Despite years of use of gold-standard therapy levodopa, therapeutic development in Parkinson disease has advanced rapidly and expanded to numerous novel pathways and targets.
PARKINSON DISEASE (PD) IS THE second most common neurodegenerative disorder in the world after Alzheimer disease, and it is projected to affect approximately 10 million patients by 2030.1,2 The disease is characterized by death of dopaminergic neurons in the substantia nigra pars compacta. Pathogenesis is thought to stem from Lewy bodies, which are the misfolding and aggregation of forms of the intracellular protein α-synuclein (ASN), leading to cell death and progressive loss of these neurons. Although there are effective symptomatic treatments for motor and nonmotor symptoms, there are no available disease-modifying therapies (DMTs) that slow, stop, or reverse disease progression. This review will cover promising early phase clinical trials of DMTs.
Small, nonfibrillar ASN aggregates drive most of the disease progression and inflammation in PD.3 Anle138b and NPT200-11 (and UCB0599, an enantiomer of NPT200-11) target these toxic oligomers and prevent their misfolding and aggregation. Anle138b inhibits oligomeric activation,4 whereas NPT200-11 and UCB0599 block pathological misfolding of ASN by stabilizing the physiologic state.5,6 In mouse models, these medications demonstrated restoration of striatal dopamine release/dopamine transporters, improved motor functioning, decreased cortical ASN, and reduced neuroinflammation.4-7
A phase 1 study is underway to assess safety and tolerability of ascending doses of anle138b in mild to moderate PD (NCT04685265). A phase 2 study is underway to determine the efficacy, safety, tolerability, and pharmacokinetics of UCB0599 in patients with early-stage PD (NCT04658186).
Cellular Abelson (c-Abl) tyrosine kinase activation is related to the neurodegenerative pathophysiology of PD.8 Thus, c-Abl inhibitors— including nilotinib, K0706 (Vodobatinib), and IkT-148009—have been studied as possible DMTs for PD.
Nilotinib (Tasigna; Novartis) is a multikinase inhibitor used in the management of chronic myelogenous leukemia via the inhibition of c-Abl. Results from early studies suggested a benefit of nilotinib in increasing dopamine in the brain and reducing ASN aggregates as well as reducing hyperphosphorylated tau levels via inhibition of discoidin domain receptor family 1, which increases autophagy.9 Other studies with nilotinib, focusing only on the c-Abl inhibition, have been misleading in suggesting that nilotinib should not be further studied.10 In fact, nilotinib has been shown to alter messenger RNA levels in the cerebrospinal fluid (CSF), fostering an epigenetic environment that stabilizes the blood-brain barrier (BBB) and reduces inflammation,11 thereby demonstrating the need for continued research in phase 3 studies in PD and other neurodegenerative disorders.
K0706 is safe and well tolerated in patients with PD, with improved BBB penetration compared with nilotinib.12,13 The ongoing phase 2 PROSEEK trial (NCT03655236) is investigating the efficacy, safety, and tolerability of varying doses of K0706 in patients with early-stage PD, as well as evaluating long-term effect of K0706 on PD disease progression.
IkT-148009, another brain-penetrant c-Abl inhibitor, has been shown to improve motor function, clear ASN in the brain and enteric system, and suppress neurodegeneration in mouse models.14 A phase 1 trial (NCT04350177) examining the safety and tolerability of IkT-148009 in healthy elderly participants was recently completed without published results yet, and a phase 2 trial (NCT05424276) looking at the efficacy of the drug in treatment-naïve patients with PD is underway.
Anti-ASN antibodies are monoclonal antibodies that target the ASN protein with the goal of enhancing immune-mediated clearance of pathological aggregates from the nervous system.10,15 Another anti-ASN approach to treatment is a specific active immunotherapy—a vaccine—that stimulates a B-cell immunogenic response and creates antibodies against aggregated ASN. There are 2 active agents in this category, PD01A and PD03. In animal models, both vaccines reduced aggregated ASN burden and neurodegeneration and improved motor function.16
In their respective phase 1 trials, PD01A (NCT01568099) and PD03A (NCT02267434) have demonstrated favorable safety profiles and good immune response in patients with PD.17-19 Phase 2 trials are still needed to further explore this treatment modality.
Glucocerebrosidase (GCase), a lysosomal enzyme involved in the metabolism of ASN, has been another target therapy for both patients with and without a mutation in the gene encoding GCase, GBA.20 Targeting this metabolic pathway has focused on 3 main categories: modulation of enzyme activity, reduction of substrate, and gene therapy.
Ambroxol, an over-the-counter cough medication outside the US, is a potential agent to modulate enzyme activity. It restores function to mutated GCase by chaperoning it to the lysosome. A completed phase 2 clinical trial (NCT02941822) demonstrated safety and tolerability as well as CSF penetration.21 Two similar phase 2 trials for ambroxol are underway, with one focusing on PD dementia population (NCT02914366) and another focusing on PD plus GBA1 mutation (AMBITIOUS; NCT05287503).
The safety of LTI-291, which activates GCase, was shown in results of a phase 1 trial for participants with PD with GBA1 mutation.22 Imiglucerase (Cerezyme; Sanofi), an analogue of human β-GCase, is the focus of 2 clinical trials (NCT04370665; NCT05565443) using MRI-guided focused ultrasound to relax the BBB for penetrance of the enzyme analogue into the targeted region of the brain. Another phase 1/2 study (NCT04127578) using gene therapy with PR001, a modified virus that delivers a functional copy of GBA1 to the cell, is underway, though results are not expected until 2028.
One of the most common mutations associated with PD is a Gly2019Ser mutation in LRRK2.23 LRRK2 mutations are thought to enhance ASN propagation and neurotoxicity. Based on this, several clinical trials targeting LRRK2 are underway.
Two LRRK2 inhibitors have undergone phase 1b studies, DNL201 (NCT03710707) and DNL151 (NCT04056689). Both DNL201 and DNL151 (previously known as BIIB122) are orally bioavailable and CNS-penetrating small molecule LRRK2 inhibitors that are well tolerated with acceptable safety profiles in healthy participants and patients with PD—both carriers and noncarriers of LRRK2 mutations—with DNL151 providing additional dosing flexibility.24,25
Another approach to LRRK2 inhibition involves antisense oligonucleotides. Preclinical studies have demonstrated LRRK2 antisense oligonucleotides may reduce ASN aggregation.16,26,27 Based on these findings, a phase 1 clinical trial (REASON; NCT03976349) is underway to evaluate the safety, tolerability, pharmacodynamics, and pharmacokinetics of BIIB094 in participants with PD.
Sargramostim is a modified recombinant human granulocyte-macrophage colony stimulating factor. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse models, sargramostim administration demonstrated the potential for disease modification.28 In an unblinded phase 1b trial (NCT03790670) in patients with PD, long-term sargramostim treatment was well tolerated and effective at restoring immune homeostasis. Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III scores were stable in the patients who were administered the drug.29 Another phase 1b study (NCT05677633) is underway to determine the safety for a duration of 48 weeks.
Azathioprine (Imuran, Azasan; Prometheus Biosciences Inc) is an effective treatment for inflammatory and autoimmune diseases, and there is growing evidence suggesting that immune system activation plays a significant role in PD. A trial (EudraCT/CTIS 2018-003089-14; ISRCTN14616801) investigating whether suppressing the immune system with azathioprine slows the progression of PD was started in the United Kingdom in 2020 and is ongoing, with the preliminary results expected in 2024.
Increasing evidence suggests that boosting cellular levels of nicotinamide adenine dinucleotide (NAD) may increase neuroprotective effects. One way this is done is through nicotinamide riboside (NR) therapy.30 A phase 1 randomized, double-blinded trial (NADPARK; NCT03816020) reported that NR was well tolerated and led to a significant, but variable, increase in cerebral NAD levels and related metabolites in CSF. NR recipients also showed mild clinical improvement and reduction in serum and CSF inflammatory markers.30 N-DOSE is a double-blinded placebo-controlled randomized trial (NCT05589766) aiming to determine the optimal biological dose of NR in patients with PD.
Investigators recently conducted the NR-SAFE safety trial (NCT05344404) comparing 3000-mg NR with placebo in 20 participants with PD over 4 weeks. The data showed no moderate or severe adverse events and no signs of acute toxicity.
Ursodeoxycholic acid (UDCA) has been shown to prevent neuronal damage in animal models. However, the role of UDCA in PD is poorly understood. UDCA rescues the function of the mitochondria in the tissue of patients with PD and other models of PD, according to findings of a phase 2 clinical trial (NCT03840005). These findings suggest that UDCA may slow down the worsening of PD and potentially be a new therapeutic drug candidate in PD.31
Previous studies have shown that glucagonlike peptide-1 (GLP-1) receptor agonists have neuroprotective effects in animal models of PD. Exenatide is a licensed GLP-1 receptor agonist used in type 2 diabetes mellitus. Some study groups have confirmed that exenatide may slow down or stop neurodegeneration in PD. The drug is well tolerated and shows encouraging effects on the movement and nonmovement aspects of the disease.
Results from a recent phase 2 trial (NCT04305002) in PD showed that patients in active treatment for 1 year were improved compared with the placebo arm with regard to their performance in the MDS-UPDRS motor subscale in the practically defined OFF medication state. A phase 3 trial (Exenatide-PD3; NCT04232969) of exenatide has also started in a multicenter setting to explore whether the neuroprotective effect of the drug remains stable or increases over time. The trial is in progress, with results expected in 2024.
Similarly, NLY-1 is a pegylated form of exenatide that has the potential to be beneficial in PD. A phase 2 study (NCT04154072) has recently finished recruiting, with the results expected in 2023. Other phase 2 trials are investigating the GLP-1 agonists liraglutide (NCT02953665), lixisenatide (NCT03439943), and semaglutide (NCT03659682).
Clinical trials using stem cells are still in the early phases of development. There are a few technologies and methods that use stem cells in disease modification. The newest is the STEM-PD trial (NCT05635409), in which the scientists will transplant a new stem cell therapy, called the STEM-PD product, into the area of the brain affected in patients with PD. There are also other trials focusing on transplanting autologous mesenchymal stem cells: NCT04146519, NCT05094011, NCT04506073, NCT05152394, and NCT04772378.
Most therapeutic progress has been made in the era of gold-standard treatment with levodopa, highlighting the importance of having a variety of therapeutic approaches in PD care. With so many potential targets and molecules being studied, the possibilities of a potential DMT or a combination of drugs to modify disease in PD appear promising.