Learning lessons from clinical trial failure

Metabesity 2021: Joan Mannick talks longevity scientific breakthroughs, healthspan endpoints, her new role at Life Biosciences, and what can be learned from resTORbio’s clinical trial failure.

With the Targeting Metabesity annual conference about to kick off on Monday, we continue to bring you perspectives from some of the key speakers at this excellent event. One of those speakers is Dr Joan Mannick, who now heads up research and development at anti-aging behemoth Life Biosciences after leaving longevity biotech resTORbio following its acquisition by Adicet.

Longevity.Technology: A leading expert in the field of aging, Dr Mannick is a big fan of the Metabesity conference, and is speaking on two panel sessions on scientific advances in geroscience and establishing clear pathways for healthspan products. We caught up with her to find out more about those sessions, and what’s happened since resTORbio’s Phase 3 clinical trial failed to meet its primary endpoint.

Mannick is hugely enthused by the progress made in the longevity field in recent years – especially the high quality science being conducted in preclinical species, and more and more programmes moving into humans and clinical trials.

“There are many more companies in this space now, and there’s serious drug development expertise being brought into the aging field, which has been lacking,” she says. “But on a more micro level, there are also a few scientific breakthroughs that are still preclinical, but are so important.”

Life at Life Biosciences

Some of the breakthroughs she highlights includes David Sinclair’s epigenetic reprogramming discoveries, Laura Niedernhofer’s progress on immune aging, Anna Maria Cuervo’s work on the role of chaperone mediated autophagy (CMA) in neurodegeneration, and Linda Partridge’s work on the memory of mTOR inhibition.

Prof Laura Niedernhofer from the University of Minnesota Medical School

Sinclair’s work in epigenetic reprogramming is, of course, in-licensed by Life Biosciences, and Mannick is thrilled to be able to work with some of the field’s best and brightest as part of her new role at the company.

“I moved to Life because I think it has in-licensed some of the best science of any company in the aging field,” she says. “When I joined, I felt like a kid in a candy store because of all the great things to work on. We’ve got three really interesting scientific platforms with very high quality science underpinning each platform.

“David Sinclair’s epigenetic reprogramming technology is a therapy that’s actually reversing aging, rather than just slowing its progression, so that whole area is really exciting. It’s just a matter of figuring out how to do it safely.”

As discussed in our recent interview with Shift Biosciences’ Daniel Ives, addressing the safety factor in cellular reprogramming is key. But Mannick is optimistic that the answers to these challenges are within reach.

“It has long been known that the epigenome of adults cells can be reprogrammed to a younger state via expression of four proteins called Yamanaka factors. However if you express all four Yamanaka factors transgenically in mice, the mice develop tumours within days,” she says. “So the question is, how many Yamanaka factors need to be expressed, at what level, and for what duration to safely reprogram tissues without inducing tumours.

“David has shown that expression of just three Yamanaka factors in a gene therapy delivered to the eye safely restored vision loss in a mouse model of glaucoma without inducing tumours, so I think it’s feasible and is just a matter of working through how to do it effectively and safely in humans.”

In addition to Sinclair’s programme, Mannick also highlights the company’s platform for mitochondrial uncoupling, as well as its work with Cuervo on autophagy.

“Ana Maria Cuervo is a world leader in the autophagy field and we have in-licensed her chaperone-mediated autophagy activator programme, which is so exciting,” says Mannick. “She’s had landmark papers published in Nature and Cell this year showing benefits of our chaperone mediated autophagy activator compounds in neurodegenerative diseases, and for improving the function of age stem cells.”

Healthspan endpoints and resTORbio

Part of Mannick’s discussions at Metabesity will focus on the role of endpoints and biomarkers in the development of interventions targeting healthspan.

“You can measure any endpoint you want in a clinical trial, but it is important to show that the benefit to patients of meeting that endpoint outweighs any risk of your therapeutic, because that is what health authorities are going to look at,” she says.

“It is really important to talk to regulatory authorities when designing a clinical trial because, in general,  regulatory authorities want a clinical trial endpoint to reflect how patients feel and function. So movement of a biomarker is not going to be an endpoint that’s likely to get regulatory approval for a therapeutic unless there is really strong data that the biomarker predicts how people feel and function.”

“There is a lot of focus right now on biomarkers, but the biomarkers have to be validated by showing that they correlate with actual functional or clinical improvement. In the aging field we need to validate the efficacy of more therapeutic interventions  so that they can be used to then benchmark the biomarkers.”

This is an area close to Mannick’s heart following events at resTORbio.
“ResTORbio was developing an mTOR inhibitor to improve the function of the aging immune system and thereby decrease the incidence of respiratory tract infections in the elderly,” she says. “The FDA acknowledged that this was a new area of medicine for them, and we would have to learn the best approach together.”

Mannick explains that the FDA decided the Phase 3 endpoint should be based on respiratory infection symptoms and not laboratory-confirmation of an infection. This was because laboratory-confirmation of an infection was not relevant to how patients feel and function.

“The Phase 3 trial missed the primary endpoint in part because it turned out to be difficult to distinguish respiratory symptoms that were due to an infection from non-infectious respiratory symptoms,” she says. “However we learned a lot from that trial that will help inform the design of future trials.

“You can’t always get the regulatory authorities to agree with you on clinical trial endpoints, but regulatory authorities are smart, and their mandates are quite sensible – to approve drugs that impact how people feel and function. It’s a matter of working together with them in what is a whole new area. There’s a lot of work to be done, but I think it’s achievable.”

The future is bright

Despite resTORbio’s clinical trial failure, Mannick still has great confidence that therapies targeting improved immune function will be successful.

“We were getting close at resTORbio,” she says. “There were clearly some benefits of targeting mTOR because it upregulated antiviral responses, even in the Phase three trial that failed. I think, with a more precise endpoint and targeted patient population, it’s possible that mTOR inhibitors will show benefit.

“You can often learn more from the trials that don’t work than the trials that work. I think that’s an important point, we need to stop and look at the data and figure out lessons learned.”

Metabesity 2021 is a virtual conference and starts next week. Register to attend absolutely FREE here!