NP001 drug can slow or temporarily stall the progression of ALS

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A new drug has been found to slow or temporarily stall the progression of ALS (amyotrophic lateral sclerosis) in a select group of patients.

The drug, a proprietary form of purified chlorite that inhibits production of pro-inflammatory cytokines, may provide a treatment option in patients aged 40 to 65 with higher levels of inflammation, according to a new study.

The study is the latest milestone in an odyssey of twists and turns for researchers and patients who have a post-diagnosis life expectancy of between two to five years. It follows a previous phase 2A study that showed no significant slowing of decline between the participants who took the drug, known as NP001, compared with those on placebo.

But researchers identified a subset of patients – those on the higher dose of the drug whose blood tests showed elevated levels of an inflammatory marker – who seemed to fare surprisingly well.

In the current phase 2B study, publishing in the journal Muscle & Nerve on Jan. 31, researchers used new data together with data from 2A, restricted to participants with elevated levels of the inflammatory marker who were on the higher drug dose, but the results were again disheartening. It was not until a post-hoc analysis, published in the same paper, which narrowed the field of 154 participants, aged 32 to 76, to 117 participants, aged 40 to 65, that a more promising picture emerged.

Age is a factor in success of new treatment

Researchers, led by senior author Michael S. McGrath, MD, Ph.D., Emeritus Professor of Medicine at UC San Francisco, found that those who had received NP001 had a 36 percent slowing of decline compared to the placebo group, according to their ALSFRS-R score, a questionnaire that ranks physical changes over time. Similarly, the NP001 recipients experienced a 51 percent slowing of decline in vital capacity, or respiratory function – a second test determining ALS progression – compared to the placebo group. These effects persisted months after treatment concluded.

Among those patients who did not decline during the six-month duration, 19 of 56 (34 percent) were on NP001, versus seven of 61 (11 percent) of those on placebo.

“It is plausible that the disease mechanism and trajectory for those patients under 40 differs from older patients and is more likely to have a genetic or heritable component as is often seen in other chronic diseases, although this has not yet been proven,” said McGrath who is also a cofounder of Neuvivo, Inc., a pharmaceutical company and the study’s sponsor.

“People over 65 have a higher level of the plasma inflammatory marker C-reactive protein, the inflammation marker we tracked in our study, so this may have allowed for an overrepresentation of older ALS patients,” he said. “These higher levels may be attributed to other conditions unrelated to ALS, like diabetes and cardiovascular disease, making interpretation of ALS-specific variables difficult and potentially confounding.”

Inflammation drives loss of motor neurons in ALS

The development of NP001 is based on the premise that chronic inflammation is a key factor in the loss of motor neurons, the hallmark of ALS. According to the researchers, ALS starts with the activation of macrophages, a type of immune cell. NP001 reverts these macrophages back to an inactive anti-inflammatory state, thus slowing or stopping the disease.

In the study, participants with a probable or definite ALS diagnosis were recruited at 21 sites in the United States and Canada. They had experienced an onset of ALS-related weakness within the last three years and had a life expectancy of at least six months. Minimal side effects were reported; the main one being burning sensation at the site of infusion.

Currently, two drugs have been approved to slow the progression of ALS: riluzole (Rilutek), shown to increase life expectancy by three months, and edaravone (Radicava), shown to decrease decline of physical function by 33 percent at 24 weeks.

“My hope is that we can continue the study of patients whose disease progression slowed or halted with NP001 as compared to placebo,” said McGrath. “We’ve still got a lot to learn about ALS pathogenesis and how best to treat, but I believe that we’ve found a path forward for use of an immunoregulatory approach to a large subset of patients with ALS.”

NP001 received fast-track status in 2011, allowing frequent communications with the U.S. Food and Drug Administration for expedited review to facilitate its development.


Neuroinflammation and glycosylation: the underexplored relationship

Neuroinflammation is broadly described as the inflammatory cascades that take place in either the peripheral nervous system (PNS) or the central nervous system (CNS), combining both immune and nervous systems, which makes it a complex concept still imperfectly understood [1.,2.].

In the CNS, neuroinflammation is associated with damage or disorders that can be caused by a direct penetrating physical injury [such as traumatic brain injury (TBI) or spinal cord injury (SCI)], or that arise from biochemical/nonpenetrating ‘injuries’, such as neurodegenerative disorders [e.g., multiple sclerosis (MS), Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS); see Glossary)] or tumours (gliomas) (Figure 1).

These conditions severely impact the lives of patients and require staff for rehabilitation therapies and support services. Although these disorders present different pathophysiological mechanisms, there are common underlying areas that remain poorly understood, such as the cause–effect interplay between neuroinflammation and neurodegeneration, and the role of each pathological molecular event in the overall diseased phenotype [3.,4.].

Figure 1
Figure 1Types of central nervous system (CNS) injuries or disorders with an underlying neuroinflammatory pathology in which glycosylation has been analysed.

In the neuroinflammatory cascades seen in these neurological conditions, the leading role is played by microglia, which are the chief surveillance agents and immune cells of the CNS [1.]. More specifically, neuroinflammation involves the innate immune system (nonspecific defence mechanisms, which activate immune cells and the complement cascade) [5.], and the adaptive immune system [i.e., T cells, B cells, and the antibodies produced in the blood (e.g., immunoglobulins (Ig)] [6.], which will step in if the innate immune system fails to overcome pathological threats.

The adaptive immune system is of particular significance if the blood–brain barrier (BBB) is compromised, allowing for the infiltration of peripheral cells into the CNS, which, in combination with astrocytes and microglia, will start secreting proinflammatory mediators, such as cytokines and chemokines [5., 6., 7.] (Figure 1). Different dynamic stages of neuroinflammation can occur that are either beneficial (usually during the initial phases of the pathological event) or detrimental (when the inflammatory cascades become chronic).

Any cellular event depends on the tight orchestration between organelles, their metabolism, and the proteins they secrete. Most of these proteins are modified at the post-translational level, mainly through the addition of glycans (i.e., glycosylation) to their peptide chains, which modulates their functions [8.].

Alterations in the cellular milieu can induce quick and dramatic alterations in the glycans produced, leading to pathological scenarios since glycosylation is highly flexible and dynamic, depending on multiple players, such as glycosylation enzymes, which add (glycosyltransferases) or remove (glycosidases) sugar resides [8.].

Thus, the sophistication of glycosylation events makes them challenging to analyse. Therefore, the characterisation of differential glycan expression in neuroimmune states in associated CNS disorders has been gradually considered over the past two decades (interplay between glycosylation and the immune system reviewed in [9.,10.]).

Furthermore, glycans are recognised by glycan-binding proteins (GBP), commonly regarded as immune checkpoints, and can initiate inflammatory responses when present in immune cells [10.]. Therefore, specific glycosylation (and the presence of GBP) on immune cells in the CNS and peripheral immune cells might alter the function of such cells and subsequently exacerbate neuroinflammation.

Consequently, the glycosignature of each condition and the cells expressing this signature in such conditions are attractive targets for exploring and understanding how this glycosignature can influence neuroinflammatory cascades. This could also help to implement novel therapeutic approaches.

For example, changes in a specific glycosylation trait might reflect dysregulation in the expression of a specific glycoenzyme, which could be targeted therapeutically. Additionally, study of the glycosylation of the serum or cerebral spinal fluid (CSF) can reveal further indications of peripheral inflammation, which could have a role in the onset of different disorders and provide information as potential biomarkers (and vice versa).

In this review, we describe current trends in the field of glyconeurobiology in neuroinflammation in human disease states and preclinical models of injured and diseased CNS, and propose paths that can be addressed when establishing new treatments. We focus on protein glycosylation changes seen upon disease in the brain/spinal cord tissue, and the modulation of GBP expression (particularly in immune cells) in neuroinflammatory-related scenarios. Furthermore, we summarise the challenges associated with tackling the glycome in CNS disorders and suggest future perspectives for developing a new class of glyco-targeted therapies, which could eventually be combined with regenerative medicine strategies.

reference link : https://www.cell.com/trends/molecular-medicine/fulltext/S1471-4914(22)00018-1


More information: Robert G. Miller et al, Phase 2B randomized controlled trial of NP001 in amyotrophic lateral sclerosis: pre‐specified and post‐hoc analyses, Muscle & Nerve (2022). DOI: 10.1002/mus.27511

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