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Anti-Amyloid CPHPC Therapy Used in a Clinical Trial for Alzheimer's Disease

CPHPC, now called miridesap, is a cautionary tale of what all too often happens to promising approaches in the field of medical development, once they advance to the point of expensive clinical trials and the requirement for partners with deep pockets to fund those trials. Miridesap was one of the earlier methodologies demonstrated to clear out transthyretin amyloid from tissues. This form of amyloid appears to be an important contribution to risk of cardiovascular disease, as well as a factor in osteoarthritis, and the evidence suggests it is the majority cause of death in supercentenarians. Its accumulation in old tissues is a form of damage, one of the root causes of aging. Ways to remove transthyretin amyloid should be pursued aggressively, but so far most of the effort in the research community has focused on the inherited form of transthyretin amyloidosis, using therapies that are not all that helpful for the age-related form of amyloidosis.

The first attempt to develop miridesap with a major pharmaceutical concern failed in the 1990s and early 2000s. The company founded to develop miridesap, Pentraxin Therapeutics, then partnered with Glaxosmithkline, GSK, at which point it took something like nine years to get to the point of running a small trial in 2015. That trial was successful, but thereafter GSK discontinued the work. The problem is less that initiatives sometimes fail, and more that (a) major pharmaceutical entities do not have the right incentives operating in order to carry out development programs rapidly and reliably, and (b) their ownership of intellectual property rights prevents anyone else from trying variants on the same approach, even when very little is being done, or the research is entirely halted. While in principal it is possible to obtain rights to a moribund program, in practice that is far from easy, and too expensive for most of the people who would consider trying it. This might all be seen as a symptom of excessive regulatory costs. Either way, research and development languishes.

Miridesap has a third act, however, one that has been in the works for a few years now. Those involved are attempting to use it as a way to remove amyloid-β in Alzheimer's disease, and are organizing a trial that is now recruiting. It will be interesting to see whether this works well enough to make it competitive. It is certainly less harsh on patients in comparison to the immunotherapies that make up the majority of attempts to treat Alzheimer's disease. Perhaps if this works, then the rights for use against transthyretin amyloid can be wrested from GSK, or GSK might be convinced to proceed again with that line of development.

NIHR-backed trial to test miridesap in Alzheimer's

Mark Pepys, who has been working on amyloidosis for 43 years, discovered way back in the 1980s that SAP, a normal, nonfibrous circulating plasma glycoprotein, is involved in the formation of amyloid deposits. He went on to show it is always present as a minor component of human amyloid deposits of all types, and that it prevents amyloid fibrils from being cleared via opsonization and phagocytosis. Despite attracting the interest of big pharma, attempts to translate those insights to the clinic have been slow to bear fruit.

A collaboration with Roche Holding AG that started in 1993 led to the discovery of miridesap (then known as CPHPC). When tested in the rare disease systemic amyloidosis, miridesap removed SAP from the blood, but could not shift large deposits of amyloid from organs. Amyloidosis patients treated with miridesap remained stable, but the deposits did not disappear. After Roche handed back rights in 2008, Pepys formed a collaboration with Glaxosmithkline to develop miridesap in combination with an anti-SAP antibody for treating amyloidosis. The rationale was to remove SAP from the blood and then use the antibody to target SAP in amyloid, activating the complement system to clear the deposits. That played out in a phase I study published in 2015, but a phase II, 30-patient study of the combination therapy recently was suspended by GSK.

Meanwhile, Pepys has been pursuing development of miridesap as a monotherapy in Alzheimer's disease. His basis for thinking miridesap can remove amyloid from the brain when it was not effective in removing it from other organs, is related to the much lower level of SAP that needs to be sponged up. SAP is generated and catabolized only in the liver and is not expressed in the brain. In a mouse model of Alzheimer's that is genetically engineered to generate human SAP, depleting SAP in the bloodstream removed all detectable SAP from amyloid in the brain.

The study is funded with $6.2 million in grants from NIHR. GSK has no commercial interest, but has assisted with the logistics of setting up the Despiad (Depletion of serum amyloid P component in Alzheimer's disease) trial. Patients in the trial will be required to inject miridesap three times a day over 12 months and to undergo a wide range of tests, including PET scans, lumbar punctures, and cognitive assessments. Pepys hopes the 100-patient, double-blind, placebo-controlled Despiad trial, will show the reduction in SAP levels translates into clinical benefit.

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