Category: APO-A1 Milano

ApoA1 Milano

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By , March 29, 2015 10:42 pm

In the end I knew that statins would be overthrown. Their time, like the dinosaurs would come to an end.  I also knew it would be nothing to do with me, or any of the other critics. Nor would it have anything to do with the fact that their terrible burden of adverse effects finally came to light.

No, it would be because their patents ran out, which meant that the big pharmaceutical companies could not make eye-watering profits from them anymore. Inevitably, therefore, they would be replaced. Indeed, for years I have watched, with varying degrees of amusement, the unending efforts to unearth the ‘new’ statins. The wonder drugs to be taken by everyone, for the rest of their lives. The ones that will make billions for the pharmaceutical companies, and several millions for the key opinion leaders promoting them.

Steven Nissen had a go with apoA-1 Milano. This is a little story you may want to look up on Wikipedia.  Basically, a small village was found in Italy (near Milan) where people had very low rates of heart disease, and they also had very low levels of HDL ‘good’ cholesterol.

Turning science on its head, it was therefore decreed that their HDL must be especially ‘good’ at preventing heart disease. [Rather than accept that HDL had bugger all to do with heart disease]. So attempts were made to synthesize their form of HDL, then inject it into patients. This was done in small scale clinical studies.

So brilliantly did Nissen sell the results of these studies that a start-up company called Esperion, which funded the trials, was sold to Pfizer for over a billion dollars on the back of the results. If you want to find out more, the HDL synthesized was called ETC-216, not apoA-1 Milano.

This is what Steven Nissen had to say about the trials.

The fact that you can actually pull major amounts of plaque out of the artery in five or six weeks is an epiphany,” Nissen says. H. Bryan Brewer, chief of the molecular disease branch at the National Heart, Blood & Lung Institute, adds: “Quite to everyone’s surprise, this indicates that we might be able to be much more successful in a shorter period of time than we thought possible.”

By golly it all sounds very exciting, does it not.  Pulling significant amounts of plaque out of artery walls, in six weeks! This is quite amazing, what a brilliant drug. In truth, though, that quote was from 2003. Has anything since happened since to this magical plaque munching HDL? Is it now on the market, saving lives? Well, as you ask, the answer is no.

However, several other HDL raising agents have also been developed in the last few years. Unfortunately, they also raised the risk of heart attacks and strokes – then disappeared. Torcetrapib, dalcetrapib, anacetrapib…. A yes, anacetrapib, not quite gone yet.

Anacetrapib has a knock-your-socks-off effect on HDL and a jaw-dropping effect on LDL,” said Chris Cannon in an AHA press release.  He also said “The lipid effects are jaw dropping in both directions,” Yes, indeed, they were.  Although I am not sure that ‘jaw dropping’ and ‘knock your socks-off’ are truly scientific terms.

But then Forbes ran this headline on the 22nd October

Merck Heart Drug Runs Into New Worry.’ 1

As an aside, you can find out far more about drugs in development by reading Forbes magazine than you will ever get from the scientific journals.

Anyway, I wouldn’t bet the house on anacetrapib as I suspect it will soon follow the other ‘trapibs’ into an early grave. But never mind, Lilly has yet another HDL raising agent waiting in the pipeline, evacetrapib. What is it with these unpronounceable names, and why don’t these companies just give up? However, perhaps this one has a better shot than most, because as Steven Nissen said of dalcetrapib…

Dalcetrapib was always a long shot,” said Steven Nissen, chairman of cardiovascular medicine at the Cleveland Clinic. “The worry all along was that it wouldn’t have enough effect to produce a benefit,”

Then, as he went on to say of evacetrapib

We got everything we could hope for from this drug, and maybe more,” remarked study co-author Steven Nissen, adding that “we are going to move evacetrapib forward as rapidly as possible” into a late-stage trial.” Gosh, he is running a study on evacetrapib too.  He was also lead investigator for Torcetrapib2.

That Steven Nissen, what a busy chap he is?  Wasn’t he the one who said about the new cardiovascular prevention guidelines.  “The evidence was never there” for the LDL targets, he said. Past committees “made them up out of thin air,” he added.  Why yes, I think he was.

Anyway. They have tried raising HDL…fail. They have tried a different way of lowering LDL using ezetimibe. It lowered LDL, and has had absolutely no effect on cardiovascular disease…fail. They have tried combing different HDL raising agents with statins….fail.

You know, you might even begin to think that raising HDL wasn’t that good an idea. Billions have been thrown this target, everything has miserably failed. It is also interesting that LDL lowering agents, other than statins, have failed to have any impact on cardiovascular disease. Has this had any effect on the lipid hypothesis? You must be joking.

Given this litany of disastrous drugs trials, why do I now believe that statins are about to be overthrown? What agents could be out there that are going to sweep them into the dustbin of history.

Clearly it cannot be an agent that lowers LDL even more than statins. Can it? Well, Steven Nissen has recently said the following about LDL lowering. This quote is in connection to new drugs being developed3.

 “….it matters how you lower cholesterol, not just by how much.”

It matters how you lower cholesterol, not just by how much….. Interesting.  Well, if cholesterol does cause heart disease, then it doesn’t really matter how you lower it, does it? The only question is, by how much? Or is Steven Nissen trying to say something else?

As a further aside, if you want to know where the really big bucks are being spent in cardiovascular research, and what is in the pipeline, all you need to do is follow Steven Nissen’s pronouncements. He is the weather vane. You don’t need to be a weather man to know which way the wind is blowing.

…… (to be continued)

 

1: http://www.forbes.com/sites/matthewherper/2013/10/22/merck-heart-drug-runs-into-new-worry/

2: http://online.wsj.com/news/articles/SB10001424052702304363104577389353232022644

3: http://www.forbes.com/sites/johnlamattina/2013/09/05/esperions-novel-approach-to-lowering-cholesterol-will-it-be-successful/

Totally blind mice get sight back

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By , January 8, 2013 11:47 pm

Totally blind mice get sight back

By James Gallagher Health and science reporter, BBC News

Eye

Totally blind mice have had their sight restored by injections of light-sensing cells into the eye, UK researchers report.

The team in Oxford said their studies closely resemble the treatments that would be needed in people with degenerative eye disease.

Similar results have already been achieved with night-blind mice.

Experts said the field was advancing rapidly, but there were still questions about the quality of vision restored.

Patients with retinitis pigmentosa gradually lose light-sensing cells from the retina and can become blind.

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It’s the first proof that you can take a completely blind mouse, put the cells in and reconstruct the entire light-sensitive layer”

Prof Robert MacLaren University of Oxford

The research team, at the University of Oxford, used mice with a complete lack of light-sensing photoreceptor cells in their retinas. The mice were unable to tell the difference between light and dark.

Reconstruction

They injected “precursor” cells which will develop into the building blocks of a retina once inside the eye. Two weeks after the injections a retina had formed, according to the findings presented in the Proceedings of the National Academy of Sciences journal.

Prof Robert MacLaren said: “We have recreated the whole structure, basically it’s the first proof that you can take a completely blind mouse, put the cells in and reconstruct the entire light-sensitive layer.”

Previous studies have achieved similar results with mice that had a partially degenerated retina. Prof MacLaren said this was like “restoring a whole computer screen rather than repairing individual pixels”.

The mice were tested to see if they fled being in a bright area, if their pupils constricted in response to light and had their brain scanned to see if visual information was being processed by the mind.

Vision

Prof Pete Coffee, from the Institute of Ophthalmology at University College London, said the findings were important as they looked at the “most clinically relevant and severe case” of blindness.

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This is probably what you would need to do to restore sight in a patient that has lost their vision”

Prof Pete Coffee University College London

“This is probably what you would need to do to restore sight in a patient that has lost their vision,” he said.

However, he said this and similar studies needed to show how good the recovered vision was as brain scans and tests of light sensitivity were not enough.

He said: “Can they tell the difference between a nasty animal and something to eat?”

Prof Robin Ali published research in the journal Nature showing that transplanting cells could restore vision in night-blind mice and then showed the same technique worked in a range of mice with degenerated retinas.

He said: “These papers demonstrate that it is possible to transplant photoreceptor cells into a range of mice even with a severe level of degeneration.

“I think it’s great that another group is showing the utility of photoreceptor transplantation.”

Researchers are already trialling human embryonic stem cells, at Moorfields Eye Hospital, in patients with Stargardt’s disease. Early results suggest the technique is safe but reliable results will take several years.

Retinal chips or bionic eyes are also being trialled in patients with retinitis pigmentosa.

Dr Thomas Challenger Challenger Mission