Waging war on cholesterol - from the laboratory to the clinic to the courtroom!

The war on cholesterol continues unabated with the new star target (PCSK9) having been the subject of a hotly contested race in the clinic over recent years, but now, perhaps inevitably, that drug development contest looks like it's going to be further contested - in a courtroom - before a single dollar has been made by anybody. 

To many it appeared that the war on cholesterol and the cholesterol (drug) wars were already far behind us, following the phenomenal success of the game-changing drug class known as statins - a class which achieved the panacea (nirvana?!) of unquestionably benefiting people's lives and health while simultaneously raking in billions of dollars to their manufacturers - eventually making them the most successful drugs in history. 

However, while they have been spectacularly successful, not everyone responds well to statins and there are some fairly serious side effects which affect patient compliance, so the door was never entirely slammed shut. Or, looking at it the other way, the spectacular success of statins and the riches they brought in were sure to keep pharmaceutically-minded researchers on the hunt for the next HMG-CoA Reductase, which is the target against which statins were discovered. 

That dream became reality with the discovery of the PCSK9 class; PCSK9 is a proprotein convertase that binds to the LDL receptor and targets it's complex with cholesterol for degradation, thereby reducing receptor quantity at the cell surface. This can lead to reduced cholesterol uptake which is an identified trigger for cardiovascular disease leading to heart attacks and strokes. A lot of hope for this new target crystallised into drug candidate reality when preclinical studies underlined that PCSK9 was a tractable target that did indeed lower cholesterol levels when inhibited.

Two of the players who are ahead in the race to market a PCSK9-targeting biologic are Sanofi/Regeneron and Amgen; pharmaceutical companies that have each completed Phase III clinical trials and have applied to the FDA for approval to market their drug candidates. It's a neck-and-neck race and the pressure mounted on Amgen with the announcement by Sanofi and Regeneron this summer that they were intending to use an extremely valuable FDA (rare pediatric disease) priority review voucher in connection with the Biologics License Application (BLA) submission for their Alirocumab. 

These priority review vouchers are worth their weight in gold to drug companies because they save time, and time is big, big money in the pharmaceutical world. Even if it simply means that you get to market six months earlier than your nearest competitor, that can make a massive difference to roll-out sales and early adoption by the medical community and patient segment. No doubt this has played a part in the recent issuance by Amgen of a lawsuit claiming that Sanofi-Regeneron are infringing on Amgen patents (# 8,563,698, 8,829,165, and 8,859,741) which detail and claim monoclonal antibodies to PCSK9. Amgen's own Evolocumab is the subject of another BLA tabled at the FDA, and they aren't going to take the possiblity of being second sitting down. 

Amgen wants an injunction to prevent the manufacture, use and sale of Sanofi and Regeneron's Alirocumab, so this is serious business - for both parties. In any case, statins have not disappeared, and they are still big business themselves, so it is not likely that PCSK9 therapeutics will dominate the market anytime soon. In fact, analysts think it will be a rather slow roll-out, with PCSK9 inhibitors used in only a selected subset of those at risk of cardiovascular disease, with a more global adoption only likely after a trouble-free introductory period. 

Why change something that's working well, will be the argument for many practioners and patients alike, and if you are on a statin with no side effects experienced, then I can see the point. But it is tempting to consider that with the doses perfected over time, the combination of a low dose statin with a to-be-determined safe dose of a PCSK9 inhibitor could be the magic bullet and might eradicate heart disease for the majority. 

We are not there yet, of course, and there is an important aside to that potentially attractive proposition in that it will only further contribute to the burgeoning population vulnerable to and suffering from age-related CNS disease. This is going to reach a pandemic-type scenario by 2050 and the lack of pharmacueutical success in this disease class is of real concern to us all - old and young alike. We are almost all either heading towards the vulnerable age group, or have loved ones living in that age group, and the abject lack of any transformative therapeutic for Alzheimer's disease, dementia more generally, Parkinson's disease etc. is (going to be) a major problem for society. 

The prevalence of CNS disease is a symptom of medical success in other key conditions that used to be a death sentence, and now we need to be focusing on some of these diseases that we are all going to face in one capacity or another in our lifetimes. The cost to the healthcare system of age-related CNS disease is a staggering one, and one which is exponentially rising; investing some of the future costs into higher priority research today is going to be essential in making any progress. 

The pharmaceutical companies who have raked in billions on statins or those about to on PCSK9 inhibitors could do well to reinvest in age-related disease areas that those drugs help us live to see. While that is perhaps an apparently ungrateful way of looking at it, pharmaceutical companies can (must) be persuaded to reignite their interest in the currently "unpopular" CNS disease segment, especially given that it will represent a massive market by 2050 and such companies don't have any problem printing money when they get it right. 

But, if they get to print their money, and we get to finally have a transformative, disease-modifying CNS disease therapeutic, well, that's a big win-win and I think we can all live with that. In the meantime, we can all focus on developing better PCSK9 inhibitors and that does include us, because AmorChem has a small molecule PCSK9 program in our own portfolio!

Valeantly making money, even in failure - now that's good business!

I am sure I am far from being the only one who sighed with some relief when the most current hostile takeover soap opera known as "Valeant vs. Allergan" came to a close with the entry of another player into the fray - a white knight who slapped an unbeatable offer onto the table. New Jersey's Actavis put an end to the never-ending shenanigans with a crisp $66B bid for Allergan which effectively sent Valeant Pharmaceuticals scurrying off with it's tail between its legs. 

This saga had been going on for the best part of a year, since the initial lowball offer of around $45B in April by Quebec-based Valeant for California-based botox maker Allergan, and it got nastier as things developed. Valeant has been on a roll of acquisitions of late, topped by the 2013 acquisition of global eye health company Bausch & Lomb for a healthy $8.7B - Valeant's biggest deal to date.

Valeant CEO J. Michael Pearson is nothing if not aggressively ambitious and he has not been shy in stating that he intends to make Valeant one of the top five global drugmakers by 2016, by market cap. While his presence at Valeant has grown the company considerably in value, they are not yet in the same ballpark as the current top five players, and Pearson saw Allergan as a key acquisition that would help them get there. 

But Pearson is known to wield a big axe in terms of cost cutting and fat trimming from overstuffed companies, and in fact it's part and parcel of his acquisition process; this is no doubt one aspect that had Allergan concerned, and it wasn't helped with the alliance of Pearson with one Bill Ackman of hedge fund Pershing Square Capital. Ackman had surreptitiously acquired a 9.7% share of Allergan using a joint fund with Valeant, making him the largest shareholder, and thus perfectly positioned to orchestrate a (hostile) takeover. 

Allergan pushed back from the get-go, even increased offers did not do the trick, and they put a poison pill into motion to push back the raiders of Valeant; but Ackman et al. simply responded by steering the deal into truly hostile waters via manoeuvering to replace the majority (or all) of Allergan's board. He wanted to take it to the shareholders in the hope that they would force Allergan CEO David Pyott to come to the table for a realistic conversation - one that never happened in the end. 

Although Pyott appeared to keep a much lower profile than either Ackman or Pearson, he did ensure that there was a healthy smear campaign against Ackman in particular, with accusations not only of accounting anomalies but actual insider trading by Ackman and Pershing Square. Lawsuits were inevitable and they did come, and it truly appeared that this deal was going to get even nastier and likely to drag on well into 2015 - undoubtedly getting in the way of Pearson's grand plans for 2016.

In the end, all's well that ends (not) well, for basically everyone involved! As it happens, the $66B deal with Actavis turns out to be a very lucrative one for Ackman's hedge fund, which will rake in over $2B on this deal. Not bad for a few month's "work", eh? (Canadian term intended!). But perhaps more intriguingly, in return for the $75.9M that Valeant pumped into the joint fund that allowed Ackman to acquire his majority stake in Allergan, Valeant in fact now stands to receive some serious pocket money - to the tune of $473.2M. That will put them around $400M up on this entire non-deal (for them), which is hardly a kick in the teeth. 

Business as usual when you are in big business, some might say. Of course, the one laughing all the way to the bank (his own) is Bill Ackman, with a $2B+ payday for having at least appeared to be ravenous for the Allergan pharmaceutical menu. If one were to be cynical, one might suggest that it was actually a brilliant manipulation to draw other (less toxic) buyers to the table, and that Ackman had less interest in Valeant acquiring Allergan than he had in driving up the price of their acquisition by a rival - delivering him a more rapid and extremely profitable exit.  Only he knows whether that was the case or not. 

The far-from-lowball offer of $219 per share from Actavis did hit the sweet spot, Valeant pulled away from the table, and Actavis acquired Allergan for $66B. So Allergan and Pyott did very, very well in the end. As did Pershing Square and Ackman. As did Valeant and Pearson. All's well that ends well, and rather amusingly, sometimes all's well that doesn't end well, and everyone heads off to the bank with something to show for their troubles. Now, that is what you have to call good business! 

Blue Mondays? Time for some changes!

 

I read something this morning about singer/songwriter and activist Bob Geldof (Sir Bob, to be correct) reincarnating "Band Aid" and also reconnecting with old band mates for a reunion tour of the Boomtown Rats, his contribution to the punk/new wave scene in the late 70s and early 80s. I am not a huge fan of such reunions as they often have more to do with nostalgic "cash-in" than any relevance of that nostalgia to today, or to the contemporary art form. 

However, Sir Biob has done a lot of good with his celebrity, even today, as he nucleates "Band Aid 30" to help tackle the current Ebola crisis in Africa. And sometimes a song resonates for an entire lifetime, bringing me back to the massive BR hit, "I Don't Like Mondays" which reached #1 in an unbelievable 32 countries - a staggering achievement for a bunch of musical scallywags from  Dún Laoghaire ("Dunleary"), a small seaside town in County Dublin, Ireland.

For us schoolkids the song hit home with us for very fundamental reasons - the imagery in the video of kids forced out of bed and into a prison-like classroom at school made us feel like they were singing about us!  Interestingly, the song was released decades ago and related to disaffected schoolkids and their desire to "shoot the whole day down" - a premonition becoming increasingly prevalent in American schools today.

As bad as that "imprisonment" feels when young, the idea in life is that we grow up and out of that situation, yet the harsh reality for many it seems is that school is simply replaced by work when we do grow up, and thus our love for the weekend and dread of Monday morning pervades almost our entire lifetime! Doesn't this seem quite absurd? Who would want to live that life? What would be the purpose of that life? 

Even though it appears ridiculous as a concept, how many of us truly jump out of bed with some fire on a Monday morning? Well, okay, let's refine the question a little - when one first wakes up at 6am on a chilly November morning, no one can blame us for feeling groggy and desirous of another hour in bed. But once up and once showered, our feelings about it should have come around considerably - ready to hit the streets and take the day!

I can imagine that some are ready to argue that it is easier to feel like that if you are a minor celebrity or own your company or do something apparently very interesting for a living. Or, if you make tons of money doing something, no matter how trivial, well it's all more fun. But it's actually not about the money, at all. Generalising somewhat, those who chose to stay on in school and get more degrees actually wanted to, and those who left school early to get a regular job and start "living" did so out of choice (often), also.

We truly are the outcome of such choices, even if they can be tinged with regret later on. But irrespective of the level of sophistication in our work, the key is doing something that we at least like, if not actually love, and being paid to do it for five days a week is a bonus. Nevertheless, anything becomes routine after a while, and everyone seems to have a boss, but these are mere facts of life. We have to get over it, and get on with it. Or, if one is truly unhappy about one's life, then the only thing that will change anything, is, well......change!

Most of us might escape change for a long period of our lives, but inevitably change is gonna come-a-knocking. People fear change for both rational and irrational reasons, but sometimes the only way to face change is to dive into the deep end of it, and see how you actually cope with it. And guess what? We can often shock even ourselves by not only how we cope with it, but how we actually begin to thrive in it!

Unquestionably, compared to waking up in a hospital bed or uniquely challenged in ways that so many have to face daily, those of us with the capacity to jump out of bed and into the shower, unaided, are completely blessed. We simply need to be reminded of it, more often. More importantly, we need to remind ourselves of it, much more often. Write it on your bathroom mirror and face it with your face, every single morning. Get those words off the mirror and onto and into your forehead, and carry them with you out into the world.

Most of us have so much to be grateful for, yet we find small things to moan about instead. It's human nature, but if so then we must fight our nature! Start counting the things that make this world and our presence in it so remarkable, and emphasise them more, and dwell on the  negative a little or a lot less. It's often only by relegating the negative things to where they belong in terms of priorities that we get to see more clearly the beauty of the things above them on the list; suddenly they don't seem to matter so much.

Get out there, and make a difference to your circumference, every single day. It doesn't matter whether it's a brilliant new idea in engineering or a work mate calling you brilliant because you helped solve a little problem they had or the fact that some junior person draws inspiration from you - as long as you project positivity and resolve, even in the face of adversity, you can make a difference and change someone else's viewpoint even without knowing it. It's also true that you can make your employer look at you very positively when one of your major attributes simply happens to be that positive attitude in solving issues and getting things done. A smile can go a long way on a tough day!

There will be enough time later for sitting by a warm fire with the pipe and slippers, and retiring to bed early. For now, it is time to say "I don't hate Mondays!", and get out there to change lives (including your own), and if necessary, lay the bricks for a reconstruction of your own life and slowly build in the change that you need to get your life back on track and on the up-and-up. It's a cliché of course, but one interlaced with truth - anything might be (I won't say, is) possible, especially if your bust your butt attempting it!

It really is in our own hands, each and every one of us, and the only sure thing is that if we do nothing and change nothing, then we are unlikely to succeed in constructing a better tomorrow. However, if we get off our rears, and at least try, most days, then we are stacking the odds in our favour and our chances increase - and trying our best is basically all that we can ask of ourselves, right?! We are all allowed a slow or bad day, but it is the accumulation of many more good days that lays the foundation from which a new future gets constructed. 

Oki doki, it is time for this boy to try to put together a steaming masterpiece involving the new "Bolivian Black Bean Breakfast Blend" that was just imported by my caffeine supplier, and word is that I will be jumping out of bed for days to come after just one large cup - even if this morning it looks like the streets I will jump out onto tomorrow will be streets of white! 

Happy Sunday to one and all. 

If you can't beat 'em, don't join 'em - just get a billion people to follow you!

Even those sleeping through modern life and wishing it was still the "good old days" are forced to face the reality that this must be 2014, upon hearing the rather confounding news bite that Facebook, a social media site that many consider nothing more than a recreational annoyance, is currently considered to have greater cash value than that venerable bastion of finance, JP Morgan Chase. I had to read it twice to make sure it was not some kind of early Halloween joke!

It's only a couple of years ago, following the financial crisis/fiasco and its aftershocks,  that JP Morgan lost the position of being the biggest US bank to Wells Fargo, based on their respective market value. I doubt that Jamie Dimon liked the idea very much, but given what I said above, well, being second to a Wells Fargo is one thing, and being second to some hoodie-wearing kid CEO and his nerdy gang of tech geeks is quite another. Ouch! 

This came about due to Facebook's acquisition of WhatsApp earlier this year for what also appeared erroneous at first or a misplacement of a decimal point; I thought it must have been $1.9B but no, I read it right, and it was in fact a staggering $19B. Unquestionably, and no doubt particularly to those dreaming of the good old days, this just looks like Monopoly money - gone crazy. Having said that, monopoly is the right term, because that's where such value is derived from: Facebook burying MySpace as the place to display a social scrapbook of your life, for example, gave them the monopoly over hundreds of millions of "member" users, and an ostensibly cherished, but occasionally ignored yet attentive target audience.  Ditto Twitter, as the place to present your 140 character howls at the moon, where it can be read by nobody, a few hundred, or even a few million, depending on who you are. 

Why their WhatsApp was in such demand was not only that it presented Facebook with a golden opportunity to dominate the smartphone messaging world in years to come, but once again, the company brought with it its real currency - some 450 million users (and a coveted database), growing at a rate of 1 million per day. That's one hell of a potential advertising audience, in and of itself. Placing a monetary value on such huge member numbers is far from easy of course, not least due to various social media services agonising over exactly how to monetize their offering, but I think we can just say that if Facebook valued it at around $20B, then it currently stands at around $20B! 

Don't get me wrong, there probably is something wrong in a world where a company offering a WiFi text messaging app can be valued that highly, but they have been spectacularly successful at growing their user base for a company that's been around a mere five years and yet has half a billion people using that app. A large part of the business model if you are in social media is dominating the space and being totally user-friendly in the brave new smartphone world and wars, and no one could ever accuse Mark Zuckerberg of a lack of ambition or little desire to dominate. So he bought WhatsApp at basically any price. 

Apparently, Facebook jumped ahead of JP Morgan due to their issuance of new shares to fund the acquisition of WhatsApp, and because the markets hadn't dented Facebook stock for any additional dilution, its market value rose. In a recent estimation, Facebook was calculated to be worth $224B compared to around $221B for JP Morgan. I can imagine Mr. Morgan himself rolling in his grave, if not actually causing Team Dimon to begin worrying about meeting an early (financial) grave, themselves! Of course, there was a degree of outrage (old), bemusement (middle age) or amusement (young) depending on the demographic involved, but the facts are the facts are the facts - Facebook is tops!

This development solidifies the stranglehold grip that the tech giants now have over financial markets, with not only Facebook, but additionally, Apple, Microsoft and Google all worth more than the veritable JP Morgan. In fact, if you take the #1 example out of that gang of four, Apple is today worth more than JP Morgan and Wells Fargo combined, and that just about says it all. Although it has been difficult to assess what the real value of some tech companies may be, in various cases they at least offer technologies that Joe Public understands and can play with; unlike extremely complex financial "instruments" such as derivatives and credit default swaps that were at the heart of the mortgage-backed securities crisis (fraud?) that almost toppled the US banking system, period. 

Add on top of that the various scandals that came to the surface after the crash, including those where JP Morgan itself was under the investigative spotlight, and you can kind of understand why people might sooner put their money where their mouth truly is - their smartphone (and its manufacturer) - rather than in the hands of an erstwhile financial giant now under investigation by Uncle Sam. JPM has already paid billions in fines arising out of the financial meltdown that began in 2009, and this week they revealed that the Department of Justice has launched a criminal investigation into their practices in foreign exchange business. 

One school of thought that's hardly new is that Jamie Dimon, as capable a banker as everyone seems to claim that he is, while being the boss, simply has too much power: that is the problem. For sure, the roles of CEO and Chairman should be split at an institution the size of JPMorgan. It is not in their interest to have one person in control of all of it, who then basically turns around and says it is too much bandwidth for one person to oversee, as his excuse for a monstrous loss in the billions that made the news in 2013. Some heads did finally roll over that repeat performance however, which comforted essentially no one. 

Back in 2013, even with 40% of shareholders supporting a split in roles as discussed above, Jamie Dimon got to keep his double job, as both CEO and Chairman. Some were appalled that Dimon should be allowed to wield an unnatural amount of power and control over the financial giant by retaining the titles of both CEO and Chairman of the Board, simultaneously. But it was not shocking to most. Even if it was expected that firebrand Lee R. Raymond (formerly CEO of Exxon Mobil) would have done more to reign Dimon in, and maybe even push for his removal as chairman, so far this has not happened. Again, hardly shocking - it's business as usual at JPM! 

Shareholders also voted in approval of Dimon's compensation for the prior year, a "healthy" $23.1M. Cough. But criminal investigations by both the FBI and the Justice Department have kept the heat on and the champagne warm, and it probably doesn't taste quite as sweet as it used to, today.  The public's tolerance for high finance shenanigans has waned since 2009, even if the governmental slaps on the wrist seem to be nothing more than actually enabling. It's all about power and money, and the theoretical abuse of the same. Perhaps not quite the "Power, Corruption and Lies" of New Order fame, but for sure there seems to have been a healthy dose of all three in the financial world over the last several years.

So, you know, much as I wouldn't want Mr. Morgan to be literally turning in his grave (none of this is his fault, after all!), there is something highly entertaining if not quite righteous about a Facebook having a greater market cap than a JP Morgan, in 2014. The fact that advertising revenue at Facebook was up almost 65% at $3B for Q3 2014 alone, and that around half of that came from smartphone revenue, well, it seems that monetization is being achieved and the big banks better get off their rear ends and attempt to compete with a company that can get an ad seen by a billion people a day on some piece of technology in their hand on a bus or a train - an inconceivable proposition in the original good old, bad old days of the JP Morgan patriarch.

It is 2014, and social media and technology have revolutionized life (and even love!), work and business. The gang of four are evidence of that, and a messaging app that sold for $20B emphasizes that beyond discussion. It's all about the offering, and how users in the world derive form, function and freedom from that offering, and until the big banks offer something tangible on even a yearly basis, well, I think we will be hearing of them being overtaken by "those bloody kids" on a more regular basis!