Parkinson’s disease: biotech’s pursuit for more therapies 

Parkinson’s disease, a condition that can impair motor function, affects about 10 million people around the world. Currently, treatments for Parkinson’s help manage symptoms but it is yet to be cured. While levodopa, the breakthrough drug regarded as the first truly effective treatment has come under fire for causing toxic side effects, it remains the gold standard for Parkinson’s treatment. Of late, however, several therapies are in the running to potentially topple levodopa’s position in Parkinson’s care. A new Parkinson’s drug is very close to approval, but how will it change patient lives for the better? 

A deficiency of dopamine: how does Parkinson’s disease affect the body? 

Unlike levodopa, which, when it reaches the brain gets converted to dopamine, the drug in question, tavapadon, activates receptors in the brain linked to dopamine production to mimic the effects of dopamine. Both a neurotransmitter – a chemical that transmits signals from a nerve cell to a target cell – and a hormone, dopamine dysfunction is implicated in several neurological and psychiatric conditions, including Parkinson’s disease. 

In fact, dopamine deficiency is the primary cause of Parkinson’s disease. When nerve cells that produce dopamine die, hormone levels drop, which leads to symptoms like tremors, stiffness, and slow movement. The condition was first described as a neurological syndrome in 1817, and was named after English surgeon James Parkinson, best known for his book ‘An Essay on the Shaking Palsy’ – a clinical account on the disabling condition that causes motor impairment. However, ancient Indian texts and Chinese sources also chronicled what seemed to be descriptions of Parkinson’s disease, back in 1000 BC.  

Its distinction from other tremorous disorders, specifically multiple sclerosis, came after French neurologist Jean-Martin Charcot, who also gave the disease its name, derived that not all individuals with Parkinson’s disease experience tremors.  

Researchers were also able to distinguish between Parkinson’s disease and Parkinsonism – an umbrella term used for neurological disorders similar to Parkinson’s, often characterized by tremors, slow movement, and stiffness as well. 

The link between dopamine and Parkinson’s was discovered more than a century after Parkinson’s book, when scientists found significantly depleted levels of dopamine in the brains of those who had died from the disease.  

Tavapadon vs levodopa in Parkinson’s: will AbbVie’s drug come out stronger? 

Tavapadon has proved that it can turn on specific dopamine receptors D1 and D5 without overstimulating other dopamine receptors, such as D2, D3, and D4, which can cause side effects like hallucinations and impulse-control disorders.  

And now it’s closer to approval than ever. Its developer, American pharma giant AbbVie, just submitted an application for its approval to the U.S. Food and Drug Administration (FDA) last month following positive results from a phase 3 trial that reinforced tavapadon’s potential to address the neurodegenerative condition.  

The treatment managed to improve patients’ scores on the Movement Disorder Society – Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), a scale that assesses the motor – physical signs that affect movement and balance – and non-motor symptoms.  

Moreover, patients experienced more ‘on’ time when on the drug and the symptoms were well controlled without any involuntary and erratic movements. ‘On times’ are the times during the day when Parkinson’s medicines work properly, and ‘off times’ are when the symptoms return before the next dosage. Off times often occur in the morning before the first dosage and during intervals between dosages. 

This is a key factor when working out whether a therapy for Parkinson’s is effective or not. The longer the on time, the better for the patient. People on tavapadon were less prone to an ‘on-off’ effect compared to levodopa as the former had a longer half-life – the time taken for a drug’s active ingredient to be halved.  

“For many people living with Parkinson’s disease, today’s oral standard of care isn’t effective enough to manage symptoms,” Roopal Thakkar, executive vice president, research and development, chief scientific officer at AbbVie, had said in a press release. “We recognize the physical and mental impact that Parkinson’s disease can cause and are committed to providing next-generation treatment options that will help individuals regain motor control and independence at all stages of this challenging disease.”   

As tavapadon’s new drug application (NDA) has been sent to the FDA for review, small molecules are gathering steam in Parkinson’s disease research. The experimental small molecule BIIB122 is part of this momentum, as it is in the clinic to treat the most common form of Parkinson’s disease caused by a genetic mutation.  

The LRRK2 gene controls a protein responsible for various pathways in cells. A mutation on the gene, however, spurs the overactivity of an enzyme called LRRK2 protein kinase, which disrupts the pathways, particularly the pathway involved in dopamine production, leading to Parkinson’s disease.  

New research related to Parkinson’s disease

• First-in-class Disease-modifying Therapy for Parkinson’s Disease – University of Colorado Boulder
• Brain Organoid Platform for Parkinson’s Disease Drug Discovery – Okinawa Institute of Science and Technology (OIST)
• Treatment of Parkinson’s Disease with an Injectable Hydrogel – Monash University

Small molecules Denali Therapeutics’ BIIB122 and NRG’s NRG5051 want to slow neurodegeneration 

The therapy BIIB122 was created by Denali Therapeutics to inhibit the enzyme’s activity, and the California-based biotech has since collaborated with American multinational pharma Biogen to speed up clinical development. But the drug has had a wobbly ride in the clinic so far. A phase 3 trial for Parkinson’s disease was canned two years ago. They claimed they wanted to “refocus efforts” towards a phase 2 study of the drug instead, which is ongoing. The trial will test the small molecule in patients aged between 30 and 80 years with early-stage Parkinson’s disease – those diagnosed within two years of entering the trial – and is expected to end in a year’s time.  

Not so far behind, there are small molecules heading towards the clinic too. Like, for instance, NRG Therapeutics’ inhibitor drug targeting the mitochondria, famously known as the powerhouse of the cell.  

NRG’s NRG5051 targets a channel called the mitochondrial permeability transition pore (mPTP) that opens into the membrane of the mitochondria under high stress conditions. This can lead to cell death when misfolded proteins such as TDP-43 and α-synuclein – both hallmarks of Parkinson’s disease – accumulate, causing the destruction of neurons.  

Having completed investigational new drug (IND)-enabling studies, it is poised to hit the clinic early next year. Just last month, it snagged £50 million ($67 million) in a series B funding round to kickstart clinical trials for Parkinson’s disease and amyotrophic lateral sclerosis, another neurodegenerative disorder that affects motor neurons. 

Mixed signals: can GLP-1s treat Parkinson’s? 

As small molecules ride the wave of growing interest in neurodegenerative disease research, scientists are investigating whether GLP-1 agonists can take on the condition. While GLP-1s have seen fame in the weight loss market, so far with Parkinson’s disease, progress has been patchy. 

A hyped-up candidate was exenatide, but poor trial results published in February quashed hopes for the Parkinson’s community. Researchers from the University College London (UCL) found no evidence that the drug curbed disease progression. Besides, semaglutide – present in famed drugs Ozempic and Wegovy – did not have much luck in treating the disease either. 

However, pharma giant Sanofi’s discontinued GLP-1 drug lixisenatide has come closer to success in early-stage clinical studies. The drug crossed the blood brain barrier, which is key for a Parkinson’s drug to work. A phase 2 study found that the drug could slow the development of movement-related symptoms in patients last year.  

The MDS-UPDRS score, which ranges from zero to 132 with increasing motor dysfunction, improved by 0.04 in the treatment group and the placebo cohort by 3.04 a year after the trial began. Then, for two months, patients were taken off the drug and placebo, and as a result, there was a three-point difference between the two treatment scores. Although this data may not seem groundbreaking on its own, study investigators think it calls for more research. 

Askbio, Prevail Therapeutics, and Capsida Biotherapeutics advance gene therapies for Parkinson’s 

While it’s uncertain where GLP-1s stand in addressing neurodegeneration, gene therapies seem more equipped to treat Parkinson’s disease now. Askbio’s gene therapy candidate seems to be going steady in the clinic. Its AB-1005 is in a phase 2 trial that is currently recruiting patients with moderate Parkinson’s disease in Poland, the U.K., and Germany. 

The gene for glial cell line-derived neurotrophic factor (GDNF) – a protein that aids the survival of neurons – is delivered to the brain to help protect and repair neurons that produce dopamine with the help of adeno-associated viral (AAV2) vector to transport it. Once the gene enters the brain, the cells in the brain can continuously make GDNF to further generate dopamine-producing neurons. 

This is a different approach from Lilly-owned American biotech Prevail Therapeutics’ gene therapy – and California-based Capsida Biotherapeutics’ CAP-003, which target the GBA mutation. This mutation is the most significant genetic risk factor for Parkinson’s disease and is found in about 5–15% of patients with Parkinson’s. It leads to the deficiency of an enzyme linked to the progression of Parkinson’s and neurodegeneration. Capsida’s CAP-003 uses an engineered AAV capsid to deliver the therapy to the brain and was awarded IND clearance from the FDA in June. 

Meanwhile, Swiss giant Novartis has been committed to developing a drug for Parkinson’s disease. Novartis’ previous collaboration with UCB saw a trial failure but it’s not giving up just yet. It sealed a $200 million licensing deal with California-based Arrowhead Pharmaceuticals to push the latter’s RNA program that targets the hallmark protein alpha-synuclein into the clinic last month. The pact worth up to $2 billion in milestones will hand over the development and commercialization rights of a small interfering RNA (siRNA) named ARO-SNCA. 

Is RNA interference the way to go? 

SiRNA are the essential thread of a process known as RNA interference wherein the RNA molecules silence genes by targeting other RNAs called messenger RNAs (mRNAs). Arrowhead’s siRNA is meant to trigger this mechanism to specifically switch off the gene that encodes alpha-synuclein protein for people with Parkinson’s disease. 

While the two players have not revealed the full timeline of ARO-SNCA’s development, Arrowhead, which has caught the attention of big pharmas like Takeda, GSK, and Sanofi in the past, announced that it would cross over to the clinic as soon as possible. 

Another deal that could take a Parkinson’s therapy to the clinic was forged between Belgian central nervous system (CNS) disease therapeutics company Clouds of Care and Swiss research company Indivi. Set on advancing precision medicine, the two will combine neuro-electrophysiology with digital health technology tools to come up with a therapy focused on cognitive and motor behaviour in people with Parkinson’s disease.  

The dealmakers have high hopes despite the field of neurodegeneration being one of the toughest challenges in medicine, with a historically low probability of technical and regulatory success. 

“Age being the principal risk factor for neurodegenerative diseases, we are facing a global pandemic,” said Michel Vounatsos, chair of the Board of Directors of Clouds of Care, in a press release. “Deep phenotyping technologies will be essential to improve drug development success in Alzheimer’s and Parkinson’s Disease and extend healthy brain ageing across the lifespan.” 

Parkinson’s: Roche’s monoclonal antibody prasinezumab moves past stumble 

With CNS research being a hot topic, many await the FDA’s decision on tavapadon. Meanwhile, tailing the small molecule is Swiss giant Roche’s phase 3 monoclonal antibody prasinezumab, but it hasn’t been smooth sailing. Like many other therapies it also targets the clusters of accumulated alpha-synuclein protein, however, it does so by binding to them to mitigate toxicity. A phase 2b study missed the endpoint, which was the time taken for motor function to decline in patients last year. But since it has demonstrated efficacy, the candidate is trudging along the clinic as trials with more than 750 people with early-stage Parkinson’s disease are ongoing. 

Clearly, the therapeutic field is bustling with research and development, with drug candidates facing ups and downs, but most of them advancing in the clinic. Tavapadon is likely to be next in line to dethrone the current gold standard levodopa, with more therapies poised to broaden therapeutic options for patients across different stages of Parkinson’s disease.