Recent advances in our understanding of psoriatic immune pathways have led to new generations of targeted therapies developed over the last 5 years. Although the pathogenesis of psoriasis remains to be fully elucidated, the success of these targeted therapies has confirmed a critical role of the IL-23/helper T cell (T_H17) axis in maintaining the psoriatic immune cascade, a positive feedback loop in which IL-17, IL-12, and IL-23 released from myeloid dendritic cells lead to activation of helperT cells. Activated helper T cells—namely T_H1, T_H17, and T_H22—release IL-17, IL-22, and other proinflammatory cytokines, amplifying the immune response and leading to keratinocyte proliferation and immune cell migration to psoriatic lesions. Inhibition of IL-17 and IL-23 by several biologics disrupts this aberrant inflammatory cascade and has led to dramatic improvements in outcomes, particularly among patients with moderate to severe disease.

Numerous biologics targeting these pathways and several oral treatments have been approved by the US Food and Drug Administration (FDA) for the treatment of psoriasis; in addition, a number of promising therapies are on the horizon, and knowledge of these medications might help guide our treatment approach to the patient with psoriasis. This article provides an update on the most recent (as of 2019) approved therapies and medications in the pipeline for moderate to severe plaque psoriasis, with a focus on systemic agents in phase 3 clinical trials. (Medications targeting psoriatic arthritis, biosimilars, and existing medications approved by the FDA prior to 2019 will not be discussed.)

Risankizumab

Risankizumab-rzaa (formerly BI 655066) is a humanized IgG1 monoclonal antibody that targets the p19 subunit of IL-23, selectively inhibiting the role of this critical cytokine in psoriatic inflammation.

Phase 1 Trial
In a phase 1 proof-of-concept study, 39 patients with moderate to severe plaque psoriasis received varying dosages of intravenous or subcutaneous risankizumab or placebo.¹ At week 12, the percentage of risankizumab-treated patients achieving reduction in the psoriasis area and severity index (PASI) score by 75% (PASI 75), 90% (PASI 90), and 100% (PASI 100) was 87% (27/31; P<.001 vs placebo), 58% (18/31; P=.007 vs placebo), and 16% (5/31; P=.590 vs placebo), respectively. Improvements in PASI scores were observed as early as week 2. Adverse events (AEs) were reported by 65% of the risankizumab group and 88% of the placebo group. Serious AEs were reported in 4 patients receiving risankizumab, none of which were considered related to the study medication.¹

Phase 2 Trial
A phase 2 comparator trial demonstrated noninferiority at higher dosages of risankizumab in comparison to the IL-12/IL-23 inhibitor ustekinumab.² Among 166 participants with moderate to severe plaque psoriasis, PASI 90 at week 12 was met by 77% of participants receiving 90 or 180 mg of risankizumab compared to 40% receiving ustekinumab (P<.001). Onset of activity with risankizumab was faster and the duration of effect longer vs ustekinumab; by week 8, at least PASI 75 was achieved by approximately 80% of participants in the 90-mg and 180-mg risankizumab groups compared to 60% in the ustekinumab group; PASI score reductions generally were maintained for as long as 20 weeks after the final dose of risankizumab was administered.²

Phase 3 Trials
The 52-week UltIMMa-1 and UltIMMa-2 phase 3 trials compared subcutaneous risankizumab (150 mg) to ustekinumab (45 or 90 mg [weight-based dosing]) or placebo administered at weeks 0, 4, 16, 28, and 40 in approximately 1000 patients with moderate to severe plaque psoriasis.³ Patients initially assigned to placebo switched to risankizumab 150 mg at week 16. At week 16, PASI 90 was achieved by 75.3% of risankizumab-treated patients, 42.0% of ustekinumab-treated patients, and 4.9% of placebo-treated patients in UltIMMa-1, and by 74.8% of risankizumab-treated patients, 47.5% of ustekinumab-treated patients, and 2.0% of placebo-treated patients in UltIMMa-2 (P<.0001 vs placebo and ustekinumab for both studies). Achievement of a static physician’s global assessment (sPGA) score of 0 or 1 at week 16 similarly favored risankizumab, with 87.8%, 63.0%, and 7.8% of patients in UltIMMa-1 meeting an sPGA score of 0 or 1 in the risankizumab, ustekinumab, and placebo groups, respectively, and 83.7%, 61.6%, and 5.1% in UltIMMa-2 meeting an sPGA score of 0 or 1 in the risankizumab, ustekinumab, and placebo groups, respectively (P<.0001 vs placebo and ustekinumab for both studies). Among patients initially assigned to risankizumab, improvements in PASI and sPGA continued to increase until week 52, with 81.9% achieving PASI 90 at week 52 compared to 44.0% on ustekinumab in UltIMMa-1, and 80.6% achieving PASI 90 at week 52 compared to 50.5% on ustekinumab in UltIMMa-2 (P<.0001 vs ustekinumab for both studies). Treatment-emergent AE profiles were similar for risankizumab and ustekinumab in both studies, and there were no unexpected safety findings.³

Risankizumab received FDA approval for the treatment of moderate to severe plaque psoriasis in April 2019.

Bimekizumab

Bimekizumab (UCB4940), a humanized IgG1 monoclonal antibody, selectively neutralizes the biologic functions of IL-17A and IL-17F, the latter of which has only recently been implicated in contributing to the psoriatic immune cascade.⁴

First-in-Human Study
Thirty-nine participants with mild psoriasis demonstrated efficacy after single-dose intravenous bimekizumab, with maximal improvements in all measures of disease activity observed between weeks 8 and 12 in participants receiving 160 to 640 mg.⁵

Proof-of-Concept Phase 1b Study
A subsequent trial of 53 participants with psoriatic arthritis demonstrated sustained efficacy to week 20 with varying dosages of intravenous bimekizumab.⁶ At week 8, PASI 100 was met by 86.7% of participants receiving the top 3 dosages of bimekizumab compared to none of the placebo-treated participants. Treatment-emergent AEs, including neutropenia and elevation of liver transaminases, were mostly mild to moderate and resolved spontaneously. There were 3 severe AEs and 3 serious AEs, none of which were related to treatment.⁶

Importantly, bimekizumab was shown in this small study to have the potential to be highly effective at treating psoriatic arthritis. American College of Rheumatology ACR20, ACR50, and ACR70 response criteria were very high, with an ACR20 of 80% and an ACR50 of 40%.⁶ Further trials are necessary to gather more data and confirm these findings; however, these levels of response are higher than those of any other biologic on the market.

Phase 2b Dose-Ranging Study
In this trial, 250 participants with moderate to severe plaque psoriasis received either 64 mg, 160 mg with a 320-mg loading dose, 320 mg, or 480 mg of subcutaneous bimekizumab or placebo at weeks 0, 4, and 8.⁷ At week 12, PASI 90 was achieved by significantly more patients in all bimekizumab-treated groups compared to the placebo group (46.2%–79.1% vs 0%; P<.0001 for all dosages); PASI 100 also was achieved by significantly more bimekizumab-treated patients (27.9%–60.0% vs 0%; P<.0002). Improvement began as early as week 4, with clinically meaningful responses observed in all bimekizumab groups across all measures of disease activity. Treatment-emergent AEs occurred more frequently in bimekizumab-treated participants (61%) than in placebo-treated participants (36%); the most common AEs were nasopharyngitis and upper respiratory tract infection. Of note, fungal infections were reported by 4.3% of participants receiving bimekizumab; all cases were localized superficial infection, and none led to discontinuation. Three serious AEs were reported, none of which were considered related to the study treatment.⁷

Mirikizumab

Mirikizumab (LY3074828) is a humanized IgG4 monoclonal antibody that selectively binds and inhibits the p19 subunit of IL-23, with no action on IL-12.

Phase 1 Trial
Mirikizumab was shown to improve PASI scores in patients with plaque psoriasis.⁸

Phase 2 Trial
Subsequently, a trial of 205 participants with moderate to severe plaque psoriasis compared 3 dosing regimens of subcutaneous mirikizumab—30, 100, or 300 mg—at weeks 0 and 8 compared to placebo.⁹ Primary end point results at week 16 demonstrated PASI 90 response rates of 0%, 29% (P=.009), 59% (P<.001), and 67% (P<.001) in the placebo, 30-mg, 100-mg, and 300-mg mirikizumab groups, respectively. Complete clearance of psoriasis, measured by PASI 100 and sPGA 0, was achieved by 0%, 16%, 31%, and 31%, respectively (P=.039 for 30 mg vs placebo; P=.007 for the higher dosage groups vs placebo). Response rates for all efficacy outcomes were statistically significantly higher for all mirikizumab treatment groups compared to placebo and were highest in the 100-mg and 300-mg treatment groups. Frequencies of participants reporting AEs were similar across treatment and placebo groups.⁹

Oral Medications

Only a few small-molecule, orally bioavailable therapies are on the market for the treatment of psoriasis, some of which are associated with unfavorable side-effect profiles that preclude long-term therapy.

BMS-986165
The intracellular signaling enzyme tyrosine kinase 2 is involved in functional responses of IL-12 and IL-23. BMS-986165, a potent oral inhibitor of tyrosine kinase 2 with greater selectivity than other tyrosine kinase inhibitors, demonstrated efficacy in a phase 2 trial of 267 participants with moderate to severe plaque psoriasis receiving any of 5 dosing regimens—3 mg every other day, 3 mg daily, 3 mg twice daily, 6 mg twice daily, and 12 mg daily—compared to placebo.¹⁰ At week 12, the percentage of patients with a 75% or greater reduction in PASI was 7% with placebo, 9% with 3 mg every other day (P=.49 vs placebo), 39% with 3 mg daily (P<.001 vs placebo), 69% with 3 mg twice daily (P<.001 vs placebo), 67% with 6 mg twice daily (P<.001 vs placebo), and 75% with 12 mg once daily (P<.001 vs placebo). Adverse events occurred in 51% of patients in the placebo group and in 55% to 80% of BMS-986165–treated patients; the most common AEs were nasopharyngitis, headache, diarrhea, nausea, and upper respiratory tract infection.¹⁰

A phase 3 trial comparing BMS-986165 with placebo and apremilast is underway (ClinicalTrials.gov Identifier NCT03611751).

Piclidenoson (CF101)
A novel small molecule that binds the Gi protein–associated A₃ adenosine receptor piclidenoson induces an anti-inflammatory response via deregulation of the Wnt and nuclear factor κB signal transduction pathways, leading to downregulation of proinflammatory cytokines, including IL-17 and IL-23.¹¹

In a phase 2 dose-ranging study, 75 patients with moderate to severe plaque psoriasis received varying dosages—1, 2, or 4 mg—of oral piclidenoson or placebo twice daily for 12 weeks.¹² Progressive improvement in the mean change from baseline PASI score was observed in the 2-mg group, with statistically significant differences at weeks 8 and 12 compared to placebo (P=.047 and P=.031, respectively). At week 12, 35.3% of the 2-mg group achieved at least PASI 50. Improvements in PASI were less pronounced in the 4-mg group, and no therapeutic benefit was observed in the 1-mg group. Of the 20 AEs reported, 15 possibly were related to the study drug; 1 AE was severe.¹²

In a subsequent phase 2/3 trial, patients with moderate to severe plaque psoriasis received piclidenoson—1 or 2 mg—or placebo twice daily.¹³ At week 12, PASI 75 was achieved by 8.5% of patients in the 2-mg group and by 6.9% of patients receiving placebo (P=.621), thereby not meeting the primary study end point. Results at week 32 were more encouraging. In the 2-mg group, PASI mean percentage improvement was 57% (P<.002) compared to baseline, with linear improvements observed in PASI 50 (63.5%), PASI 75 (35.5%), PASI 90 (24.7%), and PASI 100 (10.6%).¹³

A phase 3 trial comparing piclidenoson 2 and 3 mg to apremilast and placebo is in progress (ClinicalTrials.gov Identifier NCT03168256).

Future Directions

Despite abundant options for treating moderate to severe plaque psoriasis and psoriatic arthritis, the pipeline remains rich. Novel treatments might have improved efficacy, favorable safety profiles, and different modes of administration compared to current medications. In addition to the novel therapeutics covered here, several treatments are in development further down the pipeline, with only phase 1 or 2 data available. Remtolumab (ABT-122), a tumor necrosis factor α– and IL-17A–targeted immunoglobulin, is unique among biologics, given its dual inhibition of tumor necrosis factor α and IL-17A.¹⁴ M1095 (ALX-0761), a novel trivalent bispecific nanobody, is another intriguing candidate. This dual inhibitor of IL-17A/F might exhibit a number of advantages over conventional antibodies, including better tissue penetration, reduced immunogenicity, and a longer half-life (ClinicalTrials.gov Identifier NCT03384745).^15,16

As always with drug development, numerous medications that were under development failed to meet primary end points in phase 2 trials and have therefore been discontinued, including namilumab and prurisol. It is reassuring that the pace of drug discovery and development in psoriasis does not seem to be slowing; to our patients’ benefit, we will have an array of treatments available to tailor therapy to the individual.

Recent advances in our understanding of psoriatic immune pathways have led to new generations of targeted therapies developed over the last 5 years. Although the pathogenesis of psoriasis remains to be fully elucidated, the success of these targeted therapies has confirmed a critical role of the IL-23/helper T cell (T_H17) axis in maintaining the psoriatic immune cascade, a positive feedback loop in which IL-17, IL-12, and IL-23 released from myeloid dendritic cells lead to activation of helperT cells. Activated helper T cells—namely T_H1, T_H17, and T_H22—release IL-17, IL-22, and other proinflammatory cytokines, amplifying the immune response and leading to keratinocyte proliferation and immune cell migration to psoriatic lesions. Inhibition of IL-17 and IL-23 by several biologics disrupts this aberrant inflammatory cascade and has led to dramatic improvements in outcomes, particularly among patients with moderate to severe disease.

Numerous biologics targeting these pathways and several oral treatments have been approved by the US Food and Drug Administration (FDA) for the treatment of psoriasis; in addition, a number of promising therapies are on the horizon, and knowledge of these medications might help guide our treatment approach to the patient with psoriasis. This article provides an update on the most recent (as of 2019) approved therapies and medications in the pipeline for moderate to severe plaque psoriasis, with a focus on systemic agents in phase 3 clinical trials. (Medications targeting psoriatic arthritis, biosimilars, and existing medications approved by the FDA prior to 2019 will not be discussed.)

Risankizumab

Risankizumab-rzaa (formerly BI 655066) is a humanized IgG1 monoclonal antibody that targets the p19 subunit of IL-23, selectively inhibiting the role of this critical cytokine in psoriatic inflammation.

Phase 1 Trial
In a phase 1 proof-of-concept study, 39 patients with moderate to severe plaque psoriasis received varying dosages of intravenous or subcutaneous risankizumab or placebo.¹ At week 12, the percentage of risankizumab-treated patients achieving reduction in the psoriasis area and severity index (PASI) score by 75% (PASI 75), 90% (PASI 90), and 100% (PASI 100) was 87% (27/31; P<.001 vs placebo), 58% (18/31; P=.007 vs placebo), and 16% (5/31; P=.590 vs placebo), respectively. Improvements in PASI scores were observed as early as week 2. Adverse events (AEs) were reported by 65% of the risankizumab group and 88% of the placebo group. Serious AEs were reported in 4 patients receiving risankizumab, none of which were considered related to the study medication.¹

Phase 2 Trial
A phase 2 comparator trial demonstrated noninferiority at higher dosages of risankizumab in comparison to the IL-12/IL-23 inhibitor ustekinumab.² Among 166 participants with moderate to severe plaque psoriasis, PASI 90 at week 12 was met by 77% of participants receiving 90 or 180 mg of risankizumab compared to 40% receiving ustekinumab (P<.001). Onset of activity with risankizumab was faster and the duration of effect longer vs ustekinumab; by week 8, at least PASI 75 was achieved by approximately 80% of participants in the 90-mg and 180-mg risankizumab groups compared to 60% in the ustekinumab group; PASI score reductions generally were maintained for as long as 20 weeks after the final dose of risankizumab was administered.²

Phase 3 Trials
The 52-week UltIMMa-1 and UltIMMa-2 phase 3 trials compared subcutaneous risankizumab (150 mg) to ustekinumab (45 or 90 mg [weight-based dosing]) or placebo administered at weeks 0, 4, 16, 28, and 40 in approximately 1000 patients with moderate to severe plaque psoriasis.³ Patients initially assigned to placebo switched to risankizumab 150 mg at week 16. At week 16, PASI 90 was achieved by 75.3% of risankizumab-treated patients, 42.0% of ustekinumab-treated patients, and 4.9% of placebo-treated patients in UltIMMa-1, and by 74.8% of risankizumab-treated patients, 47.5% of ustekinumab-treated patients, and 2.0% of placebo-treated patients in UltIMMa-2 (P<.0001 vs placebo and ustekinumab for both studies). Achievement of a static physician’s global assessment (sPGA) score of 0 or 1 at week 16 similarly favored risankizumab, with 87.8%, 63.0%, and 7.8% of patients in UltIMMa-1 meeting an sPGA score of 0 or 1 in the risankizumab, ustekinumab, and placebo groups, respectively, and 83.7%, 61.6%, and 5.1% in UltIMMa-2 meeting an sPGA score of 0 or 1 in the risankizumab, ustekinumab, and placebo groups, respectively (P<.0001 vs placebo and ustekinumab for both studies). Among patients initially assigned to risankizumab, improvements in PASI and sPGA continued to increase until week 52, with 81.9% achieving PASI 90 at week 52 compared to 44.0% on ustekinumab in UltIMMa-1, and 80.6% achieving PASI 90 at week 52 compared to 50.5% on ustekinumab in UltIMMa-2 (P<.0001 vs ustekinumab for both studies). Treatment-emergent AE profiles were similar for risankizumab and ustekinumab in both studies, and there were no unexpected safety findings.³

Risankizumab received FDA approval for the treatment of moderate to severe plaque psoriasis in April 2019.

Bimekizumab

Bimekizumab (UCB4940), a humanized IgG1 monoclonal antibody, selectively neutralizes the biologic functions of IL-17A and IL-17F, the latter of which has only recently been implicated in contributing to the psoriatic immune cascade.⁴

First-in-Human Study
Thirty-nine participants with mild psoriasis demonstrated efficacy after single-dose intravenous bimekizumab, with maximal improvements in all measures of disease activity observed between weeks 8 and 12 in participants receiving 160 to 640 mg.⁵

Proof-of-Concept Phase 1b Study
A subsequent trial of 53 participants with psoriatic arthritis demonstrated sustained efficacy to week 20 with varying dosages of intravenous bimekizumab.⁶ At week 8, PASI 100 was met by 86.7% of participants receiving the top 3 dosages of bimekizumab compared to none of the placebo-treated participants. Treatment-emergent AEs, including neutropenia and elevation of liver transaminases, were mostly mild to moderate and resolved spontaneously. There were 3 severe AEs and 3 serious AEs, none of which were related to treatment.⁶

Importantly, bimekizumab was shown in this small study to have the potential to be highly effective at treating psoriatic arthritis. American College of Rheumatology ACR20, ACR50, and ACR70 response criteria were very high, with an ACR20 of 80% and an ACR50 of 40%.⁶ Further trials are necessary to gather more data and confirm these findings; however, these levels of response are higher than those of any other biologic on the market.

Phase 2b Dose-Ranging Study
In this trial, 250 participants with moderate to severe plaque psoriasis received either 64 mg, 160 mg with a 320-mg loading dose, 320 mg, or 480 mg of subcutaneous bimekizumab or placebo at weeks 0, 4, and 8.⁷ At week 12, PASI 90 was achieved by significantly more patients in all bimekizumab-treated groups compared to the placebo group (46.2%–79.1% vs 0%; P<.0001 for all dosages); PASI 100 also was achieved by significantly more bimekizumab-treated patients (27.9%–60.0% vs 0%; P<.0002). Improvement began as early as week 4, with clinically meaningful responses observed in all bimekizumab groups across all measures of disease activity. Treatment-emergent AEs occurred more frequently in bimekizumab-treated participants (61%) than in placebo-treated participants (36%); the most common AEs were nasopharyngitis and upper respiratory tract infection. Of note, fungal infections were reported by 4.3% of participants receiving bimekizumab; all cases were localized superficial infection, and none led to discontinuation. Three serious AEs were reported, none of which were considered related to the study treatment.⁷

Mirikizumab

Mirikizumab (LY3074828) is a humanized IgG4 monoclonal antibody that selectively binds and inhibits the p19 subunit of IL-23, with no action on IL-12.

Phase 1 Trial
Mirikizumab was shown to improve PASI scores in patients with plaque psoriasis.⁸

Phase 2 Trial
Subsequently, a trial of 205 participants with moderate to severe plaque psoriasis compared 3 dosing regimens of subcutaneous mirikizumab—30, 100, or 300 mg—at weeks 0 and 8 compared to placebo.⁹ Primary end point results at week 16 demonstrated PASI 90 response rates of 0%, 29% (P=.009), 59% (P<.001), and 67% (P<.001) in the placebo, 30-mg, 100-mg, and 300-mg mirikizumab groups, respectively. Complete clearance of psoriasis, measured by PASI 100 and sPGA 0, was achieved by 0%, 16%, 31%, and 31%, respectively (P=.039 for 30 mg vs placebo; P=.007 for the higher dosage groups vs placebo). Response rates for all efficacy outcomes were statistically significantly higher for all mirikizumab treatment groups compared to placebo and were highest in the 100-mg and 300-mg treatment groups. Frequencies of participants reporting AEs were similar across treatment and placebo groups.⁹

Oral Medications

Only a few small-molecule, orally bioavailable therapies are on the market for the treatment of psoriasis, some of which are associated with unfavorable side-effect profiles that preclude long-term therapy.

BMS-986165
The intracellular signaling enzyme tyrosine kinase 2 is involved in functional responses of IL-12 and IL-23. BMS-986165, a potent oral inhibitor of tyrosine kinase 2 with greater selectivity than other tyrosine kinase inhibitors, demonstrated efficacy in a phase 2 trial of 267 participants with moderate to severe plaque psoriasis receiving any of 5 dosing regimens—3 mg every other day, 3 mg daily, 3 mg twice daily, 6 mg twice daily, and 12 mg daily—compared to placebo.¹⁰ At week 12, the percentage of patients with a 75% or greater reduction in PASI was 7% with placebo, 9% with 3 mg every other day (P=.49 vs placebo), 39% with 3 mg daily (P<.001 vs placebo), 69% with 3 mg twice daily (P<.001 vs placebo), 67% with 6 mg twice daily (P<.001 vs placebo), and 75% with 12 mg once daily (P<.001 vs placebo). Adverse events occurred in 51% of patients in the placebo group and in 55% to 80% of BMS-986165–treated patients; the most common AEs were nasopharyngitis, headache, diarrhea, nausea, and upper respiratory tract infection.¹⁰

A phase 3 trial comparing BMS-986165 with placebo and apremilast is underway (ClinicalTrials.gov Identifier NCT03611751).

Piclidenoson (CF101)
A novel small molecule that binds the Gi protein–associated A₃ adenosine receptor piclidenoson induces an anti-inflammatory response via deregulation of the Wnt and nuclear factor κB signal transduction pathways, leading to downregulation of proinflammatory cytokines, including IL-17 and IL-23.¹¹

In a phase 2 dose-ranging study, 75 patients with moderate to severe plaque psoriasis received varying dosages—1, 2, or 4 mg—of oral piclidenoson or placebo twice daily for 12 weeks.¹² Progressive improvement in the mean change from baseline PASI score was observed in the 2-mg group, with statistically significant differences at weeks 8 and 12 compared to placebo (P=.047 and P=.031, respectively). At week 12, 35.3% of the 2-mg group achieved at least PASI 50. Improvements in PASI were less pronounced in the 4-mg group, and no therapeutic benefit was observed in the 1-mg group. Of the 20 AEs reported, 15 possibly were related to the study drug; 1 AE was severe.¹²

In a subsequent phase 2/3 trial, patients with moderate to severe plaque psoriasis received piclidenoson—1 or 2 mg—or placebo twice daily.¹³ At week 12, PASI 75 was achieved by 8.5% of patients in the 2-mg group and by 6.9% of patients receiving placebo (P=.621), thereby not meeting the primary study end point. Results at week 32 were more encouraging. In the 2-mg group, PASI mean percentage improvement was 57% (P<.002) compared to baseline, with linear improvements observed in PASI 50 (63.5%), PASI 75 (35.5%), PASI 90 (24.7%), and PASI 100 (10.6%).¹³

A phase 3 trial comparing piclidenoson 2 and 3 mg to apremilast and placebo is in progress (ClinicalTrials.gov Identifier NCT03168256).

Future Directions

Despite abundant options for treating moderate to severe plaque psoriasis and psoriatic arthritis, the pipeline remains rich. Novel treatments might have improved efficacy, favorable safety profiles, and different modes of administration compared to current medications. In addition to the novel therapeutics covered here, several treatments are in development further down the pipeline, with only phase 1 or 2 data available. Remtolumab (ABT-122), a tumor necrosis factor α– and IL-17A–targeted immunoglobulin, is unique among biologics, given its dual inhibition of tumor necrosis factor α and IL-17A.¹⁴ M1095 (ALX-0761), a novel trivalent bispecific nanobody, is another intriguing candidate. This dual inhibitor of IL-17A/F might exhibit a number of advantages over conventional antibodies, including better tissue penetration, reduced immunogenicity, and a longer half-life (ClinicalTrials.gov Identifier NCT03384745).^15,16

As always with drug development, numerous medications that were under development failed to meet primary end points in phase 2 trials and have therefore been discontinued, including namilumab and prurisol. It is reassuring that the pace of drug discovery and development in psoriasis does not seem to be slowing; to our patients’ benefit, we will have an array of treatments available to tailor therapy to the individual.

Recent advances in our understanding of psoriatic immune pathways have led to new generations of targeted therapies developed over the last 5 years. Although the pathogenesis of psoriasis remains to be fully elucidated, the success of these targeted therapies has confirmed a critical role of the IL-23/helper T cell (T_H17) axis in maintaining the psoriatic immune cascade, a positive feedback loop in which IL-17, IL-12, and IL-23 released from myeloid dendritic cells lead to activation of helperT cells. Activated helper T cells—namely T_H1, T_H17, and T_H22—release IL-17, IL-22, and other proinflammatory cytokines, amplifying the immune response and leading to keratinocyte proliferation and immune cell migration to psoriatic lesions. Inhibition of IL-17 and IL-23 by several biologics disrupts this aberrant inflammatory cascade and has led to dramatic improvements in outcomes, particularly among patients with moderate to severe disease.

Numerous biologics targeting these pathways and several oral treatments have been approved by the US Food and Drug Administration (FDA) for the treatment of psoriasis; in addition, a number of promising therapies are on the horizon, and knowledge of these medications might help guide our treatment approach to the patient with psoriasis. This article provides an update on the most recent (as of 2019) approved therapies and medications in the pipeline for moderate to severe plaque psoriasis, with a focus on systemic agents in phase 3 clinical trials. (Medications targeting psoriatic arthritis, biosimilars, and existing medications approved by the FDA prior to 2019 will not be discussed.)

Risankizumab

Risankizumab-rzaa (formerly BI 655066) is a humanized IgG1 monoclonal antibody that targets the p19 subunit of IL-23, selectively inhibiting the role of this critical cytokine in psoriatic inflammation.

Phase 1 Trial
In a phase 1 proof-of-concept study, 39 patients with moderate to severe plaque psoriasis received varying dosages of intravenous or subcutaneous risankizumab or placebo.¹ At week 12, the percentage of risankizumab-treated patients achieving reduction in the psoriasis area and severity index (PASI) score by 75% (PASI 75), 90% (PASI 90), and 100% (PASI 100) was 87% (27/31; P<.001 vs placebo), 58% (18/31; P=.007 vs placebo), and 16% (5/31; P=.590 vs placebo), respectively. Improvements in PASI scores were observed as early as week 2. Adverse events (AEs) were reported by 65% of the risankizumab group and 88% of the placebo group. Serious AEs were reported in 4 patients receiving risankizumab, none of which were considered related to the study medication.¹

Phase 2 Trial
A phase 2 comparator trial demonstrated noninferiority at higher dosages of risankizumab in comparison to the IL-12/IL-23 inhibitor ustekinumab.² Among 166 participants with moderate to severe plaque psoriasis, PASI 90 at week 12 was met by 77% of participants receiving 90 or 180 mg of risankizumab compared to 40% receiving ustekinumab (P<.001). Onset of activity with risankizumab was faster and the duration of effect longer vs ustekinumab; by week 8, at least PASI 75 was achieved by approximately 80% of participants in the 90-mg and 180-mg risankizumab groups compared to 60% in the ustekinumab group; PASI score reductions generally were maintained for as long as 20 weeks after the final dose of risankizumab was administered.²

Phase 3 Trials
The 52-week UltIMMa-1 and UltIMMa-2 phase 3 trials compared subcutaneous risankizumab (150 mg) to ustekinumab (45 or 90 mg [weight-based dosing]) or placebo administered at weeks 0, 4, 16, 28, and 40 in approximately 1000 patients with moderate to severe plaque psoriasis.³ Patients initially assigned to placebo switched to risankizumab 150 mg at week 16. At week 16, PASI 90 was achieved by 75.3% of risankizumab-treated patients, 42.0% of ustekinumab-treated patients, and 4.9% of placebo-treated patients in UltIMMa-1, and by 74.8% of risankizumab-treated patients, 47.5% of ustekinumab-treated patients, and 2.0% of placebo-treated patients in UltIMMa-2 (P<.0001 vs placebo and ustekinumab for both studies). Achievement of a static physician’s global assessment (sPGA) score of 0 or 1 at week 16 similarly favored risankizumab, with 87.8%, 63.0%, and 7.8% of patients in UltIMMa-1 meeting an sPGA score of 0 or 1 in the risankizumab, ustekinumab, and placebo groups, respectively, and 83.7%, 61.6%, and 5.1% in UltIMMa-2 meeting an sPGA score of 0 or 1 in the risankizumab, ustekinumab, and placebo groups, respectively (P<.0001 vs placebo and ustekinumab for both studies). Among patients initially assigned to risankizumab, improvements in PASI and sPGA continued to increase until week 52, with 81.9% achieving PASI 90 at week 52 compared to 44.0% on ustekinumab in UltIMMa-1, and 80.6% achieving PASI 90 at week 52 compared to 50.5% on ustekinumab in UltIMMa-2 (P<.0001 vs ustekinumab for both studies). Treatment-emergent AE profiles were similar for risankizumab and ustekinumab in both studies, and there were no unexpected safety findings.³

Risankizumab received FDA approval for the treatment of moderate to severe plaque psoriasis in April 2019.

Bimekizumab

Bimekizumab (UCB4940), a humanized IgG1 monoclonal antibody, selectively neutralizes the biologic functions of IL-17A and IL-17F, the latter of which has only recently been implicated in contributing to the psoriatic immune cascade.⁴

First-in-Human Study
Thirty-nine participants with mild psoriasis demonstrated efficacy after single-dose intravenous bimekizumab, with maximal improvements in all measures of disease activity observed between weeks 8 and 12 in participants receiving 160 to 640 mg.⁵

Proof-of-Concept Phase 1b Study
A subsequent trial of 53 participants with psoriatic arthritis demonstrated sustained efficacy to week 20 with varying dosages of intravenous bimekizumab.⁶ At week 8, PASI 100 was met by 86.7% of participants receiving the top 3 dosages of bimekizumab compared to none of the placebo-treated participants. Treatment-emergent AEs, including neutropenia and elevation of liver transaminases, were mostly mild to moderate and resolved spontaneously. There were 3 severe AEs and 3 serious AEs, none of which were related to treatment.⁶

Importantly, bimekizumab was shown in this small study to have the potential to be highly effective at treating psoriatic arthritis. American College of Rheumatology ACR20, ACR50, and ACR70 response criteria were very high, with an ACR20 of 80% and an ACR50 of 40%.⁶ Further trials are necessary to gather more data and confirm these findings; however, these levels of response are higher than those of any other biologic on the market.

Phase 2b Dose-Ranging Study
In this trial, 250 participants with moderate to severe plaque psoriasis received either 64 mg, 160 mg with a 320-mg loading dose, 320 mg, or 480 mg of subcutaneous bimekizumab or placebo at weeks 0, 4, and 8.⁷ At week 12, PASI 90 was achieved by significantly more patients in all bimekizumab-treated groups compared to the placebo group (46.2%–79.1% vs 0%; P<.0001 for all dosages); PASI 100 also was achieved by significantly more bimekizumab-treated patients (27.9%–60.0% vs 0%; P<.0002). Improvement began as early as week 4, with clinically meaningful responses observed in all bimekizumab groups across all measures of disease activity. Treatment-emergent AEs occurred more frequently in bimekizumab-treated participants (61%) than in placebo-treated participants (36%); the most common AEs were nasopharyngitis and upper respiratory tract infection. Of note, fungal infections were reported by 4.3% of participants receiving bimekizumab; all cases were localized superficial infection, and none led to discontinuation. Three serious AEs were reported, none of which were considered related to the study treatment.⁷

Mirikizumab

Mirikizumab (LY3074828) is a humanized IgG4 monoclonal antibody that selectively binds and inhibits the p19 subunit of IL-23, with no action on IL-12.

Phase 1 Trial
Mirikizumab was shown to improve PASI scores in patients with plaque psoriasis.⁸

Phase 2 Trial
Subsequently, a trial of 205 participants with moderate to severe plaque psoriasis compared 3 dosing regimens of subcutaneous mirikizumab—30, 100, or 300 mg—at weeks 0 and 8 compared to placebo.⁹ Primary end point results at week 16 demonstrated PASI 90 response rates of 0%, 29% (P=.009), 59% (P<.001), and 67% (P<.001) in the placebo, 30-mg, 100-mg, and 300-mg mirikizumab groups, respectively. Complete clearance of psoriasis, measured by PASI 100 and sPGA 0, was achieved by 0%, 16%, 31%, and 31%, respectively (P=.039 for 30 mg vs placebo; P=.007 for the higher dosage groups vs placebo). Response rates for all efficacy outcomes were statistically significantly higher for all mirikizumab treatment groups compared to placebo and were highest in the 100-mg and 300-mg treatment groups. Frequencies of participants reporting AEs were similar across treatment and placebo groups.⁹

Oral Medications

Only a few small-molecule, orally bioavailable therapies are on the market for the treatment of psoriasis, some of which are associated with unfavorable side-effect profiles that preclude long-term therapy.

BMS-986165
The intracellular signaling enzyme tyrosine kinase 2 is involved in functional responses of IL-12 and IL-23. BMS-986165, a potent oral inhibitor of tyrosine kinase 2 with greater selectivity than other tyrosine kinase inhibitors, demonstrated efficacy in a phase 2 trial of 267 participants with moderate to severe plaque psoriasis receiving any of 5 dosing regimens—3 mg every other day, 3 mg daily, 3 mg twice daily, 6 mg twice daily, and 12 mg daily—compared to placebo.¹⁰ At week 12, the percentage of patients with a 75% or greater reduction in PASI was 7% with placebo, 9% with 3 mg every other day (P=.49 vs placebo), 39% with 3 mg daily (P<.001 vs placebo), 69% with 3 mg twice daily (P<.001 vs placebo), 67% with 6 mg twice daily (P<.001 vs placebo), and 75% with 12 mg once daily (P<.001 vs placebo). Adverse events occurred in 51% of patients in the placebo group and in 55% to 80% of BMS-986165–treated patients; the most common AEs were nasopharyngitis, headache, diarrhea, nausea, and upper respiratory tract infection.¹⁰

A phase 3 trial comparing BMS-986165 with placebo and apremilast is underway (ClinicalTrials.gov Identifier NCT03611751).

Piclidenoson (CF101)
A novel small molecule that binds the Gi protein–associated A₃ adenosine receptor piclidenoson induces an anti-inflammatory response via deregulation of the Wnt and nuclear factor κB signal transduction pathways, leading to downregulation of proinflammatory cytokines, including IL-17 and IL-23.¹¹

In a phase 2 dose-ranging study, 75 patients with moderate to severe plaque psoriasis received varying dosages—1, 2, or 4 mg—of oral piclidenoson or placebo twice daily for 12 weeks.¹² Progressive improvement in the mean change from baseline PASI score was observed in the 2-mg group, with statistically significant differences at weeks 8 and 12 compared to placebo (P=.047 and P=.031, respectively). At week 12, 35.3% of the 2-mg group achieved at least PASI 50. Improvements in PASI were less pronounced in the 4-mg group, and no therapeutic benefit was observed in the 1-mg group. Of the 20 AEs reported, 15 possibly were related to the study drug; 1 AE was severe.¹²

In a subsequent phase 2/3 trial, patients with moderate to severe plaque psoriasis received piclidenoson—1 or 2 mg—or placebo twice daily.¹³ At week 12, PASI 75 was achieved by 8.5% of patients in the 2-mg group and by 6.9% of patients receiving placebo (P=.621), thereby not meeting the primary study end point. Results at week 32 were more encouraging. In the 2-mg group, PASI mean percentage improvement was 57% (P<.002) compared to baseline, with linear improvements observed in PASI 50 (63.5%), PASI 75 (35.5%), PASI 90 (24.7%), and PASI 100 (10.6%).¹³

A phase 3 trial comparing piclidenoson 2 and 3 mg to apremilast and placebo is in progress (ClinicalTrials.gov Identifier NCT03168256).

Future Directions

Despite abundant options for treating moderate to severe plaque psoriasis and psoriatic arthritis, the pipeline remains rich. Novel treatments might have improved efficacy, favorable safety profiles, and different modes of administration compared to current medications. In addition to the novel therapeutics covered here, several treatments are in development further down the pipeline, with only phase 1 or 2 data available. Remtolumab (ABT-122), a tumor necrosis factor α– and IL-17A–targeted immunoglobulin, is unique among biologics, given its dual inhibition of tumor necrosis factor α and IL-17A.¹⁴ M1095 (ALX-0761), a novel trivalent bispecific nanobody, is another intriguing candidate. This dual inhibitor of IL-17A/F might exhibit a number of advantages over conventional antibodies, including better tissue penetration, reduced immunogenicity, and a longer half-life (ClinicalTrials.gov Identifier NCT03384745).^15,16

As always with drug development, numerous medications that were under development failed to meet primary end points in phase 2 trials and have therefore been discontinued, including namilumab and prurisol. It is reassuring that the pace of drug discovery and development in psoriasis does not seem to be slowing; to our patients’ benefit, we will have an array of treatments available to tailor therapy to the individual.

BANGKOK – Electroconvulsive therapy is a safe and efficacious albeit off-label adjunctive therapy in adults with super-refractory status epilepticus of the NORSE subtype, Madeline Tuong-Vi Nguyen, MD, declared at the International Epilepsy Congress.

Bruce Jancin/MDedge News

“These were highly refractory patients and ECT did contribute to their status termination,” she reported at the congress, sponsored by the International League Against Epilepsy.

Dr. Nguyen, a neurologist at Oregon Health and Science University, Portland, presented a single-center retrospective case series composed of four ECT-treated patients with NORSE (new onset refractory status epilepticus), three of whom experienced marked improvement in their seizure activity, including cessation of their status epilepticus, after completing a course of eight or nine ECT sessions.

A four-patient series may not seem to be compelling evidence, but it’s a significant contribution to the sparse literature regarding this off-label usage of ECT. Indeed, the biggest case series to date consists of eight patients treated at Indiana University, five of whom displayed neurotelemetry or clinical evidence of improvement within 24 hours after completing a full course of ECT (J ECT. 2018 Mar;34[1]:e5-e9. doi: 10.1097/YCT.0000000000000450).

And realistically, these small case series are as good as the supporting evidence is likely to get.

“It would be incredibly difficult to perform a randomized trial, and even a case-control study in such refractory patients would be quite difficult,” she observed.

Super-refractory status epilepticus is the term for seizures persisting despite 24 hours of adequate treatment with benzodiazepines, loading doses of antiepileptic drugs, and anesthetic agents for medically-induced coma, or for seizures that resume after withdrawal of general anesthesia. NORSE is defined as refractory status epilepticus without a history of seizures or a readily identifiable etiology. It is often associated with an autoimmune or paraneoplastic encephalitis. Outcomes are generally poor.

The four ECT-treated patients in the Oregon series were aged 27-48 years. Two had a prodromal viral illness, and a third had a vague prodrome but a negative infectious disease workup. Three patients were on four antiepileptic drugs at the time they began ECT, one was on seven. Two patients had generalized seizures, while the other two had both generalized and focal seizures. Two had normal brain MRI scans and the other two had abnormal MRIs. The patients had CSF white blood cell counts of 2, 5, 10, and 58 per mm³. All patients were on immunotherapy with intravenous corticosteroids, and three of the four were on additional immunomodulatory drugs.

ECT was started on a compassionate-use basis 16-49 days after hospital admission. These were patients who had run out of options, according to Dr. Nguyen.

Three of the four patients returned to consciousness after completing their course of ECT and withdrawal of their general anesthesia, with attenuation of their seizure activity and cessation of their super-refractory status epilepticus. Two of the three were discharged to a rehabilitation facility, including one who eventually could ambulate with slight assistance. Another patient died after discharge, while the fourth patient died during the initial hospital stay due to septic shock unrelated to the ECT.

At discharge, one patient had a modified Rankin Scale score (mRS) of 4, and two had a score of 5. At follow-up, two patients had a score of 3 and one was a 6.

Dr. Nguyen’s presentation met with undisguised audience skepticism.

“What is the theoretical basis to treat very severe epileptic seizures with another epileptic seizure? I mean, what made you do this?” one neurologist asked.

Dr. Nguyen replied that the mechanism of benefit isn’t clear. One possibility is enhanced inhibition of gamma-aminobutyric acid.

“When I describe ECT to the family, the way I think of it is as a hard reset. We tried burst suppression. This is an alternative approach,” she explained.

Another audience member said the treatment strategy smacks of homeopathy.

“These patients have a terrible disorder,” said session co-chair Gregory Krauss, MD. “Three of your four patients ultimately did not do very well.

“The question is, what are you really accomplishing in terms of the underlying encephalopathy and irritability that’s causing this? And are the seizures really a primary factor in their outcome? Is this treatment warranted to try to improve their overall outcome?” asked Dr. Krauss, professor of neurology at Johns Hopkins University, Baltimore.

Dr. Nguyen answered that she can’t say if the seizures are the cause or result of the encephalopathy.

“ECT was done well into the patients’ admission. Our difficulty is that while we were able to stop the seizures, unfortunately we weren’t able to go back in time and save the brain that was lost due to the convulsive and nonconvulsive activity,” she said. Dr. Nguyen added that she and her coinvestigators are interested in exploring the possibility that utilizing ECT earlier might abort the super-refractory status epilepticus sooner and thereby result in better outcomes.

Still, she noted, three of the four patients were able to leave the hospital, and the two survivors show improved cognitive abilities at 51 and 100 months of follow-up.

Dr. Nguyen reported having no financial conflicts.

bjancin@mdedge.com

SOURCE: Nguyen MTV et al. IEC 2019, Abstract P031.

BANGKOK – Electroconvulsive therapy is a safe and efficacious albeit off-label adjunctive therapy in adults with super-refractory status epilepticus of the NORSE subtype, Madeline Tuong-Vi Nguyen, MD, declared at the International Epilepsy Congress.

Bruce Jancin/MDedge News

“These were highly refractory patients and ECT did contribute to their status termination,” she reported at the congress, sponsored by the International League Against Epilepsy.

Dr. Nguyen, a neurologist at Oregon Health and Science University, Portland, presented a single-center retrospective case series composed of four ECT-treated patients with NORSE (new onset refractory status epilepticus), three of whom experienced marked improvement in their seizure activity, including cessation of their status epilepticus, after completing a course of eight or nine ECT sessions.

A four-patient series may not seem to be compelling evidence, but it’s a significant contribution to the sparse literature regarding this off-label usage of ECT. Indeed, the biggest case series to date consists of eight patients treated at Indiana University, five of whom displayed neurotelemetry or clinical evidence of improvement within 24 hours after completing a full course of ECT (J ECT. 2018 Mar;34[1]:e5-e9. doi: 10.1097/YCT.0000000000000450).

And realistically, these small case series are as good as the supporting evidence is likely to get.

“It would be incredibly difficult to perform a randomized trial, and even a case-control study in such refractory patients would be quite difficult,” she observed.

Super-refractory status epilepticus is the term for seizures persisting despite 24 hours of adequate treatment with benzodiazepines, loading doses of antiepileptic drugs, and anesthetic agents for medically-induced coma, or for seizures that resume after withdrawal of general anesthesia. NORSE is defined as refractory status epilepticus without a history of seizures or a readily identifiable etiology. It is often associated with an autoimmune or paraneoplastic encephalitis. Outcomes are generally poor.

The four ECT-treated patients in the Oregon series were aged 27-48 years. Two had a prodromal viral illness, and a third had a vague prodrome but a negative infectious disease workup. Three patients were on four antiepileptic drugs at the time they began ECT, one was on seven. Two patients had generalized seizures, while the other two had both generalized and focal seizures. Two had normal brain MRI scans and the other two had abnormal MRIs. The patients had CSF white blood cell counts of 2, 5, 10, and 58 per mm³. All patients were on immunotherapy with intravenous corticosteroids, and three of the four were on additional immunomodulatory drugs.

ECT was started on a compassionate-use basis 16-49 days after hospital admission. These were patients who had run out of options, according to Dr. Nguyen.

Three of the four patients returned to consciousness after completing their course of ECT and withdrawal of their general anesthesia, with attenuation of their seizure activity and cessation of their super-refractory status epilepticus. Two of the three were discharged to a rehabilitation facility, including one who eventually could ambulate with slight assistance. Another patient died after discharge, while the fourth patient died during the initial hospital stay due to septic shock unrelated to the ECT.

At discharge, one patient had a modified Rankin Scale score (mRS) of 4, and two had a score of 5. At follow-up, two patients had a score of 3 and one was a 6.

Dr. Nguyen’s presentation met with undisguised audience skepticism.

“What is the theoretical basis to treat very severe epileptic seizures with another epileptic seizure? I mean, what made you do this?” one neurologist asked.

Dr. Nguyen replied that the mechanism of benefit isn’t clear. One possibility is enhanced inhibition of gamma-aminobutyric acid.

“When I describe ECT to the family, the way I think of it is as a hard reset. We tried burst suppression. This is an alternative approach,” she explained.

Another audience member said the treatment strategy smacks of homeopathy.

“These patients have a terrible disorder,” said session co-chair Gregory Krauss, MD. “Three of your four patients ultimately did not do very well.

“The question is, what are you really accomplishing in terms of the underlying encephalopathy and irritability that’s causing this? And are the seizures really a primary factor in their outcome? Is this treatment warranted to try to improve their overall outcome?” asked Dr. Krauss, professor of neurology at Johns Hopkins University, Baltimore.

Dr. Nguyen answered that she can’t say if the seizures are the cause or result of the encephalopathy.

“ECT was done well into the patients’ admission. Our difficulty is that while we were able to stop the seizures, unfortunately we weren’t able to go back in time and save the brain that was lost due to the convulsive and nonconvulsive activity,” she said. Dr. Nguyen added that she and her coinvestigators are interested in exploring the possibility that utilizing ECT earlier might abort the super-refractory status epilepticus sooner and thereby result in better outcomes.

Still, she noted, three of the four patients were able to leave the hospital, and the two survivors show improved cognitive abilities at 51 and 100 months of follow-up.

Dr. Nguyen reported having no financial conflicts.

bjancin@mdedge.com

SOURCE: Nguyen MTV et al. IEC 2019, Abstract P031.

BANGKOK – Electroconvulsive therapy is a safe and efficacious albeit off-label adjunctive therapy in adults with super-refractory status epilepticus of the NORSE subtype, Madeline Tuong-Vi Nguyen, MD, declared at the International Epilepsy Congress.

Bruce Jancin/MDedge News

“These were highly refractory patients and ECT did contribute to their status termination,” she reported at the congress, sponsored by the International League Against Epilepsy.

Dr. Nguyen, a neurologist at Oregon Health and Science University, Portland, presented a single-center retrospective case series composed of four ECT-treated patients with NORSE (new onset refractory status epilepticus), three of whom experienced marked improvement in their seizure activity, including cessation of their status epilepticus, after completing a course of eight or nine ECT sessions.

A four-patient series may not seem to be compelling evidence, but it’s a significant contribution to the sparse literature regarding this off-label usage of ECT. Indeed, the biggest case series to date consists of eight patients treated at Indiana University, five of whom displayed neurotelemetry or clinical evidence of improvement within 24 hours after completing a full course of ECT (J ECT. 2018 Mar;34[1]:e5-e9. doi: 10.1097/YCT.0000000000000450).

And realistically, these small case series are as good as the supporting evidence is likely to get.

“It would be incredibly difficult to perform a randomized trial, and even a case-control study in such refractory patients would be quite difficult,” she observed.

Super-refractory status epilepticus is the term for seizures persisting despite 24 hours of adequate treatment with benzodiazepines, loading doses of antiepileptic drugs, and anesthetic agents for medically-induced coma, or for seizures that resume after withdrawal of general anesthesia. NORSE is defined as refractory status epilepticus without a history of seizures or a readily identifiable etiology. It is often associated with an autoimmune or paraneoplastic encephalitis. Outcomes are generally poor.

The four ECT-treated patients in the Oregon series were aged 27-48 years. Two had a prodromal viral illness, and a third had a vague prodrome but a negative infectious disease workup. Three patients were on four antiepileptic drugs at the time they began ECT, one was on seven. Two patients had generalized seizures, while the other two had both generalized and focal seizures. Two had normal brain MRI scans and the other two had abnormal MRIs. The patients had CSF white blood cell counts of 2, 5, 10, and 58 per mm³. All patients were on immunotherapy with intravenous corticosteroids, and three of the four were on additional immunomodulatory drugs.

ECT was started on a compassionate-use basis 16-49 days after hospital admission. These were patients who had run out of options, according to Dr. Nguyen.

Three of the four patients returned to consciousness after completing their course of ECT and withdrawal of their general anesthesia, with attenuation of their seizure activity and cessation of their super-refractory status epilepticus. Two of the three were discharged to a rehabilitation facility, including one who eventually could ambulate with slight assistance. Another patient died after discharge, while the fourth patient died during the initial hospital stay due to septic shock unrelated to the ECT.

At discharge, one patient had a modified Rankin Scale score (mRS) of 4, and two had a score of 5. At follow-up, two patients had a score of 3 and one was a 6.

Dr. Nguyen’s presentation met with undisguised audience skepticism.

“What is the theoretical basis to treat very severe epileptic seizures with another epileptic seizure? I mean, what made you do this?” one neurologist asked.

Dr. Nguyen replied that the mechanism of benefit isn’t clear. One possibility is enhanced inhibition of gamma-aminobutyric acid.

“When I describe ECT to the family, the way I think of it is as a hard reset. We tried burst suppression. This is an alternative approach,” she explained.

Another audience member said the treatment strategy smacks of homeopathy.

“These patients have a terrible disorder,” said session co-chair Gregory Krauss, MD. “Three of your four patients ultimately did not do very well.

“The question is, what are you really accomplishing in terms of the underlying encephalopathy and irritability that’s causing this? And are the seizures really a primary factor in their outcome? Is this treatment warranted to try to improve their overall outcome?” asked Dr. Krauss, professor of neurology at Johns Hopkins University, Baltimore.

Dr. Nguyen answered that she can’t say if the seizures are the cause or result of the encephalopathy.

“ECT was done well into the patients’ admission. Our difficulty is that while we were able to stop the seizures, unfortunately we weren’t able to go back in time and save the brain that was lost due to the convulsive and nonconvulsive activity,” she said. Dr. Nguyen added that she and her coinvestigators are interested in exploring the possibility that utilizing ECT earlier might abort the super-refractory status epilepticus sooner and thereby result in better outcomes.

Still, she noted, three of the four patients were able to leave the hospital, and the two survivors show improved cognitive abilities at 51 and 100 months of follow-up.

Dr. Nguyen reported having no financial conflicts.

bjancin@mdedge.com

SOURCE: Nguyen MTV et al. IEC 2019, Abstract P031.

LJUBLJANA, SLOVENIA – A new age-adjusted quick Sequential Organ Failure Assessment (qSOFA) score designed for use in children presenting to the ED with fever showed good predictive value for admission to critical care within the next 48 hours, Aakash Khanijau, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.

Bruce Jancin/MDedge News

“In the needle-in-a-haystack scenario that’s seen in pediatric emergency departments, our novel, age-adjusted qSOFA score could potentially improve the rapid identification and treatment of children with suspected sepsis presenting to the ED,” said Dr. Khanijau of the University of Liverpool (England).

He presented an exceptionally large retrospective validation study of the score’s performance in 12,393 children (median age, 2.5 years) who presented to EDs with fever, of whom 1,521 were admitted for suspected sepsis. Of the hospitalized children, 145 were admitted to critical care within the first 48 hours.

The pediatric qSOFA score had 72% sensitivity and 85% specificity for critical care admission within 48 hours, with a positive predictive value of 5.4% and, more importantly, a whopping negative predictive value of 99.6%.

“That very high negative predictive value underlines the powerful discriminatory nature of our tool in the emergency department setting,” Dr. Khanijau observed, adding that the score’s area under the receiver operating characteristic curve was 0.81, which is considered a good predictive value.

The impetus for developing an age-adjusted pediatric qSOFA score stems from the fact that the original qSOFA score was designed for rapid assessment of adults with suspected sepsis and isn’t applicable in children. Other existing scores, including SIRS (the Systemic Inflammatory Response Syndrome criteria), the full SOFA, and PELOD-2 (the Pediatric Logistic Organ Dysfunction score), take longer to determine than the adapted qSOFA in a setting where speed is of the essence, he explained.

The original qSOFA components are altered mentation, systolic blood pressure, and respiratory rate. The novel score developed by Dr. Khanijau and coworkers swaps out systolic BP in favor of capillary refill time and age-adjusted heart rate using the thresholds previously established in a landmark study from the Children’s Hospital of Philadelphia (Pediatrics. 2013 Apr;131[4]:e1150-7.)

“Our reasoning here is that arterial hypertension is known to be a much later sign of circulatory compromise in children and may provide less discriminatory value than signs such as delayed capillary refill time and tachycardia early in presentation in the emergency department,” according to Dr. Khanijau.


The novel scoring system features four criteria. One point each is given for a capillary refill time of 3 seconds or longer; anything less than “Alert” on the Alert, Responds to Voice, Respond to Pain, and Unresponsive scale; a heart rate above the 99th percentile on the age-adjusted curves; and a respiratory rate above the age-adjusted 99th percentile. Thus, scores can range from 0 to 4. In the validation study, a score of 2 or more spelled a 890% increased likelihood of being admitted to a critical care setting within 48 hours. It was also associated with a 100-fold increased likelihood of death during the hospitalization, which occurred in 10 children.

Asked how the new predictive score could change clinical management, Dr. Khanijau replied, “I think the key thing it does here is it identifies the children at risk of requiring critical care and should therefore motivate us in the children achieving that threshold to promptly investigate thoroughly for suspected sepsis using the more comprehensive tools, like the full SOFA.”

He reported having no financial conflicts of interest regarding his study.

bjancin@mdedge.com

SOURCE: Khanijau A et al. ESPID 2019, Abstract.

LJUBLJANA, SLOVENIA – A new age-adjusted quick Sequential Organ Failure Assessment (qSOFA) score designed for use in children presenting to the ED with fever showed good predictive value for admission to critical care within the next 48 hours, Aakash Khanijau, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.

Bruce Jancin/MDedge News

“In the needle-in-a-haystack scenario that’s seen in pediatric emergency departments, our novel, age-adjusted qSOFA score could potentially improve the rapid identification and treatment of children with suspected sepsis presenting to the ED,” said Dr. Khanijau of the University of Liverpool (England).

He presented an exceptionally large retrospective validation study of the score’s performance in 12,393 children (median age, 2.5 years) who presented to EDs with fever, of whom 1,521 were admitted for suspected sepsis. Of the hospitalized children, 145 were admitted to critical care within the first 48 hours.

The pediatric qSOFA score had 72% sensitivity and 85% specificity for critical care admission within 48 hours, with a positive predictive value of 5.4% and, more importantly, a whopping negative predictive value of 99.6%.

“That very high negative predictive value underlines the powerful discriminatory nature of our tool in the emergency department setting,” Dr. Khanijau observed, adding that the score’s area under the receiver operating characteristic curve was 0.81, which is considered a good predictive value.

The impetus for developing an age-adjusted pediatric qSOFA score stems from the fact that the original qSOFA score was designed for rapid assessment of adults with suspected sepsis and isn’t applicable in children. Other existing scores, including SIRS (the Systemic Inflammatory Response Syndrome criteria), the full SOFA, and PELOD-2 (the Pediatric Logistic Organ Dysfunction score), take longer to determine than the adapted qSOFA in a setting where speed is of the essence, he explained.

The original qSOFA components are altered mentation, systolic blood pressure, and respiratory rate. The novel score developed by Dr. Khanijau and coworkers swaps out systolic BP in favor of capillary refill time and age-adjusted heart rate using the thresholds previously established in a landmark study from the Children’s Hospital of Philadelphia (Pediatrics. 2013 Apr;131[4]:e1150-7.)

“Our reasoning here is that arterial hypertension is known to be a much later sign of circulatory compromise in children and may provide less discriminatory value than signs such as delayed capillary refill time and tachycardia early in presentation in the emergency department,” according to Dr. Khanijau.


The novel scoring system features four criteria. One point each is given for a capillary refill time of 3 seconds or longer; anything less than “Alert” on the Alert, Responds to Voice, Respond to Pain, and Unresponsive scale; a heart rate above the 99th percentile on the age-adjusted curves; and a respiratory rate above the age-adjusted 99th percentile. Thus, scores can range from 0 to 4. In the validation study, a score of 2 or more spelled a 890% increased likelihood of being admitted to a critical care setting within 48 hours. It was also associated with a 100-fold increased likelihood of death during the hospitalization, which occurred in 10 children.

Asked how the new predictive score could change clinical management, Dr. Khanijau replied, “I think the key thing it does here is it identifies the children at risk of requiring critical care and should therefore motivate us in the children achieving that threshold to promptly investigate thoroughly for suspected sepsis using the more comprehensive tools, like the full SOFA.”

He reported having no financial conflicts of interest regarding his study.

bjancin@mdedge.com

SOURCE: Khanijau A et al. ESPID 2019, Abstract.

LJUBLJANA, SLOVENIA – A new age-adjusted quick Sequential Organ Failure Assessment (qSOFA) score designed for use in children presenting to the ED with fever showed good predictive value for admission to critical care within the next 48 hours, Aakash Khanijau, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.

Bruce Jancin/MDedge News

“In the needle-in-a-haystack scenario that’s seen in pediatric emergency departments, our novel, age-adjusted qSOFA score could potentially improve the rapid identification and treatment of children with suspected sepsis presenting to the ED,” said Dr. Khanijau of the University of Liverpool (England).

He presented an exceptionally large retrospective validation study of the score’s performance in 12,393 children (median age, 2.5 years) who presented to EDs with fever, of whom 1,521 were admitted for suspected sepsis. Of the hospitalized children, 145 were admitted to critical care within the first 48 hours.

The pediatric qSOFA score had 72% sensitivity and 85% specificity for critical care admission within 48 hours, with a positive predictive value of 5.4% and, more importantly, a whopping negative predictive value of 99.6%.

“That very high negative predictive value underlines the powerful discriminatory nature of our tool in the emergency department setting,” Dr. Khanijau observed, adding that the score’s area under the receiver operating characteristic curve was 0.81, which is considered a good predictive value.

The impetus for developing an age-adjusted pediatric qSOFA score stems from the fact that the original qSOFA score was designed for rapid assessment of adults with suspected sepsis and isn’t applicable in children. Other existing scores, including SIRS (the Systemic Inflammatory Response Syndrome criteria), the full SOFA, and PELOD-2 (the Pediatric Logistic Organ Dysfunction score), take longer to determine than the adapted qSOFA in a setting where speed is of the essence, he explained.

The original qSOFA components are altered mentation, systolic blood pressure, and respiratory rate. The novel score developed by Dr. Khanijau and coworkers swaps out systolic BP in favor of capillary refill time and age-adjusted heart rate using the thresholds previously established in a landmark study from the Children’s Hospital of Philadelphia (Pediatrics. 2013 Apr;131[4]:e1150-7.)

“Our reasoning here is that arterial hypertension is known to be a much later sign of circulatory compromise in children and may provide less discriminatory value than signs such as delayed capillary refill time and tachycardia early in presentation in the emergency department,” according to Dr. Khanijau.


The novel scoring system features four criteria. One point each is given for a capillary refill time of 3 seconds or longer; anything less than “Alert” on the Alert, Responds to Voice, Respond to Pain, and Unresponsive scale; a heart rate above the 99th percentile on the age-adjusted curves; and a respiratory rate above the age-adjusted 99th percentile. Thus, scores can range from 0 to 4. In the validation study, a score of 2 or more spelled a 890% increased likelihood of being admitted to a critical care setting within 48 hours. It was also associated with a 100-fold increased likelihood of death during the hospitalization, which occurred in 10 children.

Asked how the new predictive score could change clinical management, Dr. Khanijau replied, “I think the key thing it does here is it identifies the children at risk of requiring critical care and should therefore motivate us in the children achieving that threshold to promptly investigate thoroughly for suspected sepsis using the more comprehensive tools, like the full SOFA.”

He reported having no financial conflicts of interest regarding his study.

bjancin@mdedge.com

SOURCE: Khanijau A et al. ESPID 2019, Abstract.

SEATTLE – Procalcitonin, a marker of bacterial infection, rises and peaks sooner than C-reactive protein (CRP), and is especially useful to help rule out invasive bacterial infections in young infants and pediatric community acquired pneumonia due to typical bacteria, according to a presentation at the 2019 Pediatric Hospital Medicine Conference.

M. Alexander Otto/MDedge News

It’s “excellent for identifying low risk patients” and has the potential to decrease lumbar punctures and antibiotic exposure, but “the specificity isn’t great,” so there’s the potential for false positives, said Russell McCulloh, MD, a pediatric infectious disease specialist at the University of Nebraska Medical Center, Omaha.

There was great interest in procalcitonin at the meeting; the presentation room was packed, with a line out the door. It’s used mostly in Europe at this point. Testing is available in many U.S. hospitals, but a large majority of audience members, when polled, said they don’t currently use it in clinical practice, and that it’s not a part of diagnostic algorithms at their institutions.

Levels of procalcitonin, a calcitonin precursor normally produced by the thyroid, are low or undetectable in healthy people, but inflammation, be it from infectious or noninfectious causes, triggers production by parenchymal cells throughout the body.

Levels began to rise as early as 2.5 hours after healthy subjects in one study were injected with bacterial endotoxins, and peaked as early as 6 hours; CRP, in contrast, started to rise after 12 hours, and peaked at 30 hours. Procalcitonin levels also seem to correlate with bacterial load and severity of infection, said Nivedita Srinivas, MD, a pediatric infectious disease specialist at Stanford (Calif.) University (J Pediatr Intensive Care. 2016 Dec;5[4]:162-71).

Due to time, the presenters focused their talk on community acquired pneumonia (CAP) and invasive bacterial infections (IBI) in young infants, meaning essentially bacteremia and meningitis.

Different studies use different cutoffs, but a procalcitonin below, for instance, 0.5 ng/mL is “certainly more sensitive [for IBI] than any single biomarker we currently use,” including CRP, white blood cells, and absolute neutrophil count (ANC). “If it’s negative, you’re really confident it’s negative,” but “a positive test does not necessarily indicate the presence of IBI,” Dr. McCulloh said (Pediatrics. 2012 Nov;130[5]:815-22).

“Procalcitonin works really well as part of a validated step-wise rule” that includes, for instance, CRP and ANC; “I think that’s where its utility is. On its own, it is not a substitute for you examining the patient and doing your basic risk stratification, but it may enhance your decision making incrementally above what we currently have,” he said.

Meanwhile, in a study of 532 children a median age of 2.4 years with radiographically confirmed CAP, procalcitonin levels were a median of 6.1 ng/mL in children whose pneumonia was caused by Streptococcus pneumoniae or other typical bacteria, and no child infected with typical bacteria had a level under 0.1 ng/mL. Below that level, “you can be very sure you do not have typical bacteria pneumonia,” said Marie Wang, MD, also a pediatric infectious disease specialist at Stanford (J Pediatric Infect Dis Soc. 2018 Feb 19;7[1]:46-53).

As procalcitonin levels went up, the likelihood of having bacterial pneumonia increased; at 2 ng/mL, 26% of subjects were infected with typical bacteria, “but even in that group, 58% still had viral infection, so you are still detecting a lot of viral” disease, she said.

Prolcalcitonin-guided therapy – antibiotics until patients fall below a level of 0.25 ng/ml, for instance – has also been associated with decreased antibiotic exposure (Respir Med. 2011 Dec;105[12]:1939-45).

The speakers had no disclosures. The meeting was sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.

aotto@mdedge.com

SEATTLE – Procalcitonin, a marker of bacterial infection, rises and peaks sooner than C-reactive protein (CRP), and is especially useful to help rule out invasive bacterial infections in young infants and pediatric community acquired pneumonia due to typical bacteria, according to a presentation at the 2019 Pediatric Hospital Medicine Conference.

M. Alexander Otto/MDedge News

It’s “excellent for identifying low risk patients” and has the potential to decrease lumbar punctures and antibiotic exposure, but “the specificity isn’t great,” so there’s the potential for false positives, said Russell McCulloh, MD, a pediatric infectious disease specialist at the University of Nebraska Medical Center, Omaha.

There was great interest in procalcitonin at the meeting; the presentation room was packed, with a line out the door. It’s used mostly in Europe at this point. Testing is available in many U.S. hospitals, but a large majority of audience members, when polled, said they don’t currently use it in clinical practice, and that it’s not a part of diagnostic algorithms at their institutions.

Levels of procalcitonin, a calcitonin precursor normally produced by the thyroid, are low or undetectable in healthy people, but inflammation, be it from infectious or noninfectious causes, triggers production by parenchymal cells throughout the body.

Levels began to rise as early as 2.5 hours after healthy subjects in one study were injected with bacterial endotoxins, and peaked as early as 6 hours; CRP, in contrast, started to rise after 12 hours, and peaked at 30 hours. Procalcitonin levels also seem to correlate with bacterial load and severity of infection, said Nivedita Srinivas, MD, a pediatric infectious disease specialist at Stanford (Calif.) University (J Pediatr Intensive Care. 2016 Dec;5[4]:162-71).

Due to time, the presenters focused their talk on community acquired pneumonia (CAP) and invasive bacterial infections (IBI) in young infants, meaning essentially bacteremia and meningitis.

Different studies use different cutoffs, but a procalcitonin below, for instance, 0.5 ng/mL is “certainly more sensitive [for IBI] than any single biomarker we currently use,” including CRP, white blood cells, and absolute neutrophil count (ANC). “If it’s negative, you’re really confident it’s negative,” but “a positive test does not necessarily indicate the presence of IBI,” Dr. McCulloh said (Pediatrics. 2012 Nov;130[5]:815-22).

“Procalcitonin works really well as part of a validated step-wise rule” that includes, for instance, CRP and ANC; “I think that’s where its utility is. On its own, it is not a substitute for you examining the patient and doing your basic risk stratification, but it may enhance your decision making incrementally above what we currently have,” he said.

Meanwhile, in a study of 532 children a median age of 2.4 years with radiographically confirmed CAP, procalcitonin levels were a median of 6.1 ng/mL in children whose pneumonia was caused by Streptococcus pneumoniae or other typical bacteria, and no child infected with typical bacteria had a level under 0.1 ng/mL. Below that level, “you can be very sure you do not have typical bacteria pneumonia,” said Marie Wang, MD, also a pediatric infectious disease specialist at Stanford (J Pediatric Infect Dis Soc. 2018 Feb 19;7[1]:46-53).

As procalcitonin levels went up, the likelihood of having bacterial pneumonia increased; at 2 ng/mL, 26% of subjects were infected with typical bacteria, “but even in that group, 58% still had viral infection, so you are still detecting a lot of viral” disease, she said.

Prolcalcitonin-guided therapy – antibiotics until patients fall below a level of 0.25 ng/ml, for instance – has also been associated with decreased antibiotic exposure (Respir Med. 2011 Dec;105[12]:1939-45).

The speakers had no disclosures. The meeting was sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.

aotto@mdedge.com

SEATTLE – Procalcitonin, a marker of bacterial infection, rises and peaks sooner than C-reactive protein (CRP), and is especially useful to help rule out invasive bacterial infections in young infants and pediatric community acquired pneumonia due to typical bacteria, according to a presentation at the 2019 Pediatric Hospital Medicine Conference.

M. Alexander Otto/MDedge News

It’s “excellent for identifying low risk patients” and has the potential to decrease lumbar punctures and antibiotic exposure, but “the specificity isn’t great,” so there’s the potential for false positives, said Russell McCulloh, MD, a pediatric infectious disease specialist at the University of Nebraska Medical Center, Omaha.

There was great interest in procalcitonin at the meeting; the presentation room was packed, with a line out the door. It’s used mostly in Europe at this point. Testing is available in many U.S. hospitals, but a large majority of audience members, when polled, said they don’t currently use it in clinical practice, and that it’s not a part of diagnostic algorithms at their institutions.

Levels of procalcitonin, a calcitonin precursor normally produced by the thyroid, are low or undetectable in healthy people, but inflammation, be it from infectious or noninfectious causes, triggers production by parenchymal cells throughout the body.

Levels began to rise as early as 2.5 hours after healthy subjects in one study were injected with bacterial endotoxins, and peaked as early as 6 hours; CRP, in contrast, started to rise after 12 hours, and peaked at 30 hours. Procalcitonin levels also seem to correlate with bacterial load and severity of infection, said Nivedita Srinivas, MD, a pediatric infectious disease specialist at Stanford (Calif.) University (J Pediatr Intensive Care. 2016 Dec;5[4]:162-71).

Due to time, the presenters focused their talk on community acquired pneumonia (CAP) and invasive bacterial infections (IBI) in young infants, meaning essentially bacteremia and meningitis.

Different studies use different cutoffs, but a procalcitonin below, for instance, 0.5 ng/mL is “certainly more sensitive [for IBI] than any single biomarker we currently use,” including CRP, white blood cells, and absolute neutrophil count (ANC). “If it’s negative, you’re really confident it’s negative,” but “a positive test does not necessarily indicate the presence of IBI,” Dr. McCulloh said (Pediatrics. 2012 Nov;130[5]:815-22).

“Procalcitonin works really well as part of a validated step-wise rule” that includes, for instance, CRP and ANC; “I think that’s where its utility is. On its own, it is not a substitute for you examining the patient and doing your basic risk stratification, but it may enhance your decision making incrementally above what we currently have,” he said.

Meanwhile, in a study of 532 children a median age of 2.4 years with radiographically confirmed CAP, procalcitonin levels were a median of 6.1 ng/mL in children whose pneumonia was caused by Streptococcus pneumoniae or other typical bacteria, and no child infected with typical bacteria had a level under 0.1 ng/mL. Below that level, “you can be very sure you do not have typical bacteria pneumonia,” said Marie Wang, MD, also a pediatric infectious disease specialist at Stanford (J Pediatric Infect Dis Soc. 2018 Feb 19;7[1]:46-53).

As procalcitonin levels went up, the likelihood of having bacterial pneumonia increased; at 2 ng/mL, 26% of subjects were infected with typical bacteria, “but even in that group, 58% still had viral infection, so you are still detecting a lot of viral” disease, she said.

Prolcalcitonin-guided therapy – antibiotics until patients fall below a level of 0.25 ng/ml, for instance – has also been associated with decreased antibiotic exposure (Respir Med. 2011 Dec;105[12]:1939-45).

The speakers had no disclosures. The meeting was sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.

aotto@mdedge.com

Next-generation sequencing (NGS) of tumor samples seldom changes patient management, and even when it does prompt off-label therapy, outcomes are usually poor, one center’s experience suggests.

“NGS has allowed more personalized medicine in oncology. It is well established that treatment of certain actionable mutations improves outcomes in many cancer types,” wrote Gregory J. Kubicek, MD, of MD Anderson Cancer Center at Cooper in Camden, N.J., and colleagues.

However, evidence of its utility to date has been mixed, and key trials – NCI-MPACT (National Cancer Institute Molecular Profiling–Based Assignment of Cancer Therapy) and NCI-MATCH (National Cancer Institute Molecular Analysis for Therapy Choice)—are still ongoing. “In the interim, the oncologist must make clinical decisions with limited empiric data but an exponentially increasing number of options,” they noted.

The investigators studied outcomes of the first 305 consecutive patients at their institution for whom tissue samples were sent to FoundationOne for NGS testing between March 2014 and April 2017. On average, the patients had received two lines of therapy, and the test was ordered 1.1 years from diagnosis of metastatic disease.

Study findings reported in the Journal of Oncology Practice showed that 116 of the tests were unusable because they did not yield a report (most often as a result of insufficient tissue) or yielded a report that could not be acted on owing to follow-up issues (patient loss of contact, transfer to hospice, or death).

Of the 189 potentially usable tests, 40.2% and 66.7% showed an aberration targetable by on-label therapies and off-label therapies, respectively. And fully 89.9% had actionable aberrations via all potential avenues, including clinical trials.

However, only 11.1% of the 189 potentially usable tests (and merely 8.3% of 253 completed tests and 6.9% of all 305 ordered tests) yielded a change in management, including use of on-label or off-label therapies, enrollment in clinical trials, or discontinuation of medications with a predicted poor response.

Of the six patients who were started on an off-label therapy, the median duration of treatment was 46 days, with half of these patients each stopping therapy because of death or because of progression.

“A vast majority of NGS assay results were not actively incorporated into clinical decision making, despite many assays indicating potential on- or off-label therapies,” Dr. Kubicek and coinvestigators wrote. “Given the escalating cost of medical care and scrutiny thereof, it is important to analyze whether tests are changing management and order tests appropriately.”

Several factors may explain the observed low use of NGS test results, they noted. For example, many patients were heavily pretreated, so some NGS-detected mutations would have already been known. Also, clinicians at the center had little experience with NGS testing.

“A variety of factors make precisely defining the utility of these assays in clinical decision making difficult, but we can certainly conclude that we have observed substantial costs with few discernible benefits,” the investigators stated. “It is possible that there will be greater use in the future as familiarity with these assays increases. Similarly, although we found poor outcomes with NGS-directed off-label therapies, we will eagerly await the results of NCI-MPACT and NCI-MATCH.”

Dr. Kubicek disclosed no relevant conflicts of interest. The study did not receive any specific funding.

SOURCE: Davis W et al. J Oncol Pract. 2019 Aug 2. doi: 10.1200/JOP.19.00269.

Next-generation sequencing (NGS) of tumor samples seldom changes patient management, and even when it does prompt off-label therapy, outcomes are usually poor, one center’s experience suggests.

“NGS has allowed more personalized medicine in oncology. It is well established that treatment of certain actionable mutations improves outcomes in many cancer types,” wrote Gregory J. Kubicek, MD, of MD Anderson Cancer Center at Cooper in Camden, N.J., and colleagues.

However, evidence of its utility to date has been mixed, and key trials – NCI-MPACT (National Cancer Institute Molecular Profiling–Based Assignment of Cancer Therapy) and NCI-MATCH (National Cancer Institute Molecular Analysis for Therapy Choice)—are still ongoing. “In the interim, the oncologist must make clinical decisions with limited empiric data but an exponentially increasing number of options,” they noted.

The investigators studied outcomes of the first 305 consecutive patients at their institution for whom tissue samples were sent to FoundationOne for NGS testing between March 2014 and April 2017. On average, the patients had received two lines of therapy, and the test was ordered 1.1 years from diagnosis of metastatic disease.

Study findings reported in the Journal of Oncology Practice showed that 116 of the tests were unusable because they did not yield a report (most often as a result of insufficient tissue) or yielded a report that could not be acted on owing to follow-up issues (patient loss of contact, transfer to hospice, or death).

Of the 189 potentially usable tests, 40.2% and 66.7% showed an aberration targetable by on-label therapies and off-label therapies, respectively. And fully 89.9% had actionable aberrations via all potential avenues, including clinical trials.

However, only 11.1% of the 189 potentially usable tests (and merely 8.3% of 253 completed tests and 6.9% of all 305 ordered tests) yielded a change in management, including use of on-label or off-label therapies, enrollment in clinical trials, or discontinuation of medications with a predicted poor response.

Of the six patients who were started on an off-label therapy, the median duration of treatment was 46 days, with half of these patients each stopping therapy because of death or because of progression.

“A vast majority of NGS assay results were not actively incorporated into clinical decision making, despite many assays indicating potential on- or off-label therapies,” Dr. Kubicek and coinvestigators wrote. “Given the escalating cost of medical care and scrutiny thereof, it is important to analyze whether tests are changing management and order tests appropriately.”

Several factors may explain the observed low use of NGS test results, they noted. For example, many patients were heavily pretreated, so some NGS-detected mutations would have already been known. Also, clinicians at the center had little experience with NGS testing.

“A variety of factors make precisely defining the utility of these assays in clinical decision making difficult, but we can certainly conclude that we have observed substantial costs with few discernible benefits,” the investigators stated. “It is possible that there will be greater use in the future as familiarity with these assays increases. Similarly, although we found poor outcomes with NGS-directed off-label therapies, we will eagerly await the results of NCI-MPACT and NCI-MATCH.”

Dr. Kubicek disclosed no relevant conflicts of interest. The study did not receive any specific funding.

SOURCE: Davis W et al. J Oncol Pract. 2019 Aug 2. doi: 10.1200/JOP.19.00269.

Next-generation sequencing (NGS) of tumor samples seldom changes patient management, and even when it does prompt off-label therapy, outcomes are usually poor, one center’s experience suggests.

“NGS has allowed more personalized medicine in oncology. It is well established that treatment of certain actionable mutations improves outcomes in many cancer types,” wrote Gregory J. Kubicek, MD, of MD Anderson Cancer Center at Cooper in Camden, N.J., and colleagues.

However, evidence of its utility to date has been mixed, and key trials – NCI-MPACT (National Cancer Institute Molecular Profiling–Based Assignment of Cancer Therapy) and NCI-MATCH (National Cancer Institute Molecular Analysis for Therapy Choice)—are still ongoing. “In the interim, the oncologist must make clinical decisions with limited empiric data but an exponentially increasing number of options,” they noted.

The investigators studied outcomes of the first 305 consecutive patients at their institution for whom tissue samples were sent to FoundationOne for NGS testing between March 2014 and April 2017. On average, the patients had received two lines of therapy, and the test was ordered 1.1 years from diagnosis of metastatic disease.

Study findings reported in the Journal of Oncology Practice showed that 116 of the tests were unusable because they did not yield a report (most often as a result of insufficient tissue) or yielded a report that could not be acted on owing to follow-up issues (patient loss of contact, transfer to hospice, or death).

Of the 189 potentially usable tests, 40.2% and 66.7% showed an aberration targetable by on-label therapies and off-label therapies, respectively. And fully 89.9% had actionable aberrations via all potential avenues, including clinical trials.

However, only 11.1% of the 189 potentially usable tests (and merely 8.3% of 253 completed tests and 6.9% of all 305 ordered tests) yielded a change in management, including use of on-label or off-label therapies, enrollment in clinical trials, or discontinuation of medications with a predicted poor response.

Of the six patients who were started on an off-label therapy, the median duration of treatment was 46 days, with half of these patients each stopping therapy because of death or because of progression.

“A vast majority of NGS assay results were not actively incorporated into clinical decision making, despite many assays indicating potential on- or off-label therapies,” Dr. Kubicek and coinvestigators wrote. “Given the escalating cost of medical care and scrutiny thereof, it is important to analyze whether tests are changing management and order tests appropriately.”

Several factors may explain the observed low use of NGS test results, they noted. For example, many patients were heavily pretreated, so some NGS-detected mutations would have already been known. Also, clinicians at the center had little experience with NGS testing.

“A variety of factors make precisely defining the utility of these assays in clinical decision making difficult, but we can certainly conclude that we have observed substantial costs with few discernible benefits,” the investigators stated. “It is possible that there will be greater use in the future as familiarity with these assays increases. Similarly, although we found poor outcomes with NGS-directed off-label therapies, we will eagerly await the results of NCI-MPACT and NCI-MATCH.”

Dr. Kubicek disclosed no relevant conflicts of interest. The study did not receive any specific funding.

SOURCE: Davis W et al. J Oncol Pract. 2019 Aug 2. doi: 10.1200/JOP.19.00269.

Andrew R. Pachner, MD is the Murray B. Bornstein professor of neurology at Geisel School of Medicine at Dartmouth and director of the Multiple Sclerosis Center at Dartmouth-Hitchcock Medical Center. We spoke to Dr. Pachner about his research into the molecular processes of multiple sclerosis (MS) and the potential impact on patient management.

What do we know about the molecular processes behind relapsing-remitting and progressive MS?

DR. PACHNER:  The progress--in terms of molecules--has not been rapid in the field of MS. The only molecular biomarker we use in practice is oligoclonal bands or other measures of immunoglobulin production in the nervous system, and that biomarker was described in 1942. So, it has been a long time since we have seen a relevant molecule that we can use clinically.

But there has been a lot of progress in the general field of neuroinflammation. MS is one of a large number of diseases that results in neuroinflammation and demyelination.

One thing we have learned over time is that there are many different subtypes of MS. They probably have some shared molecular processes, but they also are likely to have divergent molecular processes.

Over the past 5 to 10 years, researchers have been interested in trying to dissect some of the molecular aspects of MS to identify biomarkers that can, in turn, differentiate subtypes of MS. This will help to identify different ways of treating MS that are optimal for individual patients. It is clear that each patient is quite different and unlikely to be standardized in the way they respond to treatment.

The degree to which relapsing-remitting and progressive MS are differentiated on the molecular level is dependent on how much influence there is of the immune system in the periphery. When MS first starts in a patient, the brain has either no or a very primitive immune system, and then over time it changes, and it becomes much more immune-oriented and populated by immune cells and molecules. So, there’s a trend over time of the central nervous system becoming increasingly populated by immune cells and able to make immune molecules.

What has your recent research on murine models representing these disease patterns shown?

DR. PACHNER:  Even though in humans there is a continuum from relapsing remitting to progressive, it is not like they are completely separate. Frequently in the middle of relapsing-remitting disease there is some progression over time.

In mouse models, we like things to be very clear and separate. We try to make things as simple as possible because of the complexity of the nervous and immune systems.

The simple model for the relapsing-remitting disease is experimental autoimmune encephalomyelitis (EAE), the most commonly studied model of neuroinflammation.

For the progressive form of MS, we use the Theiler’s virus model, which is a type of virus called the picornavirus that is injected into the brain of mice resulting in a slowly progressive, chronic viral infection that looks very much like progressive MS.

In EAE, the disease is induced by presenting an antigen to the peripheral immune system, allowing cells from the peripheral immune system to enter into the central nervous system. It is a manifestation of inflammation and the immune response is in the periphery. In the Theiler’s model, it is a localized process within the central nervous system because the virus is injected directly into the brain.

We found that in EAE the pattern is very much dominated by what happens in the periphery and the injury is very transient. There are cells that enter the nervous system that cause inflammation and damage, but there are also processes that downregulate those cells and processes and eventually the animal improves--similar to an MS attack.

By contrast, in the Theiler’s model there is progressive injury that is dominated by two molecular processes in the central nervous system that we do not see in relapsing-remitting MS or in EAE, and that is the activation of Type 1 interferons and also a very pronounced immunoglobulin production along with all the molecules that help support plasma cells making immunoglobulin.

These are two different animal models that provide us insight into how the central nervous system can be injured in the course of neuroinflammation and they look to be very different in how they manifest themselves, both in the periphery and in the central nervous system.

How may these new findings impact the future management and treatment of MS?

DR. PACHNER:  When I see a patient with MS, I tell them that we absolutely need to focus on your own disease and how it responds, rather than taking too much guidance from MS as a whole. Because each patient with MS is different.

One of the things that we have tried to do is to identify molecular markers that might help us in management and treatment. As an example, we have learned that some patients who present with their first episode of MS do very poorly. These patients have many more attacks and/or have very aggressive progression in terms of their disability so that they potentially could be in a wheelchair within a few years. Other patients have what we call a benign variant MS. These patients may have an initial episode that is not that different than the other patient, but this type of patient may not have anything else for the rest of their life.

We would like to have some differentiation of those two types of patients. In the first example you can try to be very aggressive and minimize the neuroinflammation with powerful immune-suppressing drugs that have a high risk of causing side effects, such as cancer or opportunistic infections, but on the other hand may have a high benefit in preventing future inflammatory events and progressive injury. But that would not be the correct treatment choice for the second patient example.

It would be nice to tailor treatment to a predictive biomarker. That is something we have been working very hard on. Based on some of the animal models, we have identified a molecular signature of inflammatory MS that is very predictive of future events and we are hoping that that will help us differentiate patients. In other words, not just treat every MS patient the same, but identify whether they need a very powerful immunosuppressant drug, or a mildly immunosuppressant drug, or no treatment at all.

If you have a patient who has one attack and never has any other problem with their MS, then they do not need to be on any treatment. Unfortunately, we do not have predictive value at this point for any molecule or any other attribute of the patient at this point in time. We are trying to remedy that.

That is one very practical aspect of our work in trying to understand the biology of the disease better--identifying molecules that are associated with future damage and inflammation and using those in a predictive manner in patients to guide treatment.

Another important aspect is the attempt to understand the biology of neuroinflammation and how it causes both demyelination and progressive injury to neurons.

References:

Pachner AR, DiSano K, Royce DB, Gilli F. Clinical utility of a molecular signature in inflammatory demyelinating diseases. Neurol Neuroimmunol Neuroinflamm.2019;6(1):e520.

Andrew R. Pachner, MD is the Murray B. Bornstein professor of neurology at Geisel School of Medicine at Dartmouth and director of the Multiple Sclerosis Center at Dartmouth-Hitchcock Medical Center. We spoke to Dr. Pachner about his research into the molecular processes of multiple sclerosis (MS) and the potential impact on patient management.

What do we know about the molecular processes behind relapsing-remitting and progressive MS?

DR. PACHNER:  The progress--in terms of molecules--has not been rapid in the field of MS. The only molecular biomarker we use in practice is oligoclonal bands or other measures of immunoglobulin production in the nervous system, and that biomarker was described in 1942. So, it has been a long time since we have seen a relevant molecule that we can use clinically.

But there has been a lot of progress in the general field of neuroinflammation. MS is one of a large number of diseases that results in neuroinflammation and demyelination.

One thing we have learned over time is that there are many different subtypes of MS. They probably have some shared molecular processes, but they also are likely to have divergent molecular processes.

Over the past 5 to 10 years, researchers have been interested in trying to dissect some of the molecular aspects of MS to identify biomarkers that can, in turn, differentiate subtypes of MS. This will help to identify different ways of treating MS that are optimal for individual patients. It is clear that each patient is quite different and unlikely to be standardized in the way they respond to treatment.

The degree to which relapsing-remitting and progressive MS are differentiated on the molecular level is dependent on how much influence there is of the immune system in the periphery. When MS first starts in a patient, the brain has either no or a very primitive immune system, and then over time it changes, and it becomes much more immune-oriented and populated by immune cells and molecules. So, there’s a trend over time of the central nervous system becoming increasingly populated by immune cells and able to make immune molecules.

What has your recent research on murine models representing these disease patterns shown?

DR. PACHNER:  Even though in humans there is a continuum from relapsing remitting to progressive, it is not like they are completely separate. Frequently in the middle of relapsing-remitting disease there is some progression over time.

In mouse models, we like things to be very clear and separate. We try to make things as simple as possible because of the complexity of the nervous and immune systems.

The simple model for the relapsing-remitting disease is experimental autoimmune encephalomyelitis (EAE), the most commonly studied model of neuroinflammation.

For the progressive form of MS, we use the Theiler’s virus model, which is a type of virus called the picornavirus that is injected into the brain of mice resulting in a slowly progressive, chronic viral infection that looks very much like progressive MS.

In EAE, the disease is induced by presenting an antigen to the peripheral immune system, allowing cells from the peripheral immune system to enter into the central nervous system. It is a manifestation of inflammation and the immune response is in the periphery. In the Theiler’s model, it is a localized process within the central nervous system because the virus is injected directly into the brain.

We found that in EAE the pattern is very much dominated by what happens in the periphery and the injury is very transient. There are cells that enter the nervous system that cause inflammation and damage, but there are also processes that downregulate those cells and processes and eventually the animal improves--similar to an MS attack.

By contrast, in the Theiler’s model there is progressive injury that is dominated by two molecular processes in the central nervous system that we do not see in relapsing-remitting MS or in EAE, and that is the activation of Type 1 interferons and also a very pronounced immunoglobulin production along with all the molecules that help support plasma cells making immunoglobulin.

These are two different animal models that provide us insight into how the central nervous system can be injured in the course of neuroinflammation and they look to be very different in how they manifest themselves, both in the periphery and in the central nervous system.

How may these new findings impact the future management and treatment of MS?

DR. PACHNER:  When I see a patient with MS, I tell them that we absolutely need to focus on your own disease and how it responds, rather than taking too much guidance from MS as a whole. Because each patient with MS is different.

One of the things that we have tried to do is to identify molecular markers that might help us in management and treatment. As an example, we have learned that some patients who present with their first episode of MS do very poorly. These patients have many more attacks and/or have very aggressive progression in terms of their disability so that they potentially could be in a wheelchair within a few years. Other patients have what we call a benign variant MS. These patients may have an initial episode that is not that different than the other patient, but this type of patient may not have anything else for the rest of their life.

We would like to have some differentiation of those two types of patients. In the first example you can try to be very aggressive and minimize the neuroinflammation with powerful immune-suppressing drugs that have a high risk of causing side effects, such as cancer or opportunistic infections, but on the other hand may have a high benefit in preventing future inflammatory events and progressive injury. But that would not be the correct treatment choice for the second patient example.

It would be nice to tailor treatment to a predictive biomarker. That is something we have been working very hard on. Based on some of the animal models, we have identified a molecular signature of inflammatory MS that is very predictive of future events and we are hoping that that will help us differentiate patients. In other words, not just treat every MS patient the same, but identify whether they need a very powerful immunosuppressant drug, or a mildly immunosuppressant drug, or no treatment at all.

If you have a patient who has one attack and never has any other problem with their MS, then they do not need to be on any treatment. Unfortunately, we do not have predictive value at this point for any molecule or any other attribute of the patient at this point in time. We are trying to remedy that.

That is one very practical aspect of our work in trying to understand the biology of the disease better--identifying molecules that are associated with future damage and inflammation and using those in a predictive manner in patients to guide treatment.

Another important aspect is the attempt to understand the biology of neuroinflammation and how it causes both demyelination and progressive injury to neurons.

References:

Pachner AR, DiSano K, Royce DB, Gilli F. Clinical utility of a molecular signature in inflammatory demyelinating diseases. Neurol Neuroimmunol Neuroinflamm.2019;6(1):e520.

Andrew R. Pachner, MD is the Murray B. Bornstein professor of neurology at Geisel School of Medicine at Dartmouth and director of the Multiple Sclerosis Center at Dartmouth-Hitchcock Medical Center. We spoke to Dr. Pachner about his research into the molecular processes of multiple sclerosis (MS) and the potential impact on patient management.

What do we know about the molecular processes behind relapsing-remitting and progressive MS?

DR. PACHNER:  The progress--in terms of molecules--has not been rapid in the field of MS. The only molecular biomarker we use in practice is oligoclonal bands or other measures of immunoglobulin production in the nervous system, and that biomarker was described in 1942. So, it has been a long time since we have seen a relevant molecule that we can use clinically.

But there has been a lot of progress in the general field of neuroinflammation. MS is one of a large number of diseases that results in neuroinflammation and demyelination.

One thing we have learned over time is that there are many different subtypes of MS. They probably have some shared molecular processes, but they also are likely to have divergent molecular processes.

Over the past 5 to 10 years, researchers have been interested in trying to dissect some of the molecular aspects of MS to identify biomarkers that can, in turn, differentiate subtypes of MS. This will help to identify different ways of treating MS that are optimal for individual patients. It is clear that each patient is quite different and unlikely to be standardized in the way they respond to treatment.

The degree to which relapsing-remitting and progressive MS are differentiated on the molecular level is dependent on how much influence there is of the immune system in the periphery. When MS first starts in a patient, the brain has either no or a very primitive immune system, and then over time it changes, and it becomes much more immune-oriented and populated by immune cells and molecules. So, there’s a trend over time of the central nervous system becoming increasingly populated by immune cells and able to make immune molecules.

What has your recent research on murine models representing these disease patterns shown?

DR. PACHNER:  Even though in humans there is a continuum from relapsing remitting to progressive, it is not like they are completely separate. Frequently in the middle of relapsing-remitting disease there is some progression over time.

In mouse models, we like things to be very clear and separate. We try to make things as simple as possible because of the complexity of the nervous and immune systems.

The simple model for the relapsing-remitting disease is experimental autoimmune encephalomyelitis (EAE), the most commonly studied model of neuroinflammation.

For the progressive form of MS, we use the Theiler’s virus model, which is a type of virus called the picornavirus that is injected into the brain of mice resulting in a slowly progressive, chronic viral infection that looks very much like progressive MS.

In EAE, the disease is induced by presenting an antigen to the peripheral immune system, allowing cells from the peripheral immune system to enter into the central nervous system. It is a manifestation of inflammation and the immune response is in the periphery. In the Theiler’s model, it is a localized process within the central nervous system because the virus is injected directly into the brain.

We found that in EAE the pattern is very much dominated by what happens in the periphery and the injury is very transient. There are cells that enter the nervous system that cause inflammation and damage, but there are also processes that downregulate those cells and processes and eventually the animal improves--similar to an MS attack.

By contrast, in the Theiler’s model there is progressive injury that is dominated by two molecular processes in the central nervous system that we do not see in relapsing-remitting MS or in EAE, and that is the activation of Type 1 interferons and also a very pronounced immunoglobulin production along with all the molecules that help support plasma cells making immunoglobulin.

These are two different animal models that provide us insight into how the central nervous system can be injured in the course of neuroinflammation and they look to be very different in how they manifest themselves, both in the periphery and in the central nervous system.

How may these new findings impact the future management and treatment of MS?

DR. PACHNER:  When I see a patient with MS, I tell them that we absolutely need to focus on your own disease and how it responds, rather than taking too much guidance from MS as a whole. Because each patient with MS is different.

One of the things that we have tried to do is to identify molecular markers that might help us in management and treatment. As an example, we have learned that some patients who present with their first episode of MS do very poorly. These patients have many more attacks and/or have very aggressive progression in terms of their disability so that they potentially could be in a wheelchair within a few years. Other patients have what we call a benign variant MS. These patients may have an initial episode that is not that different than the other patient, but this type of patient may not have anything else for the rest of their life.

We would like to have some differentiation of those two types of patients. In the first example you can try to be very aggressive and minimize the neuroinflammation with powerful immune-suppressing drugs that have a high risk of causing side effects, such as cancer or opportunistic infections, but on the other hand may have a high benefit in preventing future inflammatory events and progressive injury. But that would not be the correct treatment choice for the second patient example.

It would be nice to tailor treatment to a predictive biomarker. That is something we have been working very hard on. Based on some of the animal models, we have identified a molecular signature of inflammatory MS that is very predictive of future events and we are hoping that that will help us differentiate patients. In other words, not just treat every MS patient the same, but identify whether they need a very powerful immunosuppressant drug, or a mildly immunosuppressant drug, or no treatment at all.

If you have a patient who has one attack and never has any other problem with their MS, then they do not need to be on any treatment. Unfortunately, we do not have predictive value at this point for any molecule or any other attribute of the patient at this point in time. We are trying to remedy that.

That is one very practical aspect of our work in trying to understand the biology of the disease better--identifying molecules that are associated with future damage and inflammation and using those in a predictive manner in patients to guide treatment.

Another important aspect is the attempt to understand the biology of neuroinflammation and how it causes both demyelination and progressive injury to neurons.

References:

Pachner AR, DiSano K, Royce DB, Gilli F. Clinical utility of a molecular signature in inflammatory demyelinating diseases. Neurol Neuroimmunol Neuroinflamm.2019;6(1):e520.

A literature review has failed to provide new insights regarding the burden of mild hemophilia A.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

In the 17 studies reviewed, mean annual bleeding rates (ABRs) were largely unreported. Data on joint pain and damage, quality of life (QOL), societal impacts, and costs of care were limited and inconsistent across the studies.

The review “revealed a lack of evidence” in adults with mild hemophilia A, Flora Peyvandi, MD, PhD, of Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico in Milan and colleagues wrote in Haemophilia.

The researchers reviewed data from 10 studies conducted in Europe, 6 in North America, and 1 in Japan. Six studies were prospective cohort or registry studies, six were retrospective, and five studies were surveys or outcomes research.

The studies included 3,213 patients with mild hemophilia A aged 13 years or older. There were few details on treatment protocols, but patients received factor VIII concentrates, recombinant factor VIII, and desmopressin.

Most studies did not report mean ABRs. For the three that did, the mean ABRs were 0.44, 0.56, and 4.5. Six studies reported the percentage of patients with bleeding events, and those numbers ranged from 5.5% (1/18) to 90.7% (68/75).

Data on joint pain and damage were not standardized across studies, so the researchers were unable to draw any conclusions. One study showed no significant difference in Health Assessment Questionnaire pain score between patients with mild hemophilia A and control subjects. In another study, 5% of patients with mild hemophilia A reported having severe joint pain in the previous year, and 15% of patients reported moderate joint pain.

The researchers also found it difficult to draw conclusions about QOL. Three studies reported QOL data, and all used a different instrument.

In a study using the SF-36, general health and emotional role functioning were both significantly lower for patients with mild hemophilia A than for age-matched healthy control subjects (P less than .05). In a study using the SF-12, the physical component summary was significantly higher for patients with mild hemophilia A than for those with severe disease (P = .014).

In a study using the Haemo-QOL-A, there were no significant differences between patients with mild and severe hemophilia A. However, Dr. Peyvandi and colleagues noted that this study required long-term use of factor VIII concentrate, so the mild hemophilia A patients in this group were “probably not representative” of the overall mild hemophilia A population.

Societal impacts were difficult to assess because of a lack of standardization across studies. One study showed no significant difference in employment between patients with mild hemophilia A and healthy controls. In a U.S.-based study, patients with mild hemophilia A missed an average of 6.2 workdays per year, and 4.7 days were caused by their hemophilia. A study in Italy showed that patients with mild hemophilia A missed an average of 3.4 workdays per year.

Just two studies included data on health care costs for patients with mild hemophilia A. The mean cost of care was €793 per year in a study from Portugal published in 2015. In a U.S. study published in 1995, the annual cost of care was $22,182.

“Considering the limitations of the current body of evidence, higher-quality studies in this area are needed,” Dr. Peyvandi and colleagues wrote. “Such studies would report both bleeding and other clinical outcomes based on common definitions and for a representative population of mild [hemophilia A] adults. Areas for further research include more robust comparison to healthy controls or population norms, especially for QOL and other patient-reported outcomes.”

Seven of the eight researchers reported relationships, including employment, with BioMarin. Dr. Peyvandi reported relationships with Sanofi, Grifols, Novo Nordisk, Roche, Takeda, Sobi, Bioverativ, Spark Therapeutics, Sysmex, and CSL Behring.

jensmith@mdedge.com

SOURCE: Peyvandi F et al. Haemophilia. 2019 Jul 11. doi: 10.1111/hae.13777.

A literature review has failed to provide new insights regarding the burden of mild hemophilia A.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

In the 17 studies reviewed, mean annual bleeding rates (ABRs) were largely unreported. Data on joint pain and damage, quality of life (QOL), societal impacts, and costs of care were limited and inconsistent across the studies.

The review “revealed a lack of evidence” in adults with mild hemophilia A, Flora Peyvandi, MD, PhD, of Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico in Milan and colleagues wrote in Haemophilia.

The researchers reviewed data from 10 studies conducted in Europe, 6 in North America, and 1 in Japan. Six studies were prospective cohort or registry studies, six were retrospective, and five studies were surveys or outcomes research.

The studies included 3,213 patients with mild hemophilia A aged 13 years or older. There were few details on treatment protocols, but patients received factor VIII concentrates, recombinant factor VIII, and desmopressin.

Most studies did not report mean ABRs. For the three that did, the mean ABRs were 0.44, 0.56, and 4.5. Six studies reported the percentage of patients with bleeding events, and those numbers ranged from 5.5% (1/18) to 90.7% (68/75).

Data on joint pain and damage were not standardized across studies, so the researchers were unable to draw any conclusions. One study showed no significant difference in Health Assessment Questionnaire pain score between patients with mild hemophilia A and control subjects. In another study, 5% of patients with mild hemophilia A reported having severe joint pain in the previous year, and 15% of patients reported moderate joint pain.

The researchers also found it difficult to draw conclusions about QOL. Three studies reported QOL data, and all used a different instrument.

In a study using the SF-36, general health and emotional role functioning were both significantly lower for patients with mild hemophilia A than for age-matched healthy control subjects (P less than .05). In a study using the SF-12, the physical component summary was significantly higher for patients with mild hemophilia A than for those with severe disease (P = .014).

In a study using the Haemo-QOL-A, there were no significant differences between patients with mild and severe hemophilia A. However, Dr. Peyvandi and colleagues noted that this study required long-term use of factor VIII concentrate, so the mild hemophilia A patients in this group were “probably not representative” of the overall mild hemophilia A population.

Societal impacts were difficult to assess because of a lack of standardization across studies. One study showed no significant difference in employment between patients with mild hemophilia A and healthy controls. In a U.S.-based study, patients with mild hemophilia A missed an average of 6.2 workdays per year, and 4.7 days were caused by their hemophilia. A study in Italy showed that patients with mild hemophilia A missed an average of 3.4 workdays per year.

Just two studies included data on health care costs for patients with mild hemophilia A. The mean cost of care was €793 per year in a study from Portugal published in 2015. In a U.S. study published in 1995, the annual cost of care was $22,182.

“Considering the limitations of the current body of evidence, higher-quality studies in this area are needed,” Dr. Peyvandi and colleagues wrote. “Such studies would report both bleeding and other clinical outcomes based on common definitions and for a representative population of mild [hemophilia A] adults. Areas for further research include more robust comparison to healthy controls or population norms, especially for QOL and other patient-reported outcomes.”

Seven of the eight researchers reported relationships, including employment, with BioMarin. Dr. Peyvandi reported relationships with Sanofi, Grifols, Novo Nordisk, Roche, Takeda, Sobi, Bioverativ, Spark Therapeutics, Sysmex, and CSL Behring.

jensmith@mdedge.com

SOURCE: Peyvandi F et al. Haemophilia. 2019 Jul 11. doi: 10.1111/hae.13777.

A literature review has failed to provide new insights regarding the burden of mild hemophilia A.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

In the 17 studies reviewed, mean annual bleeding rates (ABRs) were largely unreported. Data on joint pain and damage, quality of life (QOL), societal impacts, and costs of care were limited and inconsistent across the studies.

The review “revealed a lack of evidence” in adults with mild hemophilia A, Flora Peyvandi, MD, PhD, of Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico in Milan and colleagues wrote in Haemophilia.

The researchers reviewed data from 10 studies conducted in Europe, 6 in North America, and 1 in Japan. Six studies were prospective cohort or registry studies, six were retrospective, and five studies were surveys or outcomes research.

The studies included 3,213 patients with mild hemophilia A aged 13 years or older. There were few details on treatment protocols, but patients received factor VIII concentrates, recombinant factor VIII, and desmopressin.

Most studies did not report mean ABRs. For the three that did, the mean ABRs were 0.44, 0.56, and 4.5. Six studies reported the percentage of patients with bleeding events, and those numbers ranged from 5.5% (1/18) to 90.7% (68/75).

Data on joint pain and damage were not standardized across studies, so the researchers were unable to draw any conclusions. One study showed no significant difference in Health Assessment Questionnaire pain score between patients with mild hemophilia A and control subjects. In another study, 5% of patients with mild hemophilia A reported having severe joint pain in the previous year, and 15% of patients reported moderate joint pain.

The researchers also found it difficult to draw conclusions about QOL. Three studies reported QOL data, and all used a different instrument.

In a study using the SF-36, general health and emotional role functioning were both significantly lower for patients with mild hemophilia A than for age-matched healthy control subjects (P less than .05). In a study using the SF-12, the physical component summary was significantly higher for patients with mild hemophilia A than for those with severe disease (P = .014).

In a study using the Haemo-QOL-A, there were no significant differences between patients with mild and severe hemophilia A. However, Dr. Peyvandi and colleagues noted that this study required long-term use of factor VIII concentrate, so the mild hemophilia A patients in this group were “probably not representative” of the overall mild hemophilia A population.

Societal impacts were difficult to assess because of a lack of standardization across studies. One study showed no significant difference in employment between patients with mild hemophilia A and healthy controls. In a U.S.-based study, patients with mild hemophilia A missed an average of 6.2 workdays per year, and 4.7 days were caused by their hemophilia. A study in Italy showed that patients with mild hemophilia A missed an average of 3.4 workdays per year.

Just two studies included data on health care costs for patients with mild hemophilia A. The mean cost of care was €793 per year in a study from Portugal published in 2015. In a U.S. study published in 1995, the annual cost of care was $22,182.

“Considering the limitations of the current body of evidence, higher-quality studies in this area are needed,” Dr. Peyvandi and colleagues wrote. “Such studies would report both bleeding and other clinical outcomes based on common definitions and for a representative population of mild [hemophilia A] adults. Areas for further research include more robust comparison to healthy controls or population norms, especially for QOL and other patient-reported outcomes.”

Seven of the eight researchers reported relationships, including employment, with BioMarin. Dr. Peyvandi reported relationships with Sanofi, Grifols, Novo Nordisk, Roche, Takeda, Sobi, Bioverativ, Spark Therapeutics, Sysmex, and CSL Behring.

jensmith@mdedge.com

SOURCE: Peyvandi F et al. Haemophilia. 2019 Jul 11. doi: 10.1111/hae.13777.

BANGKOK – The mortality rate is high in children with superrefractory status epilepticus, with fulminant cerebral edema emerging as the leading cause of death in a retrospective, single-center study presented by Maggie Lo Yee Yau, MD, at the International Epilepsy Congress.

“Death in these children usually occurred within the first few days after admission to the pediatric ICU,” she said at the congress sponsored by the International League Against Epilepsy.

Bruce Jancin/MDedge News

bjancin@mdedge.com

BANGKOK – The mortality rate is high in children with superrefractory status epilepticus, with fulminant cerebral edema emerging as the leading cause of death in a retrospective, single-center study presented by Maggie Lo Yee Yau, MD, at the International Epilepsy Congress.

“Death in these children usually occurred within the first few days after admission to the pediatric ICU,” she said at the congress sponsored by the International League Against Epilepsy.

Bruce Jancin/MDedge News

bjancin@mdedge.com

BANGKOK – The mortality rate is high in children with superrefractory status epilepticus, with fulminant cerebral edema emerging as the leading cause of death in a retrospective, single-center study presented by Maggie Lo Yee Yau, MD, at the International Epilepsy Congress.

“Death in these children usually occurred within the first few days after admission to the pediatric ICU,” she said at the congress sponsored by the International League Against Epilepsy.

Bruce Jancin/MDedge News

bjancin@mdedge.com

AUSTIN, TEX. – Adolescents with moderate to severe atopic dermatitis who used dupilumab experienced significant improvements in signs and symptoms of the condition, with minimal safety concerns, according to results of a phase 3 study.

Doug Brunk/MDedge News

“Dupilumab works as effectively in adolescents as in adults,” Randy Prescilla, MD, one of the study authors, said in an interview at the annual meeting of the Society for Pediatric Dermatology. “It gives us promise that we could go into other age groups with the same optimism. We are enrolling patients in even younger age groups.”

The double-blind, placebo-controlled study analyzed the efficacy and safety of dupilumab monotherapy in patients between the ages of 12 and 17 years with moderate to severe atopic dermatitis (AD) inadequately controlled with topical therapies. In the United States, dupilumab is approved for those aged 12 years and older with moderate to severe disease inadequately controlled by topical prescription treatments or when those therapies are not advisable.

For the 16-week study, Dr. Prescilla, global medical affairs director of pediatric dermatology for Sanofi Genzyme, and colleagues randomized 251 patients to one of three groups: dupilumab every 2 weeks (200 mg if baseline weight was less than 60 kg; 300 mg if that weight was 60 kg or more); 300 mg dupilumab every 4 weeks; or placebo every 2 weeks.

At week 16, a significantly higher proportion of patients in the two drug treatment groups had Investigator’s Global Assessment scores of 0/1, compared with those in the placebo group (24.4%, 17.9%, and 2.4%) as well as a significantly higher percentage of patients who achieved at least a 75% improvement in the Eczema Area and Severity Index (EASI-75) score (41.5%, 38.1%, and 8.2%).

In addition, patients in the two drug treatment groups experienced improved percent change in least square-means on the EASI from baseline to week 16, compared with those in the placebo group (–65.9%, –64.8%, and –23.6%), the Peak Pruritus Numerical Rating Scale (–47.9%, –45.5%, and –19.0%), body surface area affected by AD (–30.1%, –33.4%, and –11.7%), and in the SCORing AD clinical tool (P less than .001 for all comparisons).


Between baseline and week 16, scores on the Children’s Dermatology Life Quality Index and Patient-Oriented Eczema Measure improved significantly in the two dupilumab groups, compared with the placebo group. The rate of skin infection was higher in the placebo group (20%), compared with 11% in the group that received dupilumab every 2 weeks and 13.3% in the group receiving the drug every 4 weeks.

Conjunctivitis occurred more frequently with dupilumab treatment (9.8% in the every-2-weeks dupilumab group, 10.8% in the every-4-weeks dupilumab group, and 4.7% in the placebo group) as did injection site reactions (8.5%, 6.0%, and 3.5%). Two adverse events, one of which was serious, occurred in the placebo group.

Dr. Prescilla acknowledged certain limitations of the study, including its small sample size and the fact that it was limited to 16 weeks. “However, smaller sample size and duration are typical for this type of study and in line with the study design of the SOLO 1 and SOLO 2 studies in adults,” he said.

On Aug. 6, the European Commission extended the marketing authorization for dupilumab in the European Union to include adolescents 12-17 years of age with moderate to severe atopic dermatitis who are candidates for systemic therapy. On the same day, Sanofi Genzyme and Regeneron announced positive topline results in a phase 3 trial in children aged 6-11 years with severe AD.

The study’s principal investigator was Amy S. Paller, MD. The study was funded by Sanofi Genzyme and Regeneron. Dr. Prescilla is an employee of Sanofi Genzyme.

dbrunk@mdedge.com

AUSTIN, TEX. – Adolescents with moderate to severe atopic dermatitis who used dupilumab experienced significant improvements in signs and symptoms of the condition, with minimal safety concerns, according to results of a phase 3 study.

Doug Brunk/MDedge News

“Dupilumab works as effectively in adolescents as in adults,” Randy Prescilla, MD, one of the study authors, said in an interview at the annual meeting of the Society for Pediatric Dermatology. “It gives us promise that we could go into other age groups with the same optimism. We are enrolling patients in even younger age groups.”

The double-blind, placebo-controlled study analyzed the efficacy and safety of dupilumab monotherapy in patients between the ages of 12 and 17 years with moderate to severe atopic dermatitis (AD) inadequately controlled with topical therapies. In the United States, dupilumab is approved for those aged 12 years and older with moderate to severe disease inadequately controlled by topical prescription treatments or when those therapies are not advisable.

For the 16-week study, Dr. Prescilla, global medical affairs director of pediatric dermatology for Sanofi Genzyme, and colleagues randomized 251 patients to one of three groups: dupilumab every 2 weeks (200 mg if baseline weight was less than 60 kg; 300 mg if that weight was 60 kg or more); 300 mg dupilumab every 4 weeks; or placebo every 2 weeks.

At week 16, a significantly higher proportion of patients in the two drug treatment groups had Investigator’s Global Assessment scores of 0/1, compared with those in the placebo group (24.4%, 17.9%, and 2.4%) as well as a significantly higher percentage of patients who achieved at least a 75% improvement in the Eczema Area and Severity Index (EASI-75) score (41.5%, 38.1%, and 8.2%).

In addition, patients in the two drug treatment groups experienced improved percent change in least square-means on the EASI from baseline to week 16, compared with those in the placebo group (–65.9%, –64.8%, and –23.6%), the Peak Pruritus Numerical Rating Scale (–47.9%, –45.5%, and –19.0%), body surface area affected by AD (–30.1%, –33.4%, and –11.7%), and in the SCORing AD clinical tool (P less than .001 for all comparisons).


Between baseline and week 16, scores on the Children’s Dermatology Life Quality Index and Patient-Oriented Eczema Measure improved significantly in the two dupilumab groups, compared with the placebo group. The rate of skin infection was higher in the placebo group (20%), compared with 11% in the group that received dupilumab every 2 weeks and 13.3% in the group receiving the drug every 4 weeks.

Conjunctivitis occurred more frequently with dupilumab treatment (9.8% in the every-2-weeks dupilumab group, 10.8% in the every-4-weeks dupilumab group, and 4.7% in the placebo group) as did injection site reactions (8.5%, 6.0%, and 3.5%). Two adverse events, one of which was serious, occurred in the placebo group.

Dr. Prescilla acknowledged certain limitations of the study, including its small sample size and the fact that it was limited to 16 weeks. “However, smaller sample size and duration are typical for this type of study and in line with the study design of the SOLO 1 and SOLO 2 studies in adults,” he said.

On Aug. 6, the European Commission extended the marketing authorization for dupilumab in the European Union to include adolescents 12-17 years of age with moderate to severe atopic dermatitis who are candidates for systemic therapy. On the same day, Sanofi Genzyme and Regeneron announced positive topline results in a phase 3 trial in children aged 6-11 years with severe AD.

The study’s principal investigator was Amy S. Paller, MD. The study was funded by Sanofi Genzyme and Regeneron. Dr. Prescilla is an employee of Sanofi Genzyme.

dbrunk@mdedge.com

AUSTIN, TEX. – Adolescents with moderate to severe atopic dermatitis who used dupilumab experienced significant improvements in signs and symptoms of the condition, with minimal safety concerns, according to results of a phase 3 study.

Doug Brunk/MDedge News

“Dupilumab works as effectively in adolescents as in adults,” Randy Prescilla, MD, one of the study authors, said in an interview at the annual meeting of the Society for Pediatric Dermatology. “It gives us promise that we could go into other age groups with the same optimism. We are enrolling patients in even younger age groups.”

The double-blind, placebo-controlled study analyzed the efficacy and safety of dupilumab monotherapy in patients between the ages of 12 and 17 years with moderate to severe atopic dermatitis (AD) inadequately controlled with topical therapies. In the United States, dupilumab is approved for those aged 12 years and older with moderate to severe disease inadequately controlled by topical prescription treatments or when those therapies are not advisable.

For the 16-week study, Dr. Prescilla, global medical affairs director of pediatric dermatology for Sanofi Genzyme, and colleagues randomized 251 patients to one of three groups: dupilumab every 2 weeks (200 mg if baseline weight was less than 60 kg; 300 mg if that weight was 60 kg or more); 300 mg dupilumab every 4 weeks; or placebo every 2 weeks.

At week 16, a significantly higher proportion of patients in the two drug treatment groups had Investigator’s Global Assessment scores of 0/1, compared with those in the placebo group (24.4%, 17.9%, and 2.4%) as well as a significantly higher percentage of patients who achieved at least a 75% improvement in the Eczema Area and Severity Index (EASI-75) score (41.5%, 38.1%, and 8.2%).

In addition, patients in the two drug treatment groups experienced improved percent change in least square-means on the EASI from baseline to week 16, compared with those in the placebo group (–65.9%, –64.8%, and –23.6%), the Peak Pruritus Numerical Rating Scale (–47.9%, –45.5%, and –19.0%), body surface area affected by AD (–30.1%, –33.4%, and –11.7%), and in the SCORing AD clinical tool (P less than .001 for all comparisons).


Between baseline and week 16, scores on the Children’s Dermatology Life Quality Index and Patient-Oriented Eczema Measure improved significantly in the two dupilumab groups, compared with the placebo group. The rate of skin infection was higher in the placebo group (20%), compared with 11% in the group that received dupilumab every 2 weeks and 13.3% in the group receiving the drug every 4 weeks.

Conjunctivitis occurred more frequently with dupilumab treatment (9.8% in the every-2-weeks dupilumab group, 10.8% in the every-4-weeks dupilumab group, and 4.7% in the placebo group) as did injection site reactions (8.5%, 6.0%, and 3.5%). Two adverse events, one of which was serious, occurred in the placebo group.

Dr. Prescilla acknowledged certain limitations of the study, including its small sample size and the fact that it was limited to 16 weeks. “However, smaller sample size and duration are typical for this type of study and in line with the study design of the SOLO 1 and SOLO 2 studies in adults,” he said.

On Aug. 6, the European Commission extended the marketing authorization for dupilumab in the European Union to include adolescents 12-17 years of age with moderate to severe atopic dermatitis who are candidates for systemic therapy. On the same day, Sanofi Genzyme and Regeneron announced positive topline results in a phase 3 trial in children aged 6-11 years with severe AD.

The study’s principal investigator was Amy S. Paller, MD. The study was funded by Sanofi Genzyme and Regeneron. Dr. Prescilla is an employee of Sanofi Genzyme.

dbrunk@mdedge.com

Remote Electrical Neuromodulation (REN) may provide relief of migraine pain and most bothersome symptoms compared to placebo, a new study found. The efficacy and safety of a REN device for acute treatment of migraine was assessed. The randomized, double-blind, multicenter study was conducted at 7 sites in the United States and 5 sites in Israel. The study included 252 adults meeting the International Classification of Headache Disorders criteria for migraine with 2 to 8 migraine headaches per month, and the patients were randomized 1:1 to active or sham stimulation. Among the findings:

• Active stimulation was more effective than sham stimulation in achieving pain relief, pain-free, and MBS relief at 2 hours post-treatment.
• The pain relief of the active treatment was sustained 48 hours post-treatment.
• Incidence of device-related adverse events was low and similar between treatment groups.

Yarnitsky D, et al. Remote electrical neuromodulation (REN) relieves acute migraine: A randomized, double-blind, placebo-controlled, multicenter trial. [Published online ahead of print May 9, 2019]. Headache. doi: 10.1111/head.13551.

Remote Electrical Neuromodulation (REN) may provide relief of migraine pain and most bothersome symptoms compared to placebo, a new study found. The efficacy and safety of a REN device for acute treatment of migraine was assessed. The randomized, double-blind, multicenter study was conducted at 7 sites in the United States and 5 sites in Israel. The study included 252 adults meeting the International Classification of Headache Disorders criteria for migraine with 2 to 8 migraine headaches per month, and the patients were randomized 1:1 to active or sham stimulation. Among the findings:

• Active stimulation was more effective than sham stimulation in achieving pain relief, pain-free, and MBS relief at 2 hours post-treatment.
• The pain relief of the active treatment was sustained 48 hours post-treatment.
• Incidence of device-related adverse events was low and similar between treatment groups.

Yarnitsky D, et al. Remote electrical neuromodulation (REN) relieves acute migraine: A randomized, double-blind, placebo-controlled, multicenter trial. [Published online ahead of print May 9, 2019]. Headache. doi: 10.1111/head.13551.

Remote Electrical Neuromodulation (REN) may provide relief of migraine pain and most bothersome symptoms compared to placebo, a new study found. The efficacy and safety of a REN device for acute treatment of migraine was assessed. The randomized, double-blind, multicenter study was conducted at 7 sites in the United States and 5 sites in Israel. The study included 252 adults meeting the International Classification of Headache Disorders criteria for migraine with 2 to 8 migraine headaches per month, and the patients were randomized 1:1 to active or sham stimulation. Among the findings:

• Active stimulation was more effective than sham stimulation in achieving pain relief, pain-free, and MBS relief at 2 hours post-treatment.
• The pain relief of the active treatment was sustained 48 hours post-treatment.
• Incidence of device-related adverse events was low and similar between treatment groups.

Yarnitsky D, et al. Remote electrical neuromodulation (REN) relieves acute migraine: A randomized, double-blind, placebo-controlled, multicenter trial. [Published online ahead of print May 9, 2019]. Headache. doi: 10.1111/head.13551.