Ellen Kurek

No specific biochemical markers have been available to confirm the diagnosis of 

A Spanish and French research team developed a decision-tree based on results of analysis of biomarkers in the serum and cerebrospinal fluid (CSF) of 

. Lidia Fernandez-Paredes, MD (left), and Silvia Sanchez-Ramon, MD (right), both in the department of clinical immunology at Hospital Clinico San Carlos in Madrid, Spain, co-led the research team.

This lack of biomarkers often resulted in a delay in MS diagnosis and 

 while clinicians waited for a relapse to occur or for results of sequential neuroimaging studies to confirm the presence of disseminated lesions in the central nervous system. This study was undergone to provide clinicians with a means of diagnosing MS by using specific biomarkers.

In a previous, cross-sectional study in 2 independent cohorts of MS patient, the team used biologically plausible pathways to identify a panel of 12 biomarkers that might enable investigators to discriminate between the 2 main forms of MS at disease onset — relapsing-remitting MS (RRMS) and primary progressive MS (PPMS). An ability to discriminate between the 2 forms could enable clinicians to make a more specific diagnosis and provide more appropriate treatment sooner, which could delay the development of the irreversible disabling disease.

In the current study, the team determined which biomarkers in this panel could be most useful in diagnosing MS in the early phases of the disease as well as in predicting its course. To do this, they collected serum and CSF samples from 89 patients who were recently diagnosed with MS, 97 patients with other neurological diseases (59 non-inflammatory and 38 inflammatory), and 46 age-matched, healthy controls.

After analyzing levels of biomarkers in the samples, the team concluded that serum levels of interleukin-7 (IL-7) and C-X-C motif chemokine ligand 10 (CXCL10) appeared to provide the most accurate means of identifying large differences in disease risk. A serum IL-7 level <141 pg/mL identified patients with MS at onset (odds ratio (OR), 6.5; P < 0.001), and those who also had a CXCL10 level <570 pg/mL were at greatest risk of having the primary progressive form of MS (OR, 22; P = 0.01).

“We started this work years ago in close collaboration with Matthew Albert at the Pasteur Institute in Paris,” Sanchez-Ramon told 

. “This work is the continuation. Validating these markers at the beginning of clinical manifestations could be especially useful for making therapeutic decisions.”

“Once our validation is confirmed by other groups, our decision-tree will provide a practical clinical tool for identifying patients at risk of the progressive form of MS in its very early stages,” she added.

In addition to important findings regarding serum biomarkers, the study team also unexpectedly found a substantially lower level of biomarkers of inflammation and tissue regeneration in the CSF of MS patients than in that of patients with other neurological diseases. The team interpreted this finding as an indication that a defect in the intrinsic immune response contributes to the onset of MS.

 was published in the August 2017 issue of 

Articles

A lack of biomarkers can result in a delay in multiple sclerosis diagnosis and treatment.

How Biomarkers Can Improve Early Diagnosis of Multiple Sclerosis

 (MS) control autoimmune damage to the central nervous system (CNS) by reducing immune cell numbers, altering their function, or blocking their access to the brain and spinal cord, but they do not to halt disease progression entirely, so developing drugs that protect patients from neurodegeneration or that regenerate damaged nerves is crucial — especially for those with late-stage progressive MS.

Oxford researchers Calliope Dendrou, PhD, and Lars Fugger (pictured), MD, PhD, reached this conclusion in a review article that appeared in last month’s issue of 

, which focused on the theme of autoimmunity.

“This review gives a completely updated account of the therapeutic opportunities in MS,” Fugger, the chair of neuroimmunology in the department of clinical neurosciences of Oxford University Hospitals at the University of Oxford told 

. “In the last 20 years, we have progressed from using only one [class of] drugs — steroids &mdash; to using a variety of drugs that target different parts of the immune system.”

“The new drugs have also shown that MS is not only a T-cell driven disease but definitely also a B-cell driven disease,” he added.

Older, first-line immunomodulators, including the injectables glatiramer acetate (Copaxone) and interferon-β (Avonex, Betaseron, Plegridy, Rebif), are believed to work by affecting T-cells. Moderately effective and relatively safe, they decrease relapses by approximately 30% and remain cost-effective for 5 years or more. However, they do not work in all patients with 

 (RRMS), and resistance to them may develop in those who respond to them initially.

Fugger’s team also assessed several other treatments, such as Cladribine, which inhibits DNA synthesis and although highly effective may cause opportunistic infections; Dimethyl fumarate (DMF) which appears to exert its immunomodulatory effects by changing the activation of dendritic cells, differentiation of T

 cells, and induction of regulatory B cells (its anti-oxidative effects may exert neuroprotection as well), but may cause lymphopenia; and Teriflunomide, which blocks the proliferation of activated T cells, and although effective, is also teratogenic and toxic.

Second-line agents are appropriate for patients who do not respond to first-line agents, those who have 2 or more disabling relapses annually, or those with progressive MS with relapses or with active disease shown by magnetic resonance imaging. According to the review, mitoxantrone (Novantrone), a cytotoxic immunosuppressant used for secondary progressive MS, is moderately effective in treating MS but can be cardiotoxic and cause leukemia with long-term use.

Some of the other second-line agents examined were Natalizumab (Tysabri), which reduces the yearly relapse rate by nearly 70% but may cause progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection that destroys oligodendrocytes in the CNS; Fingolimod (Gilenya), the only oral second-line agent, which is highly effective in treating MS but may result in PML, other infections, and cardiac arrhythmias; and alemtuzumab (Lemtrada), which results in the depletion of a large percentage of T and B cells, including pathogenic ones, and causes secondary immune disorders such as autoimmune thyroid disease to develop in 30% to 40% of patients treated with it.

“The neurodegenerative phase of the disease is the next big challenge,” Fugger said. “We are just beginning to understand the basis for this neurodegeneration. With time, this new understanding will lead to new drugs that, when given with immunomodulatory drugs, will lead to a much better life for MS patients.”

 appeared in the September 16, 2017, issue of 

The neurodegenerative phase of multiple sclerosis remains a significant challenge for researchers.

Immunomodulatory Drugs May Boost Treatment of Late-Stage Multiple Sclerosis

In a recent editorial, Christoph Correll, MD, (pictured) professor of psychiatry and molecular medicine at Hofstra Northwell School of Medicine in Hempstead, New York, detailed the results of the AIM-TD study of deutetrabenazine (Austedo) for tardive dyskinesia (TD) and compared them with those of 2 KINECT studies of valbenazine for TD.

The AIM-TD study led to the August 2017 decision by the U.S. Food and Drug Administration (FDA) to approve deutetrabenazine for TD. Moreover, the 2 KINECT studies led to the FDA’s approval of valbenazine for TD in early April 2017.

Both agents are members of a new class of vesicular monoamine transporter-2 (VMAT-2) inhibitors developed to address movement disorders such as TD. In early April 2017, the FDA approved deutetrabenazine for Huntington’s chorea, and valbenazine manufacturer Neurocrine Biosciences has been investigating its use for Tourette’s syndrome.

Maren Carbon, MD, assistant professor of psychiatry in the division of psychiatry research at The Zucker Hillside Hospital, Northwell Health, in Glen Oaks, New York, co-authored the editorial.

Until this year, management of TD relied on off-label use of treatments with little support for their safety and efficacy in reducing TD symptoms, the editorial noted. One option was the established VMAT-2 inhibitor, tetrabenazine, which requires thrice-daily dosing and may produce clinically relevant parkinsonism, prolong the corrected QT interval, promote depression, and increase the risk of suicide.

In contrast with tetrabenazine, deutetrabenazine and valbenazine are associated with rates of depression and suicidality similar to those associated with placebo, according to the editorial. Moreover, neither new VMAT-2 inhibitor interferes with the efficacy of co-administered dopamine-receptor antagonists.

"It is exciting to see that, more than 60 years after the first descriptions of tardive dyskinesia in relationship to antipsychotic treatment and [after] an entire dearth of effective treatments, there are now 2 new-generation VMAT-2 inhibitors that have statistically and clinically relevant efficacy for this impairing syndrome,” Correll wrote.

Although questions surrounding long-term efficacy and which patient subgroups benefit the most from treatment still persist, the 2 FDA-approved agents can reduce TD symptoms, Correll wrote.

The KINECT and AIM-TD studies shared several strengths, including their use of centralized Abnormal Involuntary Movement Scale (AIMS) assessments of TD severity based on sessions videotaped by site investigators and scored by 2 central video raters who were movement disorder specialists. Raters were masked to visit number, site, and recording date, and both raters had to achieve consensus in their ratings.

However, the editorial noted a key difference in Phase III study results for deutetrabenazine and valbenazine. By the end of KINECT 3 at week 6, when analyzed as a mean score, rater-assessed response to active treatment versus placebo was not significant for either dose of valbenazine. In contrast, by the end of the 12-week AIM-TD study — which was twice the length of KINECT 3 &mdash; the same endpoint was significant for both doses of deutetrabenazine.

Moreover, unlike specialist response ratings, patient response ratings in both Phase III studies were not significantly better for either VMAT-2 inhibitor than for placebo. The editorialists interpreted this result as an indicator that some patients may be less aware of TD and its social impact than other patients are.

In addition, most patients who received active treatment in these Phase III studies did not have an improvement in AIMS total score of 50% or more by study end. The editorialists interpreted this finding as an indicator of “a relevant heterogeneity of response” to the new VMAT-2 inhibitors.

Moreover, they cautioned that clinically significant reduction in TD symptoms might not be captured by this efficacy measure “because [the] effect also depends on the location and functional or social relevance of the [abnormal] movements.”

Topics for further research should include whether VMAT-2 inhibitors can prevent progression from early to more severe dyskinesia and predictors of successful discontinuation of VMAT-2 inhibitors after TD resolves, according to the editorial.

Correll concluded that the availability of 2 new-generation VMAT-2 inhibitors approved for the treatment of TD should “stimulate research to answer these and related questions, as well as provide benefit to patients.”

A new class of VMAT-2 inhibitors for tardive dyskinesia

New FDA-approved drugs are members of a new class of vesicular monoamine transporter-2 inhibitors developed to address movement disorders.

New Treatment Options Emerge for Tardive Dyskinesia

A well-executed development program based on efficient trial design led to rapid FDA approval of valbenazine (Ingrezza) for the iatrogenic movement disorder tardive dyskinesia (TD) in April 2017.

This observation was made by a team at the FDA’s Center for Drug Evaluation and Research (CDER) in a recently published case study. The team, led by Michael Davis, MD, PhD (pictured), also included Mitchell Mathis, MD, director of the Division of Psychiatry Products at CDER.

Tardive dyskinesia, a troublesome condition that had no accepted therapy, was first described in the 1950s after the introduction of first-generation or typical antipsychotic agents such as chlorpromazine (Thorazine) and haloperidol (Haldol).

The condition, characterized by persistent, abnormal, involuntary movements such as lip smacking and pursing, was eventually recognized as an adverse side effect of long-term use of typical antipsychotics.

It was also found to result from extended use of second-generation or atypical antipsychotic, such as olanzapine (Zyprexa) and risperidone (Risperdal) — although at a lower annual incidence (3.1%) than that of typical agents (8.5%).

Tardive dyskinesia can be “disabling and can further stigmatize patients with mental illness,” Mathis said. He noted this makes valbenazine’s approval such an important advance for inflicted patients.

According to Mathis and colleagues, the FDA designated valbenazine as a breakthrough therapy in October 2014, based on an understanding of its mechanism of action (inhibition of the dopamine transporter vesicular monoamine transporter 2) and its potential to fill an unmet medical need. This designation cleared the way for the FDA to do a rolling review, which enables the drug’s sponsor to submit portions of a new drug application (NDA) for FDA review as they are completed.

The FDA then slated valbenazine’s NDA for priority review based on the drug’s potential to offer an important treatment breakthrough. This designation advanced the NDA’s completion goals by 2 months, compared with those for standard NDAs and led to valbenazine’s approval only 8 months after submission of its NDA.

Remote monitoring of patient response to the drug also helped to ensure valbenazine’s speedy approval. In the 2 key studies showing valbenazine’s efficacy for TD, the primary end-point —change in Abnormal Involuntary Movement Scale score from baseline after 6 weeks of therapy &mdash; was assessed by centrally located neurologists specializing in movement disorders.

These raters scored TD severity by reviewing videotapes of remotely monitored patients. And to minimize expectancy bias, the raters were blinded to patients’ identities, treatment, and visit number.

This severity scoring procedure was also used to determine that the 80-mg dose of valbenazine was more effective than the 40-mg dose and that, in most patients, symptoms recurred a month after treatment ended. Dose comparison, blinded rating of remotely monitored patients, and a trial design incorporating crossover from placebo to active treatment all helped to support valbenazine’s efficacy for TD.

Valbenazine’s safety review, done by Brian Miller, MD, MBA, MPH, of the University of North Carolina (UNC) Kenan-Flagler School of Business in Chapel Hill, North Carolina, was also notable in several respects. The safety review pooled controlled trials with different randomization ratios by using a mixed-effects logistic-regression model to detect abnormalities in lab test results.

Researchers also developed a prospective observational database of multiple studies and categorized patients’ exposure by dose and time, then used this database to calculate the incidence density of adverse events. These procedures helped the investigators determine that valbenazine was associated with somnolence and lengthening of the QT interval, but not with exacerbation of depression or thoughts of suicide.

Thus, according to the FDA-UNC team, the valbenazine case study teaches several important lessons in how to ensure that drug development leads to timely FDA approval. Another key lesson is that “creativity and partnership in both development and review can effectively overcome long-standing clinical challenges.”

Efficient trial design — FDA approval of valbenazine for tardive dyskinesia

FDA approval of valbenazine (Ingrezza) for the iatrogenic movement disorder tardive dyskinesia shows impact of a well-executed development program.

Tardive Dyskinesia Drug Approval Illustrates Efficient Trial Design

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in older people in the United States. AMD affects 14 million U.S. adults, and this number will increase as the "baby boomer" generation ages.

But the extent to which AMD is underdiagnosed in primary care has been unclear.

To determine the degree of AMD underdiagnosis, David Neely, MD, (pictured) and colleagues in the Department of Ophthalmology, School of Medicine, and Department of Epidemiology, School of Public Health at the University of Alabama at Birmingham, did a cross-sectional study of 644 adults who were at least 60 years old.

The medical records of these study participants — their average age being over 69 &mdash; indicated they had normal macular health based on the most recent dilated comprehensive eye examination done by a primary eye care ophthalmologist of optometrist. Participants were enrolled in the study from May 2008, through December 2011, and their data was analyzed from May 1, 2016, through December 20, 2016.

Three-field, digital color fundus photographs of the eyes of each participant were taken and used by an experienced, trained, masked grader to determine whether or not these eyes actually had AMD as defined by the Clinical Age-Related Maculopathy Staging system.

Although the team found that 968 of 1,288 eyes — or 75% &mdash; had no AMD, they also found that 320 of 1,288 eyes &mdash; 25% &mdash; had AMD despite the absence of such a diagnosis in the medical record.

Regarding eyes with AMD that went undiagnosed during the last dilated eye exam, 10% had hyperpigmentation, and 13% had hypopigmentation. Moreover, 78% had small drusen, 78% had intermediate drusen, and 30% had large drusen. In their study report, the team noted that these large drusen diagnoses were consistent with a diagnosis of intermediate AMD, which would have been treatable with nutritional supplements if diagnosed during the dilated eye exam.

The prevalence of undiagnosed AMD did not differ between ophthalmologists and optometrists (age-adjusted odds ratio (OR), 0.99; 95% confidence interval (CI), 0.71—1.36; P = 0.94). However, undiagnosed AMD was associated with older patient age (OR, 1.06; CI, 1.04–1.09; P < 0.001), male sex (OR, 1.39; CI, 1.02–1.91; P = 0.04), and having less than a high-school education (OR, 2.40; CI, 1.03–5.62; P = 0.04).

The study team concluded that if one in four patients with AMD go undiagnosed with the current methods used in primary eye care, underdiagnosis is not uncommon. However, they added the reasons underlying AMD underdiagnosis in primary eye care "remain unclear.”

In addition, these findings indicate that improvements in diagnostic methods are needed for early detection. According to the study team, this need will increase with the development of new treatments for the earliest stages of AMD.

Although no proven effective treatments for early AMD currently exist, treatments targeted towards early AMD are the next frontier of development. As a result, accessing the benefits of new interventions for early AMD will depend increasingly on correct, prompt, early detection of AMD.

Prevalence of undiagnosed age-related macular degeneration in primary eye care

,” was published online on April 27, 2017, in 

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in older people.

Many Patients with Age-Related Macular Degeneration Remain Undiagnosed After Eye Exam

A characteristic of age-related macular degeneration (AMD) is the deterioration in the function of photoreceptor and retinal pigment epithelial (RPE) cells.

Neither supplementation with nutrients identified as AMD protective in Age-related Eye Disease Study (AREDS) I and II nor treatment with anti-vascular endothelial growth factor (VEGF) agents have been shown to counteract this deterioration. 

The rapidity of adaptation to darkness provides a means of determining the health of photoreceptor and RPE cells in patients with atrophic AMD. Moreover, dark adaptation testing has been shown to be better than visual acuity testing in diagnosing and staging AMD. 

For example, results of the AdaptDx (MacuLogix) test of dark adaptation in excess of 6.5 minutes predict future onset of AMD at least 3 years before a decrease in visual acuity is detectable. And the AdaptDx test has a sensitivity and specificity of 90% for predicting AMD. 

Improvement in visual function has been reported in AMD patients taking capsules of the oral nutraceutical Longevinex, a supplement consisting of red wine solids (resveratrol) combined with 1,200 IU of vitamin D3, DNA repair nucleotides, and a cholesterol-lowering solubilizing agent, B cyclodextrin.

This combination has six times greater biological action than resveratrol alone and prevented legal blindness in a patient with a fast progressive form of exudative  macular degeneration, polypoidal choroidal vasculopathy — in whom treatment with injected drugs had failed. 

The effect of Longevinex on dark adaptation in 7 patients — or 14 eyes &mdash; with atrophic AMD was recently assessed by Stuart Richer, OD, PhD, FAAO, (pictured) director of the Ocular Preventative Medicine Eye Clinic at the Captain James A. Lovell Federal Health Care Center in North Chicago, Illinois.

Colleagues at this veterans’ hospital, at the Eye & Ear Infirmary of the University of Illinois at Chicago, and at the Chicago Medical School assisted with the study. 

All patients studied had pre-existing vision loss. Moreover, their vision had not improved after using the AREDs antioxidant supplement formulated by the National Eye Institute. The age of the patients ranged from 64 to 89 years, though all but one of the patients studied were in their 80s. 

The team conducted dark adaptation testing by using AdaptDx, an approved treatment by the U.S. Food and Drug Administration. During testing, this device removed rhodopsin from the back of the eye with a flash of light, then measured the time the eye takes to replenish rhodopsin levels.

Using this testing method, the team obtained baseline dark adaptation threshold, time, and fixation measurements for each patient. They then measured dark adaptation after patients took one capsule of Longevinex orally each morning for a period ranging from 5 weeks to 7 months. 

After patients received treatment with Longevinex, testing revealed that 12 of 14 eyes improved in one or more dark adaptation parameters. The difference between expected versus actual results — in terms of worse dark adaptation versus stable or improved dark adaptation by eye &mdash; was statistically significant by chi-square testing at the level of P < 0.01. 

The response to Longevinex was bilateral in 5 of 7 patients and, in one patient, was noted after 1 month of Longevinex therapy. Moreover, the investigators found a reduction in macular pathophysiology during spectral-domain optical coherence tomography in 3 of 7 patients and “profound multi-line improvements in visual acuity” in 4 of 7 patients. 

“If this continues to be demonstrated in larger groups, we just may have, for the first time, a preventive for the most common cause of visual decline in senior Americans,” Richer said.

Richer added that combining AdaptDx screening with therapies such as Longevinex could alter the course of AMD. 

Richer presented a poster, “Longevinex® improves human atrophic AMD photoreceptor / RPE mediated dark adaptation,” on the study on May 8, 2017, at the Annual Meeting of the Association for Research in Vision and Ophthalmology in Baltimore, Maryland.

A related review by members of the study team, “

Age-related macular degeneration beyond the Age-related Eye Disease Study II,”

 appeared in the November, 2016, issue of Advances in Ophthalmology and Optometry.

Dark adaptation testing has been shown to be better than visual acuity testing in diagnosing and staging AMD.  