakes
This article was updated 8/30/15.
