In a prior post, I told the story of how a genetic mutation provided insight that can help everyone with Parkinson's. The story of nilotinib is an exciting development leveraging that same model. As with isradipine, inosine, and other studies, this is a case where a fundamental understanding of biology informed the development of a drug we hope can make a difference.
Back in 1998, a group of Japanese researchers first connected the gene for a protein they named parkin with juvenile-onset Parkinson's disease. Parkin is one of the most important genes for Parkinson's, representing the most important recessive genetic cause of Parkinson's. Recessive genetic disorders (i.e., both parents must be carriers) are interesting to scientists because they are situations where people get a disease because a cellular process doesn't happen. Since DNA codes for proteins, and humans have two copies of each string of DNA -- one from each parent -- only when both copies of the code for a protein are damaged does the DNA not work at all. When that protein is important for a biological process to work, if the body can't synthesize it, that process won't happen.
Patients with parkin-related Parkinson's provide us with unique insight into the disease. With alpha synuclein, there are lots of ways it could be problematic. With parkin, we know we can look just at the cellular processes where the protein is necessary.
Parkin is a protein that attaches to things in cells to trigger the process of garbage collection -- cells contain tiny structures, lysosomes and proteosomes, that are involved in breaking up things in the cell that are not needed. Both lysosomes and proteosomes have been linked to Parkinson's disease. A scientist I've supported, Ted Fon, is studying parkin. His team has shown that parkin is linked to mitochondria -- the power plants in cells. Recent research has suggested that alpha synuclein converges with parkin at the mitochondria.
Since alpha synuclein is the most important protein in Parkinson's and parkin is second, this convergence probably points to something important.
As these connections are found, there is increasing enthusiasm for the idea that we could stop Parkinson's at the cellular level by addressing this "garbage collection" problem. A team led by a brilliant scientist at Johns Hopkins named Ted Dawson figured out that a cellular chemical called c-Abl, which is a tyrosine kinase (this simply means that it is involved in regulating protein activity) and is connected to a form of leukemia, was also active in the brain. Professor Dawson and his colleagues realized that c-Abl might be "turning off" parkin in the brain and that this was connected to Parkinson's. If we could block c-Abl from turning off parkin, then maybe we could reverse the build up of protein in cells that we think is important in Parkinson's disease at the cellular level.
Funded through NIH's Udall Centers program, the Dawson Lab started looking at whether c-Abl could be inhibited. Other labs also pursued this target, including animal tests of imatinib and nilotinib, two leukemia drugs -- the latter by a biologist at Georgetown, Charbel Moussa. The nilotinib results were promising and replicated at another lab. Moussa found that nilotinib reversed alpha synuclein accumulation in a mouse model of Parkinson's. The team at Dawson's lab also studied nilotinib, and recommended that a phase I trial be initiated.
Moussa, working with the director of the National Parkinson Foundation Center of Excellence at Georgetown University, a neurologist named Fernando Pagan, launched a clinical trial of nilotinib for Parkinson's. The results of that trial were presented at the Society for Neuroscience meeting in Chicago this month. The press focused on the symptomatic benefits, but most scientists will tell you that we can't tell the difference between the the drug effects and placebo effects in a trial like this. (The story of intravenous glutathione -- positive open label, negative randomized controlled trial -- is an example.) The best we can say about the phase I trial at Georgetown is that it could have contradicted the very promising animal studies, and it didn't: tests of patients' spinal fluid suggested that the benefit might be real. [Update: Ted Dawson told the Udall Center Directors meeting that he felt the dose in the Georgetown trial was too low, so it's not clear what we might see beyond placebo benefit. Update 2: Moussa says that the lower dose is effective because we don't need to inhibit c-Abl all the time, just for for a portion of the day, since these cellular processes can occur very quickly. The dose effective in cancer inhibits c-Abl around the clock.]
Further testing is clearly required. People often say this when they mean, "someone who is widely respected and/or gives out a lot of money has said something and I don't want to contradict them." In this case, however, I mean what I'm saying: we need more testing.
There is good reason to believe that it is fundamentally possible to slow or stop Parkinson's, and it is possible that if we did that, the brain would recover... somewhat. The discovery of c-Abl as a target was done through good science, with biology, hypothesis testing and replication and all the good stuff of serious science. It is possible but certainly not definite that c-Abl inhibition is the path to do this. However, remember that this is chemotherapy. Chemotherapy has a bad reputation for side-effects with good reason. There are other promising studies, too, and we need to trust the scientific process as much as we put our chips on one drug in the pipeline or another.
Saturday, October 24, 2015
Monday, October 19, 2015
The Maze of Health Finance
From the outside, the flow of funds in healthcare appears simple: Society puts money into healthcare and we get out health outcomes and revenue for the healthcare industry. This simplicity is misleading, however. It’s easy to think that you’ve figured out how to revolutionize healthcare, based on observing that one simple relationship: we put a huge amount of money into healthcare and get fairly little health out. In reality, healthcare is a lot more complex. It is a maze of interlocking financial relationships, contractual obligations, and misaligned incentives.
Let’s imagine a guy named Joe. Imagine Joe has a dog, Buddy, and Buddy gets sick. Joe takes Buddy to the vet, let’s call her Michelle. Michelle tells Joe he is in luck. It looks like Buddy has a condition that has been the subject of recent study and a newly developed surgery can help Buddy. Michelle’s partner, a surgeon, has been trained on the procedure. Buddy needs a CT scan to figure out whether he needs the surgery. If the CT scan is positive and Buddy needs the surgery, there’s a 10% chance that the surgery will kill Buddy. Even if the surgery is successful, in the best case, dogs only live about 18 months after the surgery (that’s about 10 dog-years). “Wow,” says Joe. “That sounds expensive.”
“It is,” says the Michelle. “The CT scan costs $1500. If necessary, the surgery costs $6,000 and that’s assuming there are no complications. You could be easily talking $10,000 or more.”
“Gee,” says Joe. “That’s a lot of money, and I could spend it all and have Buddy die anyway. Isn’t there a less expensive option?”
“Yes,” says Michelle. “First off, even if the CT scan is positive, you don’t have to do the surgery. There’s a chance that Buddy might just have a simple infection, and that’s what the CT scan is intended to rule out. We could, I guess, skip the CT scan and just give Buddy the antibiotics in the hopes that he just has the infection, but if he doesn’t, he’ll die.”
“Hmmm…” Joe ponders. “That’s more than I saved up all last year.”
Now imagine that Joe is your insurance company. Buddy is you.
It gets more complex. Maybe Michelle’s veterinary practice has invested in an imaging center. (The anti-kickback laws don’t apply to veterinarians.) Michelle’s failure to refer patients for CT scans could affect the imaging center’s ability to make payments on the vendor-financed digital scanner. Michelle’s partners were planning on the revenue from the imaging center to help pay their now-underwater mortgages. Daytime use of the CT scanner is reserved for human scans, but insurance companies have negotiated such low reimbursement for scans that the fully-booked daytime use, after expenses, doesn’t cover the payments on the scanner. The interest rate went up because, thanks to lower reimbursement, the credit rating of the center deteriorated. The imaging center was relying on nighttime veterinary use in order to achieve positive cash flow. Should Michelle have hard-sold the scan? The surgeon in the practice was relying on Michelle’s referrals. Without the scan, there’s no chance that Joe will even consider surgery. Michelle, as a partner in the practice, would have gotten a piece of the imaging revenue and a piece of the surgery revenue. Clearly, Michelle’s and Joe’s interests were not aligned.
Misaligned incentives don’t always result in bad care. Today I work with a wonderful group of physicians. Movement disorder neurologists are, in my experience, some of the most patient-focused physicians I’ve ever encountered. There is a real debate about the value of services that generate tremendous profits for the hospitals that employ many of these doctors, and even some of those physicians who might be under the most pressure to deliver these services seem to be unafraid to express doubt in their value.
Having said this, I also know that there are physicians who do go the other way. Drug, device, and test companies work hard to develop great products and sell them. Banks finance capital purchases at hospitals and clinics. Confirmation bias can be an insidious thing. If a salesman has extolled the virtues of a drug, scan, or procedure, and, convinced, a physician invests in it, how likely is he or she to tell that patient who might benefit from it to wait and see? Even more insidious, often the “salesman” is a respected colleague who developed it. This is the least of the problem, as this scenario assumes an honorable physician: I’ve personally spoken to doctors who unabashedly explain that they make more money from their patients who maintain a moderate level of illness.
As an investment banker, I once got a call from a physician. He was pitching to me the idea of my helping him raise money for a physician take-over of a failing hospital. We said, send us the hospital’s financials. The physician responded, “You don’t need to see the hospital’s financials. They are terrible. What you need to do is read Atul Gawande’s New Yorker article on McAllen, Texas. Physician-owned hospitals make money. It’s as simple as that.” We were led to understand that the physicians would want the hospital to be profitable. Whatever the debt service was going to be, the revenue would be greater. If, for example, a neurosurgery practice was required for the hospital to get in the black, they’d get one. Not only that, but they’d make sure it had patients. I turned away the business; I don’t know if the deal ever got done. There are rules that limit a physician’s ability to share in revenue from certain sources, but observation suggests that there are ways around this.
For the entrepreneur, these bad apples are actually the easiest to work with, as you can understand their motivations. It’s the good and well-meaning parts of the system that make reforming medicine so challenging. When I was a kid, my dentist looked in my mouth, probing my teeth and looking for trouble spots. It took him 15 minutes. My daughters’ dentist now has a technician x-ray their mouths. While my dentist used to have a staff of two hygienists, my daughters’ dentist has a staff of six. My daughters’ dentist spends less than five minutes with her. Is the new way better? Maybe it is: that’s the problem. I can’t help but noticing that this new way lets my daughters’ dentist charge a whole lot more for a whole lot less time spent per patient. The sad thing is, between staff costs, negotiated rates and interest payments on capital investment, I wouldn’t be surprised to hear that both dentists, adjusted for inflation, got about the same income. Yes, there are many new and revolutionary therapies that are changing people’s lives. However, the major consequence of medicine’s increasing complexity seems to be, in many cases, increased complexity.
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