Currently, available therapies for the treatment of Parkinson's disease fail to provide lasting and predictable relief of motor symptoms without significant risk of adverse events. Patients with Parkinson's disease report significantly less satisfaction with treatment than patients with other chronic diseases, particularly because of unpredictable motor fluctuations. Patients may experience motor fluctuations, including a sudden and unpredictable drop in efficiency. In addition, treatment with levodopa causes very serious side effects.

Therefore, new therapies for the treatment of Parkinson's disease are expected to have durable and predictable efficacy, provide effective control of motor symptoms, and improve significant adverse events associated with current therapies. Currently available dopamine treatments work either by increasing dopamine levels (e.g. levodopa, COMT and MAO-B inhibitors) or by directly activating dopamine receptors in the striatum, an area deep in the brain.

Within the striatum, dopamine acts on two distinct populations of receptors, primarily the D1/D5 and D2/D3 receptors, which differ in the neuronal populations on which they are expressed and in the G proteins to which they are coupled. Dopamine therefore promotes movement by acting:

• on D1/D5 receptors to activate direct pathway striatal neurons
• by acting on the D2/D3 receptors to inhibit the MSNs of the indirect pathway to release the inhibitory brake on the motor power.

Together, these two parallel circuits coordinate targeted motor control in the healthy brain. Progressive loss of dopamine signaling in Parkinson's disease leads to disturbances in the balance of direct and indirect pathway activation and subsequent dysregulation of striatal output.

It was hypothesized that targeting dopamine D1/D5 receptors (without targeting D2/D3 receptors) would produce strong motor benefits with reduced risk of D2/D3 receptor-related adverse events, but the development of Selective D1 agonists have previously been hampered by intolerable cardiovascular adverse events and poor pharmacokinetic properties.

Partial agonism at D1/D5 has shown promise in alleviating motor symptoms, potentially without the adverse events associated with selective D2/D3 dopamine agonists (e.g., confusion, sleep disturbances, impulsivity, hallucinations) and dopamine agonists fully selective D1/D5.

However, even activation of extrastriatal D1/D5 receptors, particularly those located outside the central nervous system, can also produce adverse effects such as cardiovascular and dyskinetic problems.

Tavapadon, a highly selective partial agonist of the D1 and D5 receptors, has been studied for some time for use in early to advanced Parkinson's disease. Early clinical and preclinical evidence suggests that tavapadon offers the potential to provide robust, durable, and predictable motor control via selective activation of direct striatal pathways, associated with a reduced risk of adverse events seen with prior dopamine agonists in due to its D1/D5 selectivity and its partial agonist properties.

Tavapadon is a highly selective partial agonist of the dopamine D1 and D5 receptors, with little or no functional activity at the D2, D3 or D4 receptors.

Tavapadon may also have advantages over previously studied fully selective D1/D5 dopamine agonists, not only in terms of sustained motor benefit, but also in terms of reduced risk of bothersome dyskinesias. The preclinical study of tavapadon was conducted in non-human primates with MPTP-induced Parkinson's disease who had previously developed dyskinesias in response to long-term levodopa treatment. The administration of tavapadon, alone or in combination with levodopa, then allowed powerful control of motor symptoms accompanied by a reduction in dyskinesia.

Thursday 18, the company Cerevel (which is in the process of being acquired by Abbvie) communicated on the good results of a phase 3 trial (TEMPO-3) among patients suffering from Parkinson's disease. Subjects were required to receive a stable dose of levodopa for at least four weeks before screening and continue taking the drug in combination with tavapadon or placebo once the trial began. The TEMPO-3 trial evaluated the effectiveness, safety and tolerability of tavapadon as an adjunct treatment to levodopa (LD) in adults. A total of 507 adults aged 40 to 80 participated in the trial. All had a confirmed diagnosis of Parkinson's disease, showed motor fluctuations, and were receiving a stable dose of LD for at least 4 weeks before screening. Patients were randomized to receive either tavapadon in addition to LD, titrated to 5-15 milligrams, or placebo and LD, orally once daily.

During the 27-week trial, patients who took tavapadon went significantly more time without bothersome uncontrolled and involuntary movements, known medically as dyskinesia, than their peers on placebo. The study, which collected data using a self-completed family diary on the status of motor function, showed that people taking the drug went 1.7 hours without bothersome dyskinesia, compared to 0.6 hours in the control group.

Cerevel also reported a significant reduction in the length of time patients experienced symptoms, but has not yet shared data on this secondary endpoint. Likewise, the biotech said the molecule was generally well tolerated, unsurprisingly, and that most side effects were mild or moderate. But we must wait for a more in-depth review of the safety data before medical meetings.

Full results from the TEMPO-3 study will be submitted for presentation at future medical meetings and used to support regulatory submissions of tavapadon as a treatment for Parkinson's disease. Initial results from Phase 3 monotherapy trials for tavapadon, TEMPO-1, and TEMPO-2, are expected in the second half of 2024. Cerevel is also conducting a fourth open-label extension (OLE) trial (TEMPO-4) to evaluate the long-term safety and tolerability of tavapadon.

These various announcements are part of a roadmap of updates on tavapadon which includes regulatory submissions and the main results of two phase 3 studies testing the molecule as a monotherapy obviously with a view to an application for marketing authorization on the market.

Two very interesting new articles have been published on the (supposed) action of a drug against Alzheimer's disease. These articles provide the reader with several points for further reflection. - One of them is that the clinical trial cannot be the only method of validating the marketing of a drug. Indeed, for diseases that develop over decades, often asymptomatically, how can the effectiveness of a drug be tested? We can always dream of a pill that will cure in a few months a patient, as this is true for diseases where there is an identified pathogen, but it is very unlikely with chronic diseases. Even for communicable diseases, this type of medication does not always exist; a patient can be considered permanently cured, even though they suffer very serious after-effects.

HIV and many other viruses rely on an enzyme, called reverse transcriptase (RT), to copy their RNA molecules and change them into complementary DNA duplicates that can then be inserted back into the host cell's DNA, producing permanent sequence changes.

As RT hijacks a host's cells to establish a chronic infection, so drugs that block the RT enzyme's activity have become a common part of treatment cocktails for keeping HIV at bay.

The team of the first article analyzed anonymized medical records with prescription claims from more than 225,000 controls and patients and found that RT inhibitor exposure was associated with a statistically significant reduced incidence and prevalence of Alzheimer's disease. There were 2.46 Alzheimer's disease diagnoses per 1,000 persons taking these inhibitors, versus 6.15 for the general population. And this with a drug that is not optimized for Alzheimer's disease. Indeed the drugs patients took in this retrospective study were designed to counter a specific form of RT used by HIV and it may only have a limited effect on many different possible forms of the enzyme in the brain. So there is significant room for progress to perfect this drug.

• Another point of reflection concerns the etiology of Alzheimer's disease. This is the subject of numerous debates and gigantic financial bets. Clearly, the pharmaceutical industry ecosystem considers that the appearance of intra and extra-cellular beta-amyloid plaques is the cause of this disease. Few scientists question why these plaques appear, or whether competing hypotheses have been properly studied. In this new article, it is shown that an anti-viral drug significantly reduces the risk of developing Alzheimer's disease.

In a second article, an explanation is proposed as to why clinical trials for this disease most often fail. The amyloid hypothesis, or the theory that the accumulation of a protein called beta-amyloid in the brain causes Alzheimer's disease, has driven Alzheimer's research to date. However, treatments that target beta-amyloid have notoriously failed in clinical trials. The authors of the second article found that most Alzheimer's disease brain samples contained an over-abundance of distinct APP gene variants, compared to samples from normal brains. Among these Alzheimer's-enriched variations, the scientists identified 11 single-nucleotide changes identical to known mutations in familial Alzheimer's disease—a very rare inherited form of the disorder. Although found in a mosaic pattern, identical APP variants were observed in the most common form of Alzheimer's disease, further linking gene recombination in neurons to disease.

“The thousands of APP gene variations in Alzheimer's disease provide a possible explanation for the failures of more than 400 clinical trials targeting single forms of beta-amyloid or involved enzymes,” says Chun. "APP gene recombination in Alzheimer's disease may be producing many other genotoxic changes as well as disease-related proteins that were therapeutically missed in prior clinical trials. The functions of APP and beta-amyloid that are central to the amyloid hypothesis can now be re-evaluated in light of our gene recombination discovery."

• We have all learned that all the cells of an organism have the same genetic heritage since they come from the same original cell. This vision, which dates from the middle of the last century, is beginning to be called into question in different cases: cancers, cases of mosaicism, and aging. These two articles, which come from the same laboratory, raise the question of how to detect these cases of mosaicism. Indeed, if a virus modifies the genome of a cell, but only in certain tissues (such as the brain) and only for a fraction of the cells, a genetic analysis of an easily accessible tissue will not necessarily highlight an alteration of the genome. of a significant fraction of the cell population of another tissue.

The researchers note that: "It is important to note that none of this work would have been possible without the altruistic generosity of brain donors and their loving families, to whom we are most grateful. Their generosity is yielding fundamental insights into the brain and is leading us toward developing new and effective ways of treating Alzheimer's disease and possibly other brain disorders—potentially helping millions of people.

As usual, it is not the first time that RT inhibitors have been proposed against Alzheimer's disease animal models, but it is the first time the effect has been shown in humans.

Atrial fibrillation is a risk factor for stroke and multiple forms of dementia, including Alzheimer’s disease. The exact reasons why atrial fibrillation (a common heart disease) increases dementia risk aren't fully understood, but there are likely several factors involved. Some of these factors directly cause damage, while others increase the chances of getting dementia over time. These factors include tiny blood blockages and bleeding in the brain's small blood vessels. Small strokes you might not even notice, reduce blood flow to the brain, increase long-term inflammation, and lead to shrinkage of brain tissue.

"Silent strokes" seem to be especially important because they're found in up to a quarter of atrial fibrillation patients. In these cases, dementia develops because of damage to the brain's tissues caused by a stroke or a temporary lack of blood flow (transient ischemic attack). So, by preventing these silent strokes, we can also reduce the risk of getting dementia or slow it down. This is why using blood thinners (anticoagulants or anticoagulants) is so important for people with atrial fibrillation.

Catheter ablation of atrial fibrillation is a minimally invasive procedure used to treat atrial fibrillation, a heart condition that causes irregular heart rhythm. Catheter ablation is typically an option for people with atrial fibrillation that is not controlled by medications or who experience significant side effects from medications. It is not a cure for atrial fibrillation, but it can significantly improve symptoms and quality of life for many people.

During the procedure, a thin, flexible tube called a catheter is inserted into a blood vessel in the groin and threaded up to the heart. The catheter uses radiofrequency energy or extreme cold (cryoablation) to create tiny scars on the heart tissue in the areas where the abnormal electrical signals originate. These scars block the faulty electrical signals, preventing them from spreading through the atria and causing irregular heartbeats.

However, studies of atrial fibrillation did not consistently report on the influence of periprocedural anticoagulation and long-term use of anticoagulants on dementia risk.

Swedish scientists evaluated the protective effect of atrial fibrillation ablation in a large cohort who received optimized anticoagulation and compared them with patients whose cases were recorded in the Swedish Patient Register.

They studied the cases of 5,912 patients who underwent first-time catheter ablation for atrial fibrillation between 2008 and 2018 and compared them with 52,681 control individuals from the Swedish Patient Register. The majority of patients were on anticoagulants. The mean follow-up time of those patients in the Swedish Patient Register was 5 years.

The Swedish authors found that catheter ablation and anticoagulation treatment were associated with a lower risk of dementia diagnosis compared with the control group. The result was similar when including patients with a stroke diagnosis, which tends to confirm the vascular origin of these cases of dementia.

These results are in line with similar findings in other countries.

The phase 2 LixiPark trial (NCT03439943) showed that treatment with lixisenatide (Adlyxin, Sanofi), a glucagon-like peptide-1 receptor agonist used as a therapy for diabetes, may have resulted in less progression of motor disability compared with placebo at 12 months in patients with early Parkinson disease (Parkinson’s disease) but was associated with gastrointestinal adverse effects. The results of this recent trial add further evidence to exenatide’s potential as a drug that might slow the progression of Parkinson’s and pave the way for the larger phase III clinical trial that is currently underway;

Diabetes mellitus is a risk factor for Parkinson's disease. UK's Cure Parkinson’s has been at the forefront of exenatide’s journey as a potential treatment for Parkinson’s from the outset. They funded the first clinical study of exenatide in people with Parkinson’s. This was a year-long pilot study in 2008 involving 45 people with Parkinson’s. Those who took exenatide did not experience the decline in their movement that is normally seen due to Parkinson’s. Actually, these participants improved a little. Crucially, some of these benefits were still present when measured one year after the participants had stopped taking exenatide, giving hope that this medicine had interfered with the underlying disease process, rather than simply masking symptoms.

Liraglutide is another drug that belongs to a class of medicines called Glucagon-like peptide 1 (GLP-1) receptor agonists. In addition to treating T2 diabetes and obesity, this class of drugs has another interesting property: taming inflammation. In animal models of Parkinson’s, liraglutide has shown strong neuroprotective effects.

Based on this, Cure Parkinson’s in 2017 funded Professor Michele Tagliati to undertake a phase II randomized, double-blind, placebo-controlled clinical trial of liraglutide in people with Parkinson’s.

70 participants were given either once-daily injections of liraglutide or placebo injections for 52 weeks. The study was primarily designed to assess changes in symptoms whilst off Parkinson’s medication for 12 hours before the assessments. Movement (motor), non-motor, and cognitive symptoms were assessed along with several secondary measures, including quality of life and daily activities. The primary analysis of the results included 37 people with Parkinson’s on liraglutide and 18 on the placebo drug.

Non-motor symptoms, activities of daily living, and quality of life appeared to significantly improve in the group on liraglutide treatment. However, there was no clear difference in motor symptoms between those on liraglutide and those on the placebo; it was noted that there appeared to be a strong placebo effect in this study, meaning the participants, even though none was aware they were taking the placebo drug, believed they were experiencing therapeutic results. This is consistent with the often-reported association of more invasive treatments causing a stronger placebo effect.

The research team also reported a significant lowering of body mass index (BMI) and average blood glucose levels in the active drug group, which are not desirable for patients in general. Interestingly, significant mobility improvements were reported by people taking liraglutide in their quality of life experiences, and this was more than in the placebo group.

In this new phase II of lixisenatide trial, the effect of lixisenatide was assessed on the progression of motor disability in persons with Parkinson’s disease.

Participants with Parkinson’s disease who were receiving a stable dose of medications to treat symptoms, and who did not have motor complications were randomly assigned in a 1:1 ratio to daily subcutaneous lixisenatide or placebo for 12 months, followed by a 2-month washout period. The primary endpoint was the change from baseline in scores on the Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III (range, 0 to 132, with higher scores indicating greater motor disability), which was assessed in patients in the on-medication state at 12 months. Secondary endpoints included other MDS-UPDRS subscores at 6, 12, and 14 months and doses of levodopa equivalent.

A total of 156 patients 40 to 75 years old with early Parkinson’s disease (diagnosed less than 3 years earlier) on stable symptomatic medications without motor complications were randomized 1:1 (with 78 assigned to each group) to subcutaneous injections of 20 µg lixisenatide or placebo once daily for 12 months, followed by a 2-month washout period. Patients randomized to lixisenatide received 10 μg/day for 14 days and then 20 μg/day administered by once-daily subcutaneous injections for 12 months. If patients were unable to tolerate the dose of 20 μg/day, it would have been reduced to 10 μg/day. Patients were expected to remain on a stable dosage of antiparkinsonian medications for at least the first 6 months of the trial, and optimally for the entire 14 months of follow-up. An interesting feature of the trial was that the drug was tested both during ON and OFF levodopamine periods.

MDS-UPDRS scores at baseline were approximately 15 in both groups.

• At 12 months, scores on the MDS-UPDRS had changed by −0.04 points (indicating improvement) in the lixisenatide group and 3.04 points (indicating worsening disability) in the placebo group.

• At 14 months, after a 2-month washout period, the mean MDS-UPDRS motor scores in the off-medication state were 17.7 (95% CI, 15.7 to 19.7) with lixisenatide and 20.6 (95% CI, 18.5 to 22.8) with placebo. Other results relative to the secondary endpoints did not differ substantially between the groups. Nausea occurred in 46% of participants receiving lixisenatide, and vomiting occurred in 13%.

What is lixisenatide?

Lixisenatide is a once-daily injectable GLP-1R agonist that is used in the treatment of Type 2 diabetes (brand name ‘Lyxumia’ in the EU and ‘Adlyxin’ in the USA). Lixisenatide can cross the blood-brain barrier.

What is a GLP-1R agonist?

Glucagon-like peptide 1 receptor agonists (or GLP-1R agonists) are a class of drugs used in the treatment of Type 2 diabetes. They act by mimicking the action of a naturally produced gut hormone called GLP-1 in the body. GLP-1 is produced by cells lining the intestines when food and drink is consumed, stimulating insulin to be released by the pancreas. Insulin helps cells absorb glucose from our food (sugar) to be used as energy.

The LixiPark study was led by Prof Olivier Rascol (University of Toulouse) and Prof Wassilios Meissner (University of Bordeaux). LixiPark is a multicenter trial performed at 21 centers of the French NS-Park/FCRIN network.

The study, sponsored by the Toulouse University Hospital, was co-funded by UK charity Cure Parkinson’s, with Van Andel Institute (VAI; in Michigan, US), and the French Ministry of Health, with drug and placebo support from pharmaceutical company Sanofi.

The LixiPark trial was a phase 2 clinical trial. Phase 2 studies often include measures of efficacy to get an idea of whether a treatment is doing what it is supposed to achieve. Phase 3 is the last stage of clinical testing and involves a very large cohort of people affected by the disease being tested for a long time to determine the effectiveness of the potential treatment alongside its long-term safety. A Phase III clinical trial of Lixisenatide in Parkinson's is ongoing.

What will happen next?

UK's Cure Parkinson’s is working with the investigators to plan the next phase of development of GLP-1R agonists for Parkinson’s. They are also awaiting the results of the phase 2 Stockholm study and the phase 3 UK trial of exenatide, another GLP-1R agonist, in Parkinson’s. These results are expected later this year and they will help to inform the next steps for this class of drugs.

Can Parkinson’s patients take lixisenatide? Lixisenatide is still considered to be experimental for use in Parkinson’s and more research is required. There are currently no GLP-1R agonists, including lixisenatide, that are approved for use in Parkinson’s. GLP-1R agonists are also currently considered an experimental class of drugs for Parkinson’s.

There is a wide range of subtle differences between the broader class of GLP-1R agonists and they have not all been tested in Parkinson’s. Some GLP-1R agonists significantly reduce body weight (which might add concerns of frailty for people with Parkinson’s). Some GLP-1R agonists do not cross the blood-brain barrier very well and therefore are not able to have an effect in the brains of people with Parkinson’s. It is important to note that more research is required to better understand these differences in the context of a potential treatment for Parkinson’s.

When are the results expected of the Phase III exenatide trial?

The study finishes in the first half of 2024, so it is hoped that the results will be available in the second half of 2024. Researchers are also waiting for the results of a large clinical trial examining the effects of a two-year course of exenatide in people with Parkinson’s disease.

“There is a number called the 'clinically meaningful threshold' and we should appreciate that the results 'fell short' of this important metric so it is not ready for prime time in patients. In my view we should not rush to prescribe this drug or to try to creatively acquire it for our patients. We have been down this road many times including leukemia drugs, cough syrups and lithium for Parkinson. The data is not yet there to proceed to prescribing,” Michael S. Okun, MD, national medical advisor for the Parkinson's Foundation, told NeurologyLive®. “More importantly, the weight loss associated with GLP-1’s is not desirable in the majority of cases of Parkinson disease and the nausea and vomiting will not be a welcome symptom. The drug and trial is a step in the right direction, though there is much work to do.”

Will effects last?

David Standaert, a neurologist at the University of Alabama at Birmingham, who was not involved in the trial, says it’s important to know whether the effect will last beyond a year.

“We’re all cautious. There’s a long history of trying different things in Parkinson’s that ultimately didn’t work,” he says. A difference of three points in the rating score is a small change, one that many people with Parkinson’s would struggle to notice. What happens at 5 years? Is it 15 points then, or is it still 3? If it’s still 3, then this is not worth it.” He said.

More questions

A bit astonishing is that apparently, French researchers did not record any imaging biomarkers in the study to monitor disease progression and changes with drug administration. Since the trial was conducted in France, data collection regarding race or ethnic group is prohibited by law. The authors only tested 1 dose of lixisenatide, and thus other doses might have better or worse effects in patients with Parkinson’s disease.

As GLP-1 is a naturally produced hormone in the gut, it would have been interesting to search for changes in microbiome. It is well known since Heiko Braak that alpha-synuclein propagation starts in the gut.

GLP-1 inhibitors are also known to reduce inflammation, was inflammation measured? It is not reported.

Among the authors, there were many consultants, who had worked for several pharmaceutical companies, including Abbvie, that has an interest in drugs for Parkinson's disease.