We have known since the 19th century that young blood has surprising curative and rejuvenation abilities. It’s quite strange, but it happens to be true. In recent years, scientific efforts to understand what it is about young blood that causes rejuvenation have ramped up.
We now know that young and old mice with surgically connected circulatory systems will experience altered aging: the young mouse will prematurely grow old, and the old mouse will, in many cases, miraculously grow young. This is known as heterochronic parabiosis, and it is a large source of the legitimate excitement about the potential of young plasma to lead to human rejuvenation [1].
The challenge, of course, is how to achieve these benefits in more acceptable and less disturbing ways.
We are now seeing companies that are trying to identify the relevant blood plasma proteins, as it’s the non-cellular aspects of blood that seem to have rejuvenation capacities. The California company Alkahest, along with its Spanish partner Grifols, is one of the leading companies in this space. It is making progress on identifying positive plasma chronokines that can lead to rejuvenation and negative chronokines that can accelerate aging.
Steven Braithwaite is Alkahest’s Chief Scientific Officer. I met Steven at the Longevity Therapeutics conference in San Francisco earlier this year. He previously led research at Circuit Therapeutics, led drug discovery at Signum Biosciences, headed the cellular neurodegeneration group at Wyeth/Pfizer, and was a program leader at AGY Therapeutics. In these roles, he has led both small molecule and biological research and development programs across a diverse range of indications in the field of neuroscience. Steven is a graduate of the University of Cambridge in the UK, received his PhD from the University of Bristol in the UK, and performed postdoctoral work at Stanford University.
This interview was conducted by email in early 2019.
Why is Alkahest focusing on plasma proteins as a promising area for rejuvenation therapies?
Alkahest is focused on developing therapeutics with a strongly supported scientific basis for treatment of a range of age-related disorders. Our founding science is based on studies conducted at Stanford University, which demonstrated that there are certain proteins present in plasma that can confer effects on biological function in aging. Their relation to the processes of aging is supported by the observation that many of these functional proteins increase or decrease with age – we have termed these functional plasma proteins chronokines.
There are beneficial chronokines known to decline with age that we can increase and thus delay the onset of aging-related disorders, and there are detrimental chronokines which increase with age that we can inhibit for this purpose. We have therefore focused on deeply understanding the plasma proteome as a source of therapies, both plasma-based and traditional pharmaceutical modalities like small-molecule inhibition.
What are your most promising results so far?
We have multiple strategies that are being tested in clinical trials and a broad pipeline of candidates that are being evaluated. Capitalizing on the beneficial chronokines we’ve discovered, we are using two plasma fractions, each composed of a selection of proteins from the full slate of proteins in whole plasma, in collaboration with our partner Grifols.
Our GRF6019 and GRF6021 programs are targeted towards Alzheimer’s disease, Parkinson’s disease, and a broader peripheral strategy. In mice, we see profound effects of these therapeutic candidates in improving the function of aged animals, particularly focusing on their memory, as well as benefiting a number of pathways that are critically compromised in aging.
We have put a great deal of work into identifying the most effective plasma fractions, ensuring they are safe to administer, effective and appropriately dosed. All of our programs are under the oversight of the FDA and other regulatory bodies, and you can see the latest on our trials on clinicaltrials.gov.
We have also identified a number of detrimental chronokines. Our most advanced program targets the signaling of one of these, eotaxin, for which we have a drug candidate called AKST4290, which is in Phase 2 clinical testing at this time. In our animal models, we have seen broad activity that improves performance in cognition, motor function, general performance and inflammation, indicating AKST4290’s potential for treating a number of aging processes and disorders.
We recently announced positive data of AKST4290 in trials in wet age-related macular degeneration patients at the Retina World Congress meeting. Remaining data for treatment refractory patients will be shown at medical congresses this spring and summer. We are in the planning phases of starting additional studies. Our excitement behind this molecule comes from our positive Phase 2a results, our great effects seen in mice, connection to multiple disease areas, and potential broad applicability across age-related macular degeneration, Parkinson’s disease, and other disorders.
Can you flesh out some details on the positive results that you’ve received from your clinical trials on Alzheimer’s patients? Have you published papers reporting these results yet?
Our trials with GRF6019, our lead plasma fraction, in Alzheimer’s disease are rigorously performed, blinded studies that are still underway. We will only understand the results of these trials at the end of the study, and we expect to report results by the end of this year in our study in mild-moderate Alzheimer’s disease and in 2020 for subjects with severe Alzheimer’s disease. Earlier in the history of the company, we supported one small study, performed at Stanford University, using young plasma in mild-moderate Alzheimer’s disease subjects in order to understand the fundamental safety and feasibility of the approach. The primary endpoints were safety and tolerability, for which there were positive results. This study has been peer reviewed and published [2]. It should be noted that this study tested a very specific dosing paradigm, and inferences from this must be taken cautiously based on this paradigm and the limited number of subjects studied.
Is Alkahest using any AI or big data tools currently to identify chronokines? Do you plan to use such tools in the future?
The identification and prioritization of chronokines is certainly a task that enters the world of big data, and AI can greatly help as a driver. We are taking the approach of generating the highest quality and deepest understandings possible of the plasma proteome in aging and disease and incorporating all additional metadata that we can to rationalize the key chronokines. We are seeking those chronokines with both the most change over age and the highest biological functioning. This integration of data, including experimental data that we generate, is leading to fascinating insights – we are using multiple machine learning techniques to generate hypotheses and prioritizations. Importantly, computational biology cannot stand alone, and we are critically integrating AI with in vitro and in vivo biology to further our understanding of the molecular basis of plasma efficacy to scientifically drive the next generation of therapeutics.
How close is Alkahest to commercially available therapies?
Alkahest is rigorously advancing therapeutics through FDA and EMA regulated processes in the US and Europe. Our therapies are currently in Phase 2 studies and we will be developing the path for commercial approval with the appropriate regulatory authorities. The indication areas we are pursuing for our therapeutics have variable timelines for advancement, but we are working in a rapid and focused way to hopefully be able to achieve approvals in the next few years.
What is the mechanism of action for the positive chronokines you’ve identified so far? Are there various mechanisms at play?
There are multiple mechanisms of action. Intriguingly, when you consider the classically described hallmarks of aging, we see chronokines that cover a range of these aging functions. This multimodality may be important in influencing the complex biology that changes over aging.
Similarly, what are the primary mechanisms of action for the negative (aging) chronokines you’ve discovered?
As with the positive chronokines, there are multiple mechanisms of action represented by the detrimental chronokines that we have identified to date. We particularly seek chronokines that may act as critical hubs in signaling and thus ultimately have multiple downstream effects. As in the example mentioned above, our most advanced program targets the signaling of eotaxin through inhibition of its primary receptor, CCR3. This strongly modulates inflammatory signaling throughout the brain and body, having effects in multiple organs and advancing interest in diverse indications. Mechanistically, modulating signaling of this negative chronokine affects inflammation, but also, due to its centrality, affects additional relevant mechanisms.
What will be your source of plasma fractions and chronokines when your products become commercially available? Are these therapies susceptible to synthesis in the lab rather than relying on actual young plasma?
We work with Grifols, a major producer of plasma fractions for a range of therapeutic indications, to produce the selected plasma fractions for age-related disorders that we test in clinical studies from pooled plasma under rigorous safety and manufacturing controls. The individual chronokine-inhibiting agents can be synthesized or modulated using other therapeutic modalities, such as small molecules or antibodies. For example, AKST4290 is a synthetic, manufacturable, small molecule inhibitor of CCR3, modulating an important chronokine biology that we identified.
Eventually, we hope to produce positive chronokines as recombinant proteins. We envisage that both plasma fractions and targeting of individual chronokines will be valid therapeutic strategies for different patient populations, and we continually seek to ensure a long-term, sustainable ability to provide these therapeutics.
Can you scale up for Alkahest’s planned commercial products without using Grifols’ plasma fraction products? In other words, is it realistic to expect that Alkahest will synthesize the required chronokines without the need for plasma fractions (and the young blood they come from) in time for production of your planned commercial therapeutics?
We are making excellent progress on both of our strategies of plasma fractions and individual chronokine-based therapeutics. Both approaches require thorough, FDA-regulated clinical trials. Given our current status in Phase 2 clinical trials, it is likely that we will advance commercial products with Grifols plasma fractions, but there will be a series of follow-on therapeutics in the future as we understand individual chronokines, synthesize them, and test their efficacy alone and in combinations. We are also inhibiting some of the detrimental chronokines through traditional pharmaceutical approaches including small molecules such as AKST4290. This multi-pronged approach is likely necessary as different people may need different therapeutic compositions.
What safe options, if any, are available today for people seeking to take advantage of the benefits of young plasma? Ambrosia LLC made the news recently, but it seems that it’s not exactly a legitimate outfit since it’s charging trial participants $8,000 to participate (though it appears to be conducting clinical trials now). Are there other options?
The FDA recently cautioned the public on the commercialization of young plasma infusions without rigorous science, evaluation, and safety considerations. Alkahest is supportive of performing clinical trials under the oversight of Institutional Review Boards (IRBs) and regulatory agencies that clearly consider, during the course of their work, the benefits and risks to patients. Although Alkahest is not performing any trials with young plasma, we are performing clinical trials with plasma fractions as indicated on www.clinicaltrials.gov. Although we are excited about the potential of these therapeutics, patient safety is our first priority. Appropriate clinical testing is the best way to understand safety and efficacy for patients.
What, in your opinion, will constitute the best suite of therapeutics for a full spectrum anti-aging regimen in humans in the coming 5-10 years? In other words, in addition to the various positive chronokines that Alkahest and others are working to identify, what else do you see as very promising therapeutics?
The anti-aging community has made great progress in advancing to truly rigorous scientific understandings. It is heartening that there is solid research in understanding mechanisms to develop therapeutics that are strongly supported and not merely the result of unsubstantiated claims. I believe that understandings of exercise and dietary restrictions are key areas in telling us how to therapeutically replicate some of the positive effects seen in these regimens in an aging population. I am excited about research on metabolic functions, protein handling, and immune effects. I think that modulating multiple aspects of the traditional hallmarks of aging that are seen through these studies will be necessary; likely, a combination of proteostasis modifiers, senolytics, and immune modulators will be the most promising avenue in the next few years. Our approaches on chronokines can intersect with these interests to provide truly multimodal therapeutics in addition.
Finally, can you explain your company’s name?
Alkahest is the mythical universal solvent. It is a term coined by the Swiss philosopher-scientist Paracelsus (the father of modern toxicology) in the 1500s and was very appropriate to us, as we believe that we are understanding, from our plasma, a multimodal therapeutic that has the ability to effect to modulate age-related processes. It is also an homage to our Swiss scientific co-founder Tony Wyss Coray, whose foundational work led to our exciting therapeutic progress.
[1] Conese, M., Carbone, A., Beccia, E., & Angiolillo, A. (2017). The Fountain of Youth: A tale of parabiosis, stem cells, and rejuvenation. Open Medicine, 12(1), 376-383.
[2] Sha et al. Safety, Tolerability, and Feasibility of Young Plasma Infusion in the Plasma for Alzheimer Symptom Amelioration Study: A Randomized Clinical Trial. JAMA Neurol. 2019;76(1):35-40.
