[ed. note: Michael Jorrin, who I call Doc Gumshoe, is a longtime medical writer (not a doctor) who writes for us about medicine and health a couple times a month. He has agreed to our trading and disclosure restrictions, but does not generally write directly about investment ideas. His ideas, thoughts and words are his own, and you can see all his past pieces here.]
A projected winner hits a snag
No sooner had the Doc Gumshoe dossier about the 2017 FDA approvals posted than a bit of bad news surfaced about one of those winners. AstraZeneca’s Imfinzi (durvalumab) was approved for the treatment of urothelial carcinoma (an advanced form of bladder cancer), and was projected to bring in about $2.8 billion. Imfinzi was being evaluated in a Phase 1 / 2 study as part of combination therapy in HPV-associated cancers with a new agent from Advaxis, axalimogene filolisbac. The short take version (and I did promise short takes, didn’t I?) is that after five doses of the combined therapy, which went just fine, a patient with advanced refractory metastatic cervical cancer developed respiratory failure while receiving the sixth dose. Despite efforts to reverse her worsening condition, the patient died.
Based on previous data in studies with Imfinzi, it seems somewhat likely that the cause of the patient’s respiratory failure and death was Imfinzi and not the Advaxis agent. One patient in AstraZeneca’s Phase 3 trial of Imfinzi in lung cancer had died of respiratory failure. That, by itself, should not be definitive proof that Imfinzi was the cause of death; the patient, after all, did have lung cancer.
In any case, the FDA stopped the Advaxis combo trial, and at this point they’re trying to figure out what to do next. The Advaxis agent, axalimogene filolisbac, is a proposed cancer vaccine based on Listeria monocytogenes, a bacterium that can cause meningitis in susceptible individuals, mostly immunocompromised children and the elderly. (Needless to say, the bacterium is modified so as to be relatively harmless.) The Listeria bacterium is taken up by cells that are active in the human immune system such as phagocytes, and can induce both CD4 and CD8 antigen-specific immune response. Thus, it is a promising candidate as a cancer-vaccine vector.
Whether this incident has any major implications for Imfinzi remains to be seen. However, this is an illustration of the perils that pharmaceutical outfits run even after FDA approval. It is usual that a pharmaceutical company would look for other indications after a drug had been initially approved in a fairly narrow slot. This is particularly the case with cancer drugs, which typically – these days, anyhow – get approval with very narrow indications such as relapsed or refractory cancers with a specific genetic footprint. But the hunt for broader indications has its risks.
(As we’ve discussed in previous installments, the only way a prospective cancer drug could gain approval for a broad indication such as solid tumors would be to go up against an established drug in a head-to-head trial and be shown to be superior. That would be hugely risky for the prospective candidate, and the FDA would be highly unlikely to approve a trial where half the patients got an untried drug when an established drug is available.)
More about oncolytic viruses
The term “oncolytic viruses” is, all by itself, an expression of optimism. The “onco” part refers to tumors, and the “lytic” to lysis, or dissolution. An oncolytic virus is thus, by this optimistic definition, a virus that dissolves tumors. Are there any such?
The answer is an unequivocal “Yes!” The first FDA-approved oncolytic virus was Imlygic (talimogene laherparepvec), from Amgen, which got its seal of approval on October 27, 2015, with, as is usually the case, a fairly narrow indication: “Indicated for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery.”
It has been known for some time that some viruses preferentially attack cancer cells rather than normal tissue, but this by itself does not make even those viruses into ready-for-action cancer fighters. Even those viruses are likely also to infect normal tissue. As a rule, viruses need to be genetically modified such that they attack tumors while leaving the human host unharmed. Imlygic is such a virus. It is a genetically modified herpes simplex virus type 1, designed to replicate within tumors and produce the immunostimulatory protein granulocyte-macrophage colony-stimulating factor (GM-CSF). It is injected directly into the melanoma lesions causing the cancer cells to rupture and dissolve. This in turn releases tumor-derived antigens, which, along with GM-CSF, promotes an antitumor immune response. In other words, what the herpes simplex virus does, after it has been tinkered with, is direct the body’s own immune system in such a way that it targets and attacks cancer cells.
Having gained its first approval for Imlygic, Amgen is not stopping there. Currently there are 35 clinical trials with Imlygic, underway or in the recruiting phase. Many of these are in combination with other drugs that have demonstrated some efficacy in treating cancer. The cancers being targeted in these trials include pancreatic cancer, non-melanoma skin cancer, some cancers in children, breast cancer recurrence and triple-negative breast cancer, some bladder cancers, rectal and colorectal cancers with liver metastases, and squamous cell carcinomas.
Imlygic is based on the herpes simplex virus, but several other viruses are being investigated for their oncolytic properties. Canadian researchers have found that the Maraba virus, part of the rhabdovirus family, can replicate inside triple-negative breast cancer tumors in mouse models. The virus, when used along with a checkpoint inhibitor, eliminated the tumors in more than 60% of the mice. By itself, the checkpoint inhibitor was entirely ineffective. The Maraba virus is considered a potentially powerful vector for anti-cancer agents.
Researchers in the UK working with viruses in the reovirus family found that they were able to cross the blood-brain barrier. This discovery was made in a trial in nine patients who were scheduled to have surgery for hard-to-reach brain tumors. The patients were given the reovirus, which was then found to have replicated in the brain tumors and triggered a influx of T-cells to attack the tumors. The UK researchers are investigating a treatment regimen that would employ the reovirus in combination with other agents after surgery, to prevent recurrence of these difficult cancers.
In a similar experiment, researchers at Washington University / St Louis have used the Zika virus to target glioblastoma stem cells. The Zika virus exhibits a preference for developing brain cells, but not mature brain cells. This is why getting bitten by a mosquito that carries the Zika virus doesn’t do too much damage to adults, but does enormous damage to the developing brains of fetuses. In mouse models of glioblastoma, the Zika virus, either alone or in combination with a chemotherapy drug, significantly slowed tumor growth and extended the lives of the little creatures, suggesting promise in treating glioblastoma in humans by this means.
An advantage of oncolytic viruses is that they are potentially inexpensive. The viruses themselves may need to be genetically modified, but that’s a far cry from cancer therapies that rely on modifying the T-cells from each patient to target that specific patient’s cancer. That doesn’t mean that when oncolytic virus therapies come on the market they will be cheap, since the research and development costs will certainly be high.
Shedding some light on the so-called “obesity paradox” and BMI
For a start, the term “obesity paradox” is a misnomer, coined by Time magazine back in 2013 when a thorough meta-analysis examining the link between body mass index (BMI) and mortality was published in the Journal of the American Medical Association. (Flegal KM, JAMA 2013;309(1):71-82) The paper analyzed 97 studies and found that persons in the overweight category (BMI greater than 25.0) lived slightly longer that those in the normal category. Time and other publications ignored the fact that while the overweight individuals had the best life-expectancy figures, those in the obese range (BMI greater than 30.0), along with those in the underweight range (BMI lower than 18.5), had markedly lower life expectancies. So it’s not an “obesity paradox,” but an “overweight” paradox, which makes for a much less catchy headline.
That finding has never gone over very well with the health-care community, which generally continues to employ BMI values as a guide to individual patient management. A group of researchers in Europe just published – last Friday, March 16, as I’m writing this – an analysis of nearly 300,000 participants in the UK biobank in which they found that the lowest incidence of cardiovascular disease events was in persons with BMIs around 22 or 23. Lower and higher BMIs were associated with higher CVD events, although, as noted above, those differences were small. (Iliodromiti S., EurHeartJ /ehy057) However, those observations supposedly disposed of the “obesity paradox.” To quote their conclusion, “Any public misconception of a potential ‘protective’ effect of fat on CVD risk should be challenged.”
The outcome measure in the European study was not overall life expectancy, as in the JAMA study, but cardiovascular events – but let’s not split hairs. Speaking more broadly, both studies found that there was a J-curve, in which a much higher incidence of the negative findings, whether death or cardiovascular events, were at the two end-slopes, which went up quite steeply from the gentler curve at the bottom. In other words, the really high-risk groups were those with BMI values well below the 18.5 cut-point for underweight and well above the 30.0 cut-point for obese. There was not much difference in cardiovascular events between the subjects clustered around the 25.0 cut-point between normal and overweight BMI values.
However, a basic question remains: should BMI, which takes into account only two body measurements, be employed in making life choices about any individual? As surely you know, BMI is calculated on the basis of height and weight alone; an individual’s height is used as a surrogate for volume. But this does not take into account what that volume consists of. Our total weight is the sum of many subcategories – bone, muscle, fluids, waste, and, of course, fat. The proportions of those vary immensely among the members of the human species. Thus, individuals with identical BMIs can have widely differing ratios of fat to the other components of our bodies.
A study published in the International Journal of Obesity (Tomiyama AJ, Int J Obes (Lond) 2016;40:883-886) a couple of years ago should have scuttled the BMI as a meaningful indication of an individual’s health status. Note, I’m perfectly willing to accept its usefulness on a population-wide basis; e.g., if the population of one state has an average BMI of 33 and that of another state an average BMI of 23, the people in that first state are likely to be at significantly higher risk. But what that study made clear is that when it comes down to individuals, BMI is worthless.
The researchers used NHANES (National Health and Nutrition Examination Survey) data to study the link between BMI and other health markers including blood pressure, blood glucose, insulin resistance, C-reactive protein, and cholesterol and lipid levels. They found that about half of individuals in the BMI-overweight category were metabolically healthy, as well as 29% of people in the BMI-obese category. Moreover, more than 30% of the supposedly normal-weight persons were unhealthy from a cardiometabolic perspective. All in all, about 75 million people in the US are misclassified as being either metabolically healthy or unhealthy based on their BMI scores.
To quote one of the authors of the International Journal of Obesity Study, Jeffrey Hunger, “That should be the final nail in the coffin for BMI.”
Perhaps as a way to make the whole affair a bit more concrete, an NPR station did some digging around in the NFL’s data base and found that not one single player on the Denver Broncos had a BMI in the normal range. All were either overweight or, Heaven forbid! – obese.
Being classified as overweight or obese according to the deeply flawed BMI criteria can have economic implications for a great many people. The Equal Employment Opportunity Commission recently passed a rule that permits employers to increase what they charge employees for health insurance by as much as 30% based on their failure to “meet health criteria,” which can include BMI.
And BMI doesn’t appear to be going away. A JAMA letter just announced that, according to NHANES data, 39.6% of American adults are obese, based on the BMI criterion. It’s as though BMI is baked into the definition of “obese.”
A couple of bits of not-so-good news: number one, measles cases soar in Europe
The first of these probably does not directly affect most of the Gumshoe faithful, but it is certainly a cautionary tale. To wit, according to the World Health Organization, the number of measles cases in Europe quadrupled in 2017, totaling 21,315, from 5,273 cases recorded in 2016. At least 35 children died as a result of this occasionally deadly disease. Most of these were in Romania, which accounted for 5,562 of the measles cases. A factor contributing to the spread of the measles epidemic in Romania is that there is a large population of Roma people in that country, and they mostly do not vaccinate their children, nor seek prompt medical assistance when their children are ill.
The second highest total number of measles cases was in Italy, with 5,006 cases and three deaths. The European Center for Prevention and Disease Control noted that 95% of the measles cases were in individuals who were unvaccinated or who had not completed the recommended schedule of doses.
It was noted that vaccination rate in Europe are lower than in the US. There are a number of long-standing anti-vaccine movements in various European countries, and some conservative Protestant denominations believe that vaccination subverts God’s will.
In response, laws have been passed in France, Germany, and Italy requiring parents to have their children vaccinated, or at a minimum consult a physician about vaccination. Italy and Germany have imposed fines ranging from $600 to $3,000 for failure to comply.
In the US, everyone born before 1957 is assumed to have had the measles as a child and is therefore immune, and the disease had been all but eliminated by about the year 2000, but travelers from other parts have brought the disease with them, and as a result there have been sporadic outbreaks of measles. The Disneyland outbreak in 2015, which caused 150 cases, was thought to have been caused by infected travelers. In response to the Disneyland outbreak, the state of California has outlawed exemptions from vaccination of schoolchildren based on “personal belief.”
This once again reinforces Doc Gumshoe’s preaching about herd immunity. Yes, it is true that vaccination is not a 100% guarantee that you will not get the disease against which you have been vaccinated. But if you and everyone with whom you have contact has been vaccinated, the odds that you will get that disease are very, very low.
Not-so-good news item: number two, decline in hip fractures levels off
From 2002 to 2015, a steady decline in the number of hip fractures sustained by women on Medicare over the age of 65 was recorded, from 931 per 100,000 in 2002 to 730 per 100,000 in 2015. But over the past three years that decline has stopped. If the reduction in the number of events had continued, it’s estimated that about 11,500 fewer women would have broken their hips.
Why has this happened? The decline in hip fractures was attributed primarily to the introduction in 1995 of the drug Fosamax (alendronate), which, admittedly, was initially overprescribed to every patient in the very first stages of bone loss, termed osteopenia. But a few years later there began to be reports of two adverse events related to bisphosphonates – fractures of the femur, and osteonecrosis of the jaw. The first of these occurs very infrequently, and the second is extremely rare.
The current views of experts on avoiding fractures associated with bone loss does not call for treatment with bisphosphonates when the first signs of osteopenia become evident, unless other factors suggest that the patient is at a significantly increased risk of breaking a major bone. Patients should be treated if bone density tests points to frank osteoporosis of the hip, spine, or forearm. And, although patients who have already sustained a bone fracture should definitely be treated with a bisphosphonate, the great majority do not receive treatment. This form of treatment has been definitively demonstrated to reduce the risk of a second bone fracture, but due to the fears related to the adverse events, very few patients agree to treatment, which declined from about 15% of patients in 2004 to just 3% in 2013.
The data points to a clear advantage for bisphosphonate treatment over non-treatment in appropriate patients. The risk of fractures is far greater than the risk from the adverse events, but that doesn’t seem to induce patients to agree to treatment. The narrative if familiar. A new drug appears, and hopes go up that the condition it treats will diminish as a threat. (My sagacious spouse recalls a friend telling her that with the introduction of Fosamax, women would no longer need to worry about osteoporosis. She was dubious.) Then, some scary side effects appear, and the current shifts. Yesterday’s miracle drug becomes today’s health threat.
What Fosamax and the other bisphosphonates do is inhibit part of the process of bone remodeling, that being the term of art for replacing old bone tissue with new, stronger bone tissue. But with age the two parts of the process can become unbalanced – osteoclasts, which remove old bone tissue, keep up their activity, while osteoblasts, which create new bone, slow down a good bit. Therefore many people, especially post-menopausal women, lose bone mass, thus making them susceptible to fractures, which can lead to swift decline in all of life’s activities. Bisphosphonates slow down the part of this remodeling process that removes the old bone. They do not affect the bone-building activity of the osteoblasts, but their net effect is to prevent weakening of bones – old bone is better than no bone. These drugs are valuable, despite their side effects, in a range of conditions, and – as with all forms of medical treatment – we need to consider carefully the balance between benefits and risks.
And, by the way, bisphosphonates are by no means the only drugs that treat osteoporosis. Doc Gumshoe will follow up soon with a whole tract on the subject.
Some more cheerful bits of news
This one popped into my in-box with the intriguing title “Baking Soda May Reduce Premature Death Risk.” If the Gumshoe faithful assume that my initial reaction was marked skepticism, that is correct. It seemed to me akin to the frequent warnings that circulate in cyberspace, such as “Did you know that you have been brushing your teeth all wrong, and IT COULD KILL YOU!!!” But the provenance of the baking soda piece does appear to be respectable, so here goes.
The data on which the baking soda / life expectancy association was based came from the Dynamics of Health, Aging, and Body Composition Study (HealthABC) funded by the National Institute of Aging (NIA) and the National Institute of Diabetic and Digestive Kidney Diseases (NIDDK). It followed a cohort of 2,287 generally healthy black and white older adults starting in 1997. The mean age of participants at the start of the study was 76 years. The general objective was to investigate the effect that changes in body composition have on functional decline in older persons. Among many other data points, the blood gas measurements of participants were grouped into three categories based on sodium bicarbonate levels (baking soda is sodium bicarbonate, in case you forgot). About 11% were found to have low bicarbonate levels and 10% had high bicarbonate levels.
Survival data on this cohort were collected through February 2014, for approximately 17 years. The finding that led to the skepticism-provoking headline was that in the 11% group that had the lowest bicarbonate levels, mortality was 24% higher than in the group that had bicarbonate levels closer to the mean for the cohort. The 10% that had the highest bicarbonate levels had a very slightly higher mortality – 3% – than those who were closer to the mean. (Raphael KL, Clin J Am Soc Nephrol 2016;11(2)308-316)
Sodium bicarbonate helps the body in balancing pH levels (acid-base levels). The study author, Dr Kalani Raphael pointed out that adding the pH measurement did not change the overall results. The study notes that we don’t have to resort to putting spoonfuls of baking soda in our drinking water. Eating more fruits and vegetables is the way to balance pH. Apples, raisins, spinach, bananas, carrots, broccoli, lemons, and even coffee will boost our bicarbonate levels … and, we hope, keep us going longer.
But, wait just a minute – is it the increased bicarbonate blood levels, or it is eating all those fruits and vegetables that add to our life spans? Yes, it might be that the bicarbonate is the driver of increased longevity, but it might also be that higher bicarbonate levels are just a side effect of the healthy diet, which is the real underlying cause of the added years of life. As usual, there’s more work to be done.
Another optimistic note: a possible way forward in Alzheimer’s?
Doc Gumshoe is fully aware that there are many differences between human brains and mouse brains. Mice, for example, are better at finding their way through mazes than we are, and have figured out ways of getting around and through spaces that would stump most humans. We, on the other hand, have learned how to do really important things like play video games and exchange vital news with our BFFs on our devices while crossing the street in heavy traffic. But there are enough areas of similarity between the murine and human brain to make the former a fruitful subject of study when combating Alzheimer’s disease (AD).
Researcher at Lancaster University in the UK have found that a treatment for type 2 diabetes (T2DM) seems to reverse memory loss in mice. The treatment targets three growth factors that affect brain function – glucagon, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP). Growth-factor signaling is impaired in individuals with AD. When this form of triple therapy was administered to mice, it appeared to reverse memory loss, which was measured by means of a spatial water maze test. Mice with a laboratory-induced model of AD termed APP/PS1 had previously performed well on this maze test but then appeared to forget how to navigate it. But the drug improved their learning and memory formation, decreased the loss of nerve cells in the brain, reduced neuroinflammation (activated microglia and astrocytes) and oxidative stress in the cortex and hippocampus, and boosted the levels of synaptophysin, a growth factor that preserved the functioning of nerve cells. And it also reduced the amount of amyloid plaque, one of the two abnormal brain growths that have been named as causative agents in AD. (Tai J. Brain Res 2018;1678;64-74)
The specific drug that targets those three receptors has not so far been named in the published research. Thus far, liraglutide (Victoza, from Novo Nordisk), a widely-used drug for T2DM, has been investigated in small clinical trials in AD patients, with somewhat interesting results particularly with reference to a reduction in amyloid plaque. However, liraglutide treatment resulted in no difference in cognitive ability between trial subjects.
The study authors modestly conclude that triple receptor agonists are a promising lead for the design of future treatment strategies for Alzheimer’s disease.
What I take from this is that these investigators were not pinning their hopes on the particular drug that they used in this study as a potential AD miracle cure. The real value of the study was, in my opinion, to point the way to a better understanding of the physiologic mechanism that leads to AD. The two big hypothetical “causes” of AD, being beta amyloid plaque and neurofibrillary tangles, both play some part in causing the dementia that characterizes the disease. But attempts to pin most of the blame for AD dementia on either or both of them have failed. It’s likely that both are contributors to AD, but that there are also other factors involved, and the total elucidation of the cause will be that a jumble of processes going on in the brain that essentially gum up the works. These processes will likely have to be spotted and countered one at a time. The study on the diabetes triple therapy may have identified some of them, and pointed the way to addressing them.
A disturbing trend
It concerns treating stroke victims with tissue plasminogen activator (TPA). Until I read a piece in the Science Times, I assumed that TPA was the standard treatment for stroke victims if instituted in the first three or four hours. TPA acts rapidly to break up the blood clot in the brain that causes the stroke. The longer the delay before TPA is used, the more damage takes place in the brain – brain cells begin to die. This causes a number of seriously disabling conditions in mind and body, and patients treated promptly with TPA are mostly spared. It’s 22 years since TPA was introduced, and millions of stroke victims have derived huge benefit from that treatment. How could it not be generally accepted?
However, it turns out that I was wrong. There is a coterie of skeptics who maintain that TPA is dangerous, causing brain hemorrhaging, and that the studies supporting it are flawed. Their view is that it’s better to let the stroke run its course. These skeptics spread their views not through clinical studies in peer-reviewed journals, but through social media. In spite of the strong endorsement of TPA treatment by both the American Heart Association and the American Stroke Association, some emergency physicians do not even offer their patients the choice of TPA, and some present the risk of brain hemorrhages as comparable to the risk of severe disability following a stroke. The weight of the evidence refutes that view. Severe disability resulting from a stroke is much, much more common that brain hemorrhage. But when the risk is presented to stroke victims and/or their families, as many as half refuse treatment.
The TPA issue is similar to the shunning of bisphophonate treatment that I discussed earlier: the risk-benefit balance is distorted by people who place their thumbs heavily on the risk side of the balance, and therefore many individuals who could benefit from those options do not receive them.
The Science Times piece, by Gina Kolata, appeared on March 27th of this year in the NYTimes. The headline is “A Stroke Treatment Mired in Controversy.” [ed. note: the article was syndicated, and the headline is now different in some editions] I consider that headline to be far too even-handed. I would have said something like “A Highly Effective Stroke Treatment Besmirched by Fake News.”
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Before starting out on this installment, I wrote out a little list of the recent developments I wanted to cover. I got to about half. Is that because I run on too long about each item? Never mind; I’ll try to get to some of the others before too long. In the meantime, keep the comments, questions, and suggestions coming.
Best to all, Michael Jorrin (aka Doc Gumshoe)