Researchers’ work with blood plasma may be the key to combating age-related disease.
When Tony Wyss-Coray discovered that young mouse blood, upon transfusion into older mice, was effective at forestalling some of the conditions associated with old age, it didn’t take long for his work to find commercial expression in Alkahest.
The San Carlos-based Alkahest team, staffed by many previous employees of Genetech, has since been working with blood plasma to pinpoint and therapise the things in our blood that helps us and harm us – and whose numbers change to damaging effect with age. Now the team may have the inside track on therapies for Alzheimer’s, Parkinson’s, Macular degeneration and possibly even the effects of aging itself.
And yet they’re cautious. This is, in many ways, understandable; while Wyss-Coray’s research is categorical about there being many things in young blood plasma that benefit the aged, the therapies emerging from these discoveries stir up controversies so old as to be archetypical. Blood is powerfully political. In feudal times, disgust at the extraction of life-essence by parasitic ruling classes was quickly allegorised into stories of aristocratic vampires — a narrative tradition brought full circle, from metaphor back into reality, by reports of North Korea’s Kim dynasty (both Kim Jong-Sung and Kim Jong-Il were rumoured to have sought out life extension through young blood transfusions, the father from young men, the son from female virgins).
The tales that Alkahest must contend with aren’t always from halfway across the world or centuries ago, sometimes they happen just down the road. Another west-coast startup, Ambrosia, offering whole blood transfusions from old to young at $8000 per litre, was promptly shut down and rebranded after a prickly FDA warning. “There is no proven clinical benefit of the infusion of plasma from young donors.” Ambrosia’s team now operate under the new name of Ivy Plasma, and have changed their strategy towards selling plasma from donors of many ages, not just from the young. But their practice is still considered dangerous by many — plasma transfusion is typically only reserved for life-threatening situations, and can otherwise cause side effects like allergic reactions, circulatory overload, lung injury and infectious disease transmission.
With vampiric rumours and dubious medical practices abounding, Alkahest take a cautious and well-planned route. Their approach is not to transfer whole plasma, but to examine and find the tiny components inside of it that are both beneficial and detrimental to the body and therefore decisive in the aging process. Once they find these, they put them through the arduous process of ‘fractionation’ to produce a cross-section, called GRF-6019, consisting solely of the beneficial components, which they are now trialling with the FDA for a future therapy into Alzheimer’s and Parkinson’s. Their strategy is two-pronged: another therapy, AKST4290, designed for macular degeneration is a drug that works by targeting a detrimental protein that increases in prevalence with age.
Now, with the team having announced last month that Alzheimer’s patients didn’t decline after treatment with GRF-6019, they are poised to release their full results at a December Alzheimer’s conference.
Chairman of the Board of Directors and Chief Executive Officer Karoly Nikolich and Chief Commercial and Strategy Officer Elizabeth Jeffords sat down with Longevity.Technology to discuss the future of the company and of aging.
Picture: Alkahest’s Chaiman and CEO, Karoly Nikolich, at work in the company’s San Carlos offices
Longevity.Technology: What happens to our blood as we age and how might treating it have a beneficial impact upon degenerative conditions like Alzheimer’s and Parkinson’s?
Karoly Nikolich: The changes to the cells in the blood as we age are fairly well-documented. What hasn’t been as sophisticated, which we’re changing, are the techniques for analysing the soluble components of blood. Our foundational science comes from Tony Wyss-Coray’s lab. He found that if you transfuse plasma from young mice to old mice, then the brains of the old mice will get a big boost in terms of cognitive ability, learning and memory. Even the cells in the brain will behave like young nerve cells and young glial cells.
So we’ve analysed plasma from donors ranging between 18 and 70 years old – thousands of samples – to really understand what happens to the proteins. The estimates of the number of proteins that circulate in plasma are between 10,000 to 20,000. The techniques that are available, micro-arrays and mass spectrometry, let us analyse between 6000 to 8000. That’s not the entire complexity, but a huge step forward from the entire plasma industry as of today, which only analyses around 16. From all of those proteins, there is a subset of around 800-1000 which change with age, about half increase and the other half decrease. And sadly, the decreasing ones tend to be the good ones and the increasing ones the bad!
Longevity.Technology: Why do you think this change happens?
Karoly Nikolich: An investor asked us this question recently. I think it’s very important to keep in mind that as of 100 years ago there’s never been any genetic or selective pressure on Longevity. The average life expectancy was in the range of 40-45 years from 1500 (when the first records existed in the UK) all the way through to about 1850. Sure, that range fluctuated a little bit, but from 1850 on there seems to be a rather linear increase. And so, for the first time in human history, we live up to 80-85 years, and sometimes even longer in Spain and Japan.
Longevity.Technology: And you’re targeting aging and not just specific diseases of aging. Why?
Elizabeth Jeffords: The average 65 year old has at least two chronic conditions. By the time you hit 85, you’re closer to three. And the statistics on specific diseases are even worse. We’ve found that if you look across some of these major diseases, particularly in neurology – age is the number one risk factor. So instead of looking at the diseases, we’ve turned it around to look at aging. Alkahest’s science and platform, is focused on that 10-15% of proteins, which we call chronokines, that change with age in a way that is either good or bad.
Our approach has been to evaluate each of those proteins as a target, and from that target we can then generate some sort of therapeutic. So, the chronokines that go up with age, and tend to be more detrimental, we’re trying to antagonize or inhibit those. And you can antagonize these proteins traditionally in a very biotech way, treating with small molecules, antibodies or even extra-corporeal removal.
On the flip-side we’re looking at those chronokines that decrease, that are beneficial, and we want to supplement those. The most practical way to do that right now is with plasma therapeutics. Long term, you can also imagine that in the next two decades we could use recombinant proteins or other ways to really narrow down and provide the benefit of 10 or so specific proteins. We really believe that sufficiently approaching the neurological diseases is going to require a multifactorial approach. Aging and Alzheimer’s is something that happens over 30/40/50 years, it’s not something we can target with one silver bullet.
Longevity.Technology: Alzheimer’s and Parkinson’s are quite different diseases, right? How are you able to treat them both simultaneously?
Elizabeth Jeffords: Parkinson’s and Alzheimer’s are different. And we’re looking at a number of other indications where cognitive symptoms are an issue as well. They could be driven by different pathways and biological activities, sure, but our therapy is intended to have both a restorative effect and an effect that prevents further inflammatory damage. Addressing a heightened inflammatory state is something that, at least preclinically, has worked across different models and different diseases.
Karoly Nikolich: The ages 65-80 are when people really develop 2, 3, even 4 diseases. And when you look at them (rheumatoid arthritis, osteoarthritis, lupus, psoriasis, cognitive issues) you have so many diseases that are based upon inflammation. There’s this incredible wave of pro-inflammatory proteins in aging, and that’s what we want to address.
Elizabeth Jeffords: This is one of our major scientific hypotheses. And that’s why we’re performing the clinical trials under really very rigorous constraints and under regulatory oversight; we want to make sure that we can find out whether our the therapies do indeed make a difference on the diseases of aging.
Longevity.Technology: So why not take a more general approach and give whole blood or whole plasma? Why are you trying to cut this down to the key proteins?
Elizabeth Jeffords: What we’re looking at is a fraction of plasma that is very much cut down from the 15 to 20,000 proteins in plasma. In our therapeutic, GRF6019 (for which we’ve recently announced top-line results) it’s just a few hundred. Importantly, we’re removing things like the clotting factors and the immunoglobulins – the factors that would make it both harder to give to elderly patients and could impact the efficacy of the treatments. So if you give whole plasma, you’re also giving all of the detrimental factors. And even in plasma from an average donor, who will typically be of a younger age than the person receiving it as a treatment, you still have detrimental factors. We’re trying to really narrow down on just giving people what they need.
Picture: Plasma research image from Alkahest
Longevity.Technology: So GRF6019 works to supplement the beneficial factors. And you have another compound, ASK4290 to remove detrimental factors. Can you tell us a little more?
Elizabeth Jeffords: One of the lessons we’ve learned from oncology is that you often need a combination therapy to treat a complex disease. We’re developing ASK4290 because, when you look at detrimental factors in the plasma that increase with aging, it seems a little bit easier to remove things than it is to add things to the system, for the most part. At least, that is, in traditional biotech development. We think there may be a way to use AKST4290 in conjunction with anti-VEGF agents to treat both the underlying causes and the symptomology of age-related macular degeneration.
Karoly Nikolich: We’ve released data earlier this year, in March and July, which shows proof-of-concept in improving the vision of patients with macular degeneration. So we’re really moving on both lines – traditional small molecule treatment with ASK4290 to remove detrimental chronokines, and the plasma treatment GRF6019 that we’ve been talking more about recently to supplement beneficial chronokines.
Longevity.Technology: You mentioned that you might be looking to move on to more recombinant methods for producing these proteins later on – once you’ve narrowed them down. That sounds to me like it will really change the pricing. If we look at plasma-derived therapeutics, like growth factors and bone marrow, they tend to be quite expensive.
Karoly Nikolich: Exactly, when you treat something by a recombinant method its much more sustainable.
Longevity.Technology: What’s the dosage period looking like for these two types of treatment? Are we looking at acute doses? Or a longer period of administration?
Elizabeth Jeffords: For the small molecule treatment for macular degeneration – twice a day is what we’re testing. You’d take it as a pill, and you’d keep taking it. Unfortunately, the disease doesn’t go away with acute treatment
I think it would be the same for the plasma fractions. We have a unique pulse dosing, based upon preclinical efforts to make sure we’re getting the right dose at the right time. The patients receive the therapy over the course of five days, with one infusion each day, then they have a treatment-free interval of twelve weeks, then they start again in the next quarter. We’d expect to see patients continuing to take it for the remainder of their lives.
Karoly Nikolich: It’s also important to keep in mind that it’s not very different from other age related therapies like high cholesterol, high blood pressure, taking statins every day etc.. Beyond a certain age, you get into that phase where you just simply have to block certain processes. So that’s what we’ve envisioned with this.
Picture: Plasma research image from Alkahest
Longevity.Technology: How is all of this going to work with the FDA? Recently they said that there was “no proven clinical benefits to whole plasma transfusions.” Is that a knee-jerk reaction?
Karoly Nikolich: When we founded the company we conducted a tiny pilot study with 18 Alzheimer’s patients with whole young plasma. Whole young plasma is just not a therapeutic, unless of course someone’s lost a lot of blood. It contains clotting factors and immunoglobulin so you’d have to look out for stroke, myocardial events, immune incompetence, on top of doing a complete match of donor and recipient plasma types. It would be a lot of work. I think use of whole plasma is impractical and for chronic use its definitely not going to be a safe procedure. The approved utility of whole plasma transfusion is not chronic, it’s for acute interventions in an emergency situation.
Elizabeth Jeffords: We really support the FDA on this one. It’s important to make sure that we do clinical trials. Good trial quality and patient safety are the number one priorities. In preclinical evidence, whole plasma can provide some benefit, but in our experiments, plasma fractions provide more benefit. We support the FDA controlling the use of these products outside of clinical trials. Of course, we’re all aging. So we’re all a bit desperate for these solutions to come along. But we want to really do it the right way by treating this as a scientific endeavour. We want to find out if our hypothesis is correct.
Longevity.Technology: So what about the company formerly known as Ambrosia. Were they a bit unscientific in their approach?
Elizabeth Jeffords: We can’t comment on what they’re doing. But we know what we’re doing, and it really is the right way to do go about clinical research. We work very closely with the FDA to make sure that our trials are correct. Even in the FDA’s posting about the ceasing of whole plasma treatments, they mentioned that plasma based therapies were okay if explored in clinical studies.
Longevity.Technology: We’re never sure when we talk to people in the biotech space whether their target really is aging. With you guys, it very clearly is. What motivated you both to be working on it?
Karoly Nikolich: I’ve been a neuroscientist all my life. I started at Genentech 36 years ago, and I led the neuroscience research department there for about 7-8 years. So I’ve always been interested in developing therapeutics for this space. From early on, I’ve been fascinated by the possibility that we’ll be able to treat neurological and maybe even psychiatric diseases through molecular approaches.
A prominent investor actually told me 7 years ago that his grandfather passed away from Alzheimer’s disease, and I knew his grandfather very well. And he said that his grandfather received a plasma transfusion for prostate cancer — a totally unrelated condition. For a few days after the transfusion, his grandfather sort of woke up, he recognised the family, his executive functions actually returned temporarily. And after this about thirty similar anecdotal cases were shared with me. Around the same time I was introduced to the work of Tony Wyss-Coray. We now have a team of almost 90 people here trying to decipher this. And now we are creating new therapies that come from a deep understanding of the science of aging.
Elizabeth Jeffords: I worked with Genentech and Roche for about 17 years before I came here. I spent a lot of my career in oncology and neurology. And it struck me that we were making such a difference in oncology. And that was because we were putting a lot of resources towards it, being open minded about the causes of the disease and looking at the needs of cancer patients.
And yet, in our neurology work and our work on most diseases of aging, we were just failing. And maybe it’s time for a more non-traditional approach to neurology, and diseases of neuro-degeneration. I was also absolutely intrigued by what we’re doing here at Alkahest with AMD, investigating an oral agent to treat AMD – this would be a game changer for patients. I think we’re all fascinated by, and would love to be looking at aging directly. But aging isn’t really treated as a disease right now. So although the World Health Organisation, and even the FDA, are moving towards that a bit (with indications like frailty) right now we need to focus on the named diseases. We’re using the aging process and the multifactorial biological functions of aging as that inspiration to treat these diseases where the unmet needs are still so high. I’m a very passion and purpose-driven person. And so I love coming to work here, because it gives me that sense that we’re actually on a mission to try to do something different. And to help patients that need it the most.