What is frailty?
Frailty is an aging-related decline in reserve and function across multiple organ systems such that there is a decreased ability to cope with “stressors”. Stressors include events such as infections, falls, fractures, and changes in medication and surgery. In normal healthy aging, you can recover from that stressor and resume normal function. People who are considered to be frail have difficulty resuming a normal life following a stressor, and unfortunately it often puts them on a path toward disability and dependence.
The clinical hallmarks of frailty are involuntary weight loss, weakness, slowing down, low activity levels and exhaustion. When an elderly individual is exhibiting those symptoms clinically, they are often at higher risk for poor clinical outcomes, such as hospitalization, institutionalization and death.
When you are developing a treatment for frailty, what are you targeting?
We are developing an off-the-shelf allogeneic mesenchymal stem cell (MSCs) therapy, which is derived from the bone marrow of young healthy donors and infused into patients. We are looking at indicators of physical function such as their walking speed, walking endurance and grip strength, which are validated predictors of health outcomes in frail individuals. We are also looking at patient-reported outcomes through questionnaires related to their physical function and their ability to perform activities of daily living. We are also looking at objective physiologic indicators, such as pro and anti-inflammatory biomarkers in their blood, and finally the effect of treatment on cognitive function, sexual function and depression.
These are all surrogate measures to assess the ability for frail elderly individuals to function independently. Can they get up out of bed, get to the kitchen and make themselves breakfast? Can they get in the car? Can they go to the grocery store? Do they feel confident enough to cross the road? These are activities that we take for granted but for the frail elderly, they may have difficulty or concern conducting these functions. Improvements in all of these areas portend improvement in these longer-term clinical outcomes.
Coming from a more traditional pharma background, is there much difference between organizing a clinical trial for a stem cell-based product as opposed to a small molecule drug?
The main difference that I'm seeing is that there has been a shift in the paradigm of traditional drug development for regenerative medicine. It’s being carved out in different countries for the express purpose of moving potentially safe and effective therapeutics more efficiently through the development process, and into the hands of people who need it the most, as quickly as possible.
Given the unique nature of regenerative medicine and the good safety profile we’ve seen so far, several countries are willing to accelerate the pathway to market for a product that has safety data with preliminary efficacy. This means developing a more thorough picture of efficacy once it is in the hands of the people who may benefit from the treatment, rather than delay it for the many, many years that it often takes to get a traditional drug to market.
The manufacturing part of this is very complex. It's something that is continually evolving as we go; it is not the typical pharmaceutical manufacturing paradigm. Therefore, there’s a difference in how the products are made, how they're regulated, the cost to manufacture them and the prices that are being charged. The critical path item for traditional pharmaceuticals is typically the clinical trials rather than the manufacturing. With regenerative medicine, the clinical trials are speeding up, and the manufacturing is on the critical path.
How have changing attitudes from regulators such as the FDA helped Longeveron to develop its product?
What the FDA is trying to do is to put into place policy and guidelines that are designed for this kind of unique set of products. Before 2014-2015, policy wasn't separate, and we were all expected to follow through with a lockstep development approach as applied to traditional pharmaceuticals.
What the FDA has implemented, and is continuing to implement, is allowing the regenerative medicine industry to have greater access to regulators for the express purpose of accelerating the development pathway. Without a doubt, many countries, including the United States, Japan and apparently China, are implementing accelerated pathways.
How does Longeveron work in these different countries?
Longeveron is based in the USA with a GMP manufacturingfacility in Miami, but we are looking at countries where there is a shift in the demographics toward the aging population, which are many of the developed countries and countries where there is regulatory framework in place to facilitate the development of regenerative medicine. Japan is a perfect example: it is the oldest and most rapidly aging society in the world, and it probably has the most progressive regulatory framework for regenerative medicine. For us, that's a natural perfect fit for what we're trying to do from a therapeutic standpoint as well as taking advantage of the regulatory framework.
When you're developing your clinical trial strategy, how do you ensure you are assessing relevant measures?
We work with a roster of frailty experts from the USA, EU and Japan, who are trying to assess early intervention, assess treatment of frailty and prevent the slide into severe frailty, to help us understand what assessments we need to be doing. The assessments do no good if it turns out the questions we are asking the patients to answer are of minimal significance to them, their daily life and their independence.
The number one issue for these people, who are at risk of developing frailty or have transitioned to frailty, is the loss of independence. Therefore, in our trials, we are trying to time the intervention at a point where they're not dependent on others yet, but they are showing signs that they are at risk for poor clinical outcomes and loss of independence. If they transition to that point, they are now relying on assistance from the health care system to provide that care. For us, there is tremendous value and need to intervene in advance of that with a safe and effective therapeutic that may extend their healthy lifespan and delay or prevent that need for long-term care.
In the Longeveron treatment, you are collecting bone marrow from healthy donors. What do you do to the MSCs once they’ve been collected and stored to maintain their quality?
The raw material arrives at the Longeveron manufacturing facility. We isolate the MSCs present in the bone marrow, incubate them and grow these special cells into the billions. The cells are then cryopreserved until they are needed for use in the clinical trials. When cryopreserved in liquid nitrogen, the MSCs can be stored for years.
When they are unfrozen, how do you ensure their quality?
There are product release criteria, which includes sterility testing. All release criteria must be met in order for the product to be administered. The potential for contamination is minimal due to controls in place in the CGMP processing facility, and well-trained production specialists.
Is that an inpatient or an outpatient procedure?
All of our trials currently are done on an outpatient basis. There has been enough safety demonstrated for peripheral IV infusion, both in general for MSCs but also for our product. For our clinical trials and the indications that we are pursuing, it is not necessary for the patient to stay overnight after the infusion in the hospital for observation.
They arrive, typically in the morning, are prepped for the infusion, which lasts about 40 minutes, and then they remain in the hospital or in the clinic for several hours for observation. Once the principal investigator and the investigative team feel it is safe for the patient to leave the clinic, they are discharged.
This is why the allogeneic component of this is so important. There is no tissue procurement procedure required for the patient like there is with an autologous treatment, there is no waiting period to incubate or grow their cells. They arrive at the clinic and the product is there waiting for them.
What is the cell dose that is administered?
Is it a single dose or are multiple infusions required?
The design of the clinical trials right now is a single infusion followed by 6–12 months of observation. The observation periods are designed to understand the effect at various time points to determine whether there is a change occurring, either for better or for worse. However, we are also looking to see when the effect may wear off, so that we can begin to determine what the safe and effective dosing interval may be.
What phase are your frailty trials at the moment?
Our most advanced trial in aging frailty syndrome is in phase IIB in the United States. We have 10 centers that are currently recruiting patients. There are five treatment arms; four treatment arms of stem cells and one treatment arm of placebo, so you have a one in five chance of receiving a placebo. That trial is over two-thirds enrolled and we expect to complete enrollment around the middle of 2019. Data from that trial should be available in the second half of 2020. This is the most advanced regenerative medicine therapeutic intervention trial in the world for frailty, so I think this is going to be a trial that many geriatricians are going to be following very closely!
If the phase IIB trial goes well and all primary outcomes are met, what will be the next steps?
In the traditional pharmaceutical framework of developing drugs, it would be at the conclusion of that trial that we would share all the safety and efficacy data we have with the FDA and establish the remaining steps and clinical data required to support a marketing application filing. Given the recent regenerative medicine product development guidelines that have been put into place, we’re hopeful that positive data may result in options for an accelerated pathway to market.
If you secure FDA approval, is your current manufacturing strategy sustainable for commercialization?
There is always ongoing process development and optimization as we prepare for industrialization. Much of Phacilitate Leaders World and the World Stem Cell Summit (January 22-25, Miami, FL, USA) has been devoted to discussing where we are now and how far we are away from industrial scale manufacturing.
I think across the board, the industry is still a way away from cost-effective, industrialized manufacturing of regenerative medicine products. As a company, Longeveron is devoted to continual improvement of our processes, techniques and procedures, in preparation for becoming a commercial stage company in the future.