Impact of Covid-19 on neurodegenerative diseases

At the virtual 15th International Conference on Alzheimer’s Disease and Parkinson’s Disease 2021, physicians and researchers analysed the impact of the Covid-19 pandemic on the neuropathology, clinical trials and social implications of neurodegenerative disorders.

It is well known that mortality rates of other respiratory illnesses are higher in people with dementia. A 2020 study showed that elderly people with Covid-19 have almost three times the mortality if they also had dementia. Most patients with dementia have comorbid medical conditions that could increase the severity of infections. Delirium can develop at the beginning of Covid-19, worsening the prognosis, and these atypical presentations of Covid-19 may impede the early recognition of the disease and increase Covid-19’s spread and mortality.

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Neuropathology studies on people who died from Covid-19 with dementia showed significant vascular injuries, with both ischemic or hemorrhagic and inflammatory pictures, including immune-induced meningoencephalitis. Immune hyperactivation involving the innate immune system inside the brain, namely microglia, appears to be a key factor in the pathogenesis of neurological damage, particularly in elderly individuals affected by neurodegenerative phenomena recruiting inflammation. However, more research is needed to confirm the mechanism of nervous system damage in Covid-19.

The pharmaceutical industry has been as affected as any other by the pandemic. Most countries’ research sites have put clinical trials on hold because of the difficulties of dosing and in-person clinic visits for treatment and prevention trials, and pharmaceutical companies have shifted their priorities away from some current indications towards Covid-19.

With full or partial lockdown in most countries, people ages 65 and older are not able to participate in clinical trials or receive care. However, physicians are staying in contact with their patients and carers through remote technology to minimise visits to hospitals. The disruption of important clinical research by the pandemic is also linked to the particular vulnerability of older adults to Covid-19, because participants of neurodegenerative disease trials dying from Covid-19 can significantly affect the outcomes of studies.

During the pandemic, Roche continued enrollment and dosing in the company’s Phase III GRADUATE trial of gantenerumab in Alzheimer’s by using home nursing to mitigate the impact of Covid-19 on trial data. The benefits of home administration include: maintaining the number of participants continuing treatment and study dosing, mitigating Covid-19-related challenges; allowing flexibility of care settings for patients and their carers; and reducing time spent travelling

to clinic visits. This trial adaptation was possible because gantenerumab is an anti-Aβ monoclonal antibody that is administered subcutaneously; such an initiative would be more difficult for other therapies that require on-site administration, such as intravenous therapies. Roche says that people vaccinated for Covid-19 are still enrolled in the trial but there must be a gap between the dose of the vaccine and the dose of the drug to avoid potential vaccine side effects being attributed to gantenerumab.

The social implications of the impact of Covid-19 on neurodegenerative diseases include: confinement, which might lead to social isolation; impaired memory, which could limit understanding of the situation; inability to participate in face-to-face activities, which can worsen cognitive function; and limited understanding, which might increase risk of exposure. The risk of infections between carers and people with dementia has impeded access to care during the pandemic.

To mitigate the disruption caused by the pandemic, new interventions need to be implemented. With the new technologies available, researchers and physicians can remotely screen potential participants rather than conducting in-person visits, and can support families and carers during these difficult and uncertain times.

Roche’s monoclonal antibody targeting alpha-synuclein, prasinezumab, may revolutionise Parkinson’s disease treatment

At the conference, Roche presented its monoclonal antibody (mAb)-targeting alpha (α)-synuclein, prasinezumab, for the treatment of Parkinson’s disease (PD), and highlighted the use of digital health technology tools (DHTTs) to enable the remote and frequent assessment of participants in the prasinezumab trial.

Prasinezumab is an α-synuclein mAb administered intravenously as an infusion. Normally, α-synuclein is found in an unstructured soluble form that exists almost exclusively in the nucleus of brain neurons and is involved in neuronal plasticity, where it acts as a molecular chaperone. In synucleinopathies, the synuclein protein misfolds and aggregates to form insoluble fibrils that contribute to the pathology of the disease. Antibodies targeting α-synuclein might slow down or reduce the neurodegeneration associated with synuclein.

Prasinezumab is being studied in a multicenter, randomized, double-blind, placebo-controlled study to evaluate its efficacy versus placebo over 52 weeks in participants with early Parkinson’s who are untreated or have been treated with monoamine oxidase B (MAO-B) inhibitors since baseline. The PASADENA study consists of three parts. There is a 52-week, double-blind, placebo-controlled treatment period (Part 1) with results already available, after which eligible participants will continue into an all-participants-on-treatment blinded dose extension for an additional 52 weeks (Part 2), with results expected in 2021. Participants who complete Part 2 will be offered participation for an additional 260 weeks (Part 3), and results are expected from 2021 onwards. In Part 1, the study did not meet the primary endpoint. However, signals of efficacy showing a reduction in disease progression were observed in both of the prasinezumab arms when compared to placebo.

In the PASADENA study, prasinezumab significantly reduced decline in motor function by 35% versus placebo after one year of treatment, according to the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III, which is a clinical examination of motor function. Furthermore, patients treated with prasinezumab demonstrated a significant delay in time to clinically meaningful worsening of motor progression on the site-rated assessment of time to at least a five-point progression on MDS-UPDRS Part III versus placebo over one year, with a hazard ratio of 0.82. Based on these findings, the company has plans for a further Phase IIb study, called PADOVA, to study the efficacy and safety of prasinezumab in an early-stage population requiring symptomatic treatments. The trial is expected to start in 2021 and will be conducted across multiple sites in North America (US and Canada) and Europe (UK, France, Spain, Italy, Austria, and Poland).

The positive signals on motor function demonstrated in the PASADENA trial were also confirmed using Roche’s PD Mobile Application v2, a smartphone app designed to measure core motor signs of Parkinson’s including several motor function tests and passive monitoring, where prasinezumab was seen to lower motor function decline by 25%. It is established that the fluctuation of symptoms makes it difficult to measure potential treatment effects from infrequent clinical data. The introduction and use of DHHTs could solve this issue and may provide highly sensitive markers of disease progression and treatment response.

Prasinezumab was unanimously highly regarded by key opinion leaders (KOLs) interviewed by GlobalData, and if approved, will have the potential to revolutionize the treatment of Parkinson’s. However, its mechanism of action (MOA) of targeting α-synuclein is yet to be proven clinically, and some KOLs expressed doubts over its likelihood of success due to uncertainty about whether targeting extracellular α-synuclein protein will offer enough benefit to PD patients. These doubts were supported by the February 2021 failure of Biogen’s cinpanemab, a mAb with a similar MOA to Roche’s prasinezumab, targeting the α-synuclein protein.

A first-in-class sigma-1 receptor agonist with potential neuroprotective effects for the treatment of Huntington’s disease

At the 15th International Virtual Conference on Alzheimer’s Disease and Parkinson’s Disease 2021, a Tel Aviv, Israel-based clinical-stage biotech start-up company, Prilenia Therapeutics, presented its product Huntexil (pridopidine hydrochloride) for Huntington’s disease (HD). Huntexil is a first-in-class sigma-1 receptor (S1R) agonist with potential neuroprotective effects.

Huntexil acts as S1R agonist and dopamine D2 receptor antagonist. S1R plays a key role in neuroprotection through the increased production of brain-derived neurotrophic factor (BDNF). Levels of BDNF are decreased in HD and other neurodegenerative disorders. Huntexil exhibits therapeutic intervention by agonising S1R, resulting in the enhancement of neuroprotection and improved neuroplasticity, and by antagonising the D2 receptor, stabilising psychomotor activity and strengthening cortical glutamate functions. Huntexil is currently in Phase III of development for the treatment of HD. Prilenia Therapeutics is also working on developing Huntexil in several other indications, such as amyotrophic lateral sclerosis in Phase III, as well as PD, AD, and fragile X syndrome in preclinical phase of development.

In Prilenia Therapeutics’ Phase II Pride-HD study, pridopidine was found to be well tolerated and demonstrated a beneficial effect on total functional capacity (TFC). The Pride-HD study was a Phase II dose-finding, randomised, parallel-group, double-blind, placebo-controlled study that aimed to evaluate the safety and efficacy of pridopidine in approximately 400 patients worldwide. This study examined pridopidine treatment at 45mg, 67.5mg, 90mg, and 112.5mg doses twice daily. The primary endpoint measure of Pride-HD was a change in the TFC of the Unified Huntington’s Disease Rating Scale (UHDRS) from baseline. Results showed that the pridopidine 45mg dosage demonstrated a beneficial effect on TFC for the entire population and also reduced the probability of TFC decline in early HD patients at week 52, with a p -value of 0.02. After these positive results, the company announced a new Phase III trial called PROOF-HD, which is a randomised, double-blind, placebo-controlled study evaluating the efficacy and safety of pridopidine in patients with early-stage HD. PROOF-HD’s primary endpoint will evaluate mean change from baseline in TFC and will have a key secondary endpoint of the proportion of patients with no worsening from baseline in UHDRS-TFC. Currently, the trial is ongoing and is expected to read out by the end of 2022.

There is a high level of unmet need in the HD market. In the absence of a disease-modifying drug, symptomatic management is the only viable treatment option available for physicians. The HD therapeutics market is considerably sparse, and there are only two drugs currently approved by the FDA, and two drugs currently approved by the European Medicines Agency (EMA), for HD drugs. The FDA has approved Bausch Health’s Xenazine (tetrabenazine) and Teva’s Austedo (deutetrabenazine), and the EMA has approved tetrabenazine and Sanofi’s Tiapride (tiapride). All four of these drugs are approved for the alleviation of chorea, which is one of the many symptoms associated with HD. As a result, there are still numerous symptoms that are not currently manageable with the available treatment options, despite the widespread use of off-label drugs.

According to KOLs interviewed by GlobalData, Huntexil has the potential to gain a large percentage of market share if it reaches the market, given the patient population it is targeting, and it will be prescribed as a first-line treatment to patients experiencing non-choreic motor symptoms associated with HD. However, some KOLs have expressed concerns that prescribing Huntexil to patients could depend on whether they were experiencing any other non-motor comorbid symptoms. Other available drugs may be efficacious at treating multiple symptoms, whereas Huntexil will likely only be able to alleviate non-choreic motor symptoms.