Multiple Sclerosis

Clinical Neurology News editorial advisory board member Jonathan L. Carter, MD, scoured the pages of the American Academy of Neurology’s annual meeting program for his “top picks” in multiple sclerosis at this year’s meeting.

NFLCs in serum as a biomarker for MS and treatment response. Multiple abstracts explore the use of NFLCs as a marker for disease progression and response to MS therapies, including:

• Hot Topics Plenary Session presentation: “Monitoring Multiple Sclerosis Using Blood Neurofilament Light Protein” by Jens Kuhle, MD.
• P5.036, Serum and CSF Neurofilament Light Chain levels normalise following Bone Marrow Transplant in MS Patients.
• S24.002, Interim Analysis of the OBOE (Ocrelizumab Biomarker Outcome Evaluation) Study in Multiple Sclerosis (MS).
• S24.003, Serum Neurofilament Light (NfL): Towards a Blood Test for Prognosis and Disease/Treatment Monitoring in Multiple Sclerosis Patients.
• S24.004, Long-term Prognosis of Disease Evolution and Evidence for Sustained Fingolimod Treatment Effect by Blood Neurofilament Light in RRMS Patients.
• S24.007, Including Blood Neurofilament Light Chain in the NEDA Concept in Relapsing Remitting Multiple Sclerosis Trials.
• S8.006, Siponimod Reduces Neurofilament Light Chain Blood Levels in Secondary Progressive Multiple Sclerosis Patients.

Cognitive function as an outcome measure in MS clinical trials. Several abstracts examine cognition as an outcome measure in clinical trials and show slowing of cognitive worsening in patients on MS disease-modifying therapies:

• S44.004, Impact of Siponimod on Cognition in Patients With Secondary Progressive Multiple Sclerosis: Results From Phase 3 EXPAND Study.
• S44.005, Time to Cognitive Worsening in Patients With Relapsing Multiple Sclerosis in Ocrelizumab Phase 3 Trials.
• S44.007, Benchmarks of Cognitive Performance in a Large, Representative Patient Population.

Improved disability outcome measures and predictors of disability in MS. Several abstracts assess novel disability outcome measures and neuroimaging techniques to better predict progression of clinical disability:

• P4.380, Overall Response Score: A Novel Disability Endpoint That Allows for the Integrated Assessment of Improvement and Worsening over Time in Patients with MS.
• S47.001, Longitudinal Changes in Quantitative Spinal Cord MRI in Multiple Sclerosis Patients: Results of a 5-year Study.
• P6.354, Effect of Fingolimod 0.5 mg/day versus Placebo on Two Newly Developed Expanded Disability Status Scale (EDSS) Subscales for Patients with Relapsing Remitting MS: EDSS Factor Analysis.

Is treatment response in MS an age-dependent or relapse-driven phenomenon, and is it safe to discontinue MS therapies with advancing age? Several abstracts address this question:

• S47.004, Meta-Analysis of the Age-Dependent Efficacy of Multiple Sclerosis Treatments.
• S8.005, Uncoupling the Impact on Relapses and Disability Progression: Siponimod in Relapsing and Nonrelapsing Patients With Secondary Progressive Multiple Sclerosis in the Phase 3 EXPAND Study.
• S8.008, Discontinuation of Disease Modifying Therapies in Stable MS Patients is Associated with Disability Progression Regardless of Age.

Neuromyelitis optica spectrum disorders and MS mimics. Multiple abstracts explore the differences between neuromyelitis optica spectrum disorder because of aquaporin-4 versus myelin oligodendrocyte glycoprotein antibodies; describe unique features of another recently described autoimmune disorder, autoimmune GFAP astrocytopathy; and explore the differential diagnosis of idiopathic transverse myelitis:

• S13.002, Clinical Characteristics of MOG and AQP associated Neuromyelitis Optica Spectrum Disorder (NMOSD) in Adults, through S13.008, It’s Not All Transverse Myelitis: The Differential Diagnosis of Spinal Cord Myelopathy.
• P6.409, The Mayo Clinic Glial Autoimmunity Study: Glial autoantibody (AQP4/MOG/GFAP) serostatus in recurrent longitudinally extensive transverse myelitis.
• P6.417, Evaluation of idiopathic transverse myelitis revealing specific myelopathy diagnoses.
• S6.003, Brain and Spinal Cord Imaging Features in Neuromyelitis Optica Spectrum Disorders.

Updated safety and efficacy data for recently approved or investigational MS therapies. Multiple abstracts report updated safety and efficacy data from MS clinical trials of ozanimod, ocrelizumab (Ocrevus), and hematopoietic stem cell transplantation:

• Clinical Trials Plenary Session presentation: “A Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis” by Robert J. Fox, MD.
• Contemporary Clinical Issues Plenary Session presentation: “Biosimilars and Nonbiologic Complex Drugs” by Jeffrey Allan Cohen, MD.
• S6.002, Brain MRI Activity and Atrophy Measures in Patients Receiving Continuous Ocrelizumab or Switching From Interferon Beta-1a to Ocrelizumab Therapy in the Open-Label Extension Period of the Phase 3 Trials of Ocrelizumab in Patients With Relapsing Multiple Sclerosis.
• P3.410, Clinical and Magnetic Resonance Imaging Results From RADIANCE Part B, a Multicenter, Randomized, Double-Blind, Phase 3 Trial of Ozanimod Versus Intramuscular Interferon beta-1a in Relapsing Multiple Sclerosis (RMS).
• P3.396, Ozanimod Demonstrates Efficacy and Safety in a Multicenter, Randomized, Double-Blind, Double-Dummy, Active-Controlled Phase 3 Trial of Relapsing Multiple Sclerosis (SUNBEAM).
• S36.001, Safety of Ocrelizumab in Multiple Sclerosis: Updated Analysis in Patients With Relapsing and Primary Progressive Multiple Sclerosis.
• S36.004, Nonmyeloablative hematopoietic stem cell transplantation (HSCT) is superior to disease modifying drug (DMD) treatment in highly active Relapsing Remitting Multiple Sclerosis (RRMS): interim results of the Multiple Sclerosis International Stem cell Transplant (MIST) Randomized Trial.
• S36.005, Efficacy of Ozanimod Versus Interferon beta-1a by Prior Treatment and Baseline Disability in Two Multicenter, Randomized, Double-Blind, Parallel-Group, Active-Controlled, Double-Dummy Phase 3 Studies in Relapsing Multiple Sclerosis (SUNBEAM and RADIANCE Part B).
• S36.006, Safety of Ozanimod Versus Interferon beta-1a in Two Multicenter, Randomized, Double-Blind, Parallel-Group, Active-Controlled, Double-Dummy Phase 3 Studies in Relapsing Multiple Sclerosis (SUNBEAM and RADIANCE Part B).

New thoughts on MS pathogenesis.

• Frontiers in Neuroscience Plenary Session presentation: “Pediatric MS: A Unique Window into Environmental and Genetic Risk Factors for MS” by Emmanuelle Waubant, MD.

Dr. Carter has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alder Pharmaceuticals. He has received research support from Roche/Genentech and MedDay Pharmaceuticals.
 

Clinical Neurology News editorial advisory board member Jonathan L. Carter, MD, scoured the pages of the American Academy of Neurology’s annual meeting program for his “top picks” in multiple sclerosis at this year’s meeting.

NFLCs in serum as a biomarker for MS and treatment response. Multiple abstracts explore the use of NFLCs as a marker for disease progression and response to MS therapies, including:

• Hot Topics Plenary Session presentation: “Monitoring Multiple Sclerosis Using Blood Neurofilament Light Protein” by Jens Kuhle, MD.
• P5.036, Serum and CSF Neurofilament Light Chain levels normalise following Bone Marrow Transplant in MS Patients.
• S24.002, Interim Analysis of the OBOE (Ocrelizumab Biomarker Outcome Evaluation) Study in Multiple Sclerosis (MS).
• S24.003, Serum Neurofilament Light (NfL): Towards a Blood Test for Prognosis and Disease/Treatment Monitoring in Multiple Sclerosis Patients.
• S24.004, Long-term Prognosis of Disease Evolution and Evidence for Sustained Fingolimod Treatment Effect by Blood Neurofilament Light in RRMS Patients.
• S24.007, Including Blood Neurofilament Light Chain in the NEDA Concept in Relapsing Remitting Multiple Sclerosis Trials.
• S8.006, Siponimod Reduces Neurofilament Light Chain Blood Levels in Secondary Progressive Multiple Sclerosis Patients.

Cognitive function as an outcome measure in MS clinical trials. Several abstracts examine cognition as an outcome measure in clinical trials and show slowing of cognitive worsening in patients on MS disease-modifying therapies:

• S44.004, Impact of Siponimod on Cognition in Patients With Secondary Progressive Multiple Sclerosis: Results From Phase 3 EXPAND Study.
• S44.005, Time to Cognitive Worsening in Patients With Relapsing Multiple Sclerosis in Ocrelizumab Phase 3 Trials.
• S44.007, Benchmarks of Cognitive Performance in a Large, Representative Patient Population.

Improved disability outcome measures and predictors of disability in MS. Several abstracts assess novel disability outcome measures and neuroimaging techniques to better predict progression of clinical disability:

• P4.380, Overall Response Score: A Novel Disability Endpoint That Allows for the Integrated Assessment of Improvement and Worsening over Time in Patients with MS.
• S47.001, Longitudinal Changes in Quantitative Spinal Cord MRI in Multiple Sclerosis Patients: Results of a 5-year Study.
• P6.354, Effect of Fingolimod 0.5 mg/day versus Placebo on Two Newly Developed Expanded Disability Status Scale (EDSS) Subscales for Patients with Relapsing Remitting MS: EDSS Factor Analysis.

Is treatment response in MS an age-dependent or relapse-driven phenomenon, and is it safe to discontinue MS therapies with advancing age? Several abstracts address this question:

• S47.004, Meta-Analysis of the Age-Dependent Efficacy of Multiple Sclerosis Treatments.
• S8.005, Uncoupling the Impact on Relapses and Disability Progression: Siponimod in Relapsing and Nonrelapsing Patients With Secondary Progressive Multiple Sclerosis in the Phase 3 EXPAND Study.
• S8.008, Discontinuation of Disease Modifying Therapies in Stable MS Patients is Associated with Disability Progression Regardless of Age.

Neuromyelitis optica spectrum disorders and MS mimics. Multiple abstracts explore the differences between neuromyelitis optica spectrum disorder because of aquaporin-4 versus myelin oligodendrocyte glycoprotein antibodies; describe unique features of another recently described autoimmune disorder, autoimmune GFAP astrocytopathy; and explore the differential diagnosis of idiopathic transverse myelitis:

• S13.002, Clinical Characteristics of MOG and AQP associated Neuromyelitis Optica Spectrum Disorder (NMOSD) in Adults, through S13.008, It’s Not All Transverse Myelitis: The Differential Diagnosis of Spinal Cord Myelopathy.
• P6.409, The Mayo Clinic Glial Autoimmunity Study: Glial autoantibody (AQP4/MOG/GFAP) serostatus in recurrent longitudinally extensive transverse myelitis.
• P6.417, Evaluation of idiopathic transverse myelitis revealing specific myelopathy diagnoses.
• S6.003, Brain and Spinal Cord Imaging Features in Neuromyelitis Optica Spectrum Disorders.

Updated safety and efficacy data for recently approved or investigational MS therapies. Multiple abstracts report updated safety and efficacy data from MS clinical trials of ozanimod, ocrelizumab (Ocrevus), and hematopoietic stem cell transplantation:

• Clinical Trials Plenary Session presentation: “A Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis” by Robert J. Fox, MD.
• Contemporary Clinical Issues Plenary Session presentation: “Biosimilars and Nonbiologic Complex Drugs” by Jeffrey Allan Cohen, MD.
• S6.002, Brain MRI Activity and Atrophy Measures in Patients Receiving Continuous Ocrelizumab or Switching From Interferon Beta-1a to Ocrelizumab Therapy in the Open-Label Extension Period of the Phase 3 Trials of Ocrelizumab in Patients With Relapsing Multiple Sclerosis.
• P3.410, Clinical and Magnetic Resonance Imaging Results From RADIANCE Part B, a Multicenter, Randomized, Double-Blind, Phase 3 Trial of Ozanimod Versus Intramuscular Interferon beta-1a in Relapsing Multiple Sclerosis (RMS).
• P3.396, Ozanimod Demonstrates Efficacy and Safety in a Multicenter, Randomized, Double-Blind, Double-Dummy, Active-Controlled Phase 3 Trial of Relapsing Multiple Sclerosis (SUNBEAM).
• S36.001, Safety of Ocrelizumab in Multiple Sclerosis: Updated Analysis in Patients With Relapsing and Primary Progressive Multiple Sclerosis.
• S36.004, Nonmyeloablative hematopoietic stem cell transplantation (HSCT) is superior to disease modifying drug (DMD) treatment in highly active Relapsing Remitting Multiple Sclerosis (RRMS): interim results of the Multiple Sclerosis International Stem cell Transplant (MIST) Randomized Trial.
• S36.005, Efficacy of Ozanimod Versus Interferon beta-1a by Prior Treatment and Baseline Disability in Two Multicenter, Randomized, Double-Blind, Parallel-Group, Active-Controlled, Double-Dummy Phase 3 Studies in Relapsing Multiple Sclerosis (SUNBEAM and RADIANCE Part B).
• S36.006, Safety of Ozanimod Versus Interferon beta-1a in Two Multicenter, Randomized, Double-Blind, Parallel-Group, Active-Controlled, Double-Dummy Phase 3 Studies in Relapsing Multiple Sclerosis (SUNBEAM and RADIANCE Part B).

New thoughts on MS pathogenesis.

• Frontiers in Neuroscience Plenary Session presentation: “Pediatric MS: A Unique Window into Environmental and Genetic Risk Factors for MS” by Emmanuelle Waubant, MD.

Dr. Carter has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alder Pharmaceuticals. He has received research support from Roche/Genentech and MedDay Pharmaceuticals.
 

Clinical Neurology News editorial advisory board member Jonathan L. Carter, MD, scoured the pages of the American Academy of Neurology’s annual meeting program for his “top picks” in multiple sclerosis at this year’s meeting.

NFLCs in serum as a biomarker for MS and treatment response. Multiple abstracts explore the use of NFLCs as a marker for disease progression and response to MS therapies, including:

• Hot Topics Plenary Session presentation: “Monitoring Multiple Sclerosis Using Blood Neurofilament Light Protein” by Jens Kuhle, MD.
• P5.036, Serum and CSF Neurofilament Light Chain levels normalise following Bone Marrow Transplant in MS Patients.
• S24.002, Interim Analysis of the OBOE (Ocrelizumab Biomarker Outcome Evaluation) Study in Multiple Sclerosis (MS).
• S24.003, Serum Neurofilament Light (NfL): Towards a Blood Test for Prognosis and Disease/Treatment Monitoring in Multiple Sclerosis Patients.
• S24.004, Long-term Prognosis of Disease Evolution and Evidence for Sustained Fingolimod Treatment Effect by Blood Neurofilament Light in RRMS Patients.
• S24.007, Including Blood Neurofilament Light Chain in the NEDA Concept in Relapsing Remitting Multiple Sclerosis Trials.
• S8.006, Siponimod Reduces Neurofilament Light Chain Blood Levels in Secondary Progressive Multiple Sclerosis Patients.

Cognitive function as an outcome measure in MS clinical trials. Several abstracts examine cognition as an outcome measure in clinical trials and show slowing of cognitive worsening in patients on MS disease-modifying therapies:

• S44.004, Impact of Siponimod on Cognition in Patients With Secondary Progressive Multiple Sclerosis: Results From Phase 3 EXPAND Study.
• S44.005, Time to Cognitive Worsening in Patients With Relapsing Multiple Sclerosis in Ocrelizumab Phase 3 Trials.
• S44.007, Benchmarks of Cognitive Performance in a Large, Representative Patient Population.

Improved disability outcome measures and predictors of disability in MS. Several abstracts assess novel disability outcome measures and neuroimaging techniques to better predict progression of clinical disability:

• P4.380, Overall Response Score: A Novel Disability Endpoint That Allows for the Integrated Assessment of Improvement and Worsening over Time in Patients with MS.
• S47.001, Longitudinal Changes in Quantitative Spinal Cord MRI in Multiple Sclerosis Patients: Results of a 5-year Study.
• P6.354, Effect of Fingolimod 0.5 mg/day versus Placebo on Two Newly Developed Expanded Disability Status Scale (EDSS) Subscales for Patients with Relapsing Remitting MS: EDSS Factor Analysis.

Is treatment response in MS an age-dependent or relapse-driven phenomenon, and is it safe to discontinue MS therapies with advancing age? Several abstracts address this question:

• S47.004, Meta-Analysis of the Age-Dependent Efficacy of Multiple Sclerosis Treatments.
• S8.005, Uncoupling the Impact on Relapses and Disability Progression: Siponimod in Relapsing and Nonrelapsing Patients With Secondary Progressive Multiple Sclerosis in the Phase 3 EXPAND Study.
• S8.008, Discontinuation of Disease Modifying Therapies in Stable MS Patients is Associated with Disability Progression Regardless of Age.

Neuromyelitis optica spectrum disorders and MS mimics. Multiple abstracts explore the differences between neuromyelitis optica spectrum disorder because of aquaporin-4 versus myelin oligodendrocyte glycoprotein antibodies; describe unique features of another recently described autoimmune disorder, autoimmune GFAP astrocytopathy; and explore the differential diagnosis of idiopathic transverse myelitis:

• S13.002, Clinical Characteristics of MOG and AQP associated Neuromyelitis Optica Spectrum Disorder (NMOSD) in Adults, through S13.008, It’s Not All Transverse Myelitis: The Differential Diagnosis of Spinal Cord Myelopathy.
• P6.409, The Mayo Clinic Glial Autoimmunity Study: Glial autoantibody (AQP4/MOG/GFAP) serostatus in recurrent longitudinally extensive transverse myelitis.
• P6.417, Evaluation of idiopathic transverse myelitis revealing specific myelopathy diagnoses.
• S6.003, Brain and Spinal Cord Imaging Features in Neuromyelitis Optica Spectrum Disorders.

Updated safety and efficacy data for recently approved or investigational MS therapies. Multiple abstracts report updated safety and efficacy data from MS clinical trials of ozanimod, ocrelizumab (Ocrevus), and hematopoietic stem cell transplantation:

• Clinical Trials Plenary Session presentation: “A Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis” by Robert J. Fox, MD.
• Contemporary Clinical Issues Plenary Session presentation: “Biosimilars and Nonbiologic Complex Drugs” by Jeffrey Allan Cohen, MD.
• S6.002, Brain MRI Activity and Atrophy Measures in Patients Receiving Continuous Ocrelizumab or Switching From Interferon Beta-1a to Ocrelizumab Therapy in the Open-Label Extension Period of the Phase 3 Trials of Ocrelizumab in Patients With Relapsing Multiple Sclerosis.
• P3.410, Clinical and Magnetic Resonance Imaging Results From RADIANCE Part B, a Multicenter, Randomized, Double-Blind, Phase 3 Trial of Ozanimod Versus Intramuscular Interferon beta-1a in Relapsing Multiple Sclerosis (RMS).
• P3.396, Ozanimod Demonstrates Efficacy and Safety in a Multicenter, Randomized, Double-Blind, Double-Dummy, Active-Controlled Phase 3 Trial of Relapsing Multiple Sclerosis (SUNBEAM).
• S36.001, Safety of Ocrelizumab in Multiple Sclerosis: Updated Analysis in Patients With Relapsing and Primary Progressive Multiple Sclerosis.
• S36.004, Nonmyeloablative hematopoietic stem cell transplantation (HSCT) is superior to disease modifying drug (DMD) treatment in highly active Relapsing Remitting Multiple Sclerosis (RRMS): interim results of the Multiple Sclerosis International Stem cell Transplant (MIST) Randomized Trial.
• S36.005, Efficacy of Ozanimod Versus Interferon beta-1a by Prior Treatment and Baseline Disability in Two Multicenter, Randomized, Double-Blind, Parallel-Group, Active-Controlled, Double-Dummy Phase 3 Studies in Relapsing Multiple Sclerosis (SUNBEAM and RADIANCE Part B).
• S36.006, Safety of Ozanimod Versus Interferon beta-1a in Two Multicenter, Randomized, Double-Blind, Parallel-Group, Active-Controlled, Double-Dummy Phase 3 Studies in Relapsing Multiple Sclerosis (SUNBEAM and RADIANCE Part B).

New thoughts on MS pathogenesis.

• Frontiers in Neuroscience Plenary Session presentation: “Pediatric MS: A Unique Window into Environmental and Genetic Risk Factors for MS” by Emmanuelle Waubant, MD.

Dr. Carter has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alder Pharmaceuticals. He has received research support from Roche/Genentech and MedDay Pharmaceuticals.
 

Rare but serious adverse events associated with alemtuzumab treatment of multiple sclerosis (MS) have recently been revealed by postmarketing surveillance, according to three new case reports and series in Neurology.

The complications include acute coronary syndrome in one patient, hemophagocytic lymphohistiocytosis (HLH) in two patients, and acute acalculous cholecystitis in eight patients.

copyright Zerbor/Thinkstock

The cardiac arrest incident occurred in a 24-year old woman with spinal-onset relapsing-remitting multiple sclerosis (RRMS) during alemtuzumab infusion. She had experienced two clinical relapses and a significant increase in cerebral and spinal MRI lesion load, despite previous treatment with natalizumab (Tysabri). The only striking thing about her medical history was allergic asthma.

On the third day of treatment, she developed severe asymptomatic sinus bradycardia (HR, 38 beats per minute), which resolved with treatment, and clinicians continued the regimen. The following morning, she experienced acute coronary syndrome, which later resolved.

The authors recommend that clinicians treating RRMS patients with alemtuzumab consider a baseline preinfusion ECG and monitoring heart rate at least hourly while infusion is being carried out.

The HLH cases occurred in a man and a woman with RRMS, both in their 20s. The woman was switched from natalizumab to alemtuzumab because of a high anti-JC virus antibody index. Both cases presented in the time frame typical of secondary autoimmunity. The female patient had an acalculous gallbladder with thickened walls and pericholecystic fluid and responded to intravenous antibiotics, but 3 weeks later she developed thrombocytopenia, coagulopathy, and anemia with abnormal liver enzymes. Treatment failed and she succumbed to the condition.

The man received alemtuzumab as first-line therapy for RRMS during the Keratinocyte Growth Factor to Prevent Autoimmunity After Alemtuzumab Treatment of Multiple Sclerosis (CAM-THY) clinical trial. He received boluses of either placebo or palifermin (Kepivance) before and after each alemtuzumab dose in order to reduce secondary autoimmunity. At 30 months after his initial cycle of alemtuzumab, he was admitted to the hospital with HLH and also developed acquired factor VIII hemophilia. He responded positively to 4 months of corticosteroid treatment combined with two doses of rituximab (Rituxan) and ultimately returned to work. However, he experienced a relapse of acquired hemophilia during later doses of corticosteroids and rituximab.

A search of the Food and Drug Administration Adverse Event Reporting System (FAERS) revealed eight cases of acute acalculous cholecystitis (AAC) – four assessed as possibly caused by alemtuzumab, and four assessed as probable – that occurred in patients with RRMS. Seven of the cases involved presentation during treatment or soon afterward, which suggests that acute cytokine release syndrome (ACRS) may be the cause. The cases did not share all of the manifestations of typical ACRS, but the researchers noted that coadministration of methylprednisolone in the RRMS dosing schedule may have masked some of the features.

Unlike typical AAC, these cases occurred primarily in females (six of eight) and were not associated with concurrent critical illnesses. Other risk factors were not consistently present. Historically, AAC is associated with treatment of older male patients in the ICU. Three of the patients underwent surgical treatment, and five received conservative treatment of antibiotics or an unspecified treatment. Seven patients recovered. The outcome in the eighth patient was not reported.

Despite these good outcomes, the authors of the report note that longer-term outcomes in this AAC population are not yet understood.

The findings led to the addition of AAC to the Warnings and Precautions section of the alemtuzumab label in October 2017.

None of the reports received funding. Some of the authors had financial ties to the pharmaceutical industry.

SOURCES: Croteau D et al. Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005422. Saarela M et al. Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005420. Ferraro D et al. Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005417.

Rare but serious adverse events associated with alemtuzumab treatment of multiple sclerosis (MS) have recently been revealed by postmarketing surveillance, according to three new case reports and series in Neurology.

The complications include acute coronary syndrome in one patient, hemophagocytic lymphohistiocytosis (HLH) in two patients, and acute acalculous cholecystitis in eight patients.

copyright Zerbor/Thinkstock

The cardiac arrest incident occurred in a 24-year old woman with spinal-onset relapsing-remitting multiple sclerosis (RRMS) during alemtuzumab infusion. She had experienced two clinical relapses and a significant increase in cerebral and spinal MRI lesion load, despite previous treatment with natalizumab (Tysabri). The only striking thing about her medical history was allergic asthma.

On the third day of treatment, she developed severe asymptomatic sinus bradycardia (HR, 38 beats per minute), which resolved with treatment, and clinicians continued the regimen. The following morning, she experienced acute coronary syndrome, which later resolved.

The authors recommend that clinicians treating RRMS patients with alemtuzumab consider a baseline preinfusion ECG and monitoring heart rate at least hourly while infusion is being carried out.

The HLH cases occurred in a man and a woman with RRMS, both in their 20s. The woman was switched from natalizumab to alemtuzumab because of a high anti-JC virus antibody index. Both cases presented in the time frame typical of secondary autoimmunity. The female patient had an acalculous gallbladder with thickened walls and pericholecystic fluid and responded to intravenous antibiotics, but 3 weeks later she developed thrombocytopenia, coagulopathy, and anemia with abnormal liver enzymes. Treatment failed and she succumbed to the condition.

The man received alemtuzumab as first-line therapy for RRMS during the Keratinocyte Growth Factor to Prevent Autoimmunity After Alemtuzumab Treatment of Multiple Sclerosis (CAM-THY) clinical trial. He received boluses of either placebo or palifermin (Kepivance) before and after each alemtuzumab dose in order to reduce secondary autoimmunity. At 30 months after his initial cycle of alemtuzumab, he was admitted to the hospital with HLH and also developed acquired factor VIII hemophilia. He responded positively to 4 months of corticosteroid treatment combined with two doses of rituximab (Rituxan) and ultimately returned to work. However, he experienced a relapse of acquired hemophilia during later doses of corticosteroids and rituximab.

A search of the Food and Drug Administration Adverse Event Reporting System (FAERS) revealed eight cases of acute acalculous cholecystitis (AAC) – four assessed as possibly caused by alemtuzumab, and four assessed as probable – that occurred in patients with RRMS. Seven of the cases involved presentation during treatment or soon afterward, which suggests that acute cytokine release syndrome (ACRS) may be the cause. The cases did not share all of the manifestations of typical ACRS, but the researchers noted that coadministration of methylprednisolone in the RRMS dosing schedule may have masked some of the features.

Unlike typical AAC, these cases occurred primarily in females (six of eight) and were not associated with concurrent critical illnesses. Other risk factors were not consistently present. Historically, AAC is associated with treatment of older male patients in the ICU. Three of the patients underwent surgical treatment, and five received conservative treatment of antibiotics or an unspecified treatment. Seven patients recovered. The outcome in the eighth patient was not reported.

Despite these good outcomes, the authors of the report note that longer-term outcomes in this AAC population are not yet understood.

The findings led to the addition of AAC to the Warnings and Precautions section of the alemtuzumab label in October 2017.

None of the reports received funding. Some of the authors had financial ties to the pharmaceutical industry.

SOURCES: Croteau D et al. Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005422. Saarela M et al. Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005420. Ferraro D et al. Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005417.

Rare but serious adverse events associated with alemtuzumab treatment of multiple sclerosis (MS) have recently been revealed by postmarketing surveillance, according to three new case reports and series in Neurology.

The complications include acute coronary syndrome in one patient, hemophagocytic lymphohistiocytosis (HLH) in two patients, and acute acalculous cholecystitis in eight patients.

copyright Zerbor/Thinkstock

The cardiac arrest incident occurred in a 24-year old woman with spinal-onset relapsing-remitting multiple sclerosis (RRMS) during alemtuzumab infusion. She had experienced two clinical relapses and a significant increase in cerebral and spinal MRI lesion load, despite previous treatment with natalizumab (Tysabri). The only striking thing about her medical history was allergic asthma.

On the third day of treatment, she developed severe asymptomatic sinus bradycardia (HR, 38 beats per minute), which resolved with treatment, and clinicians continued the regimen. The following morning, she experienced acute coronary syndrome, which later resolved.

The authors recommend that clinicians treating RRMS patients with alemtuzumab consider a baseline preinfusion ECG and monitoring heart rate at least hourly while infusion is being carried out.

The HLH cases occurred in a man and a woman with RRMS, both in their 20s. The woman was switched from natalizumab to alemtuzumab because of a high anti-JC virus antibody index. Both cases presented in the time frame typical of secondary autoimmunity. The female patient had an acalculous gallbladder with thickened walls and pericholecystic fluid and responded to intravenous antibiotics, but 3 weeks later she developed thrombocytopenia, coagulopathy, and anemia with abnormal liver enzymes. Treatment failed and she succumbed to the condition.

The man received alemtuzumab as first-line therapy for RRMS during the Keratinocyte Growth Factor to Prevent Autoimmunity After Alemtuzumab Treatment of Multiple Sclerosis (CAM-THY) clinical trial. He received boluses of either placebo or palifermin (Kepivance) before and after each alemtuzumab dose in order to reduce secondary autoimmunity. At 30 months after his initial cycle of alemtuzumab, he was admitted to the hospital with HLH and also developed acquired factor VIII hemophilia. He responded positively to 4 months of corticosteroid treatment combined with two doses of rituximab (Rituxan) and ultimately returned to work. However, he experienced a relapse of acquired hemophilia during later doses of corticosteroids and rituximab.

A search of the Food and Drug Administration Adverse Event Reporting System (FAERS) revealed eight cases of acute acalculous cholecystitis (AAC) – four assessed as possibly caused by alemtuzumab, and four assessed as probable – that occurred in patients with RRMS. Seven of the cases involved presentation during treatment or soon afterward, which suggests that acute cytokine release syndrome (ACRS) may be the cause. The cases did not share all of the manifestations of typical ACRS, but the researchers noted that coadministration of methylprednisolone in the RRMS dosing schedule may have masked some of the features.

Unlike typical AAC, these cases occurred primarily in females (six of eight) and were not associated with concurrent critical illnesses. Other risk factors were not consistently present. Historically, AAC is associated with treatment of older male patients in the ICU. Three of the patients underwent surgical treatment, and five received conservative treatment of antibiotics or an unspecified treatment. Seven patients recovered. The outcome in the eighth patient was not reported.

Despite these good outcomes, the authors of the report note that longer-term outcomes in this AAC population are not yet understood.

The findings led to the addition of AAC to the Warnings and Precautions section of the alemtuzumab label in October 2017.

None of the reports received funding. Some of the authors had financial ties to the pharmaceutical industry.

SOURCES: Croteau D et al. Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005422. Saarela M et al. Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005420. Ferraro D et al. Neurology. 2018 Mar 30. doi: 10.1212/WNL.0000000000005417.

Read the digital edition here.

Read the digital edition here.

Read the digital edition here.

SAN DIEGO—Patients with relapsing-remitting multiple sclerosis (MS) who received high doses of the novel human endogenous retrovirus-W antagonist GNbAC1 in a phase II trial had evidence of remyelination at week 24, according to research described at the ACTRIMS 2018 Forum. The treatment did not meet the primary end point of reduction in the number of active lesions seen on MRI, however.

GNbAC1 is a monoclonal antibody that targets and blocks the envelope protein pHER-W ENV, a potent agonist of Toll-like receptor 4 (TLR4), said study author Robert Glanzman, MD. It thereby inhibits TLR4-mediated pathogenicity, which includes activation of macrophages and microglia into proinflammatory phenotypes and direct inhibition of remyelination.

—Doug Brunk

SAN DIEGO—Patients with relapsing-remitting multiple sclerosis (MS) who received high doses of the novel human endogenous retrovirus-W antagonist GNbAC1 in a phase II trial had evidence of remyelination at week 24, according to research described at the ACTRIMS 2018 Forum. The treatment did not meet the primary end point of reduction in the number of active lesions seen on MRI, however.

GNbAC1 is a monoclonal antibody that targets and blocks the envelope protein pHER-W ENV, a potent agonist of Toll-like receptor 4 (TLR4), said study author Robert Glanzman, MD. It thereby inhibits TLR4-mediated pathogenicity, which includes activation of macrophages and microglia into proinflammatory phenotypes and direct inhibition of remyelination.

—Doug Brunk

SAN DIEGO—Patients with relapsing-remitting multiple sclerosis (MS) who received high doses of the novel human endogenous retrovirus-W antagonist GNbAC1 in a phase II trial had evidence of remyelination at week 24, according to research described at the ACTRIMS 2018 Forum. The treatment did not meet the primary end point of reduction in the number of active lesions seen on MRI, however.

GNbAC1 is a monoclonal antibody that targets and blocks the envelope protein pHER-W ENV, a potent agonist of Toll-like receptor 4 (TLR4), said study author Robert Glanzman, MD. It thereby inhibits TLR4-mediated pathogenicity, which includes activation of macrophages and microglia into proinflammatory phenotypes and direct inhibition of remyelination.

—Doug Brunk

SAN DIEGO—The monoclonal antibody alemtuzumab can be an effective treatment for people living with multiple sclerosis (MS), but the agent is also associated with an increased risk for developing other autoimmune diseases, leaving clinicians with a conundrum.

Alemtuzumab is an efficacious treatment in MS that can slow the rate of brain atrophy over the long term, said Alasdair Coles, MD, Professor of Neuroimmunology at the University of Cambridge, United Kingdom, at ACTRIMS 2018 Forum. “But one or two years after each cycle of alemtuzumab, patients are at high risk of autoimmune diseases. This is the not-too-worrying thyroid disease, but there are some troubling and potentially serious complications at lower frequency.”

Considering Proposed Mechanisms

Dr. Coles and other researchers are investigating the cellular mechanism underlying the paradoxical autoimmunity associated with alemtuzumab. Some have suggested that faulty immune B cells could be the culprit, but “there is no difference in B cell reconstitution between those who do and do not get autoimmunity,” said Dr. Coles. “So, we do not think that autoimmunity after alemtuzumab is primarily a B cell problem.” Other investigators have suggested that the mechanism is the depletion of a key immune regulatory cell associated with alemtuzumab. One such example is depletion in T cells as part of an autoimmune cascade that involve CD52-high expressing cells and sialic acid-binding immunoglobulin-like lectin 10. “We do not believe this,” said Dr. Coles. “We cannot replicate the finding of reduced CD52 high cells in type 1 diabetes or MS, nor the binding of SIGLEC-10 to CD52.”

Along with his colleague Joanne Jones, MD, PhD, also at the University of Cambridge, Dr. Coles and his team instead propose that autoimmunity after alemtuzumab therapy is associated with a homeostatic proliferation of T cells in the context of a defective thymus. “We see thymic function reduced after alemtuzumab for a few months. We do not know if alemtuzumab is having a direct impact on the thymus or if it is an indirect effect through a cytokine storm at the time of administering alemtuzumab.”

In addition, in contrast with B cells, both CD4-positive and CD8-positive T cells are clonally restricted after alemtuzumab treatment, said Dr. Coles. “These are the only changes that distinguish patients who do and do not develop autoimmunity,” he said. “Those who develop autoimmunity have reduced clonality and impaired thymic function, compared with those who do not.”

The theory is that the reconstitution of T cells after alemtuzumab comes preferentially from expansion of peripheral T cells, rather than naïve T cells from the thymus, which leads to a higher representation of autoreactive T cells and thus leads to B-cell- and antibody-mediated autoimmunity.

The Bigger Picture

The autoimmune phenomenon is not unique to alemtuzumab or MS. “This turns out to be one of a family of clinical situations where the reconstitution of the depleted lymphocyte repertoire leads to autoimmunity,” Dr. Coles said. A similar effect was seen years ago when very lymphopenic patients with HIV were given antiviral therapy. About 10% of treated patients had this effect. Furthermore, about 10% of patients who undergo bone marrow transplant may experience similar autoimmune concerns.

“What we do think is true is that we have tapped into a classical expression of autoimmunity,” Dr. Coles said. “Alemtuzumab is a fantastic opportunity to study the mechanisms underlying lymphopenia-associated autoimmunity.”

A Tantalizing Prospect

“It is a tantalizing prospect that susceptible individuals might be identified in the future prior to treatment,” Dr. Coles said. “We looked at IL-21. We showed that after treatment, and perhaps more interestingly, before treatment with alemtuzumab, serum levels of IL-21 are greater in those who subsequently develop autoimmune disease. This [finding] suggests [that] some individuals are prone to developing autoimmune disease and could be identified potentially prior to treatment with alemtuzumab.”

More research is needed, including the development of more sensitive IL-21 assays for use in this population, Dr. Coles said. “Please do not attempt to predict the risk of autoimmunity after alemtuzumab using the current commercial assays. This is a source of some frustration for me.” A potential route of lymphocyte repertoire reconstitution after alemtuzumab is thymic reconstitution, which could lead to a more diverse immune repertoire, Dr. Coles said. “If we can direct reconstitution through the thymic reconstitution, we should be able to prevent autoimmunity.”

Dr. Coles receives honoraria for travel and speaking from Sanofi Genzyme, which markets alemtuzumab.

—Damian McNamara

SAN DIEGO—The monoclonal antibody alemtuzumab can be an effective treatment for people living with multiple sclerosis (MS), but the agent is also associated with an increased risk for developing other autoimmune diseases, leaving clinicians with a conundrum.

Alemtuzumab is an efficacious treatment in MS that can slow the rate of brain atrophy over the long term, said Alasdair Coles, MD, Professor of Neuroimmunology at the University of Cambridge, United Kingdom, at ACTRIMS 2018 Forum. “But one or two years after each cycle of alemtuzumab, patients are at high risk of autoimmune diseases. This is the not-too-worrying thyroid disease, but there are some troubling and potentially serious complications at lower frequency.”

Considering Proposed Mechanisms

Dr. Coles and other researchers are investigating the cellular mechanism underlying the paradoxical autoimmunity associated with alemtuzumab. Some have suggested that faulty immune B cells could be the culprit, but “there is no difference in B cell reconstitution between those who do and do not get autoimmunity,” said Dr. Coles. “So, we do not think that autoimmunity after alemtuzumab is primarily a B cell problem.” Other investigators have suggested that the mechanism is the depletion of a key immune regulatory cell associated with alemtuzumab. One such example is depletion in T cells as part of an autoimmune cascade that involve CD52-high expressing cells and sialic acid-binding immunoglobulin-like lectin 10. “We do not believe this,” said Dr. Coles. “We cannot replicate the finding of reduced CD52 high cells in type 1 diabetes or MS, nor the binding of SIGLEC-10 to CD52.”

Along with his colleague Joanne Jones, MD, PhD, also at the University of Cambridge, Dr. Coles and his team instead propose that autoimmunity after alemtuzumab therapy is associated with a homeostatic proliferation of T cells in the context of a defective thymus. “We see thymic function reduced after alemtuzumab for a few months. We do not know if alemtuzumab is having a direct impact on the thymus or if it is an indirect effect through a cytokine storm at the time of administering alemtuzumab.”

In addition, in contrast with B cells, both CD4-positive and CD8-positive T cells are clonally restricted after alemtuzumab treatment, said Dr. Coles. “These are the only changes that distinguish patients who do and do not develop autoimmunity,” he said. “Those who develop autoimmunity have reduced clonality and impaired thymic function, compared with those who do not.”

The theory is that the reconstitution of T cells after alemtuzumab comes preferentially from expansion of peripheral T cells, rather than naïve T cells from the thymus, which leads to a higher representation of autoreactive T cells and thus leads to B-cell- and antibody-mediated autoimmunity.

The Bigger Picture

The autoimmune phenomenon is not unique to alemtuzumab or MS. “This turns out to be one of a family of clinical situations where the reconstitution of the depleted lymphocyte repertoire leads to autoimmunity,” Dr. Coles said. A similar effect was seen years ago when very lymphopenic patients with HIV were given antiviral therapy. About 10% of treated patients had this effect. Furthermore, about 10% of patients who undergo bone marrow transplant may experience similar autoimmune concerns.

“What we do think is true is that we have tapped into a classical expression of autoimmunity,” Dr. Coles said. “Alemtuzumab is a fantastic opportunity to study the mechanisms underlying lymphopenia-associated autoimmunity.”

A Tantalizing Prospect

“It is a tantalizing prospect that susceptible individuals might be identified in the future prior to treatment,” Dr. Coles said. “We looked at IL-21. We showed that after treatment, and perhaps more interestingly, before treatment with alemtuzumab, serum levels of IL-21 are greater in those who subsequently develop autoimmune disease. This [finding] suggests [that] some individuals are prone to developing autoimmune disease and could be identified potentially prior to treatment with alemtuzumab.”

More research is needed, including the development of more sensitive IL-21 assays for use in this population, Dr. Coles said. “Please do not attempt to predict the risk of autoimmunity after alemtuzumab using the current commercial assays. This is a source of some frustration for me.” A potential route of lymphocyte repertoire reconstitution after alemtuzumab is thymic reconstitution, which could lead to a more diverse immune repertoire, Dr. Coles said. “If we can direct reconstitution through the thymic reconstitution, we should be able to prevent autoimmunity.”

Dr. Coles receives honoraria for travel and speaking from Sanofi Genzyme, which markets alemtuzumab.

—Damian McNamara

SAN DIEGO—The monoclonal antibody alemtuzumab can be an effective treatment for people living with multiple sclerosis (MS), but the agent is also associated with an increased risk for developing other autoimmune diseases, leaving clinicians with a conundrum.

Alemtuzumab is an efficacious treatment in MS that can slow the rate of brain atrophy over the long term, said Alasdair Coles, MD, Professor of Neuroimmunology at the University of Cambridge, United Kingdom, at ACTRIMS 2018 Forum. “But one or two years after each cycle of alemtuzumab, patients are at high risk of autoimmune diseases. This is the not-too-worrying thyroid disease, but there are some troubling and potentially serious complications at lower frequency.”

Considering Proposed Mechanisms

Dr. Coles and other researchers are investigating the cellular mechanism underlying the paradoxical autoimmunity associated with alemtuzumab. Some have suggested that faulty immune B cells could be the culprit, but “there is no difference in B cell reconstitution between those who do and do not get autoimmunity,” said Dr. Coles. “So, we do not think that autoimmunity after alemtuzumab is primarily a B cell problem.” Other investigators have suggested that the mechanism is the depletion of a key immune regulatory cell associated with alemtuzumab. One such example is depletion in T cells as part of an autoimmune cascade that involve CD52-high expressing cells and sialic acid-binding immunoglobulin-like lectin 10. “We do not believe this,” said Dr. Coles. “We cannot replicate the finding of reduced CD52 high cells in type 1 diabetes or MS, nor the binding of SIGLEC-10 to CD52.”

Along with his colleague Joanne Jones, MD, PhD, also at the University of Cambridge, Dr. Coles and his team instead propose that autoimmunity after alemtuzumab therapy is associated with a homeostatic proliferation of T cells in the context of a defective thymus. “We see thymic function reduced after alemtuzumab for a few months. We do not know if alemtuzumab is having a direct impact on the thymus or if it is an indirect effect through a cytokine storm at the time of administering alemtuzumab.”

In addition, in contrast with B cells, both CD4-positive and CD8-positive T cells are clonally restricted after alemtuzumab treatment, said Dr. Coles. “These are the only changes that distinguish patients who do and do not develop autoimmunity,” he said. “Those who develop autoimmunity have reduced clonality and impaired thymic function, compared with those who do not.”

The theory is that the reconstitution of T cells after alemtuzumab comes preferentially from expansion of peripheral T cells, rather than naïve T cells from the thymus, which leads to a higher representation of autoreactive T cells and thus leads to B-cell- and antibody-mediated autoimmunity.

The Bigger Picture

The autoimmune phenomenon is not unique to alemtuzumab or MS. “This turns out to be one of a family of clinical situations where the reconstitution of the depleted lymphocyte repertoire leads to autoimmunity,” Dr. Coles said. A similar effect was seen years ago when very lymphopenic patients with HIV were given antiviral therapy. About 10% of treated patients had this effect. Furthermore, about 10% of patients who undergo bone marrow transplant may experience similar autoimmune concerns.

“What we do think is true is that we have tapped into a classical expression of autoimmunity,” Dr. Coles said. “Alemtuzumab is a fantastic opportunity to study the mechanisms underlying lymphopenia-associated autoimmunity.”

A Tantalizing Prospect

“It is a tantalizing prospect that susceptible individuals might be identified in the future prior to treatment,” Dr. Coles said. “We looked at IL-21. We showed that after treatment, and perhaps more interestingly, before treatment with alemtuzumab, serum levels of IL-21 are greater in those who subsequently develop autoimmune disease. This [finding] suggests [that] some individuals are prone to developing autoimmune disease and could be identified potentially prior to treatment with alemtuzumab.”

More research is needed, including the development of more sensitive IL-21 assays for use in this population, Dr. Coles said. “Please do not attempt to predict the risk of autoimmunity after alemtuzumab using the current commercial assays. This is a source of some frustration for me.” A potential route of lymphocyte repertoire reconstitution after alemtuzumab is thymic reconstitution, which could lead to a more diverse immune repertoire, Dr. Coles said. “If we can direct reconstitution through the thymic reconstitution, we should be able to prevent autoimmunity.”

Dr. Coles receives honoraria for travel and speaking from Sanofi Genzyme, which markets alemtuzumab.

—Damian McNamara

SAN DIEGO—Patients with multiple sclerosis (MS) who are treated by primary care physicians are significantly less likely to receive disease-modifying therapies (DMTs) than patients treated by neurologists, even though they have more symptoms, according to a study reported at the ACTRIMS 2018 Forum.

Approximately 85% of patients treated by neurologists at MS centers receive DMTs, compared with 51% of those treated at primary care offices.

In addition, patients treated at primary care practices have several kinds of symptoms. “This [finding] suggests there is a critical need for neurologists, especially MS specialists, to reach out and collaborate with these primary care providers and provide education about how to manage MS and improve both the treatment and the outcomes,” said lead study author Michael T. Halpern, MD, PhD, Associate Professor of Public Health at Temple University in Philadelphia.

—Randy Dotinga

SAN DIEGO—Patients with multiple sclerosis (MS) who are treated by primary care physicians are significantly less likely to receive disease-modifying therapies (DMTs) than patients treated by neurologists, even though they have more symptoms, according to a study reported at the ACTRIMS 2018 Forum.

Approximately 85% of patients treated by neurologists at MS centers receive DMTs, compared with 51% of those treated at primary care offices.

In addition, patients treated at primary care practices have several kinds of symptoms. “This [finding] suggests there is a critical need for neurologists, especially MS specialists, to reach out and collaborate with these primary care providers and provide education about how to manage MS and improve both the treatment and the outcomes,” said lead study author Michael T. Halpern, MD, PhD, Associate Professor of Public Health at Temple University in Philadelphia.

—Randy Dotinga

SAN DIEGO—Patients with multiple sclerosis (MS) who are treated by primary care physicians are significantly less likely to receive disease-modifying therapies (DMTs) than patients treated by neurologists, even though they have more symptoms, according to a study reported at the ACTRIMS 2018 Forum.

Approximately 85% of patients treated by neurologists at MS centers receive DMTs, compared with 51% of those treated at primary care offices.

In addition, patients treated at primary care practices have several kinds of symptoms. “This [finding] suggests there is a critical need for neurologists, especially MS specialists, to reach out and collaborate with these primary care providers and provide education about how to manage MS and improve both the treatment and the outcomes,” said lead study author Michael T. Halpern, MD, PhD, Associate Professor of Public Health at Temple University in Philadelphia.

—Randy Dotinga

SAN DIEGO—Among patients with multiple sclerosis (MS) who are positive for the John Cunningham virus (JCV), extended-interval dosing of natalizumab is associated with a clinically and statistically significant reduction in the risk of progressive multifocal leukoencephalopathy (PML), compared with standard-interval dosing, according to a study presented at the ACTRIMS 2018 Forum.

The observed risk reduction may change clinical practice and save lives, said lead study author Lana Zhovtis Ryerson, MD, Assistant Professor of Neurology at the New York University School of Medicine.

Real-World Safety Data

While natalizumab may be an effective medication for relapsing MS at the approved dose of 300 mg IV every four weeks, the treatment is associated with the risk of PML, a rare but potentially deadly brain infection. A prior retrospective study by the researchers suggested that extending the dosing interval to as long as eight weeks does not negatively affect the medication’s efficacy. The impact of extended-interval dosing on PML risk has been inconclusive, however.

To assess whether extended-interval dosing (ie, an average dosing interval of between five and 12 weeks) reduces PML risk, compared with standard-interval dosing (ie, an average dosing interval of between three and five weeks), Dr. Zhovtis Ryerson and colleagues analyzed data through June 1, 2017, from the TOUCH Prescribing Program, a mandatory US risk evaluation and mitigation program for natalizumab. The investigators included only patients who were anti–JCV antibody positive in their analyses. They excluded patients with any gap in treatment of more than 12 weeks.

The investigators analyzed the data using three definitions of standard-interval dosing and extended-interval dosing. Their first analysis defined extended-interval dosing as 15 or fewer infusions in the last 18 months, whereas standard-interval dosing was defined as more than 15 infusions in the last 18 months. The second analysis defined extended-interval dosing as at least six months of consecutive extended-interval infusions at any time in a patient’s dosing history. The third analysis defined extended-interval dosing as an average of 10 or fewer infusions per year during a patient’s total follow-up time, whereas standard-interval dosing was defined as an average of more than 10 infusions per year during a patient’s total follow-up time.

Using the life-table method, the estimated risk of PML per 1,000 patients at the highest number of doses (ie, between 61 doses and 72 doses) was 1.70 in the extended-interval dosing group, versus 4.46 in the standard-interval dosing group, for the first analysis. In the second analysis, the estimated risk was 2.04 in the extended-interval dosing group, versus 4.74 in the standard-interval dosing group.In the first analysis, Kaplan-Meier estimates found “a clinically meaningful and statistically significant divergence of cumulative risk of PML, with a 94% risk reduction” with extended-interval dosing, compared with standard-interval dosing, Dr. Zhovtis Ryerson said. There were three PML cases in the extended-interval dosing group (n = 1,988), versus 89 PML cases in the standard-interval dosing group (n = 13,132). In the second analysis, extended-interval dosing was associated with an 88% risk reduction, with 12 PML cases in the extended-interval dosing cohort (n = 3,331), versus 71 PML cases in the standard-interval dosing group (n = 15,424). In the third analysis, there were no PML cases in the extended-interval dosing group (n = 815), compared with 96 cases in the standard-interval dosing group (n = 23,168).

Parsing the TOUCH Registry

With more than 90,000 patients enrolled as of June 1, 2017, the TOUCH Prescribing Program provided the largest available data source regarding PML risk in patients on extended-interval dosing, the researchers said.

“The TOUCH database provides us with real-world data, which are complicated,” Dr. Zhovtis Ryerson said. “Accidental extended-dose infusions happen. Vacations, sicknesses, and dosing gaps due to pregnancy or other reasons occur. But these are not the patients that we are trying to parse out. We are more interested in patients with consecutive and prolonged treatment on extended dose.”

The complicated nature of the data was part of the rationale for developing the three definitions that enabled the investigators to look at extended-interval dosing in multiple ways. “For the primary definition, we utilized an approach that we see in our own clinics—where patients start out on standard dose and are slowly transitioned to extended dose after some months of treatment,” said Dr. Zhovtis Ryerson.

The methodology may have led to selection biases, however. “The patients in the extended-dosing cohorts spent more time on natalizumab—therefore potentially increasing their risk for PML,” she said. “On the other hand, these patients spent time on standard dose, a median of two years, without getting PML before moving on to the extended-dose schedule,” which could have led to fewer PML cases in the extended-interval dosing cohorts. Across all three definitions, the average dosing interval was between 35 days and 43 days for extended-interval dosing, compared with between 30 days and 31 days for standard-interval dosing.

The TOUCH registry does not include efficacy data, and prospective studies are needed to determine whether natalizumab’s efficacy is maintained with extended-interval dosing, the researchers said.

—Fred Balzac

Suggested Reading

Bomprezzi R, Pawate S. Extended interval dosing of natalizumab: a two-center, 7-year experience. Ther Adv Neurol Disord. 2014;7(5):227-231.

Fine AJ, Sorbello A, Kortepeter C, et al. Progressive multifocal leukoencephalopathy after natalizumab discontinuation. Ann Neurol. 2014;75(1):108-115.

Ho PR, Koendgen H, Campbell N, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: a retrospective analysis of data from four clinical studies. Lancet Neurol. 2017;16(11):925-933.

Zhovtis Ryerson L, Frohman TC, Foley J, et al. Extended interval dosing of natalizumab in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016;87(8):885-889.

SAN DIEGO—Among patients with multiple sclerosis (MS) who are positive for the John Cunningham virus (JCV), extended-interval dosing of natalizumab is associated with a clinically and statistically significant reduction in the risk of progressive multifocal leukoencephalopathy (PML), compared with standard-interval dosing, according to a study presented at the ACTRIMS 2018 Forum.

The observed risk reduction may change clinical practice and save lives, said lead study author Lana Zhovtis Ryerson, MD, Assistant Professor of Neurology at the New York University School of Medicine.

Real-World Safety Data

While natalizumab may be an effective medication for relapsing MS at the approved dose of 300 mg IV every four weeks, the treatment is associated with the risk of PML, a rare but potentially deadly brain infection. A prior retrospective study by the researchers suggested that extending the dosing interval to as long as eight weeks does not negatively affect the medication’s efficacy. The impact of extended-interval dosing on PML risk has been inconclusive, however.

To assess whether extended-interval dosing (ie, an average dosing interval of between five and 12 weeks) reduces PML risk, compared with standard-interval dosing (ie, an average dosing interval of between three and five weeks), Dr. Zhovtis Ryerson and colleagues analyzed data through June 1, 2017, from the TOUCH Prescribing Program, a mandatory US risk evaluation and mitigation program for natalizumab. The investigators included only patients who were anti–JCV antibody positive in their analyses. They excluded patients with any gap in treatment of more than 12 weeks.

The investigators analyzed the data using three definitions of standard-interval dosing and extended-interval dosing. Their first analysis defined extended-interval dosing as 15 or fewer infusions in the last 18 months, whereas standard-interval dosing was defined as more than 15 infusions in the last 18 months. The second analysis defined extended-interval dosing as at least six months of consecutive extended-interval infusions at any time in a patient’s dosing history. The third analysis defined extended-interval dosing as an average of 10 or fewer infusions per year during a patient’s total follow-up time, whereas standard-interval dosing was defined as an average of more than 10 infusions per year during a patient’s total follow-up time.

Using the life-table method, the estimated risk of PML per 1,000 patients at the highest number of doses (ie, between 61 doses and 72 doses) was 1.70 in the extended-interval dosing group, versus 4.46 in the standard-interval dosing group, for the first analysis. In the second analysis, the estimated risk was 2.04 in the extended-interval dosing group, versus 4.74 in the standard-interval dosing group.In the first analysis, Kaplan-Meier estimates found “a clinically meaningful and statistically significant divergence of cumulative risk of PML, with a 94% risk reduction” with extended-interval dosing, compared with standard-interval dosing, Dr. Zhovtis Ryerson said. There were three PML cases in the extended-interval dosing group (n = 1,988), versus 89 PML cases in the standard-interval dosing group (n = 13,132). In the second analysis, extended-interval dosing was associated with an 88% risk reduction, with 12 PML cases in the extended-interval dosing cohort (n = 3,331), versus 71 PML cases in the standard-interval dosing group (n = 15,424). In the third analysis, there were no PML cases in the extended-interval dosing group (n = 815), compared with 96 cases in the standard-interval dosing group (n = 23,168).

Parsing the TOUCH Registry

With more than 90,000 patients enrolled as of June 1, 2017, the TOUCH Prescribing Program provided the largest available data source regarding PML risk in patients on extended-interval dosing, the researchers said.

“The TOUCH database provides us with real-world data, which are complicated,” Dr. Zhovtis Ryerson said. “Accidental extended-dose infusions happen. Vacations, sicknesses, and dosing gaps due to pregnancy or other reasons occur. But these are not the patients that we are trying to parse out. We are more interested in patients with consecutive and prolonged treatment on extended dose.”

The complicated nature of the data was part of the rationale for developing the three definitions that enabled the investigators to look at extended-interval dosing in multiple ways. “For the primary definition, we utilized an approach that we see in our own clinics—where patients start out on standard dose and are slowly transitioned to extended dose after some months of treatment,” said Dr. Zhovtis Ryerson.

The methodology may have led to selection biases, however. “The patients in the extended-dosing cohorts spent more time on natalizumab—therefore potentially increasing their risk for PML,” she said. “On the other hand, these patients spent time on standard dose, a median of two years, without getting PML before moving on to the extended-dose schedule,” which could have led to fewer PML cases in the extended-interval dosing cohorts. Across all three definitions, the average dosing interval was between 35 days and 43 days for extended-interval dosing, compared with between 30 days and 31 days for standard-interval dosing.

The TOUCH registry does not include efficacy data, and prospective studies are needed to determine whether natalizumab’s efficacy is maintained with extended-interval dosing, the researchers said.

—Fred Balzac

Suggested Reading

Bomprezzi R, Pawate S. Extended interval dosing of natalizumab: a two-center, 7-year experience. Ther Adv Neurol Disord. 2014;7(5):227-231.

Fine AJ, Sorbello A, Kortepeter C, et al. Progressive multifocal leukoencephalopathy after natalizumab discontinuation. Ann Neurol. 2014;75(1):108-115.

Ho PR, Koendgen H, Campbell N, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: a retrospective analysis of data from four clinical studies. Lancet Neurol. 2017;16(11):925-933.

Zhovtis Ryerson L, Frohman TC, Foley J, et al. Extended interval dosing of natalizumab in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016;87(8):885-889.

SAN DIEGO—Among patients with multiple sclerosis (MS) who are positive for the John Cunningham virus (JCV), extended-interval dosing of natalizumab is associated with a clinically and statistically significant reduction in the risk of progressive multifocal leukoencephalopathy (PML), compared with standard-interval dosing, according to a study presented at the ACTRIMS 2018 Forum.

The observed risk reduction may change clinical practice and save lives, said lead study author Lana Zhovtis Ryerson, MD, Assistant Professor of Neurology at the New York University School of Medicine.

Real-World Safety Data

While natalizumab may be an effective medication for relapsing MS at the approved dose of 300 mg IV every four weeks, the treatment is associated with the risk of PML, a rare but potentially deadly brain infection. A prior retrospective study by the researchers suggested that extending the dosing interval to as long as eight weeks does not negatively affect the medication’s efficacy. The impact of extended-interval dosing on PML risk has been inconclusive, however.

To assess whether extended-interval dosing (ie, an average dosing interval of between five and 12 weeks) reduces PML risk, compared with standard-interval dosing (ie, an average dosing interval of between three and five weeks), Dr. Zhovtis Ryerson and colleagues analyzed data through June 1, 2017, from the TOUCH Prescribing Program, a mandatory US risk evaluation and mitigation program for natalizumab. The investigators included only patients who were anti–JCV antibody positive in their analyses. They excluded patients with any gap in treatment of more than 12 weeks.

The investigators analyzed the data using three definitions of standard-interval dosing and extended-interval dosing. Their first analysis defined extended-interval dosing as 15 or fewer infusions in the last 18 months, whereas standard-interval dosing was defined as more than 15 infusions in the last 18 months. The second analysis defined extended-interval dosing as at least six months of consecutive extended-interval infusions at any time in a patient’s dosing history. The third analysis defined extended-interval dosing as an average of 10 or fewer infusions per year during a patient’s total follow-up time, whereas standard-interval dosing was defined as an average of more than 10 infusions per year during a patient’s total follow-up time.

Using the life-table method, the estimated risk of PML per 1,000 patients at the highest number of doses (ie, between 61 doses and 72 doses) was 1.70 in the extended-interval dosing group, versus 4.46 in the standard-interval dosing group, for the first analysis. In the second analysis, the estimated risk was 2.04 in the extended-interval dosing group, versus 4.74 in the standard-interval dosing group.In the first analysis, Kaplan-Meier estimates found “a clinically meaningful and statistically significant divergence of cumulative risk of PML, with a 94% risk reduction” with extended-interval dosing, compared with standard-interval dosing, Dr. Zhovtis Ryerson said. There were three PML cases in the extended-interval dosing group (n = 1,988), versus 89 PML cases in the standard-interval dosing group (n = 13,132). In the second analysis, extended-interval dosing was associated with an 88% risk reduction, with 12 PML cases in the extended-interval dosing cohort (n = 3,331), versus 71 PML cases in the standard-interval dosing group (n = 15,424). In the third analysis, there were no PML cases in the extended-interval dosing group (n = 815), compared with 96 cases in the standard-interval dosing group (n = 23,168).

Parsing the TOUCH Registry

With more than 90,000 patients enrolled as of June 1, 2017, the TOUCH Prescribing Program provided the largest available data source regarding PML risk in patients on extended-interval dosing, the researchers said.

“The TOUCH database provides us with real-world data, which are complicated,” Dr. Zhovtis Ryerson said. “Accidental extended-dose infusions happen. Vacations, sicknesses, and dosing gaps due to pregnancy or other reasons occur. But these are not the patients that we are trying to parse out. We are more interested in patients with consecutive and prolonged treatment on extended dose.”

The complicated nature of the data was part of the rationale for developing the three definitions that enabled the investigators to look at extended-interval dosing in multiple ways. “For the primary definition, we utilized an approach that we see in our own clinics—where patients start out on standard dose and are slowly transitioned to extended dose after some months of treatment,” said Dr. Zhovtis Ryerson.

The methodology may have led to selection biases, however. “The patients in the extended-dosing cohorts spent more time on natalizumab—therefore potentially increasing their risk for PML,” she said. “On the other hand, these patients spent time on standard dose, a median of two years, without getting PML before moving on to the extended-dose schedule,” which could have led to fewer PML cases in the extended-interval dosing cohorts. Across all three definitions, the average dosing interval was between 35 days and 43 days for extended-interval dosing, compared with between 30 days and 31 days for standard-interval dosing.

The TOUCH registry does not include efficacy data, and prospective studies are needed to determine whether natalizumab’s efficacy is maintained with extended-interval dosing, the researchers said.

—Fred Balzac

Suggested Reading

Bomprezzi R, Pawate S. Extended interval dosing of natalizumab: a two-center, 7-year experience. Ther Adv Neurol Disord. 2014;7(5):227-231.

Fine AJ, Sorbello A, Kortepeter C, et al. Progressive multifocal leukoencephalopathy after natalizumab discontinuation. Ann Neurol. 2014;75(1):108-115.

Ho PR, Koendgen H, Campbell N, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: a retrospective analysis of data from four clinical studies. Lancet Neurol. 2017;16(11):925-933.

Zhovtis Ryerson L, Frohman TC, Foley J, et al. Extended interval dosing of natalizumab in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016;87(8):885-889.

SAN DIEGO—Absence of miR-219, a microRNA (miRNA), in CSF could be a biomarker of multiple sclerosis (MS), according to data presented at the ACTRIMS 2018 Forum. If confirmed, the results could provide an objective measure to improve the diagnosis of MS.

When demyelination occurs in healthy individuals, remyelination follows. In the latter process, oligodendrocyte precursor cells repopulate the demyelinated area and create new myelin. Although large numbers of these cells surround new MS lesions, the precursor cells may fail to differentiate into mature oligodendrocytes, and thus fail to remyelinate the lesions. Data suggest that miR-219 is necessary for oligodendrocyte precursor cell differentiation in mice and rats.

Brigit A. de Jong, MD, PhD, a neurologist at Radboud University Medical Center in Nijmegen, the Netherlands, and colleagues found decreased miR-219 expression in the tissue of patients with MS, compared with healthy controls. To investigate whether CSF levels of miR-219 could be a biomarker of MS, the investigators performed quantitative polymerase chain reaction on samples taken from patients with MS and controls.

An Analysis of Three Cohorts

Dr. de Jong and colleagues analyzed three independent cohorts in their study. Cohort 1 included 24 participants, Cohort 2 included 115 participants, and Cohort 3 included 112 participants. Study participants included healthy controls and patients with clinically isolated syndrome (CIS), relapsing-remitting MS, secondary progressive MS, primary progressive MS, inflammatory neurologic disease, noninflammatory neurologic disease, Alzheimer’s disease, or idiopathic intracranial hypertension. In all, 148 of the participants (59%) were women.

The absence of miR-219 in CSF was consistently associated with MS. In Cohort 1, the odds ratio for a diagnosis of progressive MS was 20.8, compared with controls, if CSF miR-219 was undetectable. In Cohort 2, the odds ratio for a diagnosis of MS or CIS was 2.6, compared with controls, if CSF miR-219 was undetectable. The odds ratio for a diagnosis of progressive MS was 3.6, compared with other neurologic disorders, if CSF miR-219 was undetectable in this cohort. In Cohort 3, the odds ratio for a diagnosis of MS was 39.7, compared with controls, if CSF miR-219 was undetectable.

Advantages of miRNAs

Detecting miRNAs in CSF is difficult because of the low levels at which they are present, said the authors. Nevertheless, miRNAs could be advantageous biomarkers because they are highly stable in body fluids, and the corresponding detection assays can be developed and multiplexed easily. Assessing the performance of miR-219 as a biomarker in situations in which MS cannot be differentiated from MS mimics will require future research, they concluded.

—Erik Greb

Suggested Reading

Agah E, Zardoui A, Saghazadeh A, et al. Osteopontin (OPN) as a CSF and blood biomarker for multiple sclerosis: A systematic review and meta-analysis. PLoS One. 2018 Jan 18;13(1):e0190252.

Bruinsma IB, van Dijk M, Bridel C, et al. Regulator of oligodendrocyte maturation, miR-219, a potential biomarker for MS. J Neuroinflammation. 2017;14(1):235.

Puz P, Steposz A, Lasek-Bal A, et al. Diagnostic methods used in searching for markers of atrophy in patients with multiple sclerosis. Neurol Res. 2018;40(2):110-116.

SAN DIEGO—Absence of miR-219, a microRNA (miRNA), in CSF could be a biomarker of multiple sclerosis (MS), according to data presented at the ACTRIMS 2018 Forum. If confirmed, the results could provide an objective measure to improve the diagnosis of MS.

When demyelination occurs in healthy individuals, remyelination follows. In the latter process, oligodendrocyte precursor cells repopulate the demyelinated area and create new myelin. Although large numbers of these cells surround new MS lesions, the precursor cells may fail to differentiate into mature oligodendrocytes, and thus fail to remyelinate the lesions. Data suggest that miR-219 is necessary for oligodendrocyte precursor cell differentiation in mice and rats.

Brigit A. de Jong, MD, PhD, a neurologist at Radboud University Medical Center in Nijmegen, the Netherlands, and colleagues found decreased miR-219 expression in the tissue of patients with MS, compared with healthy controls. To investigate whether CSF levels of miR-219 could be a biomarker of MS, the investigators performed quantitative polymerase chain reaction on samples taken from patients with MS and controls.

An Analysis of Three Cohorts

Dr. de Jong and colleagues analyzed three independent cohorts in their study. Cohort 1 included 24 participants, Cohort 2 included 115 participants, and Cohort 3 included 112 participants. Study participants included healthy controls and patients with clinically isolated syndrome (CIS), relapsing-remitting MS, secondary progressive MS, primary progressive MS, inflammatory neurologic disease, noninflammatory neurologic disease, Alzheimer’s disease, or idiopathic intracranial hypertension. In all, 148 of the participants (59%) were women.

The absence of miR-219 in CSF was consistently associated with MS. In Cohort 1, the odds ratio for a diagnosis of progressive MS was 20.8, compared with controls, if CSF miR-219 was undetectable. In Cohort 2, the odds ratio for a diagnosis of MS or CIS was 2.6, compared with controls, if CSF miR-219 was undetectable. The odds ratio for a diagnosis of progressive MS was 3.6, compared with other neurologic disorders, if CSF miR-219 was undetectable in this cohort. In Cohort 3, the odds ratio for a diagnosis of MS was 39.7, compared with controls, if CSF miR-219 was undetectable.

Advantages of miRNAs

Detecting miRNAs in CSF is difficult because of the low levels at which they are present, said the authors. Nevertheless, miRNAs could be advantageous biomarkers because they are highly stable in body fluids, and the corresponding detection assays can be developed and multiplexed easily. Assessing the performance of miR-219 as a biomarker in situations in which MS cannot be differentiated from MS mimics will require future research, they concluded.

—Erik Greb

Suggested Reading

Agah E, Zardoui A, Saghazadeh A, et al. Osteopontin (OPN) as a CSF and blood biomarker for multiple sclerosis: A systematic review and meta-analysis. PLoS One. 2018 Jan 18;13(1):e0190252.

Bruinsma IB, van Dijk M, Bridel C, et al. Regulator of oligodendrocyte maturation, miR-219, a potential biomarker for MS. J Neuroinflammation. 2017;14(1):235.

Puz P, Steposz A, Lasek-Bal A, et al. Diagnostic methods used in searching for markers of atrophy in patients with multiple sclerosis. Neurol Res. 2018;40(2):110-116.

SAN DIEGO—Absence of miR-219, a microRNA (miRNA), in CSF could be a biomarker of multiple sclerosis (MS), according to data presented at the ACTRIMS 2018 Forum. If confirmed, the results could provide an objective measure to improve the diagnosis of MS.

When demyelination occurs in healthy individuals, remyelination follows. In the latter process, oligodendrocyte precursor cells repopulate the demyelinated area and create new myelin. Although large numbers of these cells surround new MS lesions, the precursor cells may fail to differentiate into mature oligodendrocytes, and thus fail to remyelinate the lesions. Data suggest that miR-219 is necessary for oligodendrocyte precursor cell differentiation in mice and rats.

Brigit A. de Jong, MD, PhD, a neurologist at Radboud University Medical Center in Nijmegen, the Netherlands, and colleagues found decreased miR-219 expression in the tissue of patients with MS, compared with healthy controls. To investigate whether CSF levels of miR-219 could be a biomarker of MS, the investigators performed quantitative polymerase chain reaction on samples taken from patients with MS and controls.

An Analysis of Three Cohorts

Dr. de Jong and colleagues analyzed three independent cohorts in their study. Cohort 1 included 24 participants, Cohort 2 included 115 participants, and Cohort 3 included 112 participants. Study participants included healthy controls and patients with clinically isolated syndrome (CIS), relapsing-remitting MS, secondary progressive MS, primary progressive MS, inflammatory neurologic disease, noninflammatory neurologic disease, Alzheimer’s disease, or idiopathic intracranial hypertension. In all, 148 of the participants (59%) were women.

The absence of miR-219 in CSF was consistently associated with MS. In Cohort 1, the odds ratio for a diagnosis of progressive MS was 20.8, compared with controls, if CSF miR-219 was undetectable. In Cohort 2, the odds ratio for a diagnosis of MS or CIS was 2.6, compared with controls, if CSF miR-219 was undetectable. The odds ratio for a diagnosis of progressive MS was 3.6, compared with other neurologic disorders, if CSF miR-219 was undetectable in this cohort. In Cohort 3, the odds ratio for a diagnosis of MS was 39.7, compared with controls, if CSF miR-219 was undetectable.

Advantages of miRNAs

Detecting miRNAs in CSF is difficult because of the low levels at which they are present, said the authors. Nevertheless, miRNAs could be advantageous biomarkers because they are highly stable in body fluids, and the corresponding detection assays can be developed and multiplexed easily. Assessing the performance of miR-219 as a biomarker in situations in which MS cannot be differentiated from MS mimics will require future research, they concluded.

—Erik Greb

Suggested Reading

Agah E, Zardoui A, Saghazadeh A, et al. Osteopontin (OPN) as a CSF and blood biomarker for multiple sclerosis: A systematic review and meta-analysis. PLoS One. 2018 Jan 18;13(1):e0190252.

Bruinsma IB, van Dijk M, Bridel C, et al. Regulator of oligodendrocyte maturation, miR-219, a potential biomarker for MS. J Neuroinflammation. 2017;14(1):235.

Puz P, Steposz A, Lasek-Bal A, et al. Diagnostic methods used in searching for markers of atrophy in patients with multiple sclerosis. Neurol Res. 2018;40(2):110-116.

SAN DIEGO—A novel therapy designed to promote the maturation and activation of myelin-producing oligodendrocytes is moving to phase II clinical trials based on evidence of safety and efficacy in animal models and humans. The therapy, a suspension of clean-surfaced gold nanocrystals, may remyelinate multiple sclerosis (MS) lesions, according to research presented at the ACTRIMS 2018 Forum.

This agent, known as CNM-Au8, has been associated with improved behavioral function in animal models of MS, according to Michael Hotchkin, Head of Strategic Oper­ations at Clene Nanomedicine in Salt Lake City. Clene Nanomedicine is developing CNM-Au8. Although the mechanism of action is “multifactorial,” the benefit has been linked to bioenergetic support for the differentiation and maturation of oligodendrocyte precursor cells, said Mr. Hotchkin.

In one behavioral study of fine motor kinetics in an experimental model of MS, mice treated with CNM-Au8 “were effectively indistinguishable” from animals with no demyelination, he said.

Treatment Improved Two Models of Demyelination

Following in vitro studies that suggested that CNM-Au8 can promote the differentiation of oligodendrocyte precursor cells into mature myelin-producing oligodendrocytes, a series of studies was conducted in lysolecithin and cuprizone animal models of MS demyelination.

The studies using the lysolecithin model included vehicle controls and compared CNM-Au8’s effect on remyelinated axons after inducing spinal demyelination with lysolecithin. In the cuprizone studies, the treatments were delivered before injury to test prophylactic efficacy and after injury to test treatment efficacy. Markers of remyelination, such as oligodendrocyte maturation, myelin basic protein expression, and axonal staining, were evaluated by immunohistochemistry and transmission electron microscopy in animals sacrificed at various times after injury.

CNM-Au8 produced “striking visible evidence of progressive increase in myelin,” according to Mr. Hotchkin. The treatment was associated with reductions in myelin sheath degeneration and demyelinated areas, relative to vehicle. In one analysis of the lysolecithin model, CNM-Au8 was associated with a 43% increase in myelinated axon count. Moreover, an increase in mature oligodendrocytes localized at the site of focal demyelination injury in the CNM-Au8-treated animals was consistent with stimulation of oligodendrocyte maturation, according to Mr. Hotchkin.

In both models, investigators found evidence of increased oligodendrocyte maturation and remyelination when CNM-Au8 was administered after injury, as well as when it was administered before injury. The results suggest that CNM-Au8 has important activity in the remyelination of demyelinated axons.

Researchers also conducted behavioral studies in the cuprizone model of MS. They tracked the animals’ movement with lasers and used computer software to analyze the movement. These studies included relevant controls and compared animals with no demyelination, vehicle-treated animals dosed with cuprizone, and CNM-Au8-treated animals similarly dosed with cuprizone, to determine whether delayed treatment following initial damage from the toxin would result in functional recovery in the animals.

The investigators observed protective effects of CNM-Au8 when the drug was administered in this treatment paradigm. Improvements in several behavioral end points when the drug was administered after the demyelinating insult “demonstrated that CNM-Au8 restored behavioral function following demyelination,” said Mr. Hotchkin.

Furthermore, in a behavioral study of fine motor kinetics, function improved by 78% at week 6, compared with week 3 (ie, immediately following the start of treatment) in the group treated with CMN-Au8 that was receiving cuprizone. The animals treated with vehicle and cuprizone had a 39% functional improvement at week 6, compared with week 3. Notably, there was not a statistically significant difference in function at week 6 between CNM-Au8-treated animals and the normal healthy control animals without demyelination, indicating that the functional recovery made the former and latter animals indistinguishable.

Therapy Promotes Bioenergetics Catalysis

CNM-Au8 may generate remyelination by more than one mechanism, said Mr. Hotchkin, and evidence indicates that the drug promotes bioenergetic catalysis that is important to the maturation of oligodendrocyte precursors. Published literature suggests an association between altered oligodendrocyte energy utilization and remyelination failure in the human brain. Other evidence suggests that CNM-Au8 may trigger oligodendrocytes’ remyelinating activity by improving energy sources such as adenosine triphosphate, lactate, and oxidized nicotinamide adenine dinucleotide (NAD+), said Mr. Hotchkin. For example, CNM-Au8 increased NAD+ levels in mouse hippocampal cultures by about 40%, relative to vehicle.

In response to questions about the catalytic mechanism, Mr. Hotchkin responded, “You can fill a car’s tank with gas, but if the electrical system is fouled, the car goes nowhere. CNM-Au8 is the catalytic engine driving bioenergetic improvements in the oligodendrocytes driving them to remyelinate.” Data suggest that CNM-Au8 may have applications in other neurodegenerative diseases, based on the bioenergetic failure hypothesis of neurodegeneration and aging, said Mr. Hotchkin.

Oligodendrocyte precursor cells are known to be present in the human brain in and around MS lesions even years after an MS attack. Thus, the animal studies may be relevant to clinical MS. As an oral agent, CNM-Au8 has the potential to be a major clinical advance if human trials show activity comparable to that in animal studies, said Mr. Hotchkin.

Initial phase I human clinical work and extensive animal toxicology has supported the safety of this agent. Trials in patients with MS that examine clinical end points are planned. “A phase II study in chronic optic neuropathy in relapsing-remitting MS patients will commence in 2018,” Glen Frick, MD, PhD, Chief Medical Officer of Clene Nanomedicine, told Neurology Reviews.

—Ted Bosworth

Suggested Reading

Rone MB, Cui QL, Fang J, et al. Oligodendrogliopathy in multiple sclerosis: low glycolytic metabolic rate promotes oligodendrocyte survival. J Neurosci. 2016;36(17):4698-4707.

SAN DIEGO—A novel therapy designed to promote the maturation and activation of myelin-producing oligodendrocytes is moving to phase II clinical trials based on evidence of safety and efficacy in animal models and humans. The therapy, a suspension of clean-surfaced gold nanocrystals, may remyelinate multiple sclerosis (MS) lesions, according to research presented at the ACTRIMS 2018 Forum.

This agent, known as CNM-Au8, has been associated with improved behavioral function in animal models of MS, according to Michael Hotchkin, Head of Strategic Oper­ations at Clene Nanomedicine in Salt Lake City. Clene Nanomedicine is developing CNM-Au8. Although the mechanism of action is “multifactorial,” the benefit has been linked to bioenergetic support for the differentiation and maturation of oligodendrocyte precursor cells, said Mr. Hotchkin.

In one behavioral study of fine motor kinetics in an experimental model of MS, mice treated with CNM-Au8 “were effectively indistinguishable” from animals with no demyelination, he said.

Treatment Improved Two Models of Demyelination

Following in vitro studies that suggested that CNM-Au8 can promote the differentiation of oligodendrocyte precursor cells into mature myelin-producing oligodendrocytes, a series of studies was conducted in lysolecithin and cuprizone animal models of MS demyelination.

The studies using the lysolecithin model included vehicle controls and compared CNM-Au8’s effect on remyelinated axons after inducing spinal demyelination with lysolecithin. In the cuprizone studies, the treatments were delivered before injury to test prophylactic efficacy and after injury to test treatment efficacy. Markers of remyelination, such as oligodendrocyte maturation, myelin basic protein expression, and axonal staining, were evaluated by immunohistochemistry and transmission electron microscopy in animals sacrificed at various times after injury.

CNM-Au8 produced “striking visible evidence of progressive increase in myelin,” according to Mr. Hotchkin. The treatment was associated with reductions in myelin sheath degeneration and demyelinated areas, relative to vehicle. In one analysis of the lysolecithin model, CNM-Au8 was associated with a 43% increase in myelinated axon count. Moreover, an increase in mature oligodendrocytes localized at the site of focal demyelination injury in the CNM-Au8-treated animals was consistent with stimulation of oligodendrocyte maturation, according to Mr. Hotchkin.

In both models, investigators found evidence of increased oligodendrocyte maturation and remyelination when CNM-Au8 was administered after injury, as well as when it was administered before injury. The results suggest that CNM-Au8 has important activity in the remyelination of demyelinated axons.

Researchers also conducted behavioral studies in the cuprizone model of MS. They tracked the animals’ movement with lasers and used computer software to analyze the movement. These studies included relevant controls and compared animals with no demyelination, vehicle-treated animals dosed with cuprizone, and CNM-Au8-treated animals similarly dosed with cuprizone, to determine whether delayed treatment following initial damage from the toxin would result in functional recovery in the animals.

The investigators observed protective effects of CNM-Au8 when the drug was administered in this treatment paradigm. Improvements in several behavioral end points when the drug was administered after the demyelinating insult “demonstrated that CNM-Au8 restored behavioral function following demyelination,” said Mr. Hotchkin.

Furthermore, in a behavioral study of fine motor kinetics, function improved by 78% at week 6, compared with week 3 (ie, immediately following the start of treatment) in the group treated with CMN-Au8 that was receiving cuprizone. The animals treated with vehicle and cuprizone had a 39% functional improvement at week 6, compared with week 3. Notably, there was not a statistically significant difference in function at week 6 between CNM-Au8-treated animals and the normal healthy control animals without demyelination, indicating that the functional recovery made the former and latter animals indistinguishable.

Therapy Promotes Bioenergetics Catalysis

CNM-Au8 may generate remyelination by more than one mechanism, said Mr. Hotchkin, and evidence indicates that the drug promotes bioenergetic catalysis that is important to the maturation of oligodendrocyte precursors. Published literature suggests an association between altered oligodendrocyte energy utilization and remyelination failure in the human brain. Other evidence suggests that CNM-Au8 may trigger oligodendrocytes’ remyelinating activity by improving energy sources such as adenosine triphosphate, lactate, and oxidized nicotinamide adenine dinucleotide (NAD+), said Mr. Hotchkin. For example, CNM-Au8 increased NAD+ levels in mouse hippocampal cultures by about 40%, relative to vehicle.

In response to questions about the catalytic mechanism, Mr. Hotchkin responded, “You can fill a car’s tank with gas, but if the electrical system is fouled, the car goes nowhere. CNM-Au8 is the catalytic engine driving bioenergetic improvements in the oligodendrocytes driving them to remyelinate.” Data suggest that CNM-Au8 may have applications in other neurodegenerative diseases, based on the bioenergetic failure hypothesis of neurodegeneration and aging, said Mr. Hotchkin.

Oligodendrocyte precursor cells are known to be present in the human brain in and around MS lesions even years after an MS attack. Thus, the animal studies may be relevant to clinical MS. As an oral agent, CNM-Au8 has the potential to be a major clinical advance if human trials show activity comparable to that in animal studies, said Mr. Hotchkin.

Initial phase I human clinical work and extensive animal toxicology has supported the safety of this agent. Trials in patients with MS that examine clinical end points are planned. “A phase II study in chronic optic neuropathy in relapsing-remitting MS patients will commence in 2018,” Glen Frick, MD, PhD, Chief Medical Officer of Clene Nanomedicine, told Neurology Reviews.

—Ted Bosworth

Suggested Reading

Rone MB, Cui QL, Fang J, et al. Oligodendrogliopathy in multiple sclerosis: low glycolytic metabolic rate promotes oligodendrocyte survival. J Neurosci. 2016;36(17):4698-4707.

SAN DIEGO—A novel therapy designed to promote the maturation and activation of myelin-producing oligodendrocytes is moving to phase II clinical trials based on evidence of safety and efficacy in animal models and humans. The therapy, a suspension of clean-surfaced gold nanocrystals, may remyelinate multiple sclerosis (MS) lesions, according to research presented at the ACTRIMS 2018 Forum.

This agent, known as CNM-Au8, has been associated with improved behavioral function in animal models of MS, according to Michael Hotchkin, Head of Strategic Oper­ations at Clene Nanomedicine in Salt Lake City. Clene Nanomedicine is developing CNM-Au8. Although the mechanism of action is “multifactorial,” the benefit has been linked to bioenergetic support for the differentiation and maturation of oligodendrocyte precursor cells, said Mr. Hotchkin.

In one behavioral study of fine motor kinetics in an experimental model of MS, mice treated with CNM-Au8 “were effectively indistinguishable” from animals with no demyelination, he said.

Treatment Improved Two Models of Demyelination

Following in vitro studies that suggested that CNM-Au8 can promote the differentiation of oligodendrocyte precursor cells into mature myelin-producing oligodendrocytes, a series of studies was conducted in lysolecithin and cuprizone animal models of MS demyelination.

The studies using the lysolecithin model included vehicle controls and compared CNM-Au8’s effect on remyelinated axons after inducing spinal demyelination with lysolecithin. In the cuprizone studies, the treatments were delivered before injury to test prophylactic efficacy and after injury to test treatment efficacy. Markers of remyelination, such as oligodendrocyte maturation, myelin basic protein expression, and axonal staining, were evaluated by immunohistochemistry and transmission electron microscopy in animals sacrificed at various times after injury.

CNM-Au8 produced “striking visible evidence of progressive increase in myelin,” according to Mr. Hotchkin. The treatment was associated with reductions in myelin sheath degeneration and demyelinated areas, relative to vehicle. In one analysis of the lysolecithin model, CNM-Au8 was associated with a 43% increase in myelinated axon count. Moreover, an increase in mature oligodendrocytes localized at the site of focal demyelination injury in the CNM-Au8-treated animals was consistent with stimulation of oligodendrocyte maturation, according to Mr. Hotchkin.

In both models, investigators found evidence of increased oligodendrocyte maturation and remyelination when CNM-Au8 was administered after injury, as well as when it was administered before injury. The results suggest that CNM-Au8 has important activity in the remyelination of demyelinated axons.

Researchers also conducted behavioral studies in the cuprizone model of MS. They tracked the animals’ movement with lasers and used computer software to analyze the movement. These studies included relevant controls and compared animals with no demyelination, vehicle-treated animals dosed with cuprizone, and CNM-Au8-treated animals similarly dosed with cuprizone, to determine whether delayed treatment following initial damage from the toxin would result in functional recovery in the animals.

The investigators observed protective effects of CNM-Au8 when the drug was administered in this treatment paradigm. Improvements in several behavioral end points when the drug was administered after the demyelinating insult “demonstrated that CNM-Au8 restored behavioral function following demyelination,” said Mr. Hotchkin.

Furthermore, in a behavioral study of fine motor kinetics, function improved by 78% at week 6, compared with week 3 (ie, immediately following the start of treatment) in the group treated with CMN-Au8 that was receiving cuprizone. The animals treated with vehicle and cuprizone had a 39% functional improvement at week 6, compared with week 3. Notably, there was not a statistically significant difference in function at week 6 between CNM-Au8-treated animals and the normal healthy control animals without demyelination, indicating that the functional recovery made the former and latter animals indistinguishable.

Therapy Promotes Bioenergetics Catalysis

CNM-Au8 may generate remyelination by more than one mechanism, said Mr. Hotchkin, and evidence indicates that the drug promotes bioenergetic catalysis that is important to the maturation of oligodendrocyte precursors. Published literature suggests an association between altered oligodendrocyte energy utilization and remyelination failure in the human brain. Other evidence suggests that CNM-Au8 may trigger oligodendrocytes’ remyelinating activity by improving energy sources such as adenosine triphosphate, lactate, and oxidized nicotinamide adenine dinucleotide (NAD+), said Mr. Hotchkin. For example, CNM-Au8 increased NAD+ levels in mouse hippocampal cultures by about 40%, relative to vehicle.

In response to questions about the catalytic mechanism, Mr. Hotchkin responded, “You can fill a car’s tank with gas, but if the electrical system is fouled, the car goes nowhere. CNM-Au8 is the catalytic engine driving bioenergetic improvements in the oligodendrocytes driving them to remyelinate.” Data suggest that CNM-Au8 may have applications in other neurodegenerative diseases, based on the bioenergetic failure hypothesis of neurodegeneration and aging, said Mr. Hotchkin.

Oligodendrocyte precursor cells are known to be present in the human brain in and around MS lesions even years after an MS attack. Thus, the animal studies may be relevant to clinical MS. As an oral agent, CNM-Au8 has the potential to be a major clinical advance if human trials show activity comparable to that in animal studies, said Mr. Hotchkin.

Initial phase I human clinical work and extensive animal toxicology has supported the safety of this agent. Trials in patients with MS that examine clinical end points are planned. “A phase II study in chronic optic neuropathy in relapsing-remitting MS patients will commence in 2018,” Glen Frick, MD, PhD, Chief Medical Officer of Clene Nanomedicine, told Neurology Reviews.

—Ted Bosworth

Suggested Reading

Rone MB, Cui QL, Fang J, et al. Oligodendrogliopathy in multiple sclerosis: low glycolytic metabolic rate promotes oligodendrocyte survival. J Neurosci. 2016;36(17):4698-4707.