Today, European Bio is in a very FIT state indeed!

Everyone's allowed a little bit of self-promotion once in a while, especially as our annual AmorChem event day with Lumira Capital is happening this week, and then we are off to San Francisco for the crazy four days of partnering meetings that is BIO 2016! So, having a very busy week gives me the perfect opportunity to share an interview I recently did with those very nice people at BioFIT - this is a Europe-based mini-BIO, or younger brother/sister of the huge American convention - and I was delighted to be invited to Strasbourg as a speaker there in December of last year.

Newsletter n°4 – May 2016

"Europe is poised to become extremely competitive and productive in terms of entrepreneurs having access to venture capital across borders and achieving the growth that is essential for the sector" Read more In-depth interview with BioFIT speaker in 2015 Kevin McBride, Vice-President, Research at AmorChem in Canada This month, BioFIT speaker in 2015 Kevin McBride, Vice-President-Research at AmorChem in Canada, shared his thoughts on European entrepreneurship in Life Sciences: We have seen many new initiatives in early stage innovation financing over the past few years. How do you think these trends will evolve in the next ten years?  We will continue to see big pharma reaching back into stellar academic institutions and establishing collaborations both institutionally as well as with top tier researchers. Successes in such endeavours will continue to encourage pharma to seek out discovery-stage targets and assets externally, allowing them to essentially outsource their R&D and in-license only when a valuation point has been reached for candidates that fit into their pipelines. The reason why this activity represents the direction of early stage financing is that it is market-driven. Previously, early stage work was somewhat buried in universities with tech transfer offices utilising a “push” strategy, with only limited success. The closing-in on university-based research assets by both big pharma as well as by translational VC funds such as AmorChem represents more the need for greater innovation in the market. A “pull” strategy by that market is one of the best ways of encouraging and driving innovation forward. Although the trend of pharma collaborating with academic institutions has been thriving over the last few years, at least here in Canada, the AmorChem Fund is quite unique in that we finance early stage projects in universities and were doing so ahead of the current trend. One interesting aspect of the currently evolving situation is that we occasionally find ourselves competing with substantially larger organisations for the same assets. But again, this is the market driving an increased need for innovation, and for those involved in discovery R&D in universities, such attention and competition can only be a good thing. Johnson&Johnson are making quite a splash with their JLABS concept, whereby chosen projects are offered incubator space in chic new facilities amidst a key collective of intellectual and developmental expertise. I see that type of endeavour becoming more and more popular in the coming years. As a North American VC, how do you see the future of the European seed capital market?   We invest more or less exclusively here in Canada, hence my limited knowledge of the European situation. I see it as similar from the Canadian situation, in that the geography/potential is very large, but we lag behind the United States in terms of financial infrastructure. There, they are willing to absorb the risk and transaction costs of financing early innovation, and with access to sufficiently diversified funding sources one can take an entity from SME level and scale it into a domestic if not globally competitive company. Europe has struggled in that fashion similarly to Canada, but there have been recent EU and European Commission initiatives, such as the Innovation Union/Single Market Act/Expert Group/CIP/COSME, as well as 2013’s “Regulation on European Venture Capital Funds”. I think that Europe is poised to become extremely competitive and productive in terms of entrepreneurs having access to venture capital across borders and achieving the growth that is essential for the sector. READ MORE

The power of placebo - much ado about nothing, or the magic in our brains?

         

If there's a phenomenon in drug development that is as confounding as it is intriguing, it has to be a frequent observation seen in drug trials and everyday medicine that we call the "placebo effect". So, someone who thinks that they are receiving a therapeutic designed to impact an illness or affliction actually responds to a sugar pill with improvement in their condition. How come?

Not that you will ever hear pharmaceutical companies touting placebos as the next big thing, for obvious (financial) reasons, the phenomenon does exist and one reason why it remains a black box is because the answer resides in a very complex black box, of sorts - the human brain. If we can indeed observe a significant medical response to an empty capsule, in even some cases, then it implies that our brain itself has the power to heal.

Sounds far-fetched? Of course it does, but science itself is becoming more and more far-fetched these days, and science may indeed be able to answer the questions surrounding the mystery of the placebo effect. The power of suggestion and expectation may have a much greater impact on us than previously believed possible, and this concept was the subject of yet another fascinating episode of David Suzuki's Nature of Things recently. 

The program was captioned as "Brain Magic - The Power of Placebo", and took off right here in downtown Montreal at the MUHC's MNI with Dr. Amir Raz who specialises in the power of the mind; whether it be under hypnosis or utilising what he calls "focused attention" or "susceptibility to suggestion". It was shown that a young male who thought he was drinking several gin and tonics not only began to exhibit physical symptoms of intoxication, but further, his brain activity also seemed to mimic that of an alcohol-altered network. 

Admittedly, I remain very skeptical of that observation, and I daresay that the individual was chosen for good reason, in that he indeed was "susceptible to suggestion". I remember when a famous hypnotist came to our university union once, and a bunch of us (yes, after a few beers!) volunteered for the screening process by the inimitable Kenny Craig (no, it wasn't really him!) and the fun began. Rather remarkably, out of the six of us, the two that I had bet money on being "susceptible" were retained on stage, while the other four of us got unceremoniously kicked off the stage almost immediately. 

The things that "Kenny" made those two do had us falling off our chairs in laughter, and it is truly a shame that this happened in the pre-smartphone era because it would have been priceless to have been able to show that to our friends, after the fact. As it was, they had to live with months of "abuse" from all those that had witnessed the performance. But, although I make light of it, that show did convince me that for those "susceptible to suggestion", the power of the mind is indeed a powerful phenomenon. 

"Our shamans wear white coats instead of feathers, you might have to wait three months for an appointment to see them and they might charge you a lot of money—all of that creates a lot of expectation." says Dr. Raz.  

Things moved on to Professor Ted Kaptchuck of Harvard Medical School who has an entire program dedicated to study of the placebo effect, and based on various of his own observations with patients responding to placebos, he also buys into the power of the mind to actually change our physiology and positively impact our health. 

"There's no pharmacological agents, but the rituals and symbols of medicine activate neurotransmitters, relevant areas of the brain, that actually change the experience of illness and alleviate symptoms."

As skeptical as I still was, Kaptchuck elaborated further on an open-label study done on 80 irritable bowel syndrome patients, wherein 40 people were given some form of therapeutic, and the other 40 were given sugar pills - and they knew it. So, in this example, it was not a case of individuals thinking they were taking a drug, they knew they were taking a sugar pill, twice daily. This should sort out the placebo effect, right?!

Wrong. Astonishingly, twice as many patients in the group openly taking placebo exhibited positive responses in comparison to those taking nothing at all, which was a rather shocking result given that they knew they were swallowing a placebo. So are we saying that the mere ritual of seeing a doctor and swallowing essentially anything is sufficient to invoke a response in some people?! 

The placebo effect has even been observed in much more drastic situations such as wounded soldiers receiving saline drips in place of morphine (because they ran out of the drug in the field) or even Parkinson's disease patients reacting like they were given dopamine-releasing drugs when they were not. In each case, the power of the brain, the magic in the mind, seemsed capable of causing a therapeutic effect in the absence of any therapeutic. 

Speaking of dopamine, it seems that our response to placebo may well have something to do with the reward centres in the brain, and our potential dopamine and opioid release in response to a neutral pill may well be something that is genetically encoded in our DNA. Just like hypnosis itself in fact: some of us are very susceptible to it and some of as are not. It appears that the whole thing is wrapped up in the symbolism and ritual of medicine, the human connection and relationship with the doctor (or modern day shaman!) involved, and our inherent desire and/or belief that they will cure us.  

Children make very complex patients for drug trials in the pharmaceutical industry, in part because of their strong susceptibility to suggestion and their trust not only with caregivers but also in that they will be made better by those caregivers. The separation of the placebo effect from that of the actual drug in those trials makes life very difficult for pharma, making pediatric trials risky and not exactly a top priority. 

 We are beginning to better comprehend how the mind could possibly produce a physiological change similarly to that of a costly drug designed specifically for a given disease. Although it is far from hard science today, there are indications that there is real science (not magic) behind it. Perhaps the most intriguing aspect of the placebo effect is that with all of our technological and medical advances, we cast aside that most valued (by patients) aspect of medical treatment - doctor/patient relationship, symbol/ritual and bedside manner - and a healthy increased dose of that might do wonders for our health in and of itself?!

On that note, I am off home to the newly stained and planted terrace to ask she-who-must-be-obeyed to make me a stiff double gin and tonic, on repeat - but if she chooses to replace the gin with tonic - that's her decision. Given the potency of the placebo effect, it looks like either way, I am in for a very pain-free early summer evening! ;) 

When using "a killer against a killer" turns out to be a brilliant idea!

Immunotherapy. A very sexy word, indeed. It's the hot topic in cancer treatment these days, and in fact my last post featured an update on some of the most recent and terrifically exciting progress being made in this area, using CAR-T technology. But while retraining or reeducating or literally rebranding our T-cells and immune systems to fight cancer is one concept, using something that previously maimed and killed, in part by avoiding our immune systems, is quite another! 

Such is the case for a newly exploding area of medical research, which is the treatment of glioblastoma using the oncolytic virus approach - in this case using the feared polio virus - as reported on by the "60 Minutes" current affairs program on CBS last night.  Scott Pelley and his team followed a groundbreaking new clinical trial for two years to bring us the story. In a truly ironic state of affairs, scientists are now beginning to successfully use pathogens that have previously had the capacity to kill us, to instead kill cancer cells inside us. Now that's what I call progress!

"One of the scientists told me that it takes a killer to kill a killer...."

Although that seems like a fairly drastic take on the situation, we must remember that when our T-cells are doing what they are supposed to be doing, they also kill abnormal cells or those expressing epitopes of "non-self". So, modifying a virus such that it invades and attacks cancer cells, specifically, whilst leaving normal cells unharmed, seems to be a genius take on the problem - in principle - as long as it doesn't kill people in the process. 

Thus it was very heartwarming to hear that the FDA has granted this approach "breakthrough status" due to results obtained to date in clinical studies ongoing at the Preston Robert Tisch Brain Tumor Center of Duke University in the United States. This means that hundreds of glioblastoma patients will gain access to this audacious therapy ahead of approval by the FDA, due to it's new "fast track" status. In some cases at least, this offers patients with essentially no hope of survival, a chance at not only survival but of being cancer-free. 

Somehow, seeing patients afflicted with this deadly brain malignancy being injected with a dose of a pathogen that mankind wants globally eradicated by 2016, was both fascinating and rather fearful at the same time. Anytime scientists, clinicians or patients step into the dark unknown, there is always palpable excitement and anticipation laced with a healthy dose of foreboding - because you don't know until you try it - and the waiting can be excruciating. 

It goes without saying that the bravest individuals of them all are those who volunteer for such trials, when they already have been put through so much, often via surgery, radiation and chemotherapy.  But the demand is growing, and the Tisch screens some 1,000 glioblastoma patients each year vying for a spot on the trial, and as word spreads that number is likely to increase. When you've quite literally got nothing to lose, you will try anything. 

The fascinating outcome of this early Phase I trial is that the dream result was obtained in selected cases; one doesn't expect to see a major impact on disease in such a trial, but given that it is being conducted in cancer patients who have exhausted their options, it's always a possibility. So it is with a few individuals who manifested remarkable responses to treatment with this modified polio virus. 

One striking example was 20-year-old Stephanie Lipscomb who had been diagnosed with a brain tumor the size of a tennis ball, which was surgically resected followed by "as much radiation as you can have in a lifetime" as well as chemotherapy. That was in 2011, but by 2012 the cancer was back, and her only remaining option was that which had never been tried. The scary thing (but ultimately saving grace) in her response, was that shockingly and disappointingly, two months after her treatment began the tumor actually looked bigger. It wasn't working; or so doctors thought. 

The neuro-oncologist who was leading the charge wanted to terminate the treatment and put Stephanie back on traditional treatment, but the young woman refused. Rather remarkably, after four or five months and with the help of MRI analysis, the team realised that her tumour only looked bigger - but it's increased circumference was actually inflammation, only around the site of the tumour - and that was due to her reawakened immune system! 

This took everyone by surprise but was a lightbulb moment in that, effectively, it appeared that infection with the modified polio virus had broken down external defences of the tumour, exposing it from its protective shield, thereby allowing the young woman's (healthy) immune system to begin infiltrating and breaking down her tumour. And? Some 21 months of continued shrinkage ensued, until the cancer was gone - today she is in full remission and is cancer-free - which is a spectacular result by any standards! 

Naturally, not everyone achieved similar success, but so far for the 40-odd patients who have been in the program, they have on average extended their lives by 50%, and three patients remain cancer-free, three years later. It was amazing to see the ventricles reopen and folds in the brain reappear as the tumour shrank in 70-year-old retired cardiologist Fritz Anderson, who four years later considers himself cured and travels with his wife around the world. 

There have been crushing disappointments also, including those where classical Phase I parameters were being tested, and doctors learnt that increasing the dose (by as much as three times over what worked in the first few patients who are alive) does increase the inflammatory response, but by too much. Such was the case for Donna Clegg, who battled the inflammation bravely for many months but ultimately lost that battle and passed away about a year ago.  

She, like all the patients in the polio trial, was a "medical explorer" as Scott Pelley quipped, but I like to think of them as medical heroes as well, for how much new and vital information they have provided to modern medicine in the fight against cancer. One such unexpected piece of information was the striking observation that patients previously exposed to the polio virus treatment have greatly improved responses to chemotherapy, subsequently. That opened up the eyes of the physicians, and will be an added weapon in their arsenal moving forward.

Speaking of physicians, I would be remiss without mentioning the dedicated researchers and clinicians involved in this polio trial. They are molecular biologist Dr. Matthias Gromeier and neuro-oncologists Drs. Henry Friedman and Annick Desjardins, collectively led by Dr. Darell Bigner who directs the Tisch. I daresay that to the patients in the polio trial, as well as their families and friends, as well as more than a few of us, these individuals also merit the term "medical heroes". Let's hope that the upcoming expanded clinical study will shine an even brighter light on everyone concerned! 

The revolution may well be televised - especially if Cellectis have their way!

CAR-T cell therapy is in the news once again, with announcements this morning that a second baby's life has been saved using this revolutionary new treatment; I previously blogged about the first success at Great Ormond Street Hospital (GOSH) towards the end of last year, where a first young life was saved after all other options had run out. 

That baby (Layla) was around the 1-year-old mark which is positively mature in comparison to the child in the second case who was diagnosed with the possibly fatal, advanced leukemia a mere four weeks after birth. The groundbreaking UCART19 therapy was applied to this second baby on compassionate use grounds, and like the previous case, this baby is now in remission. Incredible but true!

This is spectacular progress even if it goes without saying that it still only represents n=2, but I bet you that the parents of those two babies aren't worrying very much about such statistics right now! Ditto the two babies who may now get to grow into children and then into young adulthood and beyond, all being well. 

Cellectis are hardly alone in this brave new world of cell therapy, and are racing ahead alongside competitors such as Novartis, Juno and Kite, but Cellectis do stand out for one very specific and not insignificant reason. While the former three are championing the use of "autologous" T-cell therapy, Cellectis are utilizing a variation on that theme referred to as "allogeneic" therapy.

The bottom line of that difference is that while the others are using the patient themselves as the donor, and are modifying patient-derived cells for subsequent reintroduction,  in the case of UCART19 the modified T-cells are derived from a healthy matched donor. That donor's T-cells are altered in three fashions to achieve what would have been impossible even a few years ago: firstly, they are designed to be resistant to a biologic being used on the patient; secondly, they are altered so as to not attack the healthy tissue of the recipient; and lastly, they are equipped with potent cancer-targeting and killing potential. 

That's a pretty nifty combination of properties when they get it right, as they clearly did in the case of these two children. Of course, this approach needs some rigorous clinical testing before regulatory approval, and Cellectis are slated to begin such trials later in the year, in collaboration with both Pfizer and Servier. Cellectis CEO Dr. André Choulika elaborated on the strategy in an interview with CNBC that was aired this morning, and one interesting aspect of the discussion was Choulika's assertion that when you use a patient's own cells, it is a procedure, not a product! 

Although the occasionally rambling interviewer got in the way of the subject matter a little, he actually did seem to have a grasp of the potential problems using this type of technology, and I think a layman audience probably benefited from his gruff and somewhat rambling questioning style. Choulika held firm to the beauties of his company's technology, which is in principle a much more "off the shelf" and less expensive version of autologous cell therapy offered by his competitors.

I am extremely interested in where this is all going, not least because it involves not only one but two key advances in modern molecular medicine, and that is the combination of gene editing and T-cell immunotherapy. The Cellectis technology uses a gene-editing tool known as "TALEN" to edit the T-cell repertoire in healthy donor cells to favourably alter their properties, and then introduces them into the recipient to invoke T-cell-mediated tumour cell death. Separately, such techniques are still considered largely avant garde, and the combination of them clinically in UCART19 is positively futuristic in nature. 

We are keeping a very close eye on such developments at AmorChem, because we have two related programs in our portfolio - one which utilises a modification of the TALEN tool used in these children's treatment, and the other which is a high-profile allogeneic immunotherapy approach also utilising donor T-cells to attack patient cancer cells, in this case via a single mismatched minor histocompatibility antigen. The results obtained at GOSH and in the CAR-T field in general are very encouraging indeed, and imply that the days of human gene editing in disease as well as using modified T-cells to eliminate cancers are both just around the drug development corner!