There’s nearly a million people in the US diagnosed with Parkinson’s disease and, with no standard treatment, many clinical trials are looking to fill that gap. There are about 84 industry-sponsored clinical trials in Phase I–III that are recruiting under different capacities, according to

4D Pharma is looking to be one of these trials from mid-year, after it secured an FDA go-ahead of a Phase I trial investigating two of its live biotherapeutic assets. Clinical Trials Arena spoke to 4D chief scientific officer Alex Stevenson who provided a preview to the Phase I’s potential trial design. But would data collected in the early phase study excite experts?

4D’s live biotherapeutics MRx0005 and MRx0029 are taken orally and each feature a single strain of bacteria. The hallmark of Parkinson’s disease is it starts at the gastrointestinal tract, says Oregon Health and Science University assistant professor of neurology Dr Delaram Safarpour. And so, the mechanism rationale of the biotherapeutic targeting the gut is logical, she adds. Yet, several unanswered questions remain.

Potential Phase I design previewed

Neuroinflammation plays a pivotal factor in neurodegenerative diseases like in Parkinson’s, considering there is sustained inflammation in the peripheral nervous system and in the brain of these patients, Safarpour explains. “This occurs even before the onset of motor symptoms,” she adds. And, even earlier, constipation is a notable symptom, which may signal the start of the process involving the peripheral nervous system, she notes.

While 4D is yet to detail its Phase I trial design, Stevenson says the study is likely to recruit around 40 mild-to-moderate Parkinson’s disease patients and would primarily investigate the assets’ safety profiles. MRx0005 and MRx0029 each feature a single strain of bacteria and were chosen based on their functionality linked to the disease.

4D Pharma chief scientific officer Alex Stevenson

Gastrointestinal-related issues would need to be monitored due to its mechanism, Safarpour notes. The dosing would likely be twice a day and, as with its other live biotherapeutic assets studied in cancer, the trial will dose patients for 2-4 weeks, Stevenson says.

There would be secondary efficacy endpoints such as ones that investigate relevant clinical scores and biomarkers that relate to the approach’s mechanism, Stevenson says. But Safarpour notes, in Phase I or even in later-stage trials, to excite the Parkinson’s disease community, efficacy measures involving quality of life, motor outcomes, and clinical response need to be monitored. Nonmotor skills is also a valuable metric, such as improvements in bowel movement, she adds.

Subgroups need investigation

The trial is targeting mild-to-moderate Parkinson’s patients. Phase I participants would receive the live biotherapeutic on top of standard of care, such as AbbVie’s Duopa (carbidopa/levodopa) which is approved to control symptoms.

From a scientific point of view, subgroups within mild-to-moderate patients should be divided, Safarpour says. They could be divided into patients whose pathology start in the peripheral nervous system and then progress to the central nervous system versus ones that start midbrain or limbic system then to the peripheral nervous system, she adds.

Having a gut-targeting approach may have value in the first group considering the biotherapeutic would be close to the initiation of pathology, Safarpour explains. But also, in the second group, there could still be value to this approach as it could prevent progression into the peripheral central nervous system. While it may be tough to divide these two groups as they may not be mutually exclusive, it is still worth doing to better understand eventual results rather than grouping all patients under one bucket, she adds.

Unanswered questions remain

While there may be encouraging preclinical data, there are still unanswered questions. It is still unclear if positive preclinical data that support the mechanism would translate in humans, Safarpour notes. In animal models, there is data showing that there is worsening of symptoms with specific microorganisms, she adds. Further, there are strains with short chain fatty acids and if there are not enough of these, this increases the likelihood of Parkinson’s disease, Safarpour explains. “But animal data may not sync into humans and the results may not be replicated.”

The patient’s diet could also be a critical factor. Some microbiome studies’ positive results are not replicated in other parts of the world due to variety in gut microbiota, she notes. Stevenson says the company is not inexperienced with the biotherapeutic approach, with ongoing trials in cancer.

4D’s live biotherapeutic assets are developed via its discovery platform called MicroRX. The platform interrogates different bacteria on how it interacts with host human cells and the subsequent impact on inflammatory gene expression and differentiation of immune system cell subsets, Stevenson explains. Its live bacteria have potential to proliferate in the gut, but its preclinical analysis shows colonisation is transient and subsides once dosing stop, Stevenson adds. “It is difficult for a single strain to colonise.”