Retirement planning, primate style - safe haven for some hard-working chimpanzees!

I saw a most intriguing documentary this weekend focused on development of a more evolved understanding and compassionate treatment of some of our closest precursors - chimpanzees. These extremely intelligent and equally strong creatures have been used in biomedical and beahvioural research for almost 100 years now, and apparently the USA is the last industrialised country to do so. 

The creation of Chimp Haven stems from a revolutionary attitude and movement dedicated to extracting these hard-working ancestors of ours and to some extent humanising them - in terms of not only freeing them of their lives-in-service (i.e. in laboratory captivity) but actually planning for their retirement - which at the same time allows them to do perhaps for the first time what they are genetically designed to do - being chimpanzees!

At the crux of the story is a website that was set up by Professor Lori Gruen, Professor of Philosophy at Wesleyan University, that monitors the journey to sanctuary of the last 1,000 chimpanzees housed in the five main research facilities that still experiment on the species. Unquestionably, the AIDS crisis saw increased use of these animals in our rather fruitless hunt for an HIV vaccine, but at least two governmental reports have found there to be very little reason to continue to use them, today, and in fact the NIH has been instructed to retire hundreds of these chimps. 

Such retirement sadly does not mean a return to what we would call a totally free existence, in part due to the fact that these animals have been in captivity for several generations and would not have the skills required to survive unaided, but also due to the fact that their natural habitat erosion (guess who's also responsible for that?} has made them an endangered species. But you know, when their previous "existence" was being jailed in a cramped cage being subject to all kinds of medical experimentation, separated from social contact with their own kind, then being admitted to a chimp spa-like retreat with their gang doesn't seem like such a bad outcome!

The purpose of Chimp Haven is true rehabilitation of these animals who served, which is not entirely straightforward, as the creatures have to become socially integrated into chimp family life, perhaps for the first time, and this introduction to such a drastic change of life needs to be very carefully monitored and controlled. But it is possible, and there was something truly heartwarming to see a stressed, tired, traumatised older male go from looking on the very edge of death itself, to it actually becoming the alpha male in its new environment and family. 

I use the word "it" in the last sentence purposefully, because it relates to another major aspect of the "humanisation" that I referred to above - that these highly intelligent, socially and emotionally sophisticated animals should no longer be referred to by mere numbers, and that they must have names. This is an argument that goes all the way back to pioneering Jane Goodall, who led a 55-year study of these animals in Tanzania, and who resented the status quo that argued that such "animals" should have numbers, not names. 

Lori Gruen believes that these incredibly sophisticated animals, with their very individual personalities and identities, deserve to be recognised as such and be given names instead of remaining as mere research subjects with numbered tags. She has a point, not least given their many years in service to mankind and contribution to countless drug discovery efforts. All of us involved in research and drug development are aware that primates are extensively used as part of the process, but it's very easy to separate ourselves from that fact. We are able to go grocery shopping and basically never think about where that piece of chicken or pork or beef comes from, even in direct contact with the product, so you can see how easily we can distance ourselves from animal experimentation in biomedical research. 

The creation of Chimp Haven and the online presence of The Last 1,000 serve as timely reminders not only of the incredible advances that have been made at the expense of animals in general but that we owe them some years of rest and retirement afterwards. People like Lori Gruen need our support in their efforts to ensure that the last 1,000 are indeed transferred to their own safe haven, and it will be a real sign of progress when her website is historic in nature, with no chimps still on the waiting list for retirement. 

The fact that some chimps can live as long as 60 years happily means that for many of them, retirement is likely to be one very long holiday. Given that they had to work for decades in order to be fed and cared for and even to survive, just like ourselves, why should we deny them that "luxury"? Given how further we like to feel that we have evolved beyond primates, the fact that we are beginning to see them as more than "just animals" and incorporating some retirement planning into their lives might just prove how far we have come. 

As challenging as this rehabilitation is for many of the animals who arrive traumatised and wary of their new "captors", it was truly charming to see them settle into early retirement lying in the grass playing with streams of ribbon, or "reading" the magazines that were thrown to them by friendly hands, or surrounding a giant bucket-sized frozen popsicle on a hot sunny day. It looked like pineapple flavour and judging by their reaction it must have been delicious!

The good people caring for these wonderful animals at Chimp Haven might just be indicative of the benefits of evolution after all - even during one lifetime - because not every positive and beneficial change needs to wait for 1,000 years to transpire, and there's no time like the present. Let's just hope that it takes less than 1,000 days to retire the very last of the last 1,000, and once they are all safely in early retirement perhaps we can get back to planning for and thinking about our own!

Addying some pink into the equation, seemingly out of the blue!

You know it truly isn't 1984 but must be 2015 when you hear on a quiet Tuesday evening in high summer that the FDA has (finally) approved the first drug specifically designed to increase female libido. Now, we all know that the little blue pill has helped improve male sexual health enormously (no pun intended!), even if Viagra has less to do with libido than actual capability, but still - it was time for women to get in on the game too! 

The approval of Sprout Pharma's Addyi™ (flibanserin) came after two previous rejections by the agency and it is also burdened by quite a bit of controversy, not least of which are serious questions surrounding the drug's safety and efficacy. Although there has been mounting pressure on the agency to approve this drug, detractors cite both the only modest effects in many responders, coupled with major safety concerns over incompatibility with alcohol. 

We all know that ethanol itself is often used as a prelude to the boudoir (if not as an actual readily available form of aphrodisiac drug) and so the reports of spontaneous fainting (!) and wooziness observed are more reminiscent of Rohipnol than a wonder drug. One can only imagine the black market and potential for abuse on this one, especially if the fainting can be more relied upon than any effect on libido. It's a little worrying, to say the least. 

Another reason for the burgeoning controversy has to do with the lobbying of the FDA that has transpired, actually placing the issue as not so much one of drug approval, but one of basic gender inequality and lack of fair play in the dimly lit and often-silent corridors of power at the FDA. This lobbying was most preeminent via an online social media campaign known as "EVEN THE SCORE", which represents an organization whose purpose is to "level the playing field when it comes to women's sexual dysfunction". That the campaign did have significant impact is not only mirrored by the FDA's approval this week, but also in the comments made by Dr. Janet Woodcock, the director of FDA's CDER division - 

"Today’s approval provides women distressed by their low sexual desire with an approved treatment option. The FDA strives to protect and advance the health of women, and we are committed to supporting the development of safe and effective treatments for female sexual dysfunction."

Sentiments I think we can all agree with, even if the key words remain "safe and effective", and there's the rub (no pun intended!) so to speak. Many seem to feel that the FDA felt huge pressure to approve the drug on this go-around; significant enough pressure to actually go soft on those two extremely important words when it comes to drug development and marketing approval. Safe. Effective. The FDA clearly acknowledges the weakness in the former word by requiring prescribing physicians to warn women of the potential dangers of mixing alcohol into this particular sexual chemistry equation, but that only goes so far to assuaging concerns. 

At the time of the approval, it seems that Sprout Pharma is a rather lean and mean affair, with a mere 34 employees; this number is now expected to swell to 200 before year end. Clearly, marketing is now going to take over, big time, and even if clearly controversial in that regard, it is an area that Sprout seems to understand well. The entire lobbying and push for Addyi™ 's approval via the use of eye-catching and thought-provoking social media, coupled with putting the issue of gender inequality front and centre, definitely raised their profile and accelerated what could have been a much longer process. Having said that, the individuals involved have incurred the wrath of the FDA in their previous lives.  

Bob and Cindy Whitehead, founders of Sprout Pharma, came under the radar of watchdogs at the FDA back in 2010, when at Slate Pharma (precursor to Sprout) they were accused of exaggerating the benefits of a testosterone-related drug that were not in compliance with the drug's label. Their overtly and overly aggressive marketing tactics drew an 11-page letter from the agency telling them to tone things down or face further action, which quite naturally, has raised eyebrows not only at this approval, but over just how far they are going to go with the marketing campaign on this one!

Somehow, I can't see the FDA laughing too raucously (outside of the safe confines of their offices, anyway) at any suggestions that the purpose of any sexual dysfunction drug (male or female) is to make you feel "as randy as a teenager". Maybe they might have to tone the videos down a little, at least in the roll out of Addyi™ ! In that regard, based on prior experiences with this team, it seems that the FDA got Sprout Pharma to agree to hold off on TV advertising for the drug for a full 18 months following approval - which kind of says it all, in effect. 

In any and all cases, while there are as many as some 25 different products that can potentially positively impact men's sexual health on the market, to date there have been none for women, so FDA approval of a female equivalent is most definitely desirable (no pun intended!), timely and warranted. I guess the big question in men's lives may be how it actually will feel to have the tables turned, whereby it is their wives/girlfriends who have the stronger libido and who become more demanding in the bedroom!

Men have had it too easy and for too long, they say, and if this drug does work as well as supporters would love to claim, then it may be men's lives that will be changed forever, not just women's! What goes around comes around, and history often repeats itself - who knows, we may even see the return of an ancient expression - "Not tonight, Josephine!"

PS Hot on the heels of finishing this one, I just heard that Valeant didn't lose any time following the approval of Addyi™, and announced mere days later that they will add some green into this equation - via acquiring Sprout Pharma for a whopping $1B, with an impressive upfront payment of $500M - I guess J. Michael Pearson also got a little hot and bothered over Addyi™ ! Personally, I think it's overpriced at that level, given that Sprout estimated annual peak sales at ~$100M, and I see sales dropping off sharply after the first year or two, with women who feel minimal benefit and who miss their glass of wine at dinner. It would have been "cheap at half the price", as we say in Ireland!

The lesser spotted double doctorate species under threat!

I heard some rather surprising news from the Canadian Institutes of Health Research (CIHR) today, regarding their long established MD-PhD program. It seems that after more than three decades of supporting the training of hundreds of Canadian medical students as both clinicians and research scientists, CIHR is now pulling the plug on the program.

That this comes as somewhat of a shock is underlined by the fact that it is totally contrary to what was recommended by two independent expert advisory panels that had weighed in on the subject. But all that is moot now, following the letter sent by Danika Goosney of CIHR to medical schools around the country, indicating that the 2015-16 academic year will be the program's last. It seems to me that in this burgeoning era of individualised, personalised medicine that we need more physician researchers, not less. 

What seems to be most disturbing about the move is that it is purely based on budgetary concerns and does not appear to reflect either a deep analysis of the cost-benefit ratio of the MD-PhD program, nor does it reflect any apparent dissatisfaction with it at the recipient or university end. Au contraire. Dr. Mark Eisenberg, who heads up the program at Montreal's McGill University, summed it all up by one very direct comment - "This is insane."

Ditto Dr.Norman Rosenblum, Dean of Physician Training at the University of Toronto, who said that "The reaction has been horror. My colleagues across the country have been mystified as to how this decision would be taken when they were not specifically consulted". Rosenblum was closer than most to CIHR, having chaired an expert panel that was asked to assess the role and need for clinician-scientists in Canada, some two years ago. That panel concluded that the program not only needed to be continued, but that further support was warranted if capability gaps in various key medical areas were to be filled in the Canadian healthcare system. 

“CIHR has no evaluation data on its training programs. It’s disturbing CIHR cancelled it without any semblance of us understanding whether there is a transition plan to ensure continuity in meeting this need". 

A similar panel advising the National Institutes of Health (NIH) in the USA on the same matter recommended that NIH  “should sustain strong support for the training of MD/PhDs.” So both CIHR and NIH expert panels concurred on the need for and benefit of such programs. In Canada, the sore point seems to be that CIHR has cancelled its program without having measured or assessed the impact the move is likely to have, nor having put in place any type of new initiative to fill the void that the dropped program will surely create. 

Goosney has made vague mention of a strategic action plan at CIHR for the next phase of backing the training of patient-oriented researchers, but that is little comfort to many today, and the transition looks like it will be a long one particularly as there doesn't appear to be any plan in place yet. Additionally, lthough budgetary constraints were cited as the reason for the move, the program was hardly exorbitant in nature: the annual cost was something like $1.8M per year, out of a CIHR budget of over $1B annually for life science research and training. 

There's something especially counter-intuitive about the cancellation given the prominence of the term "personalised medicine" these days, and the need for physicians who are closer to the lab bench in terms of finding solutions to medical problems via research as well as implementing new discoveries made in labs into daily practice at the hospital. It is felt that with no transition program in place, Canada will slide in terms of both expertise and leadership in the area of personalized medicine. 

"On the one hand we are hearing that patient-oriented research and solutions is top drawer in terms of goals for health research, and then we are also hearing that the very people who would be in the centre of the whole enterprise are not a priority, and so we're confused." said Rosenblum. 

This is a conversation that is likely to endure I feel, and yet it seems entirely likely that the medical community may find a way to come up with the $1.8M needed to run such a program each year, and maybe that's what CIHR wants them to do -even if that's historically been 100% the job of CIHR, and not the medical schools themselves. If the physician-scientist was already an endangered species in Canada, before, after this move by CIHR, its very existence will now be threatened. Let's hope a solution is found soon enough so that this exotic species does not become totally extinct! 

It's always nice to feel Apreciated - especially by the FDA!

I heard some very intriguing news this past week about the FDA's approval on August 3rd of the world's first 3D printed drug - yes, you heard right - a 3D printed drug! Now, 3D printing (3DP)  has been around for a while, mainly in the manufacturing industry as a rapid-fire way of cranking out prototypes to test, but it has also been applied to healthcare issues requiring prosthetics and tissue engineering, for example. While we tend to think of 3DP on a macro scale, nanotechnology and nanomedicine is very much in vogue in 2015, and 3DP is being applied to problems both big and small. 

The process of powder-liquid 3DP was developed at MIT decades ago, mainly for prototyping purposes, and the technique uses an aqueous liquid to essentially stitch together multilayers of powder using an innovative and patent-protected procedure which is at the heart of the new technology successfully advanced by specialty pharmaceutical company, Aprecia. The drug just approved by the FDA is called Spritam (levetiracetam) and is designed to facilitate dosing in patients with seizures or epilepsy, who are often not compliant due to the size of their pills and/or other technical reasons. 

The beauty of Aprecia's ZipDose® Technology and platform is that it not only facilitates the packing in of as much as 1000mg (a full gram!) of medication into each tablet, but also that this high dose medication disintegrates in water like a bone-dry sandcastle in a rainstorm, as demonstrated in the video above. As if that weren't enough of an advance, Aprecia is also working on the enhanced taste-masking possibilities of ZipDose®, which will resolve yet another reason for non-compliance. 

What exactly is ZipDose® Technology? Aprecia inform us that it is "a proprietary, computer-aided, 3DP manufacturing process, which is designed to enable delivery of high-dose medications in a rapidly disintegrating form." ZipDose® Technology product candidates are assembled layer-by-layer without utilising compression forces or traditional moulding techniques. Thin layers of powdered medication are repeatedly spread on top of one another, as patterns of aqueous liquid droplets are deposited or printed onto selected regions of each powder layer. Interactions between the powder and liquid bond these materials together at a microscopic level. The great advantage of this platform is that it yields highly porous structures even at high loading and doses of drug.

Aprecia's tagline is that they are "Harnessing the power of an innovative technologyy" and I think it's kind of hard to argue with that! I actually cannot help wondering how many people who worked on various failed drug candidates are staring at their screens in some mixture of frustration, disbelief and maybe even awe, because if they had had this technology then  their major problem would have been resolvable. We often hear about drug candidates failing due to lack of efficacy or toxicity, but formulation is a key part in the pharmaceutical process and once a company realises that their tablet has to be the size of a horse pill, ,well, drug candidates get sidelined. 

In my own travels I can think of two cases where dosing and pill size were major issues, one in the field of dyslipidemia and the other in idiopathic pulmonary fibrosis (IPF). As much as people were invested in their leading pipeline candidates, they were simply impossible to formulate in a way that the marketing division would accept and because ulltimately those compounds did not meet the target product profile, they were axed. It's a tough business in those situations, and I bet those folks wish they had been given access to ZipDose® back then!

While the MIT-developed process has many applications in industry in general (and is licensed for those applications), Aprecia was very smart in obtaining an exclusive license to utilise MIT's 3DP technology for pharmaceuticals. This is a move that may well pay off in the very near future, not only via Spritam, but presumably via sub-licenses with various pharma who wish to deliver their drug(s) using ZipDose® Technology. But Aprecia CEO Don Wetherhold is clearly very focused in-house for now, and he elaborated recently on where he is going in the near-term.

“By combining 3D printing technology with a highly prescribed epilepsy treatment, Spritam is designed to fill a need for patients who struggle with their current medication experience. This is the first in a line of central nervous system products Aprecia plans to introduce as part of our commitment to transform the way patients experience taking medication.”

This privately owned company seems to have its head well screwed on and is heading in the right direction, for sure. The FDA approval this week puts Aprecia on a very nice platform of its very own, given that they are world leaders at this stage of the game. They have rights to more than 50 patents pertaining to pharmaceutical applications using 3DP and have filings in place that protect their proprietary manufacturing process through to 2033. With various patents pending and additional filings in the works, it is clear tthat hey intend  to keep the wolves at bay and reap the full rewards of this game-changing technology - kudos to them! 

In my case I better get out to the terrace and protect my own territory (plants and flowers) from predator (squirrels) invasion; it's turning into a lovely sunny day and so off I go with a mugful of my newest roast - it's the Modena Miscela Mattina Magica (Modena Magical Morning) blend, which seems just about right for this lovely morning. Happy Saturday!

PS - Hot on the heels of the Aprecia approval, and just after publishng of this blog, I heard that the FDA approved the world's first 3D printed spinal implant - so 3DP sure is making big news these days!

http://ryortho.com/breaking/fda-clears-3d-printed-spinal-implant/

Rainy days and cholesterol wars!

Sometimes summer rain is not such a bad thing, especially if it does force us inside temporarily and we manage to get something done we otherwise wouldn't have, or didn't miss something that we otherwise would have. Such was the case this week, when I reluctantly came inside from the dinner table on the terrace, but very happily ran into one of my favourite programs on CBC - "The Nature of Things", with David Suzuki. 

The timing of this particular episode was very pertinent due to the recent FDA approvals for the newest class of cholesterol-lowering drugs known as PCSK9 inhibitors. This program was focused on cholesterol and it's association with heart disease, but perhaps rather unusually, the tone of the episode was more of a questioning nature, rather than simply selling the big pharma version of the story that we should essentially all be on a statin. 

Dr. Beth Abramson, cardiologist and director of the Cardiac Prevention Centre of St. Michael's Hospital, and author of the book "Heart Health for Canadians" was up first, and she clarified that while cholesterol is (of course) an issue in heart disease, she emphasized that we are all individuals and it is our overall profile that determines our vulnerability to this disease. However, her tempered tone was not matched by Dr. Barbara Roberts, who is director of the Women's Cardiac Center at the Miriam Hospital. 

Dr. Roberts, author of the book "The Truth about Statins", stated that the big statin clinical trials were all industry-sponsored trials, and said that "Industry-sponsored trials are four times more likely to report a positive result than non-sponsored trials." Additionally, she commented that statins given to healthy people (i.e. those who have not had a heart attack) only reduced the risk of a subsequent cardiac event in high risk men by a mere 1.5%. Further, she emphasised that even hardcore statin believers admit that 60-80% of all cardiac events are not prevented by statins. So what's the point here?

Dr. Roberts made the somewhat provocative statement that the only patient population who truly benefit from statins are middle-aged men who have had a heart attack, and she elaborated that beyond middle age it appears to be beneficial to have higher levels of cholesterol, which actually correlate with survival. Thus she claims that statins are essentially useful only for middle-aged men, and questions their use in women, period. 

"The benefits of statins have been vastly exaggerated and the dangers have been vastly underplayed."

We then came to a question that particularly interests me, not least as it pertains to a project in our portfolio at AmorChem, which is examining the role of CD36 in the inflammation associated with cardiovascular disease. The salient point is that while, yes, there is no doubt that high levels of LDL-cholesterol are observed in direct association with heart attack and stroke, there is a clear stratification of patients who present with the disease in the apparent absence of cholesterol elevation - so what is going on?

The answer is of course, that cardiovascular disease is both a cholesterol problem and an inflammatory condition; rather shockingly to some, statins proved efficacy in a major clinical trial of almost 18,000 patients globally, even when those 18,000 people had very normal levels of cholesterol! The positive outcome can be summarised as 50% reduction in heart attack or stroke and 20% reduction in all-cause mortality. This was a game chamger, in that a cholesterol-lowering drug was that potent in patients whose cholesterol did not need lowering. The target that was identified to be lowered in response to statins in that study was of course CRP, a biomarker of cardiovascular inflammation. 

But what about anti-inflammatory drugs that are not cholesterol-lowering in action? That's an excellent question, and it is being addressed in a major clinical trial being conducted currently in the USA and Canada - using an old arthritis drug which targets inflammation but has no effect on cholesterol levels in humans. Dr. Paul Ridker, a professor of medicine at Harvard Medical School and the Brigham and Women's Hospital in Boston, is examining the effect of methrotrexate, a drug that targets inflammation in arthritis, as a potentially novel agent for heart attack and stroke. The reasoning is underlined by the fact that otherwise healthy patients who have arthritis and who have taken methotrexate reportedly have lower occurrence of either heart attack or stroke, as an unexpected "side effect" or benefit of the drug. 

It certainly is clear that we can have elevated cholesterol in humans, which leads to increased frequency of heart attack and stroke. Conversely, there are people with normal levels of cholesterol who still have high levels of heart attack and stroke, presumably due to a high inflammatory index. Obviously, the deadly combination of both negative factors is something that is likely to be involved in the worst cases of cardiovascular disease, and we need to impact them both in the western hemisphere. 

But, as we know today, that's not the whole story either. There's another major player in this scenario, and it's not so much LDL, but rather it is its sister molecule, HDL. The benefits of HDL and it's role in reversing plaque build up were ratified by study of a small population in the town of Limone in Italy, whereby members of the population who have almost no HDL in their blood remain remarkably healthy - even in the case of certain patients with high LDL-cholesterol scores. The focus on this population by Dr. Cesare Sirtori, a professor of clinical pharmacology at the University of Milan, resulted from his intrigue at one male patient with an extremely elevated LDL level (he scored an 8.0!) and almost no HDL, but who appeared to be healthy. 

Although the Mediterranean diet no doubt plays a role in preventing heart disease, Dr. Sirtori realized that it could not be the whole story, and his research showed that in this small town of largely inbred population, the residents had a mutation in a protein component of their HDL that de facto supercharged  their HDL. Thus even with potentially deadly-low HDL levels, such people remained free of heart disease, which was and is a fascinating discovery. Dr. Steven Nissen of the Cleveland Clinic admitted to being totally skeptical at the hypothesis that HDL could reverse plaque built up over decades in patients during a mere six week infusion testing of a synthetic HDL, but also confessed to being "absolutely stunned" when it worked. Even though Pfizer picked up on the potential and seriously invested in the technology, it did not lead to a new drug. 

Another promising discovery was made by the team of Dr. Stanley Hazen of the Cleveland Cliinic's Cellular and Molecular Medicine department who identified TMAO (trimethylamine N-oxide) in the blood of cardiac patients, which was determined to come from carnitine in our diet. This molecule is produced from red meat carnitine by bacteria in our stomach, and TMAO is now known to not only enhance cholesterol deposition in artery wall plaque, but also to prevent HDL from doing its job and exiting cholesterol out of plaque - a really negative double whammy! This novel biomarker holds promise as something else to measure to determine the overall cardiovascular health of invidivduals. A most worrying aspect of this segment in the story is that carnitine is often used as a dietary supplement by bodybuilders and athletes, and TMAO is also found in many of those energy drinks lining the shelf in the grocery store!

Notwithstanding all the discussion above about the true usefulness of statins, the cholesterol wars are only ramping up further with the imminent marketing of Praluent (Sanofi-Regeneron) and Repatha (Amgen) - two much-touted biologics that are PCSK9 inhibitors. These novel agents also target LDL, albeit by a distinct mechanism from statins, and only time will tell how successful (therapeutically and financially) these agents will become, and whether they do topple statins as the #1 drug of choice for lowering cholesterol. One disadvantage is that they are injectibles, which could impact patient compliance; this point is not lost on us and is in fact the crux of another project in our portfolio searching for oral small molecules targeting PCSK9. 

Well, I better leave it there before I overstay my welcome. David Suzuki and "The Nature of Things" rarely disappoint, and this episode was no exception. Who would have thought that the hissing of early evening summer rain would have turned out so fascinatingly, and that rain did provide a rather calming backdrop soundtrack to an extremely provocative take on the cholesterol wars. Nature really did turn me on to the nature of things!