What Next for Transthyretin Amyloid Clearance Therapies?

If aging is damage, specific forms of cellular and molecular disarray, then rejuvenation is achieved through periodic repair of that damage. This is the Strategies for Engineered Negligible Senescence (SENS) vision for the future of treating aging, and it is a task that the medical research community is only just getting started on in any real way, sad to say. We are more than a decade in to advocacy and modest funding for SENS, and some progress has been achieved, however. Setting aside stem cell research and the amyloid clearing efforts of the Alzheimer's research community, as in both of those cases it is very hard to pick out the thin threads of rejuvenation biotechnology from other research that tries to compensate for damage or patch over damage, there are four SENS rejuvenation biotechnologies presently somewhere in the cusp between the laboratory and the clinic, in commercial development, and a fifth very close to that status.

Senescent cell clearance is achieved via several methods in rodents, and at least one company, Oisin Biotechnology, has been seed funded to bring such a therapy to market. Creating backup mitochondrial genes in the cell nucleus is still a matter of one gene at a time, but the technology to do that is at a comparatively advanced stage of commercial development at Gensight. Breaking down metabolic waste that contributes to atherosclerosis via the use of modified bacterial enzymes is an approach that recently moved from the SENS Research Foundation laboratories into development at Human Rejuvenation Technologies. The technology close to commercial development but not there yet is glucosepane cross-link clearance; based on recent discussions, it seems only a few years away from a viable drug candidate.

The topic for today, however, is transthyretin amyloid clearance, arguably the most advanced of the five SENS rejuvenation biotechnologies I've listed here. Amyloids are made up of misfolded proteins that in their damaged form precipitate from solution to form clumps and fibrils. There are a score of different types - the beta amyloid most people are familiar with, associated with Alzheimer's disease, is just one of them. In recent years, it has become clear that another type, transthyretin amyloid, is associated with heart failure, osteoarthritis, and a range of other conditions. In the oldest of humans, the small supercentenarian population, accumulation of transthyretin amyloid appears to be the predominant cause of death.

The small company Pentraxin signed up with GlaxoSmithKline back in 2009 to commercialize CPHPC as a treatment for transthyretin amyloidosis, a runaway version of the standard age-related accumulation of amyloid in which much more deposition occurs at a younger age, accompanied by organ failure and ultimately death. CPHPC works by clearing serum amyloid P component (SAP), a molecule associated with amyloid deposits and which seems to inhibit the normal processes of amyloid clearance. This therapy had been presented at the 4th SENS conference that same year. Like many lines of research in the Big Pharma world, this collaboration has moved forward only glacially since then, but it is moving. Along the way the use of CPHPC merged with another treatment based on the use of antibodies for SAP, and a small clinical trial of the combination therapy concluded with very positive results last year.

What next from here? At this point, a therapy exists that can, from a technical perspective, be deployed in humans with the expectation that it will clear meaningful amounts of transthyretin amyloid, with resulting improvement in the condition of patients. Unfortunately this is still very much locked up in the slow development processes at GSK, which most likely means years of trials yet, and no real urgency to move this out into the world. There is every reason to expect benefits to heart health over the long-term to result from periodic removal of transthyretin amyloid, and this is a technology I'd rather see widely used in clinics overseas, available via medical tourism, today, as opposed to being locked up behind closed regulatory doors. That outcome isn't in the GSK worldview, unfortunately, which means it will probably be an overly long time before these approaches reach the clinic. Meanwhile, diversification is a focus: finding more niches and potentially more lucrative niches in which to seek regulatory approval.

Pentraxin R&D Programmes

The single dose first in human study of anti-SAP antibodies co‚ÄĎadministered with CPHPC in patients with systemic amyloidosis remains currently underway. The initial results in the first 15 subjects to be treated have been accepted for publication and were be posted online in July 2015. The treatment has been safe and well tolerated so far and has produced unequivocal and unprecedented, swift and dramatic reduction in amyloid load, documented so far in the liver, spleen, kidneys and lymph nodes. Cardiac amyloidosis was excluded from the first part of the phase I study but subjects with cardiac involvement are now being treated.

Meanwhile alternative, novel immunotherapy approaches to treatment of amyloidosis are also being actively investigated. In a first clinical study of CPHPC in Alzheimer's disease we have shown that the drug safely and completely depletes SAP from the cerebrospinal fluid. We have now designed a comprehensive clinical trial of CPHPC in Alzheimer's disease, seeking evidence of disease modification and clinical efficacy. Preparation for and conduct of the 'Depletion of serum amyloid P component in Alzheimer's disease (DESPIAD) trial' is receiving substantial logistical and expert support from GSK and is being funded by the UCL/UCLH Biomedical Research Centre. It will start in 2016 and run to 2019.

There are alternative approaches to clearing transthyretin amyloidosis, such as the work on catalytic antibodies funded by the SENS Research Foundation. The expectation is that those, too, will be adopted by developers who set out to run the slow gauntlet of regulation, taking years longer than required for simple, sane considerations of safety and efficacy in order to get into the clinic. Even then therapies are only approved in a very limited way, and are made far more expensive by excessive regulatory costs. To my eyes the future needs much more of the distributed development and commercialization process that happened for stem cell medicine following the turn of the century, and is happening now for CRISPR gene therapies: many clinics offering services outside the restrictive regulation of the FDA and related agencies, building a market in which people can make their own informed choices on risk and early adoption, rather than being held back by the actions of self-serving, distant, and unaccountable bureaucrats.


"unequivocal and unprecedented, swift and dramatic reduction in amyloid load"

I needed some good news today, but since it's coming from a company with a WordPress blog instead of a website I'm taking it with a fat grain of salt.

Posted by: Slicer at February 2nd, 2016 12:51 AM

It is good that some of the SENS areas are in commercial development. What worries me is that it is with single small companies, and a single setback could kill progress in that area for years. Look at gene therapy in the 90s, even though dozens of well funded firms and institutions were working on it a few setbacks delayed progress for a decade. The risk is far higher with just one company in each area. Still, watching a high stakes poker game keeps life interesting!

Posted by: Jim at February 2nd, 2016 5:25 AM

Spark Therapeutics have announced that they are also developing a gene therapy for LHON. With my layman's knowledge I think that LHON is only caused by mutations in the mitochondrial DNA. So perhaps Spark will be using the same (partially SENS funded) Mitochondrial Targeting Sequence method as Gensight are doing? The more companies working on nuclear expression of mitchondrial genes, the less chance the entire field gets set back by the random failure of one company.



Posted by: Jim at February 3rd, 2016 8:35 AM

GSK is cooperating with ISIS for the development of antisense drug for ttr-amyloidosis, which will be injected once a week. With that the company will gain more money than clearance of SAP using Antibody. It is a business has nothing todo with bureaucracy.

Posted by: Aumaid Uthman at May 21st, 2016 7:52 PM

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