Treating Parkinson’s Disease: Betting on Alpha-Synuclein

Highlights

Parkinson’s disease, the second most common neurodegenerative disease after Alzheimer’s, affects over 10 million people worldwide.

Alpha-synuclein, a protein abundantly present in the brain, is most commonly found at the tips of neurons in specialized structures called presynaptic terminals, which are involved in the release of chemical messengers (neurotransmitters) from synaptic vesicles. In the case of pathological conditions associated with Lewy bodies (synucleopathies), such as Parkinson’s disease, dementia with Lewy bodies, multiple systemic atrophy, and Alzheimer’s disease, alpha-synuclein aggregates are predisposed to form insoluble fibrils that spread through the nervous system as the disease progresses and determine neurodegenerative changes.

Pharmacological efforts to combat Parkinson’s by getting rid of the neurotoxic alpha-synuclein do not look particularly impressive in terms of therapeutic efficacy. Nevertheless, pharma players are not giving up.

 

ABL301

In January 2022, Sanofi acquired a worldwide license from Korea’s ABL Bio for the experimental drug ABL301, intended to treat Parkinson’s disease.

The deal calls for a $75 million upfront payment and a follow-up amount of up to $985 million as the project develops, as well as royalties from sales of the finished drug.

In preclinical development, ABL301 is a bispecific monoclonal antibody targeting alpha-synuclein and insulin-like growth factor 1 receptor (IGF1R).

ABL301 recognizes pathological aggregates of alpha-synuclein with high affinity, bypassing its monomeric forms. The targeting of IGF1R made within the Grabody-B technology platform allows ABL301 to pass the blood-brain barrier (BBB) without difficulty. Because IGF1R is highly and relatively specifically expressed on brain endothelial cells, ABL301 penetrates the brain via receptor-mediated transcytosis (RMT).

According to ABL, ABL301 is characterized by several advantages over other monoclonal antibodies being developed by other players in the pharmaceutical industry. First, competitors’ biological drugs penetrate the BBB very poorly: approximately 0.1%–0.2% of such antibodies are detected in the brain.

Second, competitor biologics virtually indiscriminately bind aggregated and monomeric forms of alpha-synuclein, although it is the former that are involved in the pathophysiological cascades in Parkinson’s.

Third, ABL301 has a dual mechanism of action: promoting phagocytosis of extracellular alpha-synuclein by microglial cells and inhibiting the prion-like spread of alpha-synuclein from cell to cell. Competitor’s antibodies mainly carry out only the second.

 

UCB0599 and UCB7853

In December 2021, Novartis and Belgium’s UCB have agreed to jointly develop and commercialize two drugs to treat Parkinson’s disease.

Under the terms of the agreement, UCB will receive an upfront payment of $150 million from Novartis, followed by payments of up to $1.5 billion as certain milestones are reached in the development of experimental projects. If the finished drugs are commercialized, revenues will be shared geographically, with UCB handling sales in Europe and Japan and Novartis in the U.S. and other countries.

The partnership covers two drug candidates targeting the alpha-synuclein protein.

Small-molecule UCB0599 (NPT-200-11), which UCB licensed from Neuropore Therapies in 2014, inhibits alpha-synuclein aggregation. UCB0599, being a cyclic peptidomimetic molecule, is a second-generation compound optimized for oral bioavailability and blood-brain barrier penetration.

UCB0599, which interacts with the C-terminal domain of alpha-synuclein and prevents its binding to membranes with further oligomerization therein, in vitro inhibits alpha-synuclein aggregation, and in transgenic mouse models normalizes neural and inflammatory markers, eliminates motor deficits, attenuates cortical alpha-synuclein pathology and astrogliosis and normalizes striatal dopamine transporter levels.

In December 2020, UCB launched NCT04658186, an 18-month phase 2 (randomized, double-blind, placebo-controlled, multicenter, international) clinical trial testing the therapeutic effectiveness of UCB0599 in patients aged 40 years and older with early-stage Parkinson’s.

UCB7853 is a monoclonal antibody against alpha-synuclein that suppresses its extracellular spread.

The NCT04651153 phase 1 clinical trial evaluating different intravenous doses of UCB7853 in terms of safety, tolerability, and pharmacokinetics — among healthy volunteers and patients with mild-to-moderate Parkinson’s — was launched in December 2020.

UCB0599 and UCB7853 are said to complement each other seamlessly in the task of slowing the progression of Parkinson’s: the first drug is indicated in its early stages, the second is suitable for more advanced states.

 

Prasinezumab

Ireland’s Prothena and Roche are bringing the monoclonal antibody prasinezumab (RG7935, PRX002) against aggregated alpha-synuclein to fruition. But the results so far have not been impressive.

The PASADENA (NCT03100149) phase 2 clinical trial, organized among patients with newly diagnosed Parkinson’s and not adhering to dopamine replacement therapy, failed to achieve the primary endpoint claimed by improvement in the overall score on the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), which evaluates the severity and progression of the disease.

However, it turned out later on that there was still improvement, and it was related to motor functions: prasinezumab reduced decline in motor function such as slowness of movement (bradykinesia), tremor, rigidity, and gait instability by 35% relative to placebo.

The PADOVA (NCT04777331) phase 2b clinical trial was launched in May 2021, testing how well prasinezumab delays the deterioration of motor function in patients with Parkinson’s in a more advanced form than PASADENA.

 

Cinpanemab

Biogen failed with the monoclonal antibody cinpanemab (BIIB054) licensed from the Switzerland’ Neurimmune and targeted against alpha-synuclein aggregates. Although the industry considered this drug to be the most technically advanced. In the SPARK (NCT03318523) phase II clinical trial, cinpanemab did not provide any meaningful improvement on the MDS-UPDRS scale. Further development of cinpanemab was discontinued in February 2021.

 

ABBV-0805

AbbVie has in its hands a humanized monoclonal antibody ABBV-0805 (BAN0805) licensed from Sweden’s BioArctic that binds oligomeric and protofibrillar forms of alpha-synuclein of various conformations with picomolar affinity.

ABBV-0805 is characterized by a very high (100,000-fold) binding selectivity of aggregated alpha-synuclein relative to its monomeric forms. By comparison, the affinity of prasinezumab (RG7935, PRX002) and cinpanemab (BIIB054), which are backed by Roche/Prothena and Biogen/Neurimmune, are 400 and 800 times higher to aggregated alpha-synuclein than monomeric, respectively.

Given the high level of physiological monomeric alpha-synuclein in the blood, it is important to minimize its binding, first, to avoid peripheral sequestration of the antibody in plasma so that more of it reaches its targets in the brain, and second, for an improved safety profile and reduced therapeutic dose.

However, the future of ABBV-0805 is still murky, as AbbVie stopped the corresponding NCT04127695 phase 1 clinical trial in July 2020 for strategic reasons.

 

PD01A

Despite the meager success of the Big Pharma players, Switzerland’s AC Immune believes in the reasonableness of the alpha-synuclein hypothesis: PD01A, an active vaccine against alpha-synuclein, was purchased in July 2021 from Austria’s AFFiRiS.

The immunogen in PD01A is an eight-amino acid peptide (PD01) that mimics the epitope in the C-terminal region of human alpha-synuclein, but with a different amino acid sequence. The peptide is conjugated to a keyhole limpet hemocyanin (KLH) carrier protein and adsorbed to an aluminum hydroxide adjuvant. The PD01A vaccine is designed to stimulate a B-cell antigenic response but bypasses autoreactive T-cell mobilization, which can cause unnecessary neuroinflammatory responses.

Active immunization with PD01A generates antibodies that selectively recognize alpha-synuclein aggregates with much lower affinity for its monomeric forms and no reactivity to beta-synuclein. The carrier protein provides the necessary T-helper epitopes for the induction of a prolonged and enhanced antibody response, whereas the antigenic component (PD01) acts exclusively as a B-cell epitope and is responsible for the specificity of the humoral immune response.

AC is preparing to launch a Phase 2 clinical trial that will study the experimental vaccine ACI-7104 (an optimized formulation of PD01) among patients with early-stage Parkinson’s.

 

Buntanetap

Annovis Bio’s approach is interesting: its small-molecule drug candidate buntanetap (ANVS401), also known as posiphen, targets three neurotoxic proteins at once: amyloid beta, alpha-synuclein, and tau protein. All of them disrupt the axonal transport of neurotransmitters and neurotrophic factors and slow down synaptic transmission, thereby impairing neural activity in general. Such disturbances lead to activation of the immune system, which attacks nerve cells, leading to neuroinflammation, degeneration and death of nerve cells. The result is impaired cognitive and motor performance.

In a wave of clinical successes with buntanetap, Annovis intends to organize its phase 3 clinical trial in patients with early-stage Parkinson’s who show symptoms but are not yet taking any anti-Parkinsonian medications.

 

Anle138b

Germany’s Modag is evaluating a small-molecule anle138b binding oligomeric alpha-synuclein. The NCT04685265 phase 1b clinical trial, scheduled for completion in the summer of 2022, is testing the administration of various doses of anle138b to patients with mild-to-moderate Parkinson’s disease.

In late October 2021, Teva Pharmaceutical Industries joined the anle138b project, wishing to acquire worldwide rights to the drug candidate. The partnership also involves sery433, a prodrug of anle138b, which was developed with a view to increasing its bioavailability.

The oral anle138b effectively crosses the blood-brain barrier (BBB) and specifically and with nanomolar affinity binds toxic oligomeric structures of intracellular alpha-synuclein, resulting in their dissolution and prevention of new oligomer formation.

Since anle138b destroys pre-amyloid oligomers and disrupts fibril growth, it leads, in combination with cellular clearance mechanisms, to a reduction in the number of deposited amyloid fibrils. Anle138b is not a fibril disruptor, which is important because their fragmentation enhances the prion-like distribution of toxic proteins and disease progression by forming more particles capable of attracting monomers through improper folding.

Anle138b, being a diphenylpyrazole compound, suppresses the formation of alpha-synuclein and prion protein oligomers. In various mouse models of sinucleopathies and Parkinson’s disease, anle138b prevented oligomer accumulation and neuronal degeneration, improved dopamine neuron function and motor function, and inhibited disease progression, even after the clinical manifestation of Parkinson’s.

It is also argued that because pathological oligomers in neurodegenerative diseases share common structural features, although the main protein component is disease-specific, and anle138b modulates oligomer formation by acting on structure-dependent epitopes, this molecule could conceivably find its way into the treatment of various protein aggregation-related pathologies.

In mouse models of multiple systemic atrophy (MSA), anle138b reduced alpha-synuclein oligomers, preserved dopaminergic neurons and improved walking, restrained neurodegeneration in the substantia nigra and reduced microglial activation. In a model mimicking a more severe form of MSA, anle138b slightly improved motor skills but did not significantly affect neurodegeneration or alpha-synuclein accumulation.

In mouse models of tau pathology, anle138b reduced neuronal loss, improved cognitive ability, and prolonged survival, and even in older mice, anle138b reversed impaired end point glucose metabolism in the brain.

In a mouse model of Alzheimer’s disease, anle138b restored hippocampal synaptic plasticity and memory.

 

Ambroxol

Ambroxol is a mucolytic drug and the main ingredient in a number of over-the-counter cough medicines. In the United States and Canada, ambroxol is not registered.

Interest in studying ambroxol for Parkinson’s disease is due to its activity as a molecular chaperone for the lysosomal enzyme beta-glucocerebrosidase (GCase): loss-of-function mutations in the GCase gene (GBA1) are associated with a 20–30 fold increased risk of Parkinson’s, with earlier onset and accelerated cognitive and motor deterioration.

Beta-glucocerebrosidase activity and alpha-synuclein activity are interrelated: GCase deficiency causes pathological accumulation of alpha-synuclein in cell cultures, and GCase overexpression in the brain attenuates pathology and memory deficits in a mouse model of synucleinopathy. GCase activity is reduced in idiopathic Parkinson’s without GBA1 mutations, and reduced GCase activity correlates with earlier disease onset and worsened cognitive and nonmotor symptoms. GBA1 mutations were originally identified as a cause of parkinsonism in Gaucher’s disease, a lysosomal disease characterized by sphingolipid accumulation and in some cases alpha-synuclein pathology.

In cells derived from patients with Gaucher’s or Parkinson’s, ambroxol stabilized mutant GCase and promoted its movement from the endoplasmic reticulum (ER) into lysosomes, increasing protein levels, enzyme activity, and lysosome function. In flies with GCH1 mutations, ambroxol enhanced GCase activity, reduced ER stress, and protected motor function.

In wild-type and GCH1 mutant mice, ambroxol induced GCase activity in the brain, and in mice overexpressing human alpha-synuclein reduced the total amount and level of phosphorylated alpha-synuclein. In a mouse model of amyotrophic lateral sclerosis, ambroxol improved motor function and prolonged survival.

In healthy nonhuman primates, daily administration of ambroxol increased GCase activity in the brain.

The AiM-PD (NCT02941822) phase 2 clinical trial by University College London demonstrated that daily 1260 mg of ambroxol (multiple times the dose administered for cough) administered for five months improved MDS-UPDRS scores (particularly motor function) in patients with moderate Parkinson’s.

Lawson Health Research Institute is conducting a phase 2 clinical trial of NCT02914366 to see if ambroxol can improve cognitive and motor symptoms in Parkinson’s dementia.

An analysis of real data from patients with Gaucher’s, including those with Parkinson’s on its background, who took ambroxol confirmed the beneficial effects it had, manifested by stabilization or improvement of neurological status, increased physical activity, and reduced fatigue.

 

Vectorized Antibodies

An interesting idea is promoted by Voyager Therapeutics, which has come up with a solution to the problem of delivering to the brain the necessary amount of antibodies that bind pathological proteins, including alpha-synuclein. Voyager addressed the issue of bypassing the blood-brain barrier (BBB), which prevents large molecules from penetrating. Yes, frequent systemic injections of antibodies can be made, but this is not an option because of the high likelihood of adverse reactions.

The principle of so-called vectorized antibodies is as follows: an adeno-associated virus (AAV) vector is constructed that carries certain genetic instructions encoding the desired monoclonal antibody, which is synthesized by the body itself directly in the brain. It is claimed that a single intravenous injection of the AAV drug will be enough to provide the proper therapeutic effect for a very long time – possibly for life. This is explained by the fact that the target cells in the central nervous system in this case are neurons, long-lived and non-dividing.

That would be all right, but in August 2020 AbbVie terminated its partnership agreement with Voyager for vectorized antibodies against neurodegenerative diseases.