THERAPEUTIC FOCUS - Effect of NE3107 on the Pharmacokinetics Profile of Carbidopa/Levodopa in Patients With Parkinson’s Disease

INTRODUCTION

Parkinson’s disease is a progressive, debilitating neurological disease that currently affects about 1 million people in the US, with a 20% increase in the number of impacted patients through­out the next 10 years. The one symptom most people think about in Parkinson’s is tremors, especially in the hands, although pa­tients can also experience tremors in their legs, jaw, or head.

Aside from tremors, other common symptoms of Parkinson’s include muscle stiffness, balance and coordination problems, and slow movements. The disease also causes many non-movement symptoms, including dementia, emotional problems like depres­sion, urinary issues or constipation, skin problems, and difficulties with speaking, swallowing, and chewing.¹

Usually, symptoms begin gradually and get progressively worse over time. Multiple studies are underway to understand what impacts a patient’s risk factor of developing Parkinson’s, but thus far, age is the only clear factor that raises someone’s risk. Most Parkinson’s patients develop the disease after they reach 60 years of age, but 5% to 10% see their symptoms develop before they turn 50.

STANDARD OF CARE IN PARKINSON’S DISEASE

The primary driver of Parkinson’s pathogenesis and progres­sion is rapidly declining levels of dopamine in the patient’s brain. Dopamine is the chemical that transmits messages between the nerves that control muscle movements and those related to the brain’s pleasure and reward centers.

Thus, the current standard of care is a drug called levodopa, which helps replace the lost dopamine in the brain. Initially con­sidered a wonder drug, levodopa was originally prescribed to Parkinson’s patients more than 50 years ago, and the standard of care hasn’t changed over this period of time.

However, long-term use of levodopa may cause problems for some patients, with the most significant side effect being lev­odopa-induced dyskinesia, a type of tremor that develops when the drug is used for too long or at too high a dose.² Additionally, although the hallmark movement disorders associated with Parkinson’s tend to respond well to levodopa, it lacks disease-modifying potential and doesn’t help much with other non-motor symptoms, including dementia, emotional problems like depres­sion, urinary issues or constipation, skin problems, and difficulties with speaking, swallowing, and chewing.

Furthermore, levodopa’s effects typically only last about 4 hours, which means the drug tends to wear off overnight while the patient sleeps. As a result, patients often wake up with their Parkinson’s in the “off state,” mean­ing their symptoms are not well-controlled because their medication has worn off.

This off state is typically characterized by muscle rigidity and difficulties getting out of bed in the morning. One of the hopes for Parkinson’s treatments is finding a therapy that will extend patients’ “on state,” or the period during which their movement-related symptoms are well-controlled, meaning they retain sufficient muscle control.

Today, most Parkinson’s patients are treated with a combination of levodopa and carbidopa, which decreases the pe­ripheral conversion of levodopa into dopamine. The result is reduced gastroin­testinal side effects and an increase of lev­odopa bioavailability in the patient’s central nervous system, where it is most needed and offers the greatest benefits.³

THE ROLE OF NEUROINFLAMMATION IN PARKINSON’S PATHOGENESIS

Many proposed treatments aimed at improving upon levodopa’s effects or adding onto them are currently in devel­opment. These proposed new treatments for Parkinson’s address the disease from different angles. One of the most interest­ing avenues of attack in Parkinson’s and many other diseases is aimed at reducing inflammation. Throughout the past 30 years, researchers have learned that Parkinson’s patients experience inflamma­tion in their brains.⁴ However, it’s only been in recent years that inflammation has come to be seen as one of the root causes of the disease rather than a result of it.

In fact, several studies have demon­strated that patients taking non-aspirin, non-steroidal anti-inflammatories(NSAIDs) have a significantly reduced risk of devel­oping Parkinson’s.⁵ As a result, researchers are starting to believe halting the immune response could be the key to keeping Parkinson’s from progressing.

Because of the chronic inflammation in Parkinson’s patients, it’s believed that humoral immunity, the process of adaptive immunity via the production of antibodies by B cells, might play a critical role in the disease’s progression. On the other hand, T-cell immunity might have a greater im­pact in the onset of the disease.⁶

Digging deeper into the inflammatory drivers of Parkinson’s disease revealed the importance of the inflammatory pathways comprising extracellular signal-regulated kinase (ERK) and nuclear factor-kappa B. These pathways form a feedback loop trig­gering oxidative stress that drives neurode­generation. By targeting the ERK pathway, we should be able to halt this feedback loop — thereby minimizing the progres­sion of Parkinson’s or possibly even stop­ping it in its tracks.⁷

NE3107’S IMPACTS ON THE CARBIDOPA/ LEVODOPA COMBINATION

Given the longevity of treatment with levodopa + carbidopa and the positive ef­fects it has brought for many Parkinson’s patients, eliminating it entirely from the standard treatment regimen doesn’t make sense. However, much can be done by building upon the benefits of treatment with that combination while making up for its shortcomings.

Addressing Parkinson’s via the inflam­matory pathway offers a unique perspec­tive that was virtually unheard of only 10 years ago. One such treatment that targets neuroinflammation in Parkinson’s is BioVie’s drug candidate, NE3107, which is currently in Phase 2 clinical trials. It’s showing significant promise for patients treated with it and the levodopa + car­bidopa combination.

NE3107 is an oral molecule that can cross the blood-brain barrier, binding ERK and inhibiting the pro-inflammatory path­ways without affecting homeostatic func­tions. In a marmoset model of Parkinson’s, treatment with NE3107 improved mobility, enhanced the activity of levodopa, and de­creased levodopa-induced dyskinesia and neuronal death in the substantia nigra.⁸

Following the marmoset study, a Phase 2, double-blind, placebo-controlled trial was initiated to evaluate the efficacy, pharmacokinetic effects, and safety and tolerability in Parkinson’s patients also treated with the levodopa + carbidopa combination. The trial looked at these fac­tors over a 27-day period.

The trial planned to enroll 40 patients between the ages of 30 and 80 and ran­domize them 1:1 to receive 20 mg of NE3107 twice daily or a placebo for 27 days. All participants had been diagnosed with Parkinson’s disease, had responded to levodopa treatment, and experienced bradykinesia as a symptom. Patients had been taking 300 mg of levodopa/car­bidopa daily and had experienced “off states” in the early morning.

The Phase 2 trial found that 6 of 20 patients treated with NE3107 and lev­odopa/carbidopa experienced an on state in the morning after their levodopa had been withheld overnight for at least 8 hours and before taking their morning dose of levodopa. However, none of the 19 patients receiving the placebo reported an on state the morning after their usual Parkinson’s medications had been with­held for at least 8 hours overnight.⁹

Prior to the set of data on patients who received NE3107 being in the on state the next morning, another data set assessing the efficacy of the drug was re­leased. In general, patients who had re­ceived NE3107 and levodopa experienced at least a 3-point improvement in their score on part 3 of the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (UPDRS) versus those who received only levodopa.

Part 3 of this scale assesses patients’ motor-related symptoms, and a 3-point improvement on this test is clinically mean­ingful. In fact, patients under the age of 70, presumably with less-advanced dis­ease, experienced at least a six-point im­provement in this score.

Before commencing the Phase 2 trial of NE3107, participating patients who did­n’t receive their Parkinson’s medications for at least 8 hours overnight were assessed using the UPDRS first thing in the morning. Then they received their medication and were scored using the UPDRS again at 1, 2, 3, 4, and 8 hours after administration.

The findings that indicated 6 of 20 patients receiving NE3107 were in the on state first thing in the morning were con­sistent with the results from a previous non-human primate study, demonstrating the intrinsic promotoric activity of the drug candidate.¹⁰

Due to the positive results in the Phase 2 trial, plans to launch Phase 3 potential pivotal trials to continue the development of NE3107 for Parkinson’s disease are un­derway.

SUMMARY

The preliminary observational data from the latest Phase 2 clinical trial indi­cates that NE3107 shows promise for Parkinson’s patients. The finding that this treatment enables a meaningful percent­age of patients to be in the on state when they awaken the morning after receiving it is particularly significant. Having trouble getting out of bed in the morning has an especially negative effect on the patient’s quality of life, and it’s clear more treat­ments offering this benefit are needed.

Dr. Anthony Lang, the Jack Clark Chair for Parkinson’s Disease Research at the University of Toronto, who was not in­volved in the aforementioned clinical trials, described the data as “encouraging.” He added “Morning off symptoms cause sig­nificant impairment of movement and dis­ability for patients with Parkinson’s disease. A potential treatment that can ad­dress this symptom is an important thera­peutic need.”

REFERENCES

1. Parkinson’s Disease: Causes, Symptoms, and Treatments. National Institute on Aging https://www.nia.nih.gov/health/parkinsons-disease. Ac­cessed Apr. 26, 2023.
2. Pandey S, Srivanitchapoom P. Levodopa-induced Dyskine­sia: Clinical Features, Pathophysiology, and Medical Man­agement. Ann Indian Acad Neurol. 2017 Jul-Sep;20(3):190-198. doi: 10.4103/aian.AIAN_239_17. PMID: 28904447; PMCID: PMC5586110.
3. Leyden E, Tadi P. Carbidopa. [Updated 2022 Jul 22]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Pub­lishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554552/.
4. The Role of Inflammation in Parkinson’s Disease. American Parkinson Disease Association. https://www.apdaparkin­son.org/article/the-role-of-inflammation-in-parkinsons-disease/. Accessed Apr. 26, 2023.
5. Gagne JJ, Power MC. Anti-inflammatory drugs and risk of Parkinson disease: a meta-analysis. Neurology. 2010 Mar 23;74(12):995-1002. doi: 10.1212/WNL.0b013e3181d5a4a3. PMID: 20308684; PMCID: PMC2848103.
6. Saleh M, Markovic M, Olson KE, Gendelman HE, Mosley RL. Therapeutic Strategies for Immune Transformation in Parkinson’s Disease. J Parkinsons Dis. 2022;12(s1):S201-S222. doi: 10.3233/JPD-223278. PMID: 35871362; PMCID: PMC9535567.
7. Safety, Tolerability, and Efficacy of NE3107 from a Phase 2, Double-Blind, Placebo-Controlled Study in Levodopa/Carbidopa-Treated Patients with Parkinson’s Dis­ease. American Academy of Neurology. https://www.aan.com/MSA/Public/Events/AbstractDe­tails/54740. Accessed Apr. 26, 2023.
8. Safety, Tolerability, and Efficacy of NE3107 from a Phase 2, Double-Blind, Placebo-Controlled Study in Levodopa/Carbidopa-Treated Patients with Parkinson’s Dis­ease. American Academy of Neurology. https://www.aan.com/MSA/Public/Events/AbstractDe­tails/54740. Accessed Apr. 26, 2023.
9. BioVie Announces Additional Findings from Phase 2 Parkinson’s Disease Trial: More Patients Treated with NE3107 Experienced Morning “On State” with Levodopa Withheld Overnight Compared to those Treated with Placebo [Press Release]. BioVie. https://feeds.issuerdirect.com/news-release.html?newsid=8889777766147180. Accessed Apr. 26, 2023.
10. BioVie Announces Additional Findings from Phase 2 Parkinson’s Disease Trial: More Patients Treated with NE3107 Experienced Morning “On State” with Levodopa Withheld Overnight Compared to those Treated with Placebo [Press Release]. BioVie. https://feeds.issuerdi­rect.com/newsrelease.html?newsid=8889777766147180. Accessed Apr. 26, 2023.

Joseph M. Palumbo, MD, LFAPA, MACPsych, is Chief Medical Officer of BioVie Inc., where he leads the research and development functions. Dr. Palumbo has held prior Chief Medical Officer and senior worldwide governance roles at BioPharma, including the most senior scientific title at Mitsubishi Tanabe Pharma in both the United States and Japan, with earlier global leadership experiences in European and American pharma. Dr. Palumbo earned his BA from the University of Pennsylvania and a Doctor of Medicine from the George Washington University School of Medicine, where he is a member of the Medical School Council of Advisors. He was a Biological Sciences Training Program Fellow of the National Institutes of Health and chief resident for the Abraham Ribicoff Clinical Neuroscience Research Unit at Yale University.