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Anabasum shows promise in treating skin-predominant dermatomyositis, systemic sclerosis
SAN DIEGO – Results from two phase 2 studies of the investigational agent anabasum provide evidence supporting its safety and efficacy in patients with refractory skin-predominant dermatomyositis or diffuse cutaneous systemic sclerosis.
Anabasum (JBT-101) is a nonimmunosuppressive, synthetic, oral cannabinoid receptor type 2 agonist being developed by Norwood, Mass.–based Corbus Pharmaceuticals. It works by triggering resolution of innate immune responses, said Barbara White, MD, a rheumatologist who is chief medical officer for Corbus. “It restores homeostasis, gets rid of inflammation, turns off active fibrotic processes, and helps clear bacteria if it is present – all without immunosuppression,” she explained in an interview at the annual meeting of the American College of Rheumatology. “A drug that would restore homeostasis in the setting of an ongoing immune response has the potential to be helpful in multiple autoimmune diseases.”
The mean age of the study participants was 53 years and most were white. Even though 19 of the patients were on immunosuppressants at baseline, both cohorts had mean CDASI scores in the 33-35 range, which can be considered severe.
The investigators, led by Victoria P. Werth, MD, of the University of Pennsylvania, Philadelphia, reported that anabasum-treated subjects experienced a medically meaningful improvement in mean CDASI scores, with a reduction of at least 5 points at all visits after week 4 and reaching –9.3 at the end of the study, compared with –3.7 points in the placebo group (P = .02). They also found that 56% of subjects in the anabasum group had a 10-point reduction or more in CDASI score, compared with only 18% in the placebo group (P = .09). In addition, no subjects in the anabasum group developed skin erosions during the active dosing period, compared with 36% of subjects in the placebo group (P = .05).
The researchers also observed that, compared with subjects in the placebo group, those in the anabasum group had greater improvement in patient-reported global skin disease and overall disease assessments, skin symptoms (including photosensitivity and itch), fatigue, sleep, interference with activities, pain, and physical function. No serious, severe, or unexpected adverse events occurred in the anabasum group. Adverse events included dizziness, dyspepsia, headache, and increased appetite.
There is not a Food and Drug Administration or European Medicines Agency–approved drug for refractory skin-predominant dermatomyositis, “so this is encouraging,” Dr. White said.
Dr. Spiera reported that patients in the anabasum group had greater improvement in ACR CRISS, compared with placebo-treated subjects over 16 weeks (P = .044). They also had greater improvement and less worsening in individual CRISS core measures, including modified Rodnan Skin Score, Patient Global Assessment, Physician Global Assessment, and the Health Assessment Questionnaire Disability Index. Patient-reported outcomes of systemic sclerosis skin symptoms, itch, and the Patient-Reported Outcomes Measurement Information System–29 (PROMIS-29) domains of physical function, pain interference, and sleep also improved for the anabasum group, compared with the placebo group (P less than .05 for all).
An analysis of paired skin biopsies before and after treatment with the assessor blinded to treatment assignment demonstrated that patients treated with anabasum were more likely to show improvement in fibrosis and inflammation and less likely to show worsening than were those treated with placebo, consistent with what was observed clinically. In a related poster presented at the meeting, gene expression analysis from specimens before and after treatment also revealed that anabasum treatment (as opposed to treatment with placebo) was associated with changes relevant to pathways involved in fibrosis and inflammation.
“This is the first double-blind, randomized, placebo controlled trial in diffuse cutaneous systemic sclerosis to demonstrate a clinical benefit using the CRISS as an endpoint, with a drug that was safe and well tolerated in the trial,” Dr. Spiera said. “These results bring hope to patients and their physicians that anabasum may be an effective drug for systemic sclerosis where currently there are no proven treatments.”
Both studies were sponsored by Corbus, and the dermatomyositis study was also sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Some of the investigators in both studies were employees of Corbus. Dr. Spiera reported receiving research support from Corbus and many other pharmaceutical companies. He also is a consultant to Roche-Genentech, GlaxoSmithKline, Boehringer Ingelheim, and CSL Behring. He is a member of the Rheumatology News editorial advisory board.
SAN DIEGO – Results from two phase 2 studies of the investigational agent anabasum provide evidence supporting its safety and efficacy in patients with refractory skin-predominant dermatomyositis or diffuse cutaneous systemic sclerosis.
Anabasum (JBT-101) is a nonimmunosuppressive, synthetic, oral cannabinoid receptor type 2 agonist being developed by Norwood, Mass.–based Corbus Pharmaceuticals. It works by triggering resolution of innate immune responses, said Barbara White, MD, a rheumatologist who is chief medical officer for Corbus. “It restores homeostasis, gets rid of inflammation, turns off active fibrotic processes, and helps clear bacteria if it is present – all without immunosuppression,” she explained in an interview at the annual meeting of the American College of Rheumatology. “A drug that would restore homeostasis in the setting of an ongoing immune response has the potential to be helpful in multiple autoimmune diseases.”
The mean age of the study participants was 53 years and most were white. Even though 19 of the patients were on immunosuppressants at baseline, both cohorts had mean CDASI scores in the 33-35 range, which can be considered severe.
The investigators, led by Victoria P. Werth, MD, of the University of Pennsylvania, Philadelphia, reported that anabasum-treated subjects experienced a medically meaningful improvement in mean CDASI scores, with a reduction of at least 5 points at all visits after week 4 and reaching –9.3 at the end of the study, compared with –3.7 points in the placebo group (P = .02). They also found that 56% of subjects in the anabasum group had a 10-point reduction or more in CDASI score, compared with only 18% in the placebo group (P = .09). In addition, no subjects in the anabasum group developed skin erosions during the active dosing period, compared with 36% of subjects in the placebo group (P = .05).
The researchers also observed that, compared with subjects in the placebo group, those in the anabasum group had greater improvement in patient-reported global skin disease and overall disease assessments, skin symptoms (including photosensitivity and itch), fatigue, sleep, interference with activities, pain, and physical function. No serious, severe, or unexpected adverse events occurred in the anabasum group. Adverse events included dizziness, dyspepsia, headache, and increased appetite.
There is not a Food and Drug Administration or European Medicines Agency–approved drug for refractory skin-predominant dermatomyositis, “so this is encouraging,” Dr. White said.
Dr. Spiera reported that patients in the anabasum group had greater improvement in ACR CRISS, compared with placebo-treated subjects over 16 weeks (P = .044). They also had greater improvement and less worsening in individual CRISS core measures, including modified Rodnan Skin Score, Patient Global Assessment, Physician Global Assessment, and the Health Assessment Questionnaire Disability Index. Patient-reported outcomes of systemic sclerosis skin symptoms, itch, and the Patient-Reported Outcomes Measurement Information System–29 (PROMIS-29) domains of physical function, pain interference, and sleep also improved for the anabasum group, compared with the placebo group (P less than .05 for all).
An analysis of paired skin biopsies before and after treatment with the assessor blinded to treatment assignment demonstrated that patients treated with anabasum were more likely to show improvement in fibrosis and inflammation and less likely to show worsening than were those treated with placebo, consistent with what was observed clinically. In a related poster presented at the meeting, gene expression analysis from specimens before and after treatment also revealed that anabasum treatment (as opposed to treatment with placebo) was associated with changes relevant to pathways involved in fibrosis and inflammation.
“This is the first double-blind, randomized, placebo controlled trial in diffuse cutaneous systemic sclerosis to demonstrate a clinical benefit using the CRISS as an endpoint, with a drug that was safe and well tolerated in the trial,” Dr. Spiera said. “These results bring hope to patients and their physicians that anabasum may be an effective drug for systemic sclerosis where currently there are no proven treatments.”
Both studies were sponsored by Corbus, and the dermatomyositis study was also sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Some of the investigators in both studies were employees of Corbus. Dr. Spiera reported receiving research support from Corbus and many other pharmaceutical companies. He also is a consultant to Roche-Genentech, GlaxoSmithKline, Boehringer Ingelheim, and CSL Behring. He is a member of the Rheumatology News editorial advisory board.
SAN DIEGO – Results from two phase 2 studies of the investigational agent anabasum provide evidence supporting its safety and efficacy in patients with refractory skin-predominant dermatomyositis or diffuse cutaneous systemic sclerosis.
Anabasum (JBT-101) is a nonimmunosuppressive, synthetic, oral cannabinoid receptor type 2 agonist being developed by Norwood, Mass.–based Corbus Pharmaceuticals. It works by triggering resolution of innate immune responses, said Barbara White, MD, a rheumatologist who is chief medical officer for Corbus. “It restores homeostasis, gets rid of inflammation, turns off active fibrotic processes, and helps clear bacteria if it is present – all without immunosuppression,” she explained in an interview at the annual meeting of the American College of Rheumatology. “A drug that would restore homeostasis in the setting of an ongoing immune response has the potential to be helpful in multiple autoimmune diseases.”
The mean age of the study participants was 53 years and most were white. Even though 19 of the patients were on immunosuppressants at baseline, both cohorts had mean CDASI scores in the 33-35 range, which can be considered severe.
The investigators, led by Victoria P. Werth, MD, of the University of Pennsylvania, Philadelphia, reported that anabasum-treated subjects experienced a medically meaningful improvement in mean CDASI scores, with a reduction of at least 5 points at all visits after week 4 and reaching –9.3 at the end of the study, compared with –3.7 points in the placebo group (P = .02). They also found that 56% of subjects in the anabasum group had a 10-point reduction or more in CDASI score, compared with only 18% in the placebo group (P = .09). In addition, no subjects in the anabasum group developed skin erosions during the active dosing period, compared with 36% of subjects in the placebo group (P = .05).
The researchers also observed that, compared with subjects in the placebo group, those in the anabasum group had greater improvement in patient-reported global skin disease and overall disease assessments, skin symptoms (including photosensitivity and itch), fatigue, sleep, interference with activities, pain, and physical function. No serious, severe, or unexpected adverse events occurred in the anabasum group. Adverse events included dizziness, dyspepsia, headache, and increased appetite.
There is not a Food and Drug Administration or European Medicines Agency–approved drug for refractory skin-predominant dermatomyositis, “so this is encouraging,” Dr. White said.
Dr. Spiera reported that patients in the anabasum group had greater improvement in ACR CRISS, compared with placebo-treated subjects over 16 weeks (P = .044). They also had greater improvement and less worsening in individual CRISS core measures, including modified Rodnan Skin Score, Patient Global Assessment, Physician Global Assessment, and the Health Assessment Questionnaire Disability Index. Patient-reported outcomes of systemic sclerosis skin symptoms, itch, and the Patient-Reported Outcomes Measurement Information System–29 (PROMIS-29) domains of physical function, pain interference, and sleep also improved for the anabasum group, compared with the placebo group (P less than .05 for all).
An analysis of paired skin biopsies before and after treatment with the assessor blinded to treatment assignment demonstrated that patients treated with anabasum were more likely to show improvement in fibrosis and inflammation and less likely to show worsening than were those treated with placebo, consistent with what was observed clinically. In a related poster presented at the meeting, gene expression analysis from specimens before and after treatment also revealed that anabasum treatment (as opposed to treatment with placebo) was associated with changes relevant to pathways involved in fibrosis and inflammation.
“This is the first double-blind, randomized, placebo controlled trial in diffuse cutaneous systemic sclerosis to demonstrate a clinical benefit using the CRISS as an endpoint, with a drug that was safe and well tolerated in the trial,” Dr. Spiera said. “These results bring hope to patients and their physicians that anabasum may be an effective drug for systemic sclerosis where currently there are no proven treatments.”
Both studies were sponsored by Corbus, and the dermatomyositis study was also sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Some of the investigators in both studies were employees of Corbus. Dr. Spiera reported receiving research support from Corbus and many other pharmaceutical companies. He also is a consultant to Roche-Genentech, GlaxoSmithKline, Boehringer Ingelheim, and CSL Behring. He is a member of the Rheumatology News editorial advisory board.
AT ACR 2017
Key clinical point: Anabasum had a favorable safety profile and was well tolerated in patients with either refractory skin-predominant dermatomyositis or diffuse cutaneous systemic sclerosis.
Major finding: Treatment with anabasum resulted in greater improvement in the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) score at 12 weeks, compared with placebo (–9.3 vs. –3.7 points, respectively; P = .02) and also in the ACR Combined Response Index in Systemic Sclerosis (CRISS) at 16 weeks, compared with placebo (P = .044).
Study details: Two 12-week, phase 2 studies of anabasum in patients with dermatomyositis or systemic sclerosis.
Disclosures: The studies were funded by Corbus, and the dermatomyositis study was additionally supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Spiera reported receiving research support from Corbus and many other pharmaceutical companies. He is a consultant to Roche-Genentech, GlaxoSmithKline, Boehringer Ingelheim, and CSL Behring. Some of the investigators in both studies were employees of Corbus.
Putting Choosing Wisely into practice
At Mount Sinai Hospital, Choosing Wisely’s guidelines for hospital medicine inspired Harry Cho, MD, FACP, and his colleagues to work on the rates of catheter-associated urinary tract infection in their hospital.
They launched their “Lose the Tube” project, creating an electronic catheter identification tool and instituting a daily multidisciplinary query. “On our patient list, we had a column with a green or red dot, indicating if the patient had a catheter or not,” Dr. Cho said. “From there, we wanted to give the onus to the provider. During multidisciplinary rounds, we queried the doctor – we were not ordering them – ‘Does this patient need the Foley?’ After a while, people started coming into multidisciplinary rounds knowing if their patients had a Foley. It was a culture shift.”
“That’s the model that you want to build,” Dr. Cho said. “That’s the culture that you need so that whenever projects like this happen, they just move forward.”
Reference
Cho HJ et al. “Lose the Tube”: A Choosing Wisely initiative to reduce catheter-associated urinary tract infections in hospitalist-led inpatient units. Am J Infect Control. 2017 Mar 1;45(3):333-5.
At Mount Sinai Hospital, Choosing Wisely’s guidelines for hospital medicine inspired Harry Cho, MD, FACP, and his colleagues to work on the rates of catheter-associated urinary tract infection in their hospital.
They launched their “Lose the Tube” project, creating an electronic catheter identification tool and instituting a daily multidisciplinary query. “On our patient list, we had a column with a green or red dot, indicating if the patient had a catheter or not,” Dr. Cho said. “From there, we wanted to give the onus to the provider. During multidisciplinary rounds, we queried the doctor – we were not ordering them – ‘Does this patient need the Foley?’ After a while, people started coming into multidisciplinary rounds knowing if their patients had a Foley. It was a culture shift.”
“That’s the model that you want to build,” Dr. Cho said. “That’s the culture that you need so that whenever projects like this happen, they just move forward.”
Reference
Cho HJ et al. “Lose the Tube”: A Choosing Wisely initiative to reduce catheter-associated urinary tract infections in hospitalist-led inpatient units. Am J Infect Control. 2017 Mar 1;45(3):333-5.
At Mount Sinai Hospital, Choosing Wisely’s guidelines for hospital medicine inspired Harry Cho, MD, FACP, and his colleagues to work on the rates of catheter-associated urinary tract infection in their hospital.
They launched their “Lose the Tube” project, creating an electronic catheter identification tool and instituting a daily multidisciplinary query. “On our patient list, we had a column with a green or red dot, indicating if the patient had a catheter or not,” Dr. Cho said. “From there, we wanted to give the onus to the provider. During multidisciplinary rounds, we queried the doctor – we were not ordering them – ‘Does this patient need the Foley?’ After a while, people started coming into multidisciplinary rounds knowing if their patients had a Foley. It was a culture shift.”
“That’s the model that you want to build,” Dr. Cho said. “That’s the culture that you need so that whenever projects like this happen, they just move forward.”
Reference
Cho HJ et al. “Lose the Tube”: A Choosing Wisely initiative to reduce catheter-associated urinary tract infections in hospitalist-led inpatient units. Am J Infect Control. 2017 Mar 1;45(3):333-5.
CDC Updates Guidance on Infants With Possible Zika Infection
Infants with possible prenatal exposure to Zika who test positive for the virus should receive an in-depth ophthalmologic exam, intensified hearing testing, and a thorough neurologic evaluation with brain imaging within one month of birth, according to new interim guidance from the Centers for Disease Control and Prevention (CDC).
The new clinical management guidelines, published in the October 20 issue of Morbidity and Mortality Weekly Report, supersede the CDC guidance issued in August 2016. The update was the product of a forum on the diagnosis, evaluation, and management of Zika in infants that the centers convened with the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists. Practicing clinicians and federal agency representatives reviewed the evolving body of knowledge on how best to care for these infants. Since Zika emerged as a public health concern, clinicians have reported postnatal onset of some symptoms, including eye abnormalities, incident microcephaly in infants with a normal head circumference at birth, EEG abnormalities, and diaphragmatic paralysis.
Infants With Clinical Findings Consistent With Zika Syndrome
Infants with clinical findings consistent with congenital Zika syndrome who are born to mothers with possible Zika virus exposure in pregnancy should be tested for Zika virus with serum and urine tests. If those tests are negative, and there is no other apparent cause of the symptoms, they should have a CSF sample tested for Zika RNA and IgM Zika antibodies.
By one month, these infants should undergo a head ultrasound and a detailed ophthalmologic exam. The eye exam should pick up any anomalies of the anterior and posterior eye, including microphthalmia, coloboma, intraocular calcifications, optic nerve hypoplasia and atrophy, and macular scarring with focal pigmentary retinal mottling.
By one month, these infants also should undergo auditory brainstem response (ABR) audiometry, especially if the initial newborn hearing screen was done by otoacoustic emissions alone. Zika syndrome can include sensorineural hearing loss, although late-onset hearing loss has not been seen. Therefore, the follow-up ABR previously recommended at four to six months is no longer deemed necessary.
A comprehensive neurologic exam also is recommended. Seizures are sometimes part of Zika syndrome, but infants can also have subclinical EEG abnormalities. Advanced neuroimaging can identify obvious and subtle brain abnormalities, such as cortical thinning, corpus callosum abnormalities, calcifications at the junction of white and gray matter, and ventricular enlargement.
As infants grow, clinicians should be alert for signs of increased intracranial pressure that could signal postnatal hydrocephalus. Diaphragmatic paralysis also has been seen; it manifests as respiratory distress. Dysphagia that interferes with feeding can develop as well.
“The follow-up care of [these infants] requires a multidisciplinary team and an established medical home to facilitate the coordination of care and ensure that abnormal findings are addressed,” said Dr. Adebanjo and colleagues.
Asymptomatic Infants of Mothers With Possible Infection
Infants without clinical findings born to mothers with laboratory evidence of possible Zika virus infection during pregnancy should have the same early head ultrasound, hearing, and eye exams as those with clinical findings. All of these infants also should be tested for Zika virus just as those with clinical findings should be.
If tests are positive, these infants should have all the investigations and follow-up recommended for babies with clinical findings. If laboratory testing is negative, and clinical findings are normal, Zika infection is highly unlikely, and the infants can receive routine care. Clinicians and parents should be on the lookout, however, for new symptoms that might suggest postnatal Zika syndrome.
Asymptomatic Infants Whose Mothers Had Unconfirmed Zika Exposure
Infants without clinical findings consistent with congenital Zika syndrome born to mothers with possible Zika virus exposure in pregnancy, but without laboratory evidence of possible Zika virus infection during pregnancy, constitute a large group. Some women, for example, are never tested during pregnancy, and others have false negative test results. “Because the latter issues are not easily discerned, all mothers with possible exposure to Zika virus during pregnancy who do not have laboratory evidence of possible Zika virus infection, including those who tested negative with currently available technology, should be considered in this group,” said Dr. Adebanjo and colleagues.
The CDC do not recommend further Zika evaluation for these infants unless additional testing confirms maternal infection. For older infants, parents and clinicians should decide together whether further evaluations would be helpful. “If findings consistent with congenital Zika syndrome are identified at any time, referrals to the appropriate specialists should be made, and subsequent evaluation should follow recommendations for infants with clinical findings consistent with congenital Zika syndrome,” said the authors.
The CDC also reiterated their special recommendations for infants who had a prenatal diagnosis of Zika infection. For now, these recommendations remain unchanged, although “as more data become available, understanding of the diagnostic role of prenatal ultrasound and amniocentesis … will improve, and guidance will be updated.”
The optimal timing for a Zika diagnostic ultrasound is uncertain. The CDC recommend that serial ultrasounds be performed every three to four weeks for women with laboratory-confirmed prenatal Zika exposure. Women with possible exposure need only routine ultrasound screenings.
While Zika RNA has been identified in amniotic fluid, there is no consensus on the value of amniocentesis as a prenatal diagnostic tool. Investigations of serial amniocentesis suggest that viral shedding into the amniotic fluid might be transient. If amniocentesis is performed for other reasons, Zika nucleic acid testing can be incorporated.
A shared decision-making process about screening is key, said Dr. Adebanjo and colleagues. “For example, serial ultrasound examinations might be inconvenient, unpleasant, and expensive, and might prompt unnecessary interventions; amniocentesis carries additional known risks such as fetal loss. These potential harms of prenatal screening for congenital Zika syndrome might outweigh the clinical benefits for some patients; therefore, these decisions should be individualized.”
—Michele G. Sullivan
Suggested Reading
Adebanjo T, Godfred-Cato S, Viens L, et al. Update: Interim guidance for the diagnosis, evaluation, and management of infants with possible congenital Zika virus infection - United States, October 2017. MMWR Morb Mortal Wkly Rep. 2017;66(41):1089-1099.
Infants with possible prenatal exposure to Zika who test positive for the virus should receive an in-depth ophthalmologic exam, intensified hearing testing, and a thorough neurologic evaluation with brain imaging within one month of birth, according to new interim guidance from the Centers for Disease Control and Prevention (CDC).
The new clinical management guidelines, published in the October 20 issue of Morbidity and Mortality Weekly Report, supersede the CDC guidance issued in August 2016. The update was the product of a forum on the diagnosis, evaluation, and management of Zika in infants that the centers convened with the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists. Practicing clinicians and federal agency representatives reviewed the evolving body of knowledge on how best to care for these infants. Since Zika emerged as a public health concern, clinicians have reported postnatal onset of some symptoms, including eye abnormalities, incident microcephaly in infants with a normal head circumference at birth, EEG abnormalities, and diaphragmatic paralysis.
Infants With Clinical Findings Consistent With Zika Syndrome
Infants with clinical findings consistent with congenital Zika syndrome who are born to mothers with possible Zika virus exposure in pregnancy should be tested for Zika virus with serum and urine tests. If those tests are negative, and there is no other apparent cause of the symptoms, they should have a CSF sample tested for Zika RNA and IgM Zika antibodies.
By one month, these infants should undergo a head ultrasound and a detailed ophthalmologic exam. The eye exam should pick up any anomalies of the anterior and posterior eye, including microphthalmia, coloboma, intraocular calcifications, optic nerve hypoplasia and atrophy, and macular scarring with focal pigmentary retinal mottling.
By one month, these infants also should undergo auditory brainstem response (ABR) audiometry, especially if the initial newborn hearing screen was done by otoacoustic emissions alone. Zika syndrome can include sensorineural hearing loss, although late-onset hearing loss has not been seen. Therefore, the follow-up ABR previously recommended at four to six months is no longer deemed necessary.
A comprehensive neurologic exam also is recommended. Seizures are sometimes part of Zika syndrome, but infants can also have subclinical EEG abnormalities. Advanced neuroimaging can identify obvious and subtle brain abnormalities, such as cortical thinning, corpus callosum abnormalities, calcifications at the junction of white and gray matter, and ventricular enlargement.
As infants grow, clinicians should be alert for signs of increased intracranial pressure that could signal postnatal hydrocephalus. Diaphragmatic paralysis also has been seen; it manifests as respiratory distress. Dysphagia that interferes with feeding can develop as well.
“The follow-up care of [these infants] requires a multidisciplinary team and an established medical home to facilitate the coordination of care and ensure that abnormal findings are addressed,” said Dr. Adebanjo and colleagues.
Asymptomatic Infants of Mothers With Possible Infection
Infants without clinical findings born to mothers with laboratory evidence of possible Zika virus infection during pregnancy should have the same early head ultrasound, hearing, and eye exams as those with clinical findings. All of these infants also should be tested for Zika virus just as those with clinical findings should be.
If tests are positive, these infants should have all the investigations and follow-up recommended for babies with clinical findings. If laboratory testing is negative, and clinical findings are normal, Zika infection is highly unlikely, and the infants can receive routine care. Clinicians and parents should be on the lookout, however, for new symptoms that might suggest postnatal Zika syndrome.
Asymptomatic Infants Whose Mothers Had Unconfirmed Zika Exposure
Infants without clinical findings consistent with congenital Zika syndrome born to mothers with possible Zika virus exposure in pregnancy, but without laboratory evidence of possible Zika virus infection during pregnancy, constitute a large group. Some women, for example, are never tested during pregnancy, and others have false negative test results. “Because the latter issues are not easily discerned, all mothers with possible exposure to Zika virus during pregnancy who do not have laboratory evidence of possible Zika virus infection, including those who tested negative with currently available technology, should be considered in this group,” said Dr. Adebanjo and colleagues.
The CDC do not recommend further Zika evaluation for these infants unless additional testing confirms maternal infection. For older infants, parents and clinicians should decide together whether further evaluations would be helpful. “If findings consistent with congenital Zika syndrome are identified at any time, referrals to the appropriate specialists should be made, and subsequent evaluation should follow recommendations for infants with clinical findings consistent with congenital Zika syndrome,” said the authors.
The CDC also reiterated their special recommendations for infants who had a prenatal diagnosis of Zika infection. For now, these recommendations remain unchanged, although “as more data become available, understanding of the diagnostic role of prenatal ultrasound and amniocentesis … will improve, and guidance will be updated.”
The optimal timing for a Zika diagnostic ultrasound is uncertain. The CDC recommend that serial ultrasounds be performed every three to four weeks for women with laboratory-confirmed prenatal Zika exposure. Women with possible exposure need only routine ultrasound screenings.
While Zika RNA has been identified in amniotic fluid, there is no consensus on the value of amniocentesis as a prenatal diagnostic tool. Investigations of serial amniocentesis suggest that viral shedding into the amniotic fluid might be transient. If amniocentesis is performed for other reasons, Zika nucleic acid testing can be incorporated.
A shared decision-making process about screening is key, said Dr. Adebanjo and colleagues. “For example, serial ultrasound examinations might be inconvenient, unpleasant, and expensive, and might prompt unnecessary interventions; amniocentesis carries additional known risks such as fetal loss. These potential harms of prenatal screening for congenital Zika syndrome might outweigh the clinical benefits for some patients; therefore, these decisions should be individualized.”
—Michele G. Sullivan
Suggested Reading
Adebanjo T, Godfred-Cato S, Viens L, et al. Update: Interim guidance for the diagnosis, evaluation, and management of infants with possible congenital Zika virus infection - United States, October 2017. MMWR Morb Mortal Wkly Rep. 2017;66(41):1089-1099.
Infants with possible prenatal exposure to Zika who test positive for the virus should receive an in-depth ophthalmologic exam, intensified hearing testing, and a thorough neurologic evaluation with brain imaging within one month of birth, according to new interim guidance from the Centers for Disease Control and Prevention (CDC).
The new clinical management guidelines, published in the October 20 issue of Morbidity and Mortality Weekly Report, supersede the CDC guidance issued in August 2016. The update was the product of a forum on the diagnosis, evaluation, and management of Zika in infants that the centers convened with the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists. Practicing clinicians and federal agency representatives reviewed the evolving body of knowledge on how best to care for these infants. Since Zika emerged as a public health concern, clinicians have reported postnatal onset of some symptoms, including eye abnormalities, incident microcephaly in infants with a normal head circumference at birth, EEG abnormalities, and diaphragmatic paralysis.
Infants With Clinical Findings Consistent With Zika Syndrome
Infants with clinical findings consistent with congenital Zika syndrome who are born to mothers with possible Zika virus exposure in pregnancy should be tested for Zika virus with serum and urine tests. If those tests are negative, and there is no other apparent cause of the symptoms, they should have a CSF sample tested for Zika RNA and IgM Zika antibodies.
By one month, these infants should undergo a head ultrasound and a detailed ophthalmologic exam. The eye exam should pick up any anomalies of the anterior and posterior eye, including microphthalmia, coloboma, intraocular calcifications, optic nerve hypoplasia and atrophy, and macular scarring with focal pigmentary retinal mottling.
By one month, these infants also should undergo auditory brainstem response (ABR) audiometry, especially if the initial newborn hearing screen was done by otoacoustic emissions alone. Zika syndrome can include sensorineural hearing loss, although late-onset hearing loss has not been seen. Therefore, the follow-up ABR previously recommended at four to six months is no longer deemed necessary.
A comprehensive neurologic exam also is recommended. Seizures are sometimes part of Zika syndrome, but infants can also have subclinical EEG abnormalities. Advanced neuroimaging can identify obvious and subtle brain abnormalities, such as cortical thinning, corpus callosum abnormalities, calcifications at the junction of white and gray matter, and ventricular enlargement.
As infants grow, clinicians should be alert for signs of increased intracranial pressure that could signal postnatal hydrocephalus. Diaphragmatic paralysis also has been seen; it manifests as respiratory distress. Dysphagia that interferes with feeding can develop as well.
“The follow-up care of [these infants] requires a multidisciplinary team and an established medical home to facilitate the coordination of care and ensure that abnormal findings are addressed,” said Dr. Adebanjo and colleagues.
Asymptomatic Infants of Mothers With Possible Infection
Infants without clinical findings born to mothers with laboratory evidence of possible Zika virus infection during pregnancy should have the same early head ultrasound, hearing, and eye exams as those with clinical findings. All of these infants also should be tested for Zika virus just as those with clinical findings should be.
If tests are positive, these infants should have all the investigations and follow-up recommended for babies with clinical findings. If laboratory testing is negative, and clinical findings are normal, Zika infection is highly unlikely, and the infants can receive routine care. Clinicians and parents should be on the lookout, however, for new symptoms that might suggest postnatal Zika syndrome.
Asymptomatic Infants Whose Mothers Had Unconfirmed Zika Exposure
Infants without clinical findings consistent with congenital Zika syndrome born to mothers with possible Zika virus exposure in pregnancy, but without laboratory evidence of possible Zika virus infection during pregnancy, constitute a large group. Some women, for example, are never tested during pregnancy, and others have false negative test results. “Because the latter issues are not easily discerned, all mothers with possible exposure to Zika virus during pregnancy who do not have laboratory evidence of possible Zika virus infection, including those who tested negative with currently available technology, should be considered in this group,” said Dr. Adebanjo and colleagues.
The CDC do not recommend further Zika evaluation for these infants unless additional testing confirms maternal infection. For older infants, parents and clinicians should decide together whether further evaluations would be helpful. “If findings consistent with congenital Zika syndrome are identified at any time, referrals to the appropriate specialists should be made, and subsequent evaluation should follow recommendations for infants with clinical findings consistent with congenital Zika syndrome,” said the authors.
The CDC also reiterated their special recommendations for infants who had a prenatal diagnosis of Zika infection. For now, these recommendations remain unchanged, although “as more data become available, understanding of the diagnostic role of prenatal ultrasound and amniocentesis … will improve, and guidance will be updated.”
The optimal timing for a Zika diagnostic ultrasound is uncertain. The CDC recommend that serial ultrasounds be performed every three to four weeks for women with laboratory-confirmed prenatal Zika exposure. Women with possible exposure need only routine ultrasound screenings.
While Zika RNA has been identified in amniotic fluid, there is no consensus on the value of amniocentesis as a prenatal diagnostic tool. Investigations of serial amniocentesis suggest that viral shedding into the amniotic fluid might be transient. If amniocentesis is performed for other reasons, Zika nucleic acid testing can be incorporated.
A shared decision-making process about screening is key, said Dr. Adebanjo and colleagues. “For example, serial ultrasound examinations might be inconvenient, unpleasant, and expensive, and might prompt unnecessary interventions; amniocentesis carries additional known risks such as fetal loss. These potential harms of prenatal screening for congenital Zika syndrome might outweigh the clinical benefits for some patients; therefore, these decisions should be individualized.”
—Michele G. Sullivan
Suggested Reading
Adebanjo T, Godfred-Cato S, Viens L, et al. Update: Interim guidance for the diagnosis, evaluation, and management of infants with possible congenital Zika virus infection - United States, October 2017. MMWR Morb Mortal Wkly Rep. 2017;66(41):1089-1099.
Radiofrequency ablation improves stent patency in malignant biliary strictures
In patients with malignant biliary strictures, radiofrequency ablation may improve stent patency and prolong survival, according to results of a recent meta-analysis.
Radiofrequency ablation was also safe and well tolerated. The report appears in Gastrointestinal Endoscopy (2017. doi: 10.1016/j.gie.2017.10.029).
Although the data to date are limited and mostly observational, radiofrequency ablation “may be a promising adjuvant therapy in patients with malignant biliary obstruction who otherwise have dismal outcomes with current standard of therapy,” wrote Aijaz Ahmed Sofi, MD, of the department of gastroenterology, Arizona Center for Digestive Health, Gilbert, and coauthors.
Use of radiofrequency ablation is thought to improve the patency of biliary stents placed as a palliative measure in patients with unresectable malignant biliary strictures. However, several studies evaluating this and other endpoints have produced “variable results,” the authors said in the report.
In a comprehensive literature search, Dr. Sofi and colleagues identified nine studies including 505 patients. Only one of the studies was randomized and controlled, and results from it were preliminary, they noted.
Combined results showed a 50.6-day pooled weighted mean difference in stent patency (95% confidence interval, 32.83-68.48) in favor of radiofrequency ablation, according to reported data. In addition, there was a significant difference in survival favoring use of radiofrequency ablation (hazard ratio, 1.395; 95% confidence interval, 1.145-1.7; P less than .001).
While there was no difference between groups in risk of cholangitis, pancreatitis, hemobilia, and acute cholecystitis, abdominal pain after the procedure was more frequent in the radiofrequency ablation group (31% vs. 20%, P = .003).
This is the first systematic review and meta-analysis evaluating radiofrequency ablation as an adjuvant therapy in patients who receive biliary stents for malignant biliary obstruction, according to the investigators.
Despite the findings, Dr. Sofi and colleagues were careful to emphasize the limitations of the analysis, writing that it provides “very low quality evidence” in favor of radiofrequency ablation therapy for management of malignant biliary strictures.
“The results of currently ongoing controlled studies examining the role of RFA [radiofrequency ablation] in malignant biliary obstruction are keenly awaited,” they wrote.
Dr. Sofi and colleagues reported no potential conflicts of interest associated with the study.
In patients with malignant biliary strictures, radiofrequency ablation may improve stent patency and prolong survival, according to results of a recent meta-analysis.
Radiofrequency ablation was also safe and well tolerated. The report appears in Gastrointestinal Endoscopy (2017. doi: 10.1016/j.gie.2017.10.029).
Although the data to date are limited and mostly observational, radiofrequency ablation “may be a promising adjuvant therapy in patients with malignant biliary obstruction who otherwise have dismal outcomes with current standard of therapy,” wrote Aijaz Ahmed Sofi, MD, of the department of gastroenterology, Arizona Center for Digestive Health, Gilbert, and coauthors.
Use of radiofrequency ablation is thought to improve the patency of biliary stents placed as a palliative measure in patients with unresectable malignant biliary strictures. However, several studies evaluating this and other endpoints have produced “variable results,” the authors said in the report.
In a comprehensive literature search, Dr. Sofi and colleagues identified nine studies including 505 patients. Only one of the studies was randomized and controlled, and results from it were preliminary, they noted.
Combined results showed a 50.6-day pooled weighted mean difference in stent patency (95% confidence interval, 32.83-68.48) in favor of radiofrequency ablation, according to reported data. In addition, there was a significant difference in survival favoring use of radiofrequency ablation (hazard ratio, 1.395; 95% confidence interval, 1.145-1.7; P less than .001).
While there was no difference between groups in risk of cholangitis, pancreatitis, hemobilia, and acute cholecystitis, abdominal pain after the procedure was more frequent in the radiofrequency ablation group (31% vs. 20%, P = .003).
This is the first systematic review and meta-analysis evaluating radiofrequency ablation as an adjuvant therapy in patients who receive biliary stents for malignant biliary obstruction, according to the investigators.
Despite the findings, Dr. Sofi and colleagues were careful to emphasize the limitations of the analysis, writing that it provides “very low quality evidence” in favor of radiofrequency ablation therapy for management of malignant biliary strictures.
“The results of currently ongoing controlled studies examining the role of RFA [radiofrequency ablation] in malignant biliary obstruction are keenly awaited,” they wrote.
Dr. Sofi and colleagues reported no potential conflicts of interest associated with the study.
In patients with malignant biliary strictures, radiofrequency ablation may improve stent patency and prolong survival, according to results of a recent meta-analysis.
Radiofrequency ablation was also safe and well tolerated. The report appears in Gastrointestinal Endoscopy (2017. doi: 10.1016/j.gie.2017.10.029).
Although the data to date are limited and mostly observational, radiofrequency ablation “may be a promising adjuvant therapy in patients with malignant biliary obstruction who otherwise have dismal outcomes with current standard of therapy,” wrote Aijaz Ahmed Sofi, MD, of the department of gastroenterology, Arizona Center for Digestive Health, Gilbert, and coauthors.
Use of radiofrequency ablation is thought to improve the patency of biliary stents placed as a palliative measure in patients with unresectable malignant biliary strictures. However, several studies evaluating this and other endpoints have produced “variable results,” the authors said in the report.
In a comprehensive literature search, Dr. Sofi and colleagues identified nine studies including 505 patients. Only one of the studies was randomized and controlled, and results from it were preliminary, they noted.
Combined results showed a 50.6-day pooled weighted mean difference in stent patency (95% confidence interval, 32.83-68.48) in favor of radiofrequency ablation, according to reported data. In addition, there was a significant difference in survival favoring use of radiofrequency ablation (hazard ratio, 1.395; 95% confidence interval, 1.145-1.7; P less than .001).
While there was no difference between groups in risk of cholangitis, pancreatitis, hemobilia, and acute cholecystitis, abdominal pain after the procedure was more frequent in the radiofrequency ablation group (31% vs. 20%, P = .003).
This is the first systematic review and meta-analysis evaluating radiofrequency ablation as an adjuvant therapy in patients who receive biliary stents for malignant biliary obstruction, according to the investigators.
Despite the findings, Dr. Sofi and colleagues were careful to emphasize the limitations of the analysis, writing that it provides “very low quality evidence” in favor of radiofrequency ablation therapy for management of malignant biliary strictures.
“The results of currently ongoing controlled studies examining the role of RFA [radiofrequency ablation] in malignant biliary obstruction are keenly awaited,” they wrote.
Dr. Sofi and colleagues reported no potential conflicts of interest associated with the study.
FROM GASTROINTESTINAL ENDOSCOPY
Key clinical point: Although data to date are limited and mostly observational, radiofrequency ablation appears to improve stent patency and may prolong survival in patients with malignant biliary strictures.
Major finding: There was a significant difference in survival (P less than .001) and 50.6-day pooled weighted mean difference in stent patency (95% CI, 32.83-68.48) in favor of radiofrequency ablation.
Data source: A meta-analysis of 505 patients from nine studies that were identified through a comprehensive literature search.
Disclosures: There was no funding source for the study. The authors reported no potential conflicts of interest.
Observing BP measurement made no difference in SPRINT
ANAHEIM, CALIF. – More than half of the BP measurements of patients in the SPRINT trial were at least partially attended by clinic staff, but those efforts made no difference in outcomes, according to a survey presented by SPRINT investigators at the American Heart Association scientific sessions.
“It really didn’t matter” whether measurements were observed or not; blood pressure control and outcomes – fewer deaths and cardiovascular events when hypertension was treated to below 120 mm Hg instead of below 140 mm Hg – were largely the same either way, said the survey’s lead investigator Karen C. Johnson, MD, professor of women’s health and preventive medicine at the University of Tennessee in Memphis. 
What did matter were the other measures SPRINT [Systolic Blood Pressure Intervention Trial] took to ensure accurate blood pressure measurement, including patients resting for 5 minutes; three automated readings taken afterward then averaged; proper cuff size; feet flat on the floor while patients sat; arms at proper level, and no talking, texting, or filling out forms during the reading, Dr. Johnson said (N Engl J Med. 2015 Nov 26;373[22]:2103-16).
“If you do [those things], then it doesn’t matter if somebody is in the room or not; you can treat to the levels we are talking about,” said William Cushman, MD, professor of medicine and physiology at the university, and also a SPRINT investigator. 
Although the SPRINT researchers hadn’t addressed the issue before the AHA meeting, it’s been widely thought, and even reported in some places, that blood pressures in the trial were unattended. The misperception has led to anxiety about how to apply SPRINT to everyday practice, since few clinics are set up to have patients sit alone for 5 or 10 minutes for a blood pressure.
To address the concern, the SPRINT team surveyed study sites after the trial ended. It turned out that 4,082 subjects were at sites where patients were usually left alone for both the 5-minute rest period and the three BP readings, and 2,247 were at sites where staff usually attended both; 1,746 were at sites that left patients alone for the rest period only; and 570 were at sites where patients were alone only for the BP readings.
Observation had no impact on blood pressure. In the intensive arm, participants achieved and maintained an average systolic BP of about 120 mm Hg in all four groups. In the standard treatment arm, that average was about 135 mm Hg in all four groups. “When we look at the number of medications used, they were very similar in all four blood pressure groups,” with intensive treatment patients taking an average of one extra drug, Dr. Johnson said.
Intensive treatment, versus standard treatment, reduced cardiovascular events to a similar extent in patients who were alone for the entire blood pressure reading (by 38%) and those who were accompanied throughout (by 36%). For reasons that are not clear, intensive treatment did not significantly reduce risk among subjects who were observed during rest or observed for blood pressure readings. Both groups had lower Framingham 10-year cardiovascular disease risk scores, which may have been a confounder.
Meanwhile, the rate of adverse events and total mortality – lower with intensive treatment – did not vary by observation, Dr. Johnson said.
The survey excluded 716 subjects at 14 study sites who could not be classified into one of the four BP observation categories.
SPRINT was sponsored by the National Institutes of Health. Doctors Johnson and Cushman didn’t have any disclosures.
ANAHEIM, CALIF. – More than half of the BP measurements of patients in the SPRINT trial were at least partially attended by clinic staff, but those efforts made no difference in outcomes, according to a survey presented by SPRINT investigators at the American Heart Association scientific sessions.
“It really didn’t matter” whether measurements were observed or not; blood pressure control and outcomes – fewer deaths and cardiovascular events when hypertension was treated to below 120 mm Hg instead of below 140 mm Hg – were largely the same either way, said the survey’s lead investigator Karen C. Johnson, MD, professor of women’s health and preventive medicine at the University of Tennessee in Memphis.
What did matter were the other measures SPRINT [Systolic Blood Pressure Intervention Trial] took to ensure accurate blood pressure measurement, including patients resting for 5 minutes; three automated readings taken afterward then averaged; proper cuff size; feet flat on the floor while patients sat; arms at proper level, and no talking, texting, or filling out forms during the reading, Dr. Johnson said (N Engl J Med. 2015 Nov 26;373[22]:2103-16).
“If you do [those things], then it doesn’t matter if somebody is in the room or not; you can treat to the levels we are talking about,” said William Cushman, MD, professor of medicine and physiology at the university, and also a SPRINT investigator.
Although the SPRINT researchers hadn’t addressed the issue before the AHA meeting, it’s been widely thought, and even reported in some places, that blood pressures in the trial were unattended. The misperception has led to anxiety about how to apply SPRINT to everyday practice, since few clinics are set up to have patients sit alone for 5 or 10 minutes for a blood pressure.
To address the concern, the SPRINT team surveyed study sites after the trial ended. It turned out that 4,082 subjects were at sites where patients were usually left alone for both the 5-minute rest period and the three BP readings, and 2,247 were at sites where staff usually attended both; 1,746 were at sites that left patients alone for the rest period only; and 570 were at sites where patients were alone only for the BP readings.
Observation had no impact on blood pressure. In the intensive arm, participants achieved and maintained an average systolic BP of about 120 mm Hg in all four groups. In the standard treatment arm, that average was about 135 mm Hg in all four groups. “When we look at the number of medications used, they were very similar in all four blood pressure groups,” with intensive treatment patients taking an average of one extra drug, Dr. Johnson said.
Intensive treatment, versus standard treatment, reduced cardiovascular events to a similar extent in patients who were alone for the entire blood pressure reading (by 38%) and those who were accompanied throughout (by 36%). For reasons that are not clear, intensive treatment did not significantly reduce risk among subjects who were observed during rest or observed for blood pressure readings. Both groups had lower Framingham 10-year cardiovascular disease risk scores, which may have been a confounder.
Meanwhile, the rate of adverse events and total mortality – lower with intensive treatment – did not vary by observation, Dr. Johnson said.
The survey excluded 716 subjects at 14 study sites who could not be classified into one of the four BP observation categories.
SPRINT was sponsored by the National Institutes of Health. Doctors Johnson and Cushman didn’t have any disclosures.
ANAHEIM, CALIF. – More than half of the BP measurements of patients in the SPRINT trial were at least partially attended by clinic staff, but those efforts made no difference in outcomes, according to a survey presented by SPRINT investigators at the American Heart Association scientific sessions.
“It really didn’t matter” whether measurements were observed or not; blood pressure control and outcomes – fewer deaths and cardiovascular events when hypertension was treated to below 120 mm Hg instead of below 140 mm Hg – were largely the same either way, said the survey’s lead investigator Karen C. Johnson, MD, professor of women’s health and preventive medicine at the University of Tennessee in Memphis.
What did matter were the other measures SPRINT [Systolic Blood Pressure Intervention Trial] took to ensure accurate blood pressure measurement, including patients resting for 5 minutes; three automated readings taken afterward then averaged; proper cuff size; feet flat on the floor while patients sat; arms at proper level, and no talking, texting, or filling out forms during the reading, Dr. Johnson said (N Engl J Med. 2015 Nov 26;373[22]:2103-16).
“If you do [those things], then it doesn’t matter if somebody is in the room or not; you can treat to the levels we are talking about,” said William Cushman, MD, professor of medicine and physiology at the university, and also a SPRINT investigator.
Although the SPRINT researchers hadn’t addressed the issue before the AHA meeting, it’s been widely thought, and even reported in some places, that blood pressures in the trial were unattended. The misperception has led to anxiety about how to apply SPRINT to everyday practice, since few clinics are set up to have patients sit alone for 5 or 10 minutes for a blood pressure.
To address the concern, the SPRINT team surveyed study sites after the trial ended. It turned out that 4,082 subjects were at sites where patients were usually left alone for both the 5-minute rest period and the three BP readings, and 2,247 were at sites where staff usually attended both; 1,746 were at sites that left patients alone for the rest period only; and 570 were at sites where patients were alone only for the BP readings.
Observation had no impact on blood pressure. In the intensive arm, participants achieved and maintained an average systolic BP of about 120 mm Hg in all four groups. In the standard treatment arm, that average was about 135 mm Hg in all four groups. “When we look at the number of medications used, they were very similar in all four blood pressure groups,” with intensive treatment patients taking an average of one extra drug, Dr. Johnson said.
Intensive treatment, versus standard treatment, reduced cardiovascular events to a similar extent in patients who were alone for the entire blood pressure reading (by 38%) and those who were accompanied throughout (by 36%). For reasons that are not clear, intensive treatment did not significantly reduce risk among subjects who were observed during rest or observed for blood pressure readings. Both groups had lower Framingham 10-year cardiovascular disease risk scores, which may have been a confounder.
Meanwhile, the rate of adverse events and total mortality – lower with intensive treatment – did not vary by observation, Dr. Johnson said.
The survey excluded 716 subjects at 14 study sites who could not be classified into one of the four BP observation categories.
SPRINT was sponsored by the National Institutes of Health. Doctors Johnson and Cushman didn’t have any disclosures.
AT THE AHA SCIENTIFIC SESSIONS
Key clinical point:
Major finding: Blood pressure and CV event reductions were similar in the 4,082 subjects at sites where patients were usually left alone for both the 5-minute rest period and the three BP readings, the 2,247 patients at sites where staff usually attended both, the 1,746 at sites that left patients alone for the rest period only, and the 570 at sites where patients were alone only for the BP readings.
Data source: A survey of SPRINT study sites.
Disclosures: SPRINT was sponsored by the National Institutes of Health. The presenter had no disclosures.
Intepirdine flops in phase 3 study of mild to moderate Alzheimer’s patients
BOSTON – An investigational Alzheimer’s drug intended to potentiate acetylcholine release didn’t pass muster in a global phase 3 study, despite a successful phase 2 trial.
Intepirdine on a background of stable-dose donepezil failed to confer any cognitive or functional benefit in patients with mild to moderate Alzheimer’s disease, Ilise Lombardo, PhD, said at the Clinical Trials on Alzheimer’s Disease conference.
Intepirdine blocks the 5-hydroxytryptamine receptor 6 and increases the release of acetylcholine, according to Dr. Lombardo. By giving it on a stable background of an acetylcholinesterase inhibitor, researchers hoped to improve cognition by increasing acetylcholine signaling between neurons. In a modestly successful phase 2b study reported out last summer, intepirdine did confer some cognitive and functional benefits.
The study was scheduled to be presented at the Alzheimer’s Association International Conference, but was pulled at the last minute when Axovant announced its initial public offering of stock shortly before the July meeting. However, Dr. Lombardo did review study 866 at CTAD. It randomized 269 patients with mild to moderate AD to placebo or intepirdine at 15 mg or 35 mg/day for 24 weeks. By 12 weeks, patients taking the 35-mg dose had declined 1.6 points less than those on placebo on the Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS-cog) and 1.94 points on the Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL). Both differences were statistically significant. The drug moved into a phase 3 study, dubbed MINDSET, at 35 mg.
MINDSET enrolled 1, 315 patients with mild to moderate Alzheimer’s disease and randomized them to placebo or 35 mg intepirdine for 24 weeks. All patients were on stable background donepezil. Again, the coprimary endpoints were the ADAS-cog and the ADCS-ADL at the end of the study. There were three secondary endpoints: the Clinician Interview-Based Impression of Change plus caregiver interview (CIBIC+), the Dependence Scale, and the Neuropsychiatric Inventory.
Patients were a mean of 70 years old with a mean Mini-Mental State Exam (MMSE) score of 18.5. The mean ADAS-cog score was 24 and the mean ADCS-ADL score, 58.
On the ADAS-cog, both groups exhibited a positive placebo response in the first 6 weeks, followed by a mean decline of 0.36 points. There was no statistically significant between-group difference. The story was much the same on the ADCS-ADL measure. Both groups had a brief placebo response, followed by a mean decline of 1.06 points. Again, the intepirdine and placebo groups declined similarly. There were no significant differences on either measure when the groups were broken down into patients with mild and moderate disease.
The CIBIC+ score was the only positive response among the secondary endpoints. Compared with those taking placebo, those taking intepirdine were more likely to be rated as minimally improved or unchanged.
The drug was safe however, with virtually no between-group difference in the occurrence of or the type of serious adverse events (about 6% in each group). Five patents died during the study; none of the deaths were related to the study drug.
Although Axovant no longer lists intepirdine as a potential Alzheimer’s treatment, investigation continues in a phase 3 placebo-controlled study in patients with Lewy body dementia. HEADWAY is testing a 70-mg dose, Dr. Lombardo said.
“Enrollment is finished and we are looking forward to results,” in early 2018. Answering a question about why the company went with 35 mg instead of 70 mg in MINDSET, she said that Axovant wanted to recreate the success of study 866.
“Since we had statistical significance even at 12 weeks with 35 mg, that’s what we went with,” she said. However, reviewing the adverse events told investigators that “we were not even near the maximum tolerated dose” at 35 mg. “Certainly we are now faced with the question of whether there will be a better response with 70 mg, and we are looking forward to answering that question with HEADWAY.”
Dr. Lombardo is senior vice president for clinical research at Axovant Sciences.
[email protected]
On Twitter @alz_gal
BOSTON – An investigational Alzheimer’s drug intended to potentiate acetylcholine release didn’t pass muster in a global phase 3 study, despite a successful phase 2 trial.
Intepirdine on a background of stable-dose donepezil failed to confer any cognitive or functional benefit in patients with mild to moderate Alzheimer’s disease, Ilise Lombardo, PhD, said at the Clinical Trials on Alzheimer’s Disease conference.
Intepirdine blocks the 5-hydroxytryptamine receptor 6 and increases the release of acetylcholine, according to Dr. Lombardo. By giving it on a stable background of an acetylcholinesterase inhibitor, researchers hoped to improve cognition by increasing acetylcholine signaling between neurons. In a modestly successful phase 2b study reported out last summer, intepirdine did confer some cognitive and functional benefits.
The study was scheduled to be presented at the Alzheimer’s Association International Conference, but was pulled at the last minute when Axovant announced its initial public offering of stock shortly before the July meeting. However, Dr. Lombardo did review study 866 at CTAD. It randomized 269 patients with mild to moderate AD to placebo or intepirdine at 15 mg or 35 mg/day for 24 weeks. By 12 weeks, patients taking the 35-mg dose had declined 1.6 points less than those on placebo on the Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS-cog) and 1.94 points on the Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL). Both differences were statistically significant. The drug moved into a phase 3 study, dubbed MINDSET, at 35 mg.
MINDSET enrolled 1, 315 patients with mild to moderate Alzheimer’s disease and randomized them to placebo or 35 mg intepirdine for 24 weeks. All patients were on stable background donepezil. Again, the coprimary endpoints were the ADAS-cog and the ADCS-ADL at the end of the study. There were three secondary endpoints: the Clinician Interview-Based Impression of Change plus caregiver interview (CIBIC+), the Dependence Scale, and the Neuropsychiatric Inventory.
Patients were a mean of 70 years old with a mean Mini-Mental State Exam (MMSE) score of 18.5. The mean ADAS-cog score was 24 and the mean ADCS-ADL score, 58.
On the ADAS-cog, both groups exhibited a positive placebo response in the first 6 weeks, followed by a mean decline of 0.36 points. There was no statistically significant between-group difference. The story was much the same on the ADCS-ADL measure. Both groups had a brief placebo response, followed by a mean decline of 1.06 points. Again, the intepirdine and placebo groups declined similarly. There were no significant differences on either measure when the groups were broken down into patients with mild and moderate disease.
The CIBIC+ score was the only positive response among the secondary endpoints. Compared with those taking placebo, those taking intepirdine were more likely to be rated as minimally improved or unchanged.
The drug was safe however, with virtually no between-group difference in the occurrence of or the type of serious adverse events (about 6% in each group). Five patents died during the study; none of the deaths were related to the study drug.
Although Axovant no longer lists intepirdine as a potential Alzheimer’s treatment, investigation continues in a phase 3 placebo-controlled study in patients with Lewy body dementia. HEADWAY is testing a 70-mg dose, Dr. Lombardo said.
“Enrollment is finished and we are looking forward to results,” in early 2018. Answering a question about why the company went with 35 mg instead of 70 mg in MINDSET, she said that Axovant wanted to recreate the success of study 866.
“Since we had statistical significance even at 12 weeks with 35 mg, that’s what we went with,” she said. However, reviewing the adverse events told investigators that “we were not even near the maximum tolerated dose” at 35 mg. “Certainly we are now faced with the question of whether there will be a better response with 70 mg, and we are looking forward to answering that question with HEADWAY.”
Dr. Lombardo is senior vice president for clinical research at Axovant Sciences.
[email protected]
On Twitter @alz_gal
BOSTON – An investigational Alzheimer’s drug intended to potentiate acetylcholine release didn’t pass muster in a global phase 3 study, despite a successful phase 2 trial.
Intepirdine on a background of stable-dose donepezil failed to confer any cognitive or functional benefit in patients with mild to moderate Alzheimer’s disease, Ilise Lombardo, PhD, said at the Clinical Trials on Alzheimer’s Disease conference.
Intepirdine blocks the 5-hydroxytryptamine receptor 6 and increases the release of acetylcholine, according to Dr. Lombardo. By giving it on a stable background of an acetylcholinesterase inhibitor, researchers hoped to improve cognition by increasing acetylcholine signaling between neurons. In a modestly successful phase 2b study reported out last summer, intepirdine did confer some cognitive and functional benefits.
The study was scheduled to be presented at the Alzheimer’s Association International Conference, but was pulled at the last minute when Axovant announced its initial public offering of stock shortly before the July meeting. However, Dr. Lombardo did review study 866 at CTAD. It randomized 269 patients with mild to moderate AD to placebo or intepirdine at 15 mg or 35 mg/day for 24 weeks. By 12 weeks, patients taking the 35-mg dose had declined 1.6 points less than those on placebo on the Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS-cog) and 1.94 points on the Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL). Both differences were statistically significant. The drug moved into a phase 3 study, dubbed MINDSET, at 35 mg.
MINDSET enrolled 1, 315 patients with mild to moderate Alzheimer’s disease and randomized them to placebo or 35 mg intepirdine for 24 weeks. All patients were on stable background donepezil. Again, the coprimary endpoints were the ADAS-cog and the ADCS-ADL at the end of the study. There were three secondary endpoints: the Clinician Interview-Based Impression of Change plus caregiver interview (CIBIC+), the Dependence Scale, and the Neuropsychiatric Inventory.
Patients were a mean of 70 years old with a mean Mini-Mental State Exam (MMSE) score of 18.5. The mean ADAS-cog score was 24 and the mean ADCS-ADL score, 58.
On the ADAS-cog, both groups exhibited a positive placebo response in the first 6 weeks, followed by a mean decline of 0.36 points. There was no statistically significant between-group difference. The story was much the same on the ADCS-ADL measure. Both groups had a brief placebo response, followed by a mean decline of 1.06 points. Again, the intepirdine and placebo groups declined similarly. There were no significant differences on either measure when the groups were broken down into patients with mild and moderate disease.
The CIBIC+ score was the only positive response among the secondary endpoints. Compared with those taking placebo, those taking intepirdine were more likely to be rated as minimally improved or unchanged.
The drug was safe however, with virtually no between-group difference in the occurrence of or the type of serious adverse events (about 6% in each group). Five patents died during the study; none of the deaths were related to the study drug.
Although Axovant no longer lists intepirdine as a potential Alzheimer’s treatment, investigation continues in a phase 3 placebo-controlled study in patients with Lewy body dementia. HEADWAY is testing a 70-mg dose, Dr. Lombardo said.
“Enrollment is finished and we are looking forward to results,” in early 2018. Answering a question about why the company went with 35 mg instead of 70 mg in MINDSET, she said that Axovant wanted to recreate the success of study 866.
“Since we had statistical significance even at 12 weeks with 35 mg, that’s what we went with,” she said. However, reviewing the adverse events told investigators that “we were not even near the maximum tolerated dose” at 35 mg. “Certainly we are now faced with the question of whether there will be a better response with 70 mg, and we are looking forward to answering that question with HEADWAY.”
Dr. Lombardo is senior vice president for clinical research at Axovant Sciences.
[email protected]
On Twitter @alz_gal
AT CTAD
Key clinical point:
Major finding: On the ADAS-cog at 24 weeks, there was a mean decline of 0.36 points; on the ADCS-ADL, the mean decline was 1.06 points. There were no between-group differences, either overall or in the mild to moderate groups separately.
Data source: The placebo-controlled study randomized 1,315 patients to placebo or 35 mg daily intepirdine.
Disclosures: Dr. Lombardo is senior vice president for clinical research at Axovant Sciences, which is developing the drug.
Biologics during pregnancy did not affect infant vaccine response
The use of biologic therapy during pregnancy did not lower antibody titers among infants vaccinated against Haemophilus influenzae B (HiB) or tetanus toxin, according to the results of a study of 179 mothers reported in the January issue of Clinical Gastroenterology and Hepatology (2017. doi: 10.1016/j.cgh.2017.08.041).
Additionally, there was no link between median infliximab concentration in uterine cord blood and antibody titers among infants aged 7 months and older, wrote Dawn B. Beaulieu, MD, with her associates. “In a limited cohort of exposed infants given the rotavirus vaccine, there was no association with significant adverse reactions,” they also reported.
Experts now recommend against live vaccinations for infants who may have detectable concentrations of biologics, but it remained unclear whether these infants can mount adequate responses to inactive vaccines. Therefore, the researchers analyzed data from the Pregnancy in IBD and Neonatal Outcomes (PIANO) registry collected between 2007 and 2016 and surveyed women about their infants’ vaccination history. They also quantified antibodies in serum samples from infants aged 7 months and older and analyzed measured concentrations of biologics in cord blood.
Among 179 mothers with IBD, most had inactive (77%) or mild disease activity (18%) during pregnancy, the researchers said. Eleven (6%) mothers were not on immunosuppressives while pregnant, 15 (8%) were on an immunomodulator, and the rest were on biologic monotherapy (65%) or a biologic plus an immunomodulator (21%). A total of 46 infants had available HiB titer data, of whom 38 were potentially exposed to biologics; among 49 infants with available tetanus titers, 41 were potentially exposed. In all, 71% of exposed infants had protective levels of antibodies against HiB, and 80% had protective titers to tetanus toxoid. Proportions among unexposed infants were 50% and 75%, respectively. Proportions of protective antibody titers did not significantly differ between groups even after excluding infants whose mothers received certolizumab pegol, which has negligible rates of placental transfer.
A total of 39 infants received live rotavirus vaccine despite having detectable levels of biologics in cord blood at birth. Seven developed mild vaccine reactions consisting of fever (six infants) or diarrhea (one infant). This proportion (18%) resembles that from a large study (N Engl J Med. 2006;354:23-33) of healthy infants who were vaccinated against rotavirus, the researchers noted. “Despite our data suggesting a lack of severe side effects with the rotavirus vaccine in these infants, in the absence of robust evidence, one should continue to avoid live vaccines in infants born to mothers on biologic therapy (excluding certolizumab) during the first year of life or until drug clearance is confirmed,” they suggested. “With the growing availability of tests, one conceivably could test serum drug concentration in infants, and, if undetectable, consider live vaccination at that time, if appropriate for the vaccine, particularly in infants most likely to benefit from such vaccines.”
The Crohn’s and Colitis Foundation provided funding. Dr. Beaulieu disclosed a consulting relationship with AbbVie, and four coinvestigators also reported ties to pharmaceutical companies.
The use of biologic therapy during pregnancy did not lower antibody titers among infants vaccinated against Haemophilus influenzae B (HiB) or tetanus toxin, according to the results of a study of 179 mothers reported in the January issue of Clinical Gastroenterology and Hepatology (2017. doi: 10.1016/j.cgh.2017.08.041).
Additionally, there was no link between median infliximab concentration in uterine cord blood and antibody titers among infants aged 7 months and older, wrote Dawn B. Beaulieu, MD, with her associates. “In a limited cohort of exposed infants given the rotavirus vaccine, there was no association with significant adverse reactions,” they also reported.
Experts now recommend against live vaccinations for infants who may have detectable concentrations of biologics, but it remained unclear whether these infants can mount adequate responses to inactive vaccines. Therefore, the researchers analyzed data from the Pregnancy in IBD and Neonatal Outcomes (PIANO) registry collected between 2007 and 2016 and surveyed women about their infants’ vaccination history. They also quantified antibodies in serum samples from infants aged 7 months and older and analyzed measured concentrations of biologics in cord blood.
Among 179 mothers with IBD, most had inactive (77%) or mild disease activity (18%) during pregnancy, the researchers said. Eleven (6%) mothers were not on immunosuppressives while pregnant, 15 (8%) were on an immunomodulator, and the rest were on biologic monotherapy (65%) or a biologic plus an immunomodulator (21%). A total of 46 infants had available HiB titer data, of whom 38 were potentially exposed to biologics; among 49 infants with available tetanus titers, 41 were potentially exposed. In all, 71% of exposed infants had protective levels of antibodies against HiB, and 80% had protective titers to tetanus toxoid. Proportions among unexposed infants were 50% and 75%, respectively. Proportions of protective antibody titers did not significantly differ between groups even after excluding infants whose mothers received certolizumab pegol, which has negligible rates of placental transfer.
A total of 39 infants received live rotavirus vaccine despite having detectable levels of biologics in cord blood at birth. Seven developed mild vaccine reactions consisting of fever (six infants) or diarrhea (one infant). This proportion (18%) resembles that from a large study (N Engl J Med. 2006;354:23-33) of healthy infants who were vaccinated against rotavirus, the researchers noted. “Despite our data suggesting a lack of severe side effects with the rotavirus vaccine in these infants, in the absence of robust evidence, one should continue to avoid live vaccines in infants born to mothers on biologic therapy (excluding certolizumab) during the first year of life or until drug clearance is confirmed,” they suggested. “With the growing availability of tests, one conceivably could test serum drug concentration in infants, and, if undetectable, consider live vaccination at that time, if appropriate for the vaccine, particularly in infants most likely to benefit from such vaccines.”
The Crohn’s and Colitis Foundation provided funding. Dr. Beaulieu disclosed a consulting relationship with AbbVie, and four coinvestigators also reported ties to pharmaceutical companies.
The use of biologic therapy during pregnancy did not lower antibody titers among infants vaccinated against Haemophilus influenzae B (HiB) or tetanus toxin, according to the results of a study of 179 mothers reported in the January issue of Clinical Gastroenterology and Hepatology (2017. doi: 10.1016/j.cgh.2017.08.041).
Additionally, there was no link between median infliximab concentration in uterine cord blood and antibody titers among infants aged 7 months and older, wrote Dawn B. Beaulieu, MD, with her associates. “In a limited cohort of exposed infants given the rotavirus vaccine, there was no association with significant adverse reactions,” they also reported.
Experts now recommend against live vaccinations for infants who may have detectable concentrations of biologics, but it remained unclear whether these infants can mount adequate responses to inactive vaccines. Therefore, the researchers analyzed data from the Pregnancy in IBD and Neonatal Outcomes (PIANO) registry collected between 2007 and 2016 and surveyed women about their infants’ vaccination history. They also quantified antibodies in serum samples from infants aged 7 months and older and analyzed measured concentrations of biologics in cord blood.
Among 179 mothers with IBD, most had inactive (77%) or mild disease activity (18%) during pregnancy, the researchers said. Eleven (6%) mothers were not on immunosuppressives while pregnant, 15 (8%) were on an immunomodulator, and the rest were on biologic monotherapy (65%) or a biologic plus an immunomodulator (21%). A total of 46 infants had available HiB titer data, of whom 38 were potentially exposed to biologics; among 49 infants with available tetanus titers, 41 were potentially exposed. In all, 71% of exposed infants had protective levels of antibodies against HiB, and 80% had protective titers to tetanus toxoid. Proportions among unexposed infants were 50% and 75%, respectively. Proportions of protective antibody titers did not significantly differ between groups even after excluding infants whose mothers received certolizumab pegol, which has negligible rates of placental transfer.
A total of 39 infants received live rotavirus vaccine despite having detectable levels of biologics in cord blood at birth. Seven developed mild vaccine reactions consisting of fever (six infants) or diarrhea (one infant). This proportion (18%) resembles that from a large study (N Engl J Med. 2006;354:23-33) of healthy infants who were vaccinated against rotavirus, the researchers noted. “Despite our data suggesting a lack of severe side effects with the rotavirus vaccine in these infants, in the absence of robust evidence, one should continue to avoid live vaccines in infants born to mothers on biologic therapy (excluding certolizumab) during the first year of life or until drug clearance is confirmed,” they suggested. “With the growing availability of tests, one conceivably could test serum drug concentration in infants, and, if undetectable, consider live vaccination at that time, if appropriate for the vaccine, particularly in infants most likely to benefit from such vaccines.”
The Crohn’s and Colitis Foundation provided funding. Dr. Beaulieu disclosed a consulting relationship with AbbVie, and four coinvestigators also reported ties to pharmaceutical companies.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: In utero biologic exposure did not prevent immune response to Haemophilus influenzae B and tetanus vaccines during infancy.
Major finding: Proportions of protective antibody titers did not significantly differ among groups.
Data source: A prospective study of 179 mothers with IBD and their infants.
Disclosures: The Crohn’s and Colitis Foundation provided funding. Dr. Beaulieu disclosed a consulting relationship with AbbVie, and four coinvestigators also reported ties to pharmaceutical companies.
VIDEO: Canakinumab’s cardiovascular benefits linked with hsCRP cuts
ANAHEIM, CALIF. – Targeting the anti-inflammatory drug canakinumab to cardiovascular disease patients with a robust response to a single dose may be an effective way to enhance the cost benefit of this novel treatment that is effective but also expensive.
A post hoc analysis of data collected in the ground-breaking CANTOS trial showed that among patients with a robust anti-inflammatory response to their first dose of canakinumab, the 4-year rate of major adverse cardiovascular events fell by 25% compared with patients who received placebo, a much higher relative risk reduction compared with all canakinumab recipients in the study. In this responsive subgroup, which constituted 55% of all patients assessed after their first dose, canakinumab also cut both cardiovascular death and all-cause death by 31% each relative to placebo, statistically significant reductions that had not been seen in the trial’s primary analysis that included all drug recipients, Paul M. Ridker, MD, said at the American Heart Association scientific sessions.
“The current analysis suggests that the magnitude of hsCRP [high sensitivity C-reactive protein] reduction following a single dose of canakinumab may provide a simple clinical method to identify individuals most likely to accrue the largest cardiovascular and cancer benefits from continued treatment.” The findings have importance “for patient selection, cost-effectiveness, and personalized medicine” as researchers and clinicians begin using anti-inflammatory drugs such as canakinumab to treat cardiovascular disease patients, said Dr. Ridker, professor of medicine at Harvard Medical School and director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital, both in Boston.
“The magnitude of the hsCRP reduction” after the first dose “is telling us who benefits most,” Dr. Ridker said in a video interview.
The Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) enrolled patients with a history of a MI and a “residual” inflammatory risk based on having an hsCRP level above 2 mg/L at baseline despite receiving optimized standard treatments and having a median LDL cholesterol level of 82 mg/dL. Dr. Ridker and his associates reported the study’s primary outcome results in August at the European Society of Cardiology meeting and in a simultaneously-published article (N Engl J Med. 2017 Sept 21; 377[12]:1119-31).
For the current analyses they defined a robust anti-inflammatory response as CANTOS patients who maintained an hsCRP level below 2 mg/L when measured 3 months after their first canakinumab dose. When the researchers divided all canakinumab recipients into tertiles based on their achieved hsCRP level after one dose, those with the lowest level, less than 1.2 mg/L, also had the best outcome, with a 4-year rate of major adverse cardiovascular events that was 29% lower than the placebo patients. Patients in the middle tertile of achieved hsCRP, from 1.2 up to but not including 2.6 mg/L, showed a smaller but still statistically significant relative 17% reduction in events, while patients with the tertile with the highest hsCRP levels following one canakinumab dose had essentially no difference in their outcomes compared with placebo-treated control patients.
These findings suggest that for hsCRP, “lower is better,” Dr. Ridker noted. “It’s similar to where we were in 1994” when trial results showed how LDL levels related to cardiovascular disease events and the potential that statin treatment held had for reducing event rates.
The new analyses included three additional notable findings:
• The main serious adverse effect from canakinumab treatment, fatal infections, which occurred at a small but significantly higher rate than in control patients, had a similar incidence of about one episode/300 patient years regardless of whether the achieved hsCRP level fell below 2 mg/L or remained above that level. The placebo rate of fatal infections was about one for every 500 patient years.
• The substantially reduced incidence of lung cancer seen in the primary CANTOS results also tracked with achieved hsCRP. Patients with an achieved hsCRP that was below the median for all treated patients had a 71% cut in new-onset lung cancer compared with controls, while patients with hsCRP levels that fell above the median showed no significant difference compared with control patients.
• All three doses of canakinumab tested in CANTOS – 50 mg, 150 mg, and 300 mg administered by subcutaneous injection once every 3 months – produced a drop in hsCRP to below 2 mg/L in some patients, but the rate at which patients reached this level differed depending on dose: 44% among patients who received the lowest dose, 55% of those who received a 150-mg dose, and 65% among those on the highest dose.
But this “responder analysis” of patients who received canakinumab received a strong cautionary caveat from Robert M. Califf, MD, professor of medicine and vice chancellor for health data sciences at Duke University in Durham, N.C.
“Beware of responder analyses,” Dr. Califf said during a talk at the meeting in which he commented on the new CANTOS findings. “There is a long history in cardiology of being misled” by responder analyses, he said.
Dr. Ridker added that the mechanism that determines whether patients have a robust or modest response to canakinumab remains unclear, although it likely depends on genetic factors. He also noted that research being done by himself and others is investigating the efficacy of other anti-inflammatory drugs that could potentially cut cardiovascular disease rates, including methotrexate and colchicine.
Canakinumab (Ilaris) had Food and Drug Administration marketing approval to treat systemic juvenile idiopathic arthritis and pediatric fever syndromes. Concurrently with the meeting report, the results appeared in an article online (Lancet 2017 Nov 13. doi: 10.1016/S0140-6736[17]32814-3).
CANTOS was sponsored by Novartis, the company that markets canakinumab. Dr. Ridker has been a consultant to Novartis and was lead investigator of CANTOS. He also holds patents on using hsCRP to assess cardiovascular disease risk. Dr. Califf is an adviser to Verily Health Sciences.
[email protected]
On Twitter @mitchelzoler
CANTOS is a landmark trial for showing the importance of inflammation in causing cardiovascular disease events. The new analyses from CANTOS strengthen the biological premise of the study and better address some concerns about the magnitude of benefit raised following the first report of the CANTOS findings. We now see an increased effect on major cardiovascular disease events and, for the first time, an impact from treatment on cardiovascular death and all-cause death in the subgroup of patients with a robust anti-inflammatory response to the drug. This shows the possibility of an enhanced benefit-to-risk balance by focusing canakinumab treatment on responsive patients.
New anti-inflammatory agents now in development offer the prospect for oral drugs that could have similar benefits, and by targeting such treatments to selected patients we can envision using an anti-inflammatory strategy for primary prevention of cardiovascular disease events as well as for secondary prevention. We can also anticipate studies that will show how to better integrate anti-inflammatory interventions with lipid-lowering drugs, as well as selected drugs used to treat diabetes.
The data from CANTOS has opened a new world of possibilities related to anti-inflammatory treatments for preventing and treating cardiovascular diseases.
Ira Tabas, MD , is professor of medicine, cell biology, and physiology at Columbia University in New York. He had no disclosures. He made these comments as designated discussant for Dr. Ridker’s report.
CANTOS is a landmark trial for showing the importance of inflammation in causing cardiovascular disease events. The new analyses from CANTOS strengthen the biological premise of the study and better address some concerns about the magnitude of benefit raised following the first report of the CANTOS findings. We now see an increased effect on major cardiovascular disease events and, for the first time, an impact from treatment on cardiovascular death and all-cause death in the subgroup of patients with a robust anti-inflammatory response to the drug. This shows the possibility of an enhanced benefit-to-risk balance by focusing canakinumab treatment on responsive patients.
New anti-inflammatory agents now in development offer the prospect for oral drugs that could have similar benefits, and by targeting such treatments to selected patients we can envision using an anti-inflammatory strategy for primary prevention of cardiovascular disease events as well as for secondary prevention. We can also anticipate studies that will show how to better integrate anti-inflammatory interventions with lipid-lowering drugs, as well as selected drugs used to treat diabetes.
The data from CANTOS has opened a new world of possibilities related to anti-inflammatory treatments for preventing and treating cardiovascular diseases.
Ira Tabas, MD , is professor of medicine, cell biology, and physiology at Columbia University in New York. He had no disclosures. He made these comments as designated discussant for Dr. Ridker’s report.
CANTOS is a landmark trial for showing the importance of inflammation in causing cardiovascular disease events. The new analyses from CANTOS strengthen the biological premise of the study and better address some concerns about the magnitude of benefit raised following the first report of the CANTOS findings. We now see an increased effect on major cardiovascular disease events and, for the first time, an impact from treatment on cardiovascular death and all-cause death in the subgroup of patients with a robust anti-inflammatory response to the drug. This shows the possibility of an enhanced benefit-to-risk balance by focusing canakinumab treatment on responsive patients.
New anti-inflammatory agents now in development offer the prospect for oral drugs that could have similar benefits, and by targeting such treatments to selected patients we can envision using an anti-inflammatory strategy for primary prevention of cardiovascular disease events as well as for secondary prevention. We can also anticipate studies that will show how to better integrate anti-inflammatory interventions with lipid-lowering drugs, as well as selected drugs used to treat diabetes.
The data from CANTOS has opened a new world of possibilities related to anti-inflammatory treatments for preventing and treating cardiovascular diseases.
Ira Tabas, MD , is professor of medicine, cell biology, and physiology at Columbia University in New York. He had no disclosures. He made these comments as designated discussant for Dr. Ridker’s report.
ANAHEIM, CALIF. – Targeting the anti-inflammatory drug canakinumab to cardiovascular disease patients with a robust response to a single dose may be an effective way to enhance the cost benefit of this novel treatment that is effective but also expensive.
A post hoc analysis of data collected in the ground-breaking CANTOS trial showed that among patients with a robust anti-inflammatory response to their first dose of canakinumab, the 4-year rate of major adverse cardiovascular events fell by 25% compared with patients who received placebo, a much higher relative risk reduction compared with all canakinumab recipients in the study. In this responsive subgroup, which constituted 55% of all patients assessed after their first dose, canakinumab also cut both cardiovascular death and all-cause death by 31% each relative to placebo, statistically significant reductions that had not been seen in the trial’s primary analysis that included all drug recipients, Paul M. Ridker, MD, said at the American Heart Association scientific sessions.
“The current analysis suggests that the magnitude of hsCRP [high sensitivity C-reactive protein] reduction following a single dose of canakinumab may provide a simple clinical method to identify individuals most likely to accrue the largest cardiovascular and cancer benefits from continued treatment.” The findings have importance “for patient selection, cost-effectiveness, and personalized medicine” as researchers and clinicians begin using anti-inflammatory drugs such as canakinumab to treat cardiovascular disease patients, said Dr. Ridker, professor of medicine at Harvard Medical School and director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital, both in Boston.
“The magnitude of the hsCRP reduction” after the first dose “is telling us who benefits most,” Dr. Ridker said in a video interview.
The Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) enrolled patients with a history of a MI and a “residual” inflammatory risk based on having an hsCRP level above 2 mg/L at baseline despite receiving optimized standard treatments and having a median LDL cholesterol level of 82 mg/dL. Dr. Ridker and his associates reported the study’s primary outcome results in August at the European Society of Cardiology meeting and in a simultaneously-published article (N Engl J Med. 2017 Sept 21; 377[12]:1119-31).
For the current analyses they defined a robust anti-inflammatory response as CANTOS patients who maintained an hsCRP level below 2 mg/L when measured 3 months after their first canakinumab dose. When the researchers divided all canakinumab recipients into tertiles based on their achieved hsCRP level after one dose, those with the lowest level, less than 1.2 mg/L, also had the best outcome, with a 4-year rate of major adverse cardiovascular events that was 29% lower than the placebo patients. Patients in the middle tertile of achieved hsCRP, from 1.2 up to but not including 2.6 mg/L, showed a smaller but still statistically significant relative 17% reduction in events, while patients with the tertile with the highest hsCRP levels following one canakinumab dose had essentially no difference in their outcomes compared with placebo-treated control patients.
These findings suggest that for hsCRP, “lower is better,” Dr. Ridker noted. “It’s similar to where we were in 1994” when trial results showed how LDL levels related to cardiovascular disease events and the potential that statin treatment held had for reducing event rates.
The new analyses included three additional notable findings:
• The main serious adverse effect from canakinumab treatment, fatal infections, which occurred at a small but significantly higher rate than in control patients, had a similar incidence of about one episode/300 patient years regardless of whether the achieved hsCRP level fell below 2 mg/L or remained above that level. The placebo rate of fatal infections was about one for every 500 patient years.
• The substantially reduced incidence of lung cancer seen in the primary CANTOS results also tracked with achieved hsCRP. Patients with an achieved hsCRP that was below the median for all treated patients had a 71% cut in new-onset lung cancer compared with controls, while patients with hsCRP levels that fell above the median showed no significant difference compared with control patients.
• All three doses of canakinumab tested in CANTOS – 50 mg, 150 mg, and 300 mg administered by subcutaneous injection once every 3 months – produced a drop in hsCRP to below 2 mg/L in some patients, but the rate at which patients reached this level differed depending on dose: 44% among patients who received the lowest dose, 55% of those who received a 150-mg dose, and 65% among those on the highest dose.
But this “responder analysis” of patients who received canakinumab received a strong cautionary caveat from Robert M. Califf, MD, professor of medicine and vice chancellor for health data sciences at Duke University in Durham, N.C.
“Beware of responder analyses,” Dr. Califf said during a talk at the meeting in which he commented on the new CANTOS findings. “There is a long history in cardiology of being misled” by responder analyses, he said.
Dr. Ridker added that the mechanism that determines whether patients have a robust or modest response to canakinumab remains unclear, although it likely depends on genetic factors. He also noted that research being done by himself and others is investigating the efficacy of other anti-inflammatory drugs that could potentially cut cardiovascular disease rates, including methotrexate and colchicine.
Canakinumab (Ilaris) had Food and Drug Administration marketing approval to treat systemic juvenile idiopathic arthritis and pediatric fever syndromes. Concurrently with the meeting report, the results appeared in an article online (Lancet 2017 Nov 13. doi: 10.1016/S0140-6736[17]32814-3).
CANTOS was sponsored by Novartis, the company that markets canakinumab. Dr. Ridker has been a consultant to Novartis and was lead investigator of CANTOS. He also holds patents on using hsCRP to assess cardiovascular disease risk. Dr. Califf is an adviser to Verily Health Sciences.
[email protected]
On Twitter @mitchelzoler
ANAHEIM, CALIF. – Targeting the anti-inflammatory drug canakinumab to cardiovascular disease patients with a robust response to a single dose may be an effective way to enhance the cost benefit of this novel treatment that is effective but also expensive.
A post hoc analysis of data collected in the ground-breaking CANTOS trial showed that among patients with a robust anti-inflammatory response to their first dose of canakinumab, the 4-year rate of major adverse cardiovascular events fell by 25% compared with patients who received placebo, a much higher relative risk reduction compared with all canakinumab recipients in the study. In this responsive subgroup, which constituted 55% of all patients assessed after their first dose, canakinumab also cut both cardiovascular death and all-cause death by 31% each relative to placebo, statistically significant reductions that had not been seen in the trial’s primary analysis that included all drug recipients, Paul M. Ridker, MD, said at the American Heart Association scientific sessions.
“The current analysis suggests that the magnitude of hsCRP [high sensitivity C-reactive protein] reduction following a single dose of canakinumab may provide a simple clinical method to identify individuals most likely to accrue the largest cardiovascular and cancer benefits from continued treatment.” The findings have importance “for patient selection, cost-effectiveness, and personalized medicine” as researchers and clinicians begin using anti-inflammatory drugs such as canakinumab to treat cardiovascular disease patients, said Dr. Ridker, professor of medicine at Harvard Medical School and director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital, both in Boston.
“The magnitude of the hsCRP reduction” after the first dose “is telling us who benefits most,” Dr. Ridker said in a video interview.
The Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) enrolled patients with a history of a MI and a “residual” inflammatory risk based on having an hsCRP level above 2 mg/L at baseline despite receiving optimized standard treatments and having a median LDL cholesterol level of 82 mg/dL. Dr. Ridker and his associates reported the study’s primary outcome results in August at the European Society of Cardiology meeting and in a simultaneously-published article (N Engl J Med. 2017 Sept 21; 377[12]:1119-31).
For the current analyses they defined a robust anti-inflammatory response as CANTOS patients who maintained an hsCRP level below 2 mg/L when measured 3 months after their first canakinumab dose. When the researchers divided all canakinumab recipients into tertiles based on their achieved hsCRP level after one dose, those with the lowest level, less than 1.2 mg/L, also had the best outcome, with a 4-year rate of major adverse cardiovascular events that was 29% lower than the placebo patients. Patients in the middle tertile of achieved hsCRP, from 1.2 up to but not including 2.6 mg/L, showed a smaller but still statistically significant relative 17% reduction in events, while patients with the tertile with the highest hsCRP levels following one canakinumab dose had essentially no difference in their outcomes compared with placebo-treated control patients.
These findings suggest that for hsCRP, “lower is better,” Dr. Ridker noted. “It’s similar to where we were in 1994” when trial results showed how LDL levels related to cardiovascular disease events and the potential that statin treatment held had for reducing event rates.
The new analyses included three additional notable findings:
• The main serious adverse effect from canakinumab treatment, fatal infections, which occurred at a small but significantly higher rate than in control patients, had a similar incidence of about one episode/300 patient years regardless of whether the achieved hsCRP level fell below 2 mg/L or remained above that level. The placebo rate of fatal infections was about one for every 500 patient years.
• The substantially reduced incidence of lung cancer seen in the primary CANTOS results also tracked with achieved hsCRP. Patients with an achieved hsCRP that was below the median for all treated patients had a 71% cut in new-onset lung cancer compared with controls, while patients with hsCRP levels that fell above the median showed no significant difference compared with control patients.
• All three doses of canakinumab tested in CANTOS – 50 mg, 150 mg, and 300 mg administered by subcutaneous injection once every 3 months – produced a drop in hsCRP to below 2 mg/L in some patients, but the rate at which patients reached this level differed depending on dose: 44% among patients who received the lowest dose, 55% of those who received a 150-mg dose, and 65% among those on the highest dose.
But this “responder analysis” of patients who received canakinumab received a strong cautionary caveat from Robert M. Califf, MD, professor of medicine and vice chancellor for health data sciences at Duke University in Durham, N.C.
“Beware of responder analyses,” Dr. Califf said during a talk at the meeting in which he commented on the new CANTOS findings. “There is a long history in cardiology of being misled” by responder analyses, he said.
Dr. Ridker added that the mechanism that determines whether patients have a robust or modest response to canakinumab remains unclear, although it likely depends on genetic factors. He also noted that research being done by himself and others is investigating the efficacy of other anti-inflammatory drugs that could potentially cut cardiovascular disease rates, including methotrexate and colchicine.
Canakinumab (Ilaris) had Food and Drug Administration marketing approval to treat systemic juvenile idiopathic arthritis and pediatric fever syndromes. Concurrently with the meeting report, the results appeared in an article online (Lancet 2017 Nov 13. doi: 10.1016/S0140-6736[17]32814-3).
CANTOS was sponsored by Novartis, the company that markets canakinumab. Dr. Ridker has been a consultant to Novartis and was lead investigator of CANTOS. He also holds patents on using hsCRP to assess cardiovascular disease risk. Dr. Califf is an adviser to Verily Health Sciences.
[email protected]
On Twitter @mitchelzoler
AT THE AHA SCIENTIFIC SESSIONS
Key clinical point:
Major finding: Patients with a strong hsCRP canakinumab response had a 25% drop in cardiovascular disease events compared with controls.
Data source: Post hoc analyses of data collected in CANTOS, a multicenter trial with 10,061 patients.
Disclosures: CANTOS was sponsored by Novartis, the company that markets canakinumab (Ilaris). Dr. Ridker has been a consultant to Novartis and was lead investigator of CANTOS. He also holds patents on using hsCRP to assess cardiovascular disease risk. Dr. Califf is an adviser to Verily Health Sciences.
What Is the Prevalence of Truly Benign MS?
PARIS—Benign multiple sclerosis (MS) appears to be rare. Its estimated prevalence is less than 4%, according to a study described at the Seventh Joint ECTRIMS–ACTRIMS Meeting.
The existence of benign MS has been proposed, but it remains controversial. Neurologists are uncertain about the frequency and pathologic explanation for a favorable outcome in MS. Identifying and studying individuals with benign MS would have “considerable implications for patient management and for our understanding of the biology of the disease,” said Emma Tallantyre, BMBS, PhD, Clinical Senior Lecturer in the Division of Psychological Medicine and Clinical Neurosciences at Cardiff University in the United Kingdom, and colleagues. 
Most definitions of benign MS are focused on walking ability after 10 or 15 years, despite the far wider effects of MS on ability. Dr. Tallantyre and colleagues screened a prevalent population of more than 2,000 people with MS and found 275 individuals who had unlimited walking ability after 15 or more years from onset. The investigators undertook detailed assessments of 56 of the individuals within this group (ie, those recorded to have unlimited walking ability after the longest disease durations). Assessment incorporated scores of cognition, fatigue, mood, vision, bladder symptoms, and arm and leg function.
All patients were considered to have relapsing-remitting MS, but they showed a wide range of relapse frequency and severity. In a group of 32 patients who fulfilled a contemporary definition of benign MS based on the Expanded Disability Status Scale, the researchers considered less than 25% to be truly benign, which was defined as having normal function in all domains. Patient-reported scores of MS impact correlated strongly with the outcomes of clinical assessment, but patients’ own perceptions of their condition was more benign than clinicians’ perceptions.
MR imaging was used to explore the biology underlying benign MS using a global approach and a tract-based approach. The study provides early insights into the phenotypic and imaging characteristics of benign MS and could provide information about the biologic mechanisms of a favorable outcome in MS, said Dr. Tallantyre.
PARIS—Benign multiple sclerosis (MS) appears to be rare. Its estimated prevalence is less than 4%, according to a study described at the Seventh Joint ECTRIMS–ACTRIMS Meeting.
The existence of benign MS has been proposed, but it remains controversial. Neurologists are uncertain about the frequency and pathologic explanation for a favorable outcome in MS. Identifying and studying individuals with benign MS would have “considerable implications for patient management and for our understanding of the biology of the disease,” said Emma Tallantyre, BMBS, PhD, Clinical Senior Lecturer in the Division of Psychological Medicine and Clinical Neurosciences at Cardiff University in the United Kingdom, and colleagues.
Most definitions of benign MS are focused on walking ability after 10 or 15 years, despite the far wider effects of MS on ability. Dr. Tallantyre and colleagues screened a prevalent population of more than 2,000 people with MS and found 275 individuals who had unlimited walking ability after 15 or more years from onset. The investigators undertook detailed assessments of 56 of the individuals within this group (ie, those recorded to have unlimited walking ability after the longest disease durations). Assessment incorporated scores of cognition, fatigue, mood, vision, bladder symptoms, and arm and leg function.
All patients were considered to have relapsing-remitting MS, but they showed a wide range of relapse frequency and severity. In a group of 32 patients who fulfilled a contemporary definition of benign MS based on the Expanded Disability Status Scale, the researchers considered less than 25% to be truly benign, which was defined as having normal function in all domains. Patient-reported scores of MS impact correlated strongly with the outcomes of clinical assessment, but patients’ own perceptions of their condition was more benign than clinicians’ perceptions.
MR imaging was used to explore the biology underlying benign MS using a global approach and a tract-based approach. The study provides early insights into the phenotypic and imaging characteristics of benign MS and could provide information about the biologic mechanisms of a favorable outcome in MS, said Dr. Tallantyre.
PARIS—Benign multiple sclerosis (MS) appears to be rare. Its estimated prevalence is less than 4%, according to a study described at the Seventh Joint ECTRIMS–ACTRIMS Meeting.
The existence of benign MS has been proposed, but it remains controversial. Neurologists are uncertain about the frequency and pathologic explanation for a favorable outcome in MS. Identifying and studying individuals with benign MS would have “considerable implications for patient management and for our understanding of the biology of the disease,” said Emma Tallantyre, BMBS, PhD, Clinical Senior Lecturer in the Division of Psychological Medicine and Clinical Neurosciences at Cardiff University in the United Kingdom, and colleagues.
Most definitions of benign MS are focused on walking ability after 10 or 15 years, despite the far wider effects of MS on ability. Dr. Tallantyre and colleagues screened a prevalent population of more than 2,000 people with MS and found 275 individuals who had unlimited walking ability after 15 or more years from onset. The investigators undertook detailed assessments of 56 of the individuals within this group (ie, those recorded to have unlimited walking ability after the longest disease durations). Assessment incorporated scores of cognition, fatigue, mood, vision, bladder symptoms, and arm and leg function.
All patients were considered to have relapsing-remitting MS, but they showed a wide range of relapse frequency and severity. In a group of 32 patients who fulfilled a contemporary definition of benign MS based on the Expanded Disability Status Scale, the researchers considered less than 25% to be truly benign, which was defined as having normal function in all domains. Patient-reported scores of MS impact correlated strongly with the outcomes of clinical assessment, but patients’ own perceptions of their condition was more benign than clinicians’ perceptions.
MR imaging was used to explore the biology underlying benign MS using a global approach and a tract-based approach. The study provides early insights into the phenotypic and imaging characteristics of benign MS and could provide information about the biologic mechanisms of a favorable outcome in MS, said Dr. Tallantyre.
Marketplace confusion opens door to questions about skinny plans
Consumers coping with the high cost of health insurance are the target market for new plans claiming to be lower-cost alternatives to the Affordable Care Act that fulfill the law’s requirement for health coverage.
But experts and regulators warn consumers to be cautious – and are raising red flags about one set of limited benefit plans marketed to individuals for as little as $93 a month. Offered through brokers and online ads, the plans promise to be an “ACA compliant, affordable, integrated solution that help ... individuals avoid the penalties under [the health care law].”
Such skinny plans – sold for the first time to individuals – come amid uncertainty over the fate of the ACA and whether the Trump administration will ease rules on plans for individuals. Dozens of brokers are offering the plans.
“The Trump administration is injecting a significant amount of confusion into the implementation of the ACA,” said Kevin Lucia, project director at Georgetown University’s Health Policy Institute. “So it doesn’t surprise me that we would have arrangements popping up that might be trying to take advantage of that confusion.”
Apex Management Group of the Chicago area and Pennsylvania-based Xpress Healthcare have teamed up to offer the plans, and executives from both companies say they don’t need approval from state regulators to sell them. They are selling the policies across the country, although their websites note one state – Massachusetts – where the plans are not offered.
David Shull, Apex’s director of business development, said “this is not insurance” and the plans are designed to meet the “bulk of someone’s day-to-day needs.”
Legal and policy experts have raised concerns that the new plans could leave buyers incorrectly thinking they are exempt from paying a penalty for not having coverage. Additionally, they say, plans sold to individuals must be state-licensed – and one regulator has already asked for an investigation.
“Generally speaking, any entity selling health insurance in the state of California has to have a license,” Dave Jones, the Golden State’s insurance commissioner, said earlier this month. “I have asked the Department of Insurance staff to open an investigation with regard to this company to ascertain whether it is in violation of California law if they are selling it in California.”
Asked about a possible investigation, Apex owner Jeffrey Bemoras emailed a statement last week saying the firm is not offering plans to individuals in California. He also noted that the individual market accounts for only 2% of the company’s business.
“To be clear, Apex Management group adheres closely to all state and federal rules and regulations surrounding offering a self-insured MEC [minimal essential coverage] program,” he wrote. “We are test marketing our product in the individual environment. If at some point it doesn’t make sense to continue that investment we will not invest or focus in on that market.”
Price-tag appeal, but what about coverage?
The new plans promise to be a solution for individuals who say that conventional health insurance is too expensive. Those looking for alternatives to the ACA often earn too much to qualify for tax subsidies under the federal law.
Donna Harper, an insurance agent who runs a two-person brokerage in Crystal Lake, Ill., found herself in that situation. She sells the Xpress plans – and decided to buy one herself.
Ms. Harper says she canceled her BlueCross BlueShield plan, which did meet the ACA’s requirements, after it rose to nearly $11,000 in premiums this year, with a $6,000 annual deductible.
“Self-employed people are being priced out of the market,” she said, noting the new Xpress plan will save her more than $500 a month.
The Xpress Minimum Essential Coverage plans come in three levels, costing as little as $93 a month for individuals to as much as $516 for a family. They cover preventive care – including certain cancer screenings and vaccinations – while providing limited benefits for doctor visits, lab tests, and lower-cost prescription drugs.
There is little or no coverage for hospital, emergency room care, and expensive prescription drugs, such as chemotherapy.
Ms. Harper said she generally recommends that her clients who sign up for an Xpress plan also buy a hospital-only policy offered by other insurers. That extra policy would pay a set amount toward inpatient care – often ranging from $1,500 to $5,000 or so a day.
Still, experts caution that hospital bills are generally much higher than those amounts. A three-day stay averages $30,000, according to the federal government’s insurance website. And hospital plans can have tougher requirements. Unlike the Xpress programs, which don’t reject applicants who have preexisting medical conditions, hospital-only plans often do. Ms. Harper says she personally was rejected for one.
“I haven’t been in the hospital for 40 years, so I’m going to roll the dice,” she said. And if she winds up in the hospital? “I’ll just pay the bill.”
About 100 brokers nationwide are selling the plans, and interest “is picking up quick,” said Edward Pettola, co-owner and founder of Xpress, which for years has sold programs that offer discounts on dental, vision, and prescription services.
Caveat emptor
Experts question whether the plans exempt policyholders from the ACA’s tax penalty for not having “qualified” coverage, defined as a policy from an employer, a government program or a licensed product purchased on the individual market.
The penalty for tax year 2017 is the greater of a flat fee or a percentage of income. The annual total could range from as little as $695 for an individual to as much as $3,264 for a family.
President Trump issued an executive order in October designed to loosen insurance restrictions on lower-cost, alternative forms of coverage, but the administration has not signaled its view on what would be deemed qualified coverage.
Responding to questions from KHN, officials from Apex and Xpress said their plans are designed to be affordable, not to mimic ACA health plans.
“If that is what we are expected to do, just deliver what every Marketplace plan or carriers do, provide a Bronze, Silver Plan, etc., it would not solve the problem in addressing a benefit plan that is affordable,” the companies said in a joint email on Nov. 14. “Individuals are not required to have an insurance plan, but a plan that meets minimum essential coverage, the required preventive care services.”
Mr. Bemoras, in a separate interview, said his company has been selling a version of the plan to employers since 2015.
“As we see the political environment moving and wavering and not understanding what needs to be done, the individual market became extremely attractive to us,” Mr. Bemoras said.
Still, experts who reviewed the plans for KHN said policies sold to individuals must cover 10 broad categories of health care to qualify as ACA-compliant, including hospitalization and emergency room care, and cannot set annual or lifetime limits.
The Xpress/Apex programs do set limits, paying zero to $2,500 annually toward hospital care. Doctor visits are covered for a $20 copayment, but coverage is limited to three per year. Lab tests are limited to 5 services annually. To get those prices, patients have to use a physician or facility in the PHCS network, which says it has 900,000 providers nationwide. Low-cost generics are covered for as little as a $1 copay, but the amount patients pay rises sharply for more expensive drugs.
“I’m very skeptical,” said attorney Alden J. Bianchi of Mintz Levin, who advises firms on employee benefits. “That would be hard [to do] because in the individual market, you have to cover all the essential health benefits.”
The details can be confusing, partly because federal law allows group health plans – generally those offered by large employers – to provide workers with self-funded, minimal coverage plans like those offered by Apex, Mr. Bianchi said.
Apex’s Mr. Shull recently said in an email that the firm simply wants to offer coverage to people who otherwise could not afford an ACA plan.
“There will be states that want to halt this. Why, I do not understand,” he wrote. “Would an individual be better off going without anything? If they need prescriptions, lab or imaging services subject to a small copay, would you want to be the one to deny them?”
Some consumers might find the price attractive, but also find themselves vulnerable to unexpected costs, including the tax liability.
Ms. Harper, the broker who signed up for one of the plans, remains confident: “As long as Xpress satisfies the [mandate], which I’m told it does, my clients are in good hands. Even if it doesn’t, I don’t think it’s a big deal. You are saving that [the tax penalty amount] a month.”
Kaiser Health News is a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation.
Consumers coping with the high cost of health insurance are the target market for new plans claiming to be lower-cost alternatives to the Affordable Care Act that fulfill the law’s requirement for health coverage.
But experts and regulators warn consumers to be cautious – and are raising red flags about one set of limited benefit plans marketed to individuals for as little as $93 a month. Offered through brokers and online ads, the plans promise to be an “ACA compliant, affordable, integrated solution that help ... individuals avoid the penalties under [the health care law].”
Such skinny plans – sold for the first time to individuals – come amid uncertainty over the fate of the ACA and whether the Trump administration will ease rules on plans for individuals. Dozens of brokers are offering the plans.
“The Trump administration is injecting a significant amount of confusion into the implementation of the ACA,” said Kevin Lucia, project director at Georgetown University’s Health Policy Institute. “So it doesn’t surprise me that we would have arrangements popping up that might be trying to take advantage of that confusion.”
Apex Management Group of the Chicago area and Pennsylvania-based Xpress Healthcare have teamed up to offer the plans, and executives from both companies say they don’t need approval from state regulators to sell them. They are selling the policies across the country, although their websites note one state – Massachusetts – where the plans are not offered.
David Shull, Apex’s director of business development, said “this is not insurance” and the plans are designed to meet the “bulk of someone’s day-to-day needs.”
Legal and policy experts have raised concerns that the new plans could leave buyers incorrectly thinking they are exempt from paying a penalty for not having coverage. Additionally, they say, plans sold to individuals must be state-licensed – and one regulator has already asked for an investigation.
“Generally speaking, any entity selling health insurance in the state of California has to have a license,” Dave Jones, the Golden State’s insurance commissioner, said earlier this month. “I have asked the Department of Insurance staff to open an investigation with regard to this company to ascertain whether it is in violation of California law if they are selling it in California.”
Asked about a possible investigation, Apex owner Jeffrey Bemoras emailed a statement last week saying the firm is not offering plans to individuals in California. He also noted that the individual market accounts for only 2% of the company’s business.
“To be clear, Apex Management group adheres closely to all state and federal rules and regulations surrounding offering a self-insured MEC [minimal essential coverage] program,” he wrote. “We are test marketing our product in the individual environment. If at some point it doesn’t make sense to continue that investment we will not invest or focus in on that market.”
Price-tag appeal, but what about coverage?
The new plans promise to be a solution for individuals who say that conventional health insurance is too expensive. Those looking for alternatives to the ACA often earn too much to qualify for tax subsidies under the federal law.
Donna Harper, an insurance agent who runs a two-person brokerage in Crystal Lake, Ill., found herself in that situation. She sells the Xpress plans – and decided to buy one herself.
Ms. Harper says she canceled her BlueCross BlueShield plan, which did meet the ACA’s requirements, after it rose to nearly $11,000 in premiums this year, with a $6,000 annual deductible.
“Self-employed people are being priced out of the market,” she said, noting the new Xpress plan will save her more than $500 a month.
The Xpress Minimum Essential Coverage plans come in three levels, costing as little as $93 a month for individuals to as much as $516 for a family. They cover preventive care – including certain cancer screenings and vaccinations – while providing limited benefits for doctor visits, lab tests, and lower-cost prescription drugs.
There is little or no coverage for hospital, emergency room care, and expensive prescription drugs, such as chemotherapy.
Ms. Harper said she generally recommends that her clients who sign up for an Xpress plan also buy a hospital-only policy offered by other insurers. That extra policy would pay a set amount toward inpatient care – often ranging from $1,500 to $5,000 or so a day.
Still, experts caution that hospital bills are generally much higher than those amounts. A three-day stay averages $30,000, according to the federal government’s insurance website. And hospital plans can have tougher requirements. Unlike the Xpress programs, which don’t reject applicants who have preexisting medical conditions, hospital-only plans often do. Ms. Harper says she personally was rejected for one.
“I haven’t been in the hospital for 40 years, so I’m going to roll the dice,” she said. And if she winds up in the hospital? “I’ll just pay the bill.”
About 100 brokers nationwide are selling the plans, and interest “is picking up quick,” said Edward Pettola, co-owner and founder of Xpress, which for years has sold programs that offer discounts on dental, vision, and prescription services.
Caveat emptor
Experts question whether the plans exempt policyholders from the ACA’s tax penalty for not having “qualified” coverage, defined as a policy from an employer, a government program or a licensed product purchased on the individual market.
The penalty for tax year 2017 is the greater of a flat fee or a percentage of income. The annual total could range from as little as $695 for an individual to as much as $3,264 for a family.
President Trump issued an executive order in October designed to loosen insurance restrictions on lower-cost, alternative forms of coverage, but the administration has not signaled its view on what would be deemed qualified coverage.
Responding to questions from KHN, officials from Apex and Xpress said their plans are designed to be affordable, not to mimic ACA health plans.
“If that is what we are expected to do, just deliver what every Marketplace plan or carriers do, provide a Bronze, Silver Plan, etc., it would not solve the problem in addressing a benefit plan that is affordable,” the companies said in a joint email on Nov. 14. “Individuals are not required to have an insurance plan, but a plan that meets minimum essential coverage, the required preventive care services.”
Mr. Bemoras, in a separate interview, said his company has been selling a version of the plan to employers since 2015.
“As we see the political environment moving and wavering and not understanding what needs to be done, the individual market became extremely attractive to us,” Mr. Bemoras said.
Still, experts who reviewed the plans for KHN said policies sold to individuals must cover 10 broad categories of health care to qualify as ACA-compliant, including hospitalization and emergency room care, and cannot set annual or lifetime limits.
The Xpress/Apex programs do set limits, paying zero to $2,500 annually toward hospital care. Doctor visits are covered for a $20 copayment, but coverage is limited to three per year. Lab tests are limited to 5 services annually. To get those prices, patients have to use a physician or facility in the PHCS network, which says it has 900,000 providers nationwide. Low-cost generics are covered for as little as a $1 copay, but the amount patients pay rises sharply for more expensive drugs.
“I’m very skeptical,” said attorney Alden J. Bianchi of Mintz Levin, who advises firms on employee benefits. “That would be hard [to do] because in the individual market, you have to cover all the essential health benefits.”
The details can be confusing, partly because federal law allows group health plans – generally those offered by large employers – to provide workers with self-funded, minimal coverage plans like those offered by Apex, Mr. Bianchi said.
Apex’s Mr. Shull recently said in an email that the firm simply wants to offer coverage to people who otherwise could not afford an ACA plan.
“There will be states that want to halt this. Why, I do not understand,” he wrote. “Would an individual be better off going without anything? If they need prescriptions, lab or imaging services subject to a small copay, would you want to be the one to deny them?”
Some consumers might find the price attractive, but also find themselves vulnerable to unexpected costs, including the tax liability.
Ms. Harper, the broker who signed up for one of the plans, remains confident: “As long as Xpress satisfies the [mandate], which I’m told it does, my clients are in good hands. Even if it doesn’t, I don’t think it’s a big deal. You are saving that [the tax penalty amount] a month.”
Kaiser Health News is a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation.
Consumers coping with the high cost of health insurance are the target market for new plans claiming to be lower-cost alternatives to the Affordable Care Act that fulfill the law’s requirement for health coverage.
But experts and regulators warn consumers to be cautious – and are raising red flags about one set of limited benefit plans marketed to individuals for as little as $93 a month. Offered through brokers and online ads, the plans promise to be an “ACA compliant, affordable, integrated solution that help ... individuals avoid the penalties under [the health care law].”
Such skinny plans – sold for the first time to individuals – come amid uncertainty over the fate of the ACA and whether the Trump administration will ease rules on plans for individuals. Dozens of brokers are offering the plans.
“The Trump administration is injecting a significant amount of confusion into the implementation of the ACA,” said Kevin Lucia, project director at Georgetown University’s Health Policy Institute. “So it doesn’t surprise me that we would have arrangements popping up that might be trying to take advantage of that confusion.”
Apex Management Group of the Chicago area and Pennsylvania-based Xpress Healthcare have teamed up to offer the plans, and executives from both companies say they don’t need approval from state regulators to sell them. They are selling the policies across the country, although their websites note one state – Massachusetts – where the plans are not offered.
David Shull, Apex’s director of business development, said “this is not insurance” and the plans are designed to meet the “bulk of someone’s day-to-day needs.”
Legal and policy experts have raised concerns that the new plans could leave buyers incorrectly thinking they are exempt from paying a penalty for not having coverage. Additionally, they say, plans sold to individuals must be state-licensed – and one regulator has already asked for an investigation.
“Generally speaking, any entity selling health insurance in the state of California has to have a license,” Dave Jones, the Golden State’s insurance commissioner, said earlier this month. “I have asked the Department of Insurance staff to open an investigation with regard to this company to ascertain whether it is in violation of California law if they are selling it in California.”
Asked about a possible investigation, Apex owner Jeffrey Bemoras emailed a statement last week saying the firm is not offering plans to individuals in California. He also noted that the individual market accounts for only 2% of the company’s business.
“To be clear, Apex Management group adheres closely to all state and federal rules and regulations surrounding offering a self-insured MEC [minimal essential coverage] program,” he wrote. “We are test marketing our product in the individual environment. If at some point it doesn’t make sense to continue that investment we will not invest or focus in on that market.”
Price-tag appeal, but what about coverage?
The new plans promise to be a solution for individuals who say that conventional health insurance is too expensive. Those looking for alternatives to the ACA often earn too much to qualify for tax subsidies under the federal law.
Donna Harper, an insurance agent who runs a two-person brokerage in Crystal Lake, Ill., found herself in that situation. She sells the Xpress plans – and decided to buy one herself.
Ms. Harper says she canceled her BlueCross BlueShield plan, which did meet the ACA’s requirements, after it rose to nearly $11,000 in premiums this year, with a $6,000 annual deductible.
“Self-employed people are being priced out of the market,” she said, noting the new Xpress plan will save her more than $500 a month.
The Xpress Minimum Essential Coverage plans come in three levels, costing as little as $93 a month for individuals to as much as $516 for a family. They cover preventive care – including certain cancer screenings and vaccinations – while providing limited benefits for doctor visits, lab tests, and lower-cost prescription drugs.
There is little or no coverage for hospital, emergency room care, and expensive prescription drugs, such as chemotherapy.
Ms. Harper said she generally recommends that her clients who sign up for an Xpress plan also buy a hospital-only policy offered by other insurers. That extra policy would pay a set amount toward inpatient care – often ranging from $1,500 to $5,000 or so a day.
Still, experts caution that hospital bills are generally much higher than those amounts. A three-day stay averages $30,000, according to the federal government’s insurance website. And hospital plans can have tougher requirements. Unlike the Xpress programs, which don’t reject applicants who have preexisting medical conditions, hospital-only plans often do. Ms. Harper says she personally was rejected for one.
“I haven’t been in the hospital for 40 years, so I’m going to roll the dice,” she said. And if she winds up in the hospital? “I’ll just pay the bill.”
About 100 brokers nationwide are selling the plans, and interest “is picking up quick,” said Edward Pettola, co-owner and founder of Xpress, which for years has sold programs that offer discounts on dental, vision, and prescription services.
Caveat emptor
Experts question whether the plans exempt policyholders from the ACA’s tax penalty for not having “qualified” coverage, defined as a policy from an employer, a government program or a licensed product purchased on the individual market.
The penalty for tax year 2017 is the greater of a flat fee or a percentage of income. The annual total could range from as little as $695 for an individual to as much as $3,264 for a family.
President Trump issued an executive order in October designed to loosen insurance restrictions on lower-cost, alternative forms of coverage, but the administration has not signaled its view on what would be deemed qualified coverage.
Responding to questions from KHN, officials from Apex and Xpress said their plans are designed to be affordable, not to mimic ACA health plans.
“If that is what we are expected to do, just deliver what every Marketplace plan or carriers do, provide a Bronze, Silver Plan, etc., it would not solve the problem in addressing a benefit plan that is affordable,” the companies said in a joint email on Nov. 14. “Individuals are not required to have an insurance plan, but a plan that meets minimum essential coverage, the required preventive care services.”
Mr. Bemoras, in a separate interview, said his company has been selling a version of the plan to employers since 2015.
“As we see the political environment moving and wavering and not understanding what needs to be done, the individual market became extremely attractive to us,” Mr. Bemoras said.
Still, experts who reviewed the plans for KHN said policies sold to individuals must cover 10 broad categories of health care to qualify as ACA-compliant, including hospitalization and emergency room care, and cannot set annual or lifetime limits.
The Xpress/Apex programs do set limits, paying zero to $2,500 annually toward hospital care. Doctor visits are covered for a $20 copayment, but coverage is limited to three per year. Lab tests are limited to 5 services annually. To get those prices, patients have to use a physician or facility in the PHCS network, which says it has 900,000 providers nationwide. Low-cost generics are covered for as little as a $1 copay, but the amount patients pay rises sharply for more expensive drugs.
“I’m very skeptical,” said attorney Alden J. Bianchi of Mintz Levin, who advises firms on employee benefits. “That would be hard [to do] because in the individual market, you have to cover all the essential health benefits.”
The details can be confusing, partly because federal law allows group health plans – generally those offered by large employers – to provide workers with self-funded, minimal coverage plans like those offered by Apex, Mr. Bianchi said.
Apex’s Mr. Shull recently said in an email that the firm simply wants to offer coverage to people who otherwise could not afford an ACA plan.
“There will be states that want to halt this. Why, I do not understand,” he wrote. “Would an individual be better off going without anything? If they need prescriptions, lab or imaging services subject to a small copay, would you want to be the one to deny them?”
Some consumers might find the price attractive, but also find themselves vulnerable to unexpected costs, including the tax liability.
Ms. Harper, the broker who signed up for one of the plans, remains confident: “As long as Xpress satisfies the [mandate], which I’m told it does, my clients are in good hands. Even if it doesn’t, I don’t think it’s a big deal. You are saving that [the tax penalty amount] a month.”
Kaiser Health News is a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation.