Please indulge Doc Gumshoe while he presents his musings on what’s going on in general in the health-care arena, and in particular, which new drugs are getting the FDA blessing and why, as well as which ones are getting the short straw. My impressions and conclusions are in some cases only loosely based on specific data. Some of these are notions that have taken up residency in my noggin after a year (or several years) of looking over the happenings and developments in medicine and pharmacology. With no further ado, I will plunge in.
Are we doing better or worse than a few years ago, say 2010? For those of us who are somewhat well-educated and well-off, my answer is that we are unquestionably doing better. As I have pointed out repeatedly in my rants, the death rate from heart disease is significantly lower and keeps going lower, and the cancer death rate, although the improvement is not huge, is also dropping. The reason that the cancer death rate is not dropping as fast is that a certain percentage of the heart disease survivors die of cancer instead. Recent years have seen quite a number of cancers – cancers that were previously nearly impossible to treat – succumb to treatment. Or to put it in more positive terms, cancer patients who previously had few chances of survival now have treatment options that improve their odds considerably.
However, the improvement that many of us are experiencing has evaded a fairly large sector of the population. The less well-off and less educated are disproportionately walloped by opioid addiction and by a high suicide rate. The blame for this is spread around fairly widely – and indiscriminately, I might add – ranging from drug pushing by the pharmaceutical companies, to MDs who have been in essence bribed by the pharmaceutical companies to dispense those addictive opioids inappropriately, to a shortage of health-care providers in rural areas, to income inequality that leaves people without hope, and perhaps also to a general culture of pill-swallowing as a means of combating all evils.
The consequence of this inequality is that life expectancy in the United States has declined for the past three years. This is the first time in our history that life expectancy has taken a U-turn, and it should be a matter of the gravest concern, not just in the health-care profession, but to all of us, including our highest leaders.
This is despite the cheerful little statistic that smoking rates in the US are at an all-time low. Just 14% of the US population are smokers. The Surgeon General wags a finger, however – it seems that about half of our MDs do not take the trouble to advise their smoking patients to quit, despite the statistic that smoking is the top-ranked cause of preventable disease, death, and disability.
The unequal benefits of our health-care system are at least in part due to a shortage of medical professionals, especially in primary care. As older providers retire, there doesn’t seem to be an equal number of younger ones entering the field. It’s more than a bit surprising, since health-care providers are generally decently rewarded and well-respected. But medical practice at all levels has become increasingly stressful, as the demands of electronic medical records and the bureaucratic procedures required by patient’s medical insurance gobble up the provider’s time and attention, diverting it away from the patient. As a result, we hear increasingly of physician burn-out, which occurs in many cases in mid-career.
Having mentioned electronic medical records (EMRs), these certainly have their benefits, but they are also saddled with cumbersome baggage that unnecessarily consumes the time and attention of providers. The obvious benefit is that when a patient is ambulanced to the hospital with a TIA (a transient ischemic event, or “mini-stroke”), the hospital is immediately able to communicate with that patient’s primary physician, obtain the patient’s medical records, and keep the patient’s primary provider current on the patient’s status. In other words, all the patient’s medical records are immediately available to whoever needs them.
But the EMRs have an inevitable downside, which is that the provider is required to answer a great number of questions that often have nothing whatever to do with the patient’s current medical needs. For that reason, in some practices the physician works with a “scribe,” so that the physician can pay attention to the patient and not to the computer screen. The algorithms that drive the EMR appear to be focused on getting all the information into the record and not so much on meeting the patient’s needs in the moment.
What’s happening over at the FDA?
How has the FDA been behaving in the past year or so? The general sense is that they have become somewhat friendlier to the pharmaceutical industry. According to the FDA’s count, they gave the imprimatur to 48 new molecular entities in 2019, which was down from the 59 approved in 2018, but a bit more than the 46 approved in 2017 and way more than the 22 that got the nod in 2016. Part of what accounted for the growth in the number of new drugs approved in the past few years is that an increasing number have made use of special development and approval programs, which were instituted to speed the approval process for drugs which were considered urgently needed – the Orphan Drug Act, Fast Tracking, Priority Review, and Breakthrough Therapies. In the years just before the turn of the millennium (i.e., the 1990’s), about 48% of applicants for FDA approval qualified for one of those programs. By 2018, more than 80% of new drug applications qualified.
Those programs have made it quite a bit easier to gain FDA approval. The clinical trials are smaller – about 100 versus about 300 participants. Also they are more often not randomized – about 30% versus 80% for drugs not qualifying for those programs. The drugs that were qualified to be in one of those programs got the FDA blessing in about half the time – 4 years compared to 8 years for most other drugs. Half were approved based on Phase I or Phase II clinical trials, and nearly half of those on Phase I trials alone.
Also, and potentially of considerable importance, is that an increasing amount of the FDA’s budget came from the pharmaceutical industry’s users fees, which amounted to about $4 billion in the past few years, compared with about $300 million in the 1990s. It was estimated that in 2018, users’ fees from the drug industry paid about 80% of the FDA reviewers’ salaries.
Does that mean that the FDA is “friendly” to the pharmaceutical sector? Or that, as some would claim, that the FDA is under the thumb of Big Pharma? On the whole, I would say “yes” to the first question and “no” to the second. Permit me to tell you a story that may illuminate those questions.
Back in October 2017, I posted a Doc Gumshoe piece, entitled “Pain Management vs. Opioid Abuse: Glimmers of Light,” which included an optimistic prediction about a drug, then in development, from Nektar Therapeutics, called oxycodegol, but then just labeled NKTR-181. Based on the information then available, I thought that the drug was likely to fill a much needed niche in pain management.
My optimism was based on several of the drug’s basic characteristics. First, that is was absorbed very slowly and took about eight hours to cross the blood-brain barrier, which would make it extremely unlikely that seekers of an opioid high would find it the least bit attractive.
Also, at higher than the recommended dosage, the Nektar drug produced highly disagreeable side effects – nausea, vomiting, constipation, headache, fatigue. At high doses, these nasty side effects emerged before any signs of narcotic highs.
Therefore, the Nektar drug looked like an excellent candidate for chronic pain relief, which is what the company was targeting. Nektar therefore applied to the FDA for a fast track indication for their drug for the treatment of chronic pain in cancer patients, based on a single clinical trial. It was a shock and surprise when, on January 15, 2020, the FDA Advisory Committee rejected the application by a vote of 27 to 0.
This was based not so much on the data supplied to the Advisory Committee as on the fact that Nektar wanted approval based on just one clinical trial. Nonetheless, Nektar has announced that it would do no further development work on oxycodegol, claiming that spending the additional $125 million that it would take to do a further clinical trial and submit it to the FDA would be wasted.
Another proposed pain medication, Aximris XR from Intellipharmaceutics also got a big thumbs down from the FDA Advisory Committee, which voted 24 to 2 to reject the application Aximris XR is supposedly an abuse-deterrent controlled-release oral formulation of oxycodone hydrochloride developed for long-term 24-hour pain release.
Overall, despite the general sense that the FDA is somewhat more friendly to the pharmaceutical industry than formerly, they are evidently very cautious when it comes to potentially addictive pain-killing drugs. As advisory committee member Steve Meisel, PharmD, of Fairview Health Services in Minneapolis, said at the oxycodegol review, “We can’t approve a drug in the midst of a public health crisis on the basis of speculation.”
It’s not the FDA’s official position by any means, but several individuals within the agency have noted with concern that very little is being done in the pharmaceutical sector to develop new antimicrobials, in spite of the increasing frequency of both viral and bacterial pathogens that have developed resistance to most – or in some cases, all – available drugs. Doc Gumshoe devoted an entire encyclical to that subject, “Update on Antibiotic Resistance,” which posted on December 19th.
Big Pharma’s attitude seems to be that it’s just not worth the money needed to research and develop a new drug and then bring it to market, because the path to recovering their investment – let alone make a decent return on the investment – is steep and full of obstacles. Permit me to hammer home the reason for that position:
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- One, the new drug that works when other, older drugs don’t work, is apt to be reserved for those relatively few cases when the older drugs have been tried and failed. It’s held in reserve, and not commonly used. That makes excellent sense from the clinical perspective, but results in a much diminished market for the drug.
- Two, while the new drug is being used sparingly in the developed world, there’s a high probability that it will be copied and that generic versions, sometimes of very poor quality, will be used much more widely, especially in the less developed world.
- Three, that wider use will invariably lead to the emergence of resistant pathogens, so that the billions spent in developing this new drug will eventually go down the drain.
So, what did the FDA actually approve?
At least a couple of new antibiotics got the FDA blessing. One, Xenleta (from Nabriva Therapeutics, in Dublin) , is the first drug in a new class of agents called pleuromutilins. It binds to a different protein synthesis binding site than other drugs, and effectively treats resistant variants of several pathogens that cause pneumonia. To prevent the indiscriminate use of this drug, the terms of the FDA approval specify that those pathogens should be identified in the patient as a condition of using the drug. It supposedly works in about five days with mostly moderate adverse effects. Xenleta is the first antibiotic with a completely new mechanism of action to receive FDA approval in about 20 years.
Another antibiotic approved by the FDA in 2019 is pretomanid (formerly PA-824, from the nonprofit Global Alliance for TB Drug Development. It is approved for use in combination with bedaquiline and linezolid for the treatment of extensively drug resistant (XDR) of multidrug resistant (MDR) tuberculosis.
These drugs two are exceptions. The World Health Organization just issued a statement that of the 52 antibiotics now somewhere in the clinical pipeline, the great majority have little or no benefit compared with the standard antibiotics, and only two are active against known resistant bacteria.
In contrast with the lack of antibiotic approvals, cancer drugs led the pack with 11 winners. Most of these are narrowly targeted drugs. An exception is Eli Lilly’s Vitravki (larotrecinib), which targets tumors not based on their location, but on a specific genetic receptor, called neurotrophic receptor tyrosine kinase (NTRK). Vitravki is approved for the treatment of solid cancers without a known resistance mutation.
Here’s what FDA Commissioner Scott Gottlieb said about the Vitravki approval:
“Today’s approval marks another step in an important shift toward treating cancers based on their tumor genetics rather than their site of origin in the body. This new site-agnostic oncology therapy isn’t specific to a cancer arising in a particular body organ, such as breast or colon cancer. Its approval reflects advances in the use of biomarkers to guide drug development and the more targeted delivery of medicine.”
Despite Gottlieb’s enthusiasm about “agnostic” – i.e. not site-specific – cancer drugs, the other drugs were decidedly site-specific. In fact, in recent years cancer drugs have become increasingly site-specific. For example, Johnson & Johnson’s sole winner, Balversa, is the first treatment targeted exclusively for bladder cancer, and Bristol-Myers’ Inrebic was approved for front-line and follow-up treatment of myelofibrosis, a rare cancer that attacks bone-marrow, preventing it from generating healthy blood cells.
The pharma outfit that got the most candidates over the goal line was Novartis, with six drugs hitting the gold, including Piqray, its breast cancer drug. Also Zolgensma , a gene therapy agent for spinal muscular atrophy, Mayzent for multiple sclerosis, Adakveo for sickle cell anemia, Beovu for wet age-related macular degeneration, and Egaten for treating persons with liver flukes.
The thin end of the wedge
I strongly suspect that many or most of these narrowly targeted drugs are not so intrinsically site-specific. Balversa is likely to be demonstrated to be an effective treatment for cancers at other sites – eventually! But J & J followed the crafty path of picking a treatment area where there was essentially no competition. This is now a common practice when pharmaceutical outfits are trying to bring a candidate all the way from an investigational agent to a money-making prescription drug. There are numerous reasons for this, the first being that the FDA looks more benignly at candidates that treat diseases and conditions for which there are few options or none. If the new would-be drug demonstrates even a little benefit, well, little is better than none, isn’t it?
This is in contrast with a drug for common conditions like elevated cholesterol or diabetes, where there are many, many options already in the market that do a pretty good job. To score a hit in elevated cholesterol, for example, the PCSK9 candidates couldn’t just go head to head with statins. Eventually they had to demonstrate success in populations at somewhat high risk for cardiac events who had not been able to lower their LDL-C levels to the 70 mg/dL target using conventional drugs – i.e., statins – or who are intolerant to statins.
Another group would be individuals with very high cholesterol levels related to genetic anomalies – a disorder called heterozygous familial hypercholesterolemia, which manifests in high levels of LDL-C unrelated to lifestyle. Picking a group like that for a clinical trial has obvious difficulties, but also substantial advantages. Since the condition is uncommon, the clinical trial can be fairly small, and therefore fairly inexpensive. Also, it is easier to recruit subjects for a clinical trial when the subjects know that there are very few options for their disease. And, finally, the FDA goes along with it.
I mentioned before that about 80% of the drugs approved recently have made use of those special development and approval programs – the Orphan Drug Act, Fast Tracking, Priority Review, and Breakthrough Therapies. Those programs mean that the pharmaceutical company saves both time and money. And, at the conclusion of the approval process, the drugs that have gotten their diplomas through those programs are every bit as FDA certified as the ones who got there the long way, through several large clinical trials, several years of uncertainty (and no revenue), and at a huge cost.
Then, after the candidate gets the FDA designation for a specific relatively rare disease the pharmaceutical company can go after other, more lucrative patient populations. If it works in muscle-invasive bladder cancer, might it not also work in bladder cancer in general? And if it works in bladder cancer, might it not also work in other cancers?
Because once a drug is FDA-approved, licensed physicians can and do prescribe it for other conditions than the ones for which the drug is specifically approved. In a sense, these physicians are doing part of the work of the pharmaceutical company, which would otherwise be paying for their own research. And clinical trials to extend a drug’s footprint – i.e., the diseases and conditions for which it is approved – tend to be a good deal smaller and cheaper than trials to demonstrate safety and efficacy in a common condition like hypertension.
So getting a drug approved in a relatively rare treatment area is a way into the big time. The thin end of the wedge, we might say.
The FDA turns a favorable eye on CRISPR-related therapies
The first approved CRISPR-CAR-t therapy was Kymriah (tisagenlecleucel ), from Novartis, which received its seal of approval on August 30, 2017. Kymriah’s first approval was for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse. Then, on May 1, 2018, Kymriah won a second approval as an intravenous infusion for its second indication – the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL), high grade B-cell lymphoma and DLBCL arising from follicular lymphoma.
That paragraph quotes precisely from the FDA’s approval statement. I stuck it in there so that you faithful and patient readers could see just how precise and narrow the terms of approval can be. Kymriah will almost certainly go on to demonstrate efficacy in other forms of lymphoma, although, in each case, the T-cells will have to be harvested from the patient and genetically modified to attack the particular malignancy.
Since that first official blessing of the research that was going on in the highly promising field of genetic manipulation, it looks to me as though that early trickle is going to turn into a torrent of new therapeutic options. A number of new agents in that area have been approved or are considerably far along on the pathway to approval – more than I have time or space for in this piece. So I will devote a forthcoming installment in my opus to the actual new CRISPR-related agents.
Here’s what the FDA Commissioner, Scott Gottlieb at the time, said in connection with Kymriah’s elevation (as you see, he likes to take credit whenever possible):
“We’re entering a new frontier in medical innovation with the ability to reprogram a patient’s own cells to attack a deadly cancer. New technologies such as gene and cell therapies hold out the potential to transform medicine and create an inflection point in our ability to treat and even cure many intractable illnesses. At the FDA, we’re committed to helping expedite the development and review of groundbreaking treatments that have the potential to be life-saving.”
I would add my own somewhat speculative comment on the question of bringing these new agents to market. Namely, my guess is that although the basic research involved in gene editing is exceedingly complex, the overall process of getting a CRISPR therapy to market is almost certain to be a good deal less costly than, say, getting a new pain medication or antihypertensive approved. For the latter, the candidate agent would necessarily have to be tested in really big clinical trials, with lots of subjects. I can’t at this moment give you specifics about the process CRISPR candidates have to go through, but I’m pretty sure the trials are much, much smaller. Instead of having to demonstrate efficacy in a fairly large population, it’s enough to demonstrate the effectiveness of the process through which a patient’s T cells are modified so as to attack the specific cancer cells in that patient. And therefore, a whole lot less expensive, since few patients are needed.
Again, the CRISPR candidates will likely get approval for extremely narrow indications, and then build on those, one at a time, until perhaps they attain the status of cancer drugs like Merck’s Keytruda, which achieved blockbuster status –$3 billion sales in the third quarter of 2019 – one Lego block at a time.
A modest disclaimer
Speaking of blockbuster status, I am keenly aware that perhaps most of you in the Gumshoe orbit are greatly interested in the investment side of the pharmaceutical industry. Doc Gumshoe is not likely to have any specific useful insights or clues as to what all this means to your stock portfolios. My observations of the financial fortunes of companies engaged in the development of medicines have led me to the general conclusion that over the long run, the big and rich pharmas will continue to do very well. As for the smaller outfits, there are way too many factors on which their fortunes depend that we can’t know about or predict. Yes, if the Phase 2 results of their clinical trial come out as positively as they hoped, it’s a good thing. Their stock might zoom up, or they might get bought out by one of the big players. But then a Phase 3 trial might flop. Interpreting the financial effects of a mid-stage clinical trial result is highly chancy, and Doc Gumshoe is not going to venture into those waters.
A note about the new coronavirus from Wuhan, China
Just about 10 days ago, on January 19th, the first travel-related case of a coronavirus variant was detected in the US, in a man arriving at the Seattle-Tacoma International Airport in a flight from Asia. This virus emerged in Wuhan, China, and has sickened hundreds of people there, and, as of today (January 29th) has resulted in the deaths of about 300 individuals in China, and as many as 4,515 are infected, according to Chinese authorities. As of this moment, travelers on all flights to the US connecting with that area will be screened for coronavirus.
This new coronavirus, designated 2019-nCoV, is sometimes referred to as the Wuhan virus, after the large city in central China where it emerged. It causes a form of pneumonia, similar to SARS and MERS. As with those diseases, the Wuhan virus is thought originally to have been transmitted to humans from animals. SARS, as some of us may remember, came from palm civets and other small mammals, and MERS from camels. The original source of infection in both SARS and MERS is thought to be bats.
However – again as with SARS and MERS – this coronavirus has now been shown to be transmissible between humans, which greatly increases the odds that it will become a pandemic. And, another somewhat dire factor is that infected persons can be contagious before symptoms appear, which means that one can acquire the virus from a seemingly healthy person.
Up to now, the fatalities connected with the Wuhan virus have been in elderly people with other health conditions, exactly as one would expect. This of course does not mean that healthy younger people might not also suffer – it’s usually the sicker, older folks that get hit the hardest.
Incidentally, Gilead is said to be considering trying remdesivir for this new coronavirus. Remdesivir was originally developed as a vaccine against the Ebola virus, but was dropped because a couple of other vaccines were somewhat more effective. It has shown efficacy against other coronaviruses, such as in MERS and SARS, and could be effective against the Wuhan virus. Numerous other groups, including drug companies and other institutions, have been working to develop vaccines since the virus was first identified.
At last report, China has instituted a travel ban on all people living in Wuhan and the surrounding area. About 22 million people are thought to be affected by the travel ban. Chinese medical facilities are struggling to keep up with the growing epidemic, and many Chinese have been unable to get access to care. The Chinese government is trying to look like they’re really “on top of it.” Whether or not they really are is open to question.
And also open to question is whether this Wuhan virus will become a global pandemic. My guess is that it will not.
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Yes, it’s true that Doc Gumshoe is an optimist. Recent legitimate research has, by the way, confirmed my conviction that optimists, by not overly triggering their fight-or-flight response, have lower levels of stress and inflammation and therefore better health. But it’s possible that that conviction of mine at least in part arises out of my fundamentally optimistic outlook. In any case, the Wuhan virus appears to be a good deal less deadly than either SARS or MERS, which killed about one in ten infected persons. The death toll from Wuhan so far is not nearly so ominous.
In any case, I put my thoughts and speculations before you, inviting comments of all flavors. Be well, keep washing your hands, and thank you! Michael Jorrin (aka Doc Gumshoe)
Ed. Note: Michael Jorrin is not a doctor, though I dubbed him “Doc Gumshoe” many years ago. He is a longtime medical writer who shares his thoughts with our readers a couple times a month. His articles generally do not focus on investment ideas, but he has agreed to our trading restrictions. You can see all of his past commentaries here.