Phase 1 Trial Set to Test First Live Biotherapeutics in Parkinson’s

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by Marta Figueiredo, PhD |

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The U.S. Food and Drug Administration (FDA) has approved 4D Pharma’s request to launch a Phase 1 clinical trial in the U.S. evaluating the safety and tolerability of MRx0005 and MRx0029, its experimental live biotherapeutic products (LBPs) for Parkinson’s disease.

LBPs, a new class of therapies, are defined by the FDA as biological products containing whole, live microorganisms, such as a bacteria or yeast, aimed at preventing, treating, or curing a disease.

Expected to start by mid-year, the first-in-human trial will separately test both candidates — orally delivered single strains of bacteria naturally found in the healthy human gut — in people with Parkinson’s.

Parkinson’s treatments now available “focus on symptoms but do not address the underlying causes of neurodegeneration,” highlighting a need for “new, more effective treatment options,” Alex Stevenson, PhD, 4D Pharma’s chief scientific officer, said in a press release.

“The gut-brain axis is an exciting area of innovation with the potential to change the way we approach Parkinson’s treatment,” Stevenson said. “We believe that our LBPs MRx0005 and MRx0029, which each have different mechanisms of action worthy of investigation, provide a unique opportunity to address the high unmet needs of those living with Parkinson’s disease.”

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Peter LeWitt, MD, the trial’s coordinating investigator and a professor of neurology at Wayne State University School of Medicine, in Michigan, said that “oral, gut-targeted treatments such as 4D pharma’s live biotherapeutics MRx0005 and MRx0029 offer an exciting new way for possibly slowing Parkinson’s disease progression.”

“The development of these potential new therapies is really breaking new ground in the field,” added LeWitt, also the Sastry Foundation endowed chair in neurology at Wayne State.

Gut microbiota comprises the vast community of friendly bacteria, fungi, and viruses that colonize the gastrointestinal tract. This community helps to maintain a balanced gut function, protect against disease-causing organisms, and influence a person’s immune system and inflammatory responses.

A microbiota imbalance, known as dysbiosis, has been shown to trigger or worsen a number of health conditions, ranging from gastrointestinal problems to inflammatory and autoimmune diseases.

“There is growing evidence suggesting that the gut-brain axis could be key to developing new treatments for several neurological disorders, particularly Parkinson’s disease,” LeWitt said.

Notably, Parkinson’s patients show dysbiosis, and these changes have been associated with early risk markers. Also, gut inflammation has been linked to Parkinson’s occurrence and development.

As such, identifying bacterial strains with the potential to lessen the neuroinflammatory and/or neurodegenerative processes associated with Parkinson’s may lead to the development of new therapeutic approaches.

MRx0005 (Parabacteroides distasonis) and MRx0029 (Megasphaera massiliensis) are two bacterial strains discovered — using 4D pharma’s MicroRx platform — to have potent anti-inflammatory and antioxidant effects. The company’s proprietary screening platform identifies potentially beneficial strains based on an understanding of their function and mechanisms.

In lab-grown human brain cells and a mouse model of Parkinson’s, both strains were shown to reduce neuroinflammation, including that associated with alpha-synuclein — the protein that accumulates in toxic clumps in Parkinson’s. Both also were shown to protect nerve cells from oxidative stress-induced death.

Oxidative stress is a type of cellular damage involved in Parkinson’s that results from an imbalance between the production of potentially harmful oxidant molecules and the cells’ ability to clear them with antioxidants.

In addition, MRx0005 increased the levels of neuroactive molecules and their signaling, and protected against loss of dopamine byproducts in the mice’s brain. MRx0029, meanwhile, improved gut barrier integrity, promoted the maturation of dopamine-producing nerve cells, and prevented the loss of these cells.

Of note, dopamine is the major brain chemical messenger lost in Parkinson’s due to the gradual death of dopamine-producing nerve cells, while impaired gut barrier and gut leakage are thought to potentially contribute to Parkinson’s development or progression.

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These data suggest that both live biotherapeutics, MRx0005 and MRx0029, may help slow Parkinson’s progression.

The upcoming multicenter Phase 1 trial will test each of these live biotherapeutics against a placebo in people living with Parkinson’s. Besides safety and tolerability measures, the study also will assess changes in the levels of biomarkers related to the mechanisms of action of these candidates.

“We believe MRx0005 and MRx0029 are the first ever live biotherapeutic products for Parkinson’s to enter the clinic,” Stevenson said, adding that the upcoming study “will represent an important step for 4D pharma’s continued growth and leadership in the [gut microbiota] field.”

Besides neurodegenerative conditions, the company is working on the development of LBPs for several types of cancer, irritable bowel syndrome, and asthma.

Notably, in 2020, 4D pharma joined the Parkinson’s Progression Markers Initiative, an observational study sponsored by the Michael J. Fox Foundation that aims to identify biomarkers of Parkinson’s progression and new ways of treating the disease.

The company also has established a patient advisory board, comprised of people with Parkinson’s disease and supported by Parkinson’s UK. The board is expected to provide a unique perspective on the needs of this patient population.