PureTech targeting dysfunctions in brain, gut, immune system

Bharatt Chowrira, president and chief of business and strategy

Bharatt Chowrira, president and chief of business and strategy

With eight clinical-stage studies underway, including two pivotal trials expected to readout later this year, PureTech Health (LSE:PRTC) is taking a novel approach to drug development, targeting serious diseases caused by dysfunctions in the brain, gut and immune system.

“We believe these three body systems are interconnected in a number of different ways that underlie chronic diseases,” Bharatt Chowrira, president and chief of business and strategy, says in an interview with BioTuesdays.

“So that by understanding the underlying biology affecting the brain, gut and immune system, and the dysfunctions in these three systems, we can tackle chronic diseases effectively,” he adds.

Dr. Chowrira explains that PureTech is focused on slowing, halting, or reversing disease progression in chronic diseases that are the biggest burden to the healthcare system, accounting for 85% of healthcare costs.

“Oftentimes, when a patient sees his or her doctor, their disease is too advanced to change the course of the disease. At this point, only maintenance therapy is available so the disease does not progress. Our focus is to detect and intervene early in a chronic disease with a treatment that has a chance at changing the direction of the disease.”

Dr. Chowrira explains that PureTech is focused on slowing, halting, or reversing disease progression in chronic diseases that are the biggest burden to the healthcare system, accounting for 85% of healthcare costs

Dr. Chowrira explains that PureTech is focused on slowing, halting, or reversing disease progression in chronic diseases that are the biggest burden to the healthcare system, accounting for 85% of healthcare costs

According to Dr. Chowrira, the approach of some biopharma companies has been to develop a “therapy or solution and then look for a human problem to solve, which can often result in a low success rate. Our approach is to start with a problem and then identify innovative approaches to address it.” 

For example, Dr. Chowrira explains that in PureTech’s late-stage GI program, the challenge was that obesity and obesity-related comorbidities represent a global health challenge, with medical costs exceeding $190-billion annually in the U.S. alone, making this area a high priority for health insurance companies.

“So we put together a group of key opinion leaders to understand the drawbacks of existing approaches with pharmaceuticals and bariatric surgery, especially for those patients who are not morbidly obese,” he adds. “And we came up with this idea: what if you could have an effective oral therapy that acts mechanically in the GI tract, but without the invasive procedure of bariatric surgery and side effects of weight loss drugs?”

The result, he contends, is Gelesis100, which is orally administered and has the potential to be a transformative treatment. It is designed to be safe and efficacious and work mechanically in the gastrointestinal system.

The FDA and European regulators are treating Gelesis100, PureTech’s lead program, as a medical device, which makes the hurdle for approval lower.

In a mechanical solution, he says, the body does not absorb a drug, but the outcome is similar to surgical interventions like gastric balloons. Specifically, a patient feels less hungry, takes in less food and the food that is eaten, is absorbed more slowly. All of which leads to weight loss and improved comorbidities, such as diabetes.

Dr. Chowrira explains that Gelesis100 is scientifically grounded with two safe building blocks: a modified cellulose and citric acid found in fruits. By cross-linking the two components in a novel matrix, he says Gelesis100 is a hydrogel, swelling with water and occupying a certain volume in the GI tract, thus creating the feeling of fullness so a patient eats less. And as it passes through the GI tract, it does not interfere with the body’s ability to absorb nutrients from food, he adds.

In an earlier three-month human proof-of-concept study with 125 patients, a 2.25-gram dose of Gelesis100 achieved a statistically significant 6.1% total body weight loss, Dr. Chowrira says. In 29 prediabetic patients, there was an even greater 10.9% total body weight loss. In addition, 56% of prediabetic patients returned to normal glucose status.

PureTech’s six-month pivotal trial with Gelesis100 in the U.S. and Europe is fully enrolled with 436 overweight and obese patients, including about 30% who have been diagnosed with prediabetes and mild Type 2 diabetes. Dr. Chowrira says top-line data is expected later this year.

The co-primary endpoints include a 3% or greater placebo-adjusted weight loss and a total weight loss of 5% or greater in 35% or more patients. A secondary endpoint is change is glycemic control parameters.

In an earlier three-month human proof-of-concept study with 125 patients, a 2.25-gram dose of Gelesis100 achieved a statistically significant 6.1% total body weight loss, Dr. Chowrira says

In an earlier three-month human proof-of-concept study with 125 patients, a 2.25-gram dose of Gelesis100 achieved a statistically significant 6.1% total body weight loss, Dr. Chowrira says

“Gelesis100 has a unique opportunity to target many chronic diseases associated with obesity,” Dr. Chowrira says, pointing to Type 2 diabetes, non-alcoholic fatty liver disease, osteoarthritis and cardiovascular disease.

“Treatments for all of these diseases suggest that a sustained weight loss of 3% to 5% would have clinically meaningful health benefits,” he adds. “Yet there is nothing doctors feel comfortable prescribing primarily due to safety concerns. So, we see a good potential for Gelesis100 to be prescribed along with any treatment for diabetes, for example.”

The company also is testing Gelesis 200, a second product candidate, to potentially address other GI conditions, including glycemic control, and inflammatory bowel and liver disease, with proof-of-concept and preclinical studies scheduled to readout later this year and in mid-2018.

PureTech has taken a similar approach in its immune system program, where Dr. Chowrira says the aging population presents a looming global healthcare crisis, attracting massive investments in innovation.

Despite these efforts, he contends that many of the afflictions of aging, such as immunosenescence, are unmet medical needs. Immunosenescence is the gradual weakening in the ability of the aging immune system to fight off respiratory tract infections that are particularly common during winter cold and flu season. “Limited therapeutic options exist today to prevent and treat patients with respiratory tract infections.”

Pneumonia and influenza are the fourth and eighth leading causes of death in people aged 85 and 65, and over, respectively, in the U.S. In addition, hospitalizations for respiratory tract infections increase the risk of people over the age of 85 being admitted to a nursing home.

To tackle the problem, the company set out to utilize the mTOR pathway, by selectively targeting mTORC1, which has been linked in animal and human studies to immunosenescence and other diseases of aging. “By selectively inhibiting mTORC1, we believe we can boost the immune system to reverse age-related immunosenescence,” he suggests.

Dr. Chowrira says the company in-licensed two compounds for aging-related indications from Novartis, which had previously explored the immune-enhancing potential of the compounds in two successful Phase 2a studies with almost 500 elderly patients. The results from one of those studies are being submitted to a peer-reviewed journal later this year.

PureTech is now testing its RTB 101 compound in a Phase 2b trial in elderly subjects at a high risk of respiratory tract infections. The primary endpoint is percentage reduction in respiratory tract infections during 16 weeks of winter cold and flu season.

Part one of the trial is currently underway with more than 150 subjects enrolled during winter cold and flu season in New Zealand. An interim analysis later this year will help determine an optimal dose of RTB 101 for the second part of the trial that will enroll up to 430 patients in the U.S. when flu season begins at the end of this year. The Phase 2b data will be released in the second half of 2018.

Another PureTech asset in its nervous system focus is Akili, which is developing a treatment for pediatric attention-deficit hyperactivity disorder (ADHD), currently called Project:EVO, and a potential screening device for early diagnosis of Alzheimer’s disease, which has been studied in collaboration with Pfizer.

Dr. Chowrira explains that Akili is a digital medicine platform based on cognitive science developed by Dr. Adam Gazzaley at the UCSF and in-house-developed proprietary adaptive algorithms, delivered in the form of an action video game. Dr. Gazzaley’s initial research demonstrated that neural networks in elderly patients could be rewired to improve the ability to perform certain functions.

A pivotal trial in pediatric ADHD is expected to readout at the end of 2017. About 20% of children with ADHD do not respond to current treatments and 30% are not treated.

“The challenge with Alzheimer’s has been an inability to find patients early enough with the disease,” Dr. Chowrira points out.  “By the time they exhibit symptoms, they do not respond to therapies and drugs in clinical development have failed. Our approach has the potential to detect people at risk of developing Alzheimer’s long before they develop symptoms.”

Data supporting this approach were recently presented by Pfizer at the International Conference on Clinical Trials for Alzheimer's disease.

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