This is the third in a series of Forum interviews with PRF science advisors.
William Schmidt is an independent consultant to drug companies and emerging biotech companies around the world, helping to design clinical trials of new analgesic compounds. He also heads clinical research at CrystalGenomics in Seoul, South Korea, and its US subsidiary, CG Pharmaceuticals in Emeryville, California, as well as at Arcion Therapeutics in Baltimore, Maryland, US. He has been deeply involved in pain drug development and clinical research throughout his career, having previously worked at biotech and pharmaceutical companies including Limerick BioPharma, Renovis, Adolor, and DuPont Merck. Schmidt took some time out of his busy schedule (which includes launching six clinical trials in pain this year) to talk to Megan Talkington about his current projects, the questions he thinks the pain field needs to focus on, and his hopes for the future of pain therapy. The following is an edited transcript of their conversation.
Is there something you’re working on right now that you’re really excited about?
The wonderful part of my job as a consultant is that I have a chance to see a lot of different technologies. I have an opportunity to choose to work on those things that I think are unique, and my day is more than filled with wonderful new opportunities and products that are truly innovative.
At CrystalGenomics in Korea, we’ve been working for the last six years on evaluating CG100649, a potential successor to Vioxx. Our ideal compound would be an anti-inflammatory analgesic that is more effective than many of the NSAIDs [non-steroidal anti-inflammatory drugs] that we have today, with greater cardiovascular and gastrointestinal safety built into a single molecule. CG100649 has a COX-1/COX-2 [cyclooxygenase-1 and -2] inhibitory profile, but it also binds to carbonic anhydrase isozymes (CA-I and CA-II) in a unique way for potentially enhanced cardiovascular and gastrointestinal safety. We have just finished a Phase 2b direct comparison to Celebrex for efficacy and safety, and plan to initiate Phase 3 clinical studies later this year.
What makes you so optimistic about this drug’s potential to avoid the safety concerns of NSAIDs?
It has a different molecular signature than other drugs on the market—this particular compound is significantly different from anything that I’ve seen before. Knowing the history behind Vioxx, I designed the clinical trials to include intensive cardiovascular monitoring from the very first trial we did, and I’ve not seen any increases in blood pressure or other cardiovascular events with CG100649 to date. That’s a different profile than what is seen with all of the other NSAIDs on the market today, all of which have been associated with hypertension in susceptible individuals.
CG100649 is a COX-2 and COX-1 inhibitor, but the difference is that it also has high-affinity binding to carbonic anhydrase. Carbonic anhydrase inhibitors are FDA-approved for decreasing blood pressure, but I’m not sure that this explains the favorable cardiovascular or gastrointestinal results with CG100649. Carbonic anhydrase exists in very high concentrations in red blood cells and other tissues throughout the body. The strong association between carbonic anhydrase isozymes and CG100649 creates a stealth technology for sequestering and transporting the compound through the body wherein the vast majority of the drug is protected against interactions with the rest of the cardiovascular system—with endothelial cells, for example, or with gastrointestinal tissues that are quite sensitive to COX-1 inhibitors.
The compound has a very unusual pharmacokinetic profile, with very little variation in plasma levels following once-daily dosing, because it’s using the carbonic anhydrase-bound erythrocyte stores to replace the plasma compartment as the drug is eliminated. So we don’t see peaks and valleys as we do with drugs you need to take two or three times a day. Even when patients skip a dose or two, they continue to have a strong therapeutic response. That profile is very different from all other NSAIDs that I’ve worked on, and I’ve been working on NSAIDs and COX-2 inhibitors for 30 years.
Are there any other ventures that you’re particularly enthusiastic about?
Another project I’m really excited about is a topical clonidine gel that I’m working on with Arcion Therapeutics in Baltimore. The clonidine gel is used to treat painful diabetic neuropathy, which is a huge and growing problem. Patients become severely disabled if they have burning pain in their feet—they often become wheelchair-bound. There are two FDA [US Food and Drug Administration]-approved drugs for treating painful diabetic neuropathy, Lyrica (pregabalin) and Cymbalta (duloxetine), both of which work at the level of the central nervous system. The topical clonidine gel I’m working on with Arcion is applied to the feet three times daily. It works peripherally at the source of the problem, on C fiber nociceptors that are firing spontaneously in aberrant patterns that cause severe, burning pain in the feet. Very little of the drug is absorbed into the circulation, so the adverse event profile is exceptionally low; we have seen no adverse effects on the central nervous system or the cardiovascular system. Yet we have efficacy that is as good as that of the other approved products, as shown in a recently completed Phase 2b trial. Our manuscript was just accepted for publication in an upcoming issue of the journal Pain.
Looking across the field, is there a therapeutic approach or drug target that’s at an earlier stage, but that you think is really promising?
I’m excited about a number of emerging targets. For a variety of reasons, I can’t say I favor a P2X7 approach over Cav2.2 or Nav1.7… I could give you 20 different molecular targets at this point that are promising, but it really is going to take several years to prove whether any one of them is going to become a commercial success.
The thing that makes my job such a joy is that I get a chance to work on so many different individual products. I don’t have to bet my career on any single product or mechanism of action. I am more excited and influenced by the diversity of work that’s going on, and optimizing and promoting those compounds and approaches that are showing promise.
Is there a question you think the pain field needs to address, but isn’t?
There are probably two main areas that I’m concerned about. One is persistent postoperative pain. We see a significant number of patients every year who have major surgeries—thoracotomies, limb amputations, mastectomies—who then go on to have chronic pain at three months, six months, one year, or longer after the initial surgery. For those three surgeries, the estimates are that anywhere from 25 to 75 percent of patients have persistent pain at three months, and a substantial number of these continue to have persistent pain at a year or longer. We’re not talking about minor types of pain—this is moderate to severe chronic pain that significantly interferes with quality of life.
If you look at the many other types of surgeries that are done, even low rates of chronic postoperative pain translate into big problems. For example, hernia operations may have a 1 percent incidence of chronic pain, but because of the huge number of surgeries performed, it puts a greater burden on society than the 30 percent incidence of post-mastectomy chronic pain.
This problem of persistent postoperative pain remains unsolved—it’s a frontier where nobody has managed to find significant inroads. But it’s one that I’ve been thinking about very actively with a startup company that I’ve been working with for the past three years in San Francisco.
Another issue, which I’ve really only begun to think of recently, has to do with the practice of pain management, rather than the utility of drugs that we have today. We’ve become pretty good at treating acute postoperative pain under most circumstances. Hospitals and surgeons are ranked on their ability to control acute postoperative pain properly. But what has not been looked at is what the patient goes through before surgery. We have guidelines for the perioperative and postoperative use of analgesic products, but not for the two months or two weeks or two days prior to surgery. The lack of preoperative treatment guidelines for patients in chronic pain prior to surgery creates enormous disparities in practice and recommendations from one surgeon to another. For some patients who have to suffer through weeks or months of no effective analgesic therapy, on the recommendation of a surgeon who believes that patients should be opioid- and NSAID-free at the initiation of surgery, this can be exceptionally problematic.
There are some surgeons who will not do elective surgery on a patient who’s been taking chronic narcotics prior to surgery; there are other surgeons who will go ahead and say they can manage these patients and get a good outcome. We certainly appreciate that we need to take patients off NSAIDs for several days prior to surgery, to reduce the amount of bleeding that’s going to occur following surgery. But the issue of when, or whether, to stop narcotics prior to surgery is one that has received very little attention. I would love to get greater discussion on developing an evidence-based approach to see whether it makes any difference if patients have been taking narcotics, or how much or which narcotics, prior to surgery. Does it affect the outcome of the surgery in any way, and if so, can we develop some standards? Are there some patients who are more vulnerable to developing chronic postoperative pain than others, and if so, should we have different pre-treatment protocols for them? And then, if you need to wash out the narcotics, are there alternative pain-relieving drugs that can be used to help patients prior to surgery? This has never been looked at in a controlled and systematic way.
What are the surgeons concerned about?
The concern expressed to me by some orthopedic surgeons is that, if patients have been on narcotics prior to surgery, they have a much more difficult time with pain management after surgery. Some surgeons have the impression that patients receiving opioid therapy prior to surgery have “burned out” their morphine receptors.
I know that this doesn’t occur at the molecular level, and I know there are ways to manage acute postoperative pain for patients who are on chronic opioids for pain or for methadone maintenance therapy, but apparently that is not appreciated by all surgeons. And, quite frankly, nobody has done well-controlled outcome studies to see whether prior use of opioids makes any difference or not.
Are there ways in which the field needs to change course—are you and your colleagues getting stuck somewhere?
Yes, people are getting stuck. One example is the difficulty of getting new NSAIDs and other anti-inflammatory and anti-pyretic analgesics to market. Many of the drugs in this area have turned out to have a variety of toxicities over the past 125 years. Each time these toxicities have become known, the thoughtful people in the field have adjusted their preclinical and clinical testing strategies to be able to recognize these issues earlier on, and to develop better products that would overcome these liabilities. But now, the concern is that it’s impossible to develop any new NSAID or COX-2 inhibitor because the regulatory bar is too high.
The FDA has said publicly on multiple occasions that in order to bring a new drug to market in this area, it is going to require cardiovascular outcome testing. That makes a lot of people throw their hands in the air—as I have, too, believe me. The size of the required studies could be anywhere from 10,000 to 30,000 patients. There is no pharma company in the world that has the resources to support this on a preapproval basis.
What’s forgotten in this discussion is that there are far more GI bleeds due to NSAID use than there have been cardiovascular problems with COX-2 inhibitors. There are over 100,000 individuals per year in the United States who are admitted to a hospital due to serious GI bleeding induced by NSAIDs. The rate fell somewhat when COX-2 inhibitors were introduced in 1998, and continued to fall until 2004, when Vioxx and several others were taken off the market, but GI toxicities have trended back upwards since then. This may have been improved a bit with the recent approvals of a proton pump inhibitor, or a histamine H2 receptor antagonist combined in a single tablet with traditional NSAIDs such as naproxen or ibuprofen. We’ve also gotten better by controlling bacteria, in particular, H. pylori, which can cause stomach ulcers. But we have not eliminated this problem, and it’s an enormous burden on the healthcare system, so we need more effective and safer drugs in this area. We can’t abandon this—there is still an enormous need for better anti-inflammatory analgesics.
Are there other places where things are stalled?
A lot of people have been stuck trying to develop better, safer opioid-related analgesics. Although there have been many new formulations of older opioid-related drugs, we haven’t had any new chemical-entity opioid-related analgesics introduced into the market in the last 20 years. We thought that agonist-antagonist analgesics developed in the 1980s, such as nalbuphine and buprenorphine, would have lower abuse liability, and some of them do, but at the same time, they did not necessarily have an equal analgesic profile compared to the traditional narcotics, and they certainly didn’t have stronger analgesic profiles. Also, none of them had sufficient oral bioavailability to facilitate development of oral tablets that are preferred by patients, and that are the least expensive ways to deliver new drug products.
There was strong interest in developing κ-opioid receptor agonists as analgesics that would not have the same respiratory depression, gastrointestinal inhibition, or addiction liability profiles as traditional μ agonist analgesics, but centrally acting κ-opioids were found to have psychotomimetic effects and other significant central nervous system adverse effects. We had an era when people tried to develop peripherally acting opioid analgesics, but to date we’ve not found peripherally acting opioids that have the same level of efficacy as centrally active narcotic analgesics. That doesn’t mean it’s not possible, but we have not succeeded yet.
I believe that this area will change significantly in the next few years with newer opioid-related drugs that interact with different opioid receptor subtypes, or that have different secondary messenger activation patterns. I’m fortunate to have the chance to work with several companies and academic laboratories that are making significant advances in this area.
We also need to understand the genetics that make one group of patients different from another. One thing I remember from studies I did about 12 years ago on narcotic analgesics for postoperative pain is that, if you take a population of patients who are having the same type of surgical procedure, you will find that some patients require only 10 milligrams of morphine following surgery, and that’s the last narcotic that they need until hospital discharge. Yet another group of patients with the same procedure may require 100 milligrams per day for three days, and still have pain that is 8 or 9 on a 0-10 scale.
I think SNPs [single-nucleotide polymorphisms] that regulate the different types of opiate receptors expressed in different patients will become very important. Just as we have personalized medicine in cancer, I think it may be necessary to have personalized medicine in the analgesic field, to find the drugs a patient will respond to best.
This is also a significant problem with the NSAIDs we have today, too. For any particular NSAID, some patients respond, some patients don’t, and we don’t know why. Starting six years ago with several of the clinical trials I’ve designed, I’ve been taking blood samples that I store for future genetic analysis. I may not understand today why one patient responds or does not respond to a drug, but I am hoping that as molecular genetics and pain medicine get better, we’ll be able to solve some of these problems. In the future, I hope to go back and take a look at the stored samples to see if there is a genetic signature that can predict either the efficacy or adverse effect profiles of the drugs that the patients used.
Do you see any especially promising research being done in pain genetics?
There’s a lot of very promising work coming out of the NIH [US National Institutes of Health] and several academic centers. It’s still too early to know exactly where that’s going, but I pay a lot of attention to it.
Are there any papers that you think every pain researcher should read?
One that I will mention immediately is a paper on tanezumab, a nerve growth factor (NGF) inhibitor [Lane et al., 2010]. This is a drug that I have not worked on in the past, so I have no proprietary interest in this study. However, I believe that this was a landmark study because the drug showed tremendous efficacy in patients with osteoarthritis of the knee, and it works through an entirely new mechanism. Nancy Lane [at the University of California at Davis Medical School, US] was the lead investigator. If you look at the figures in this article, you see that the level of efficacy is phenomenal—I’d just never seen figures like that before. We need to have drugs work like that.
Unfortunately, tanezumab and several other anti-NGF drugs were found to cause osteonecrosis leading to early joint replacement in a number of subjects during advanced Phase 3 clinical trials. Pfizer stopped most of their anti-NGF studies in June 2010, and the FDA put nearly all of the anti-NGF clinical trials on hold in December 2010. A review of existing data by the FDA’s Arthritis Advisory Committee in March of this year confirmed an association between anti-NGF therapy and osteonecrosis (30 cases), and rapidly progressing osteoarthritis with rapid deterioration of bone and cartilage (83 cases) in 353 subjects who required joint replacement during clinical trials. The association was highest in patients who used traditional NSAIDs in combination with anti-NGF therapy. In a 21-0 vote, the Advisory Committee recommended restarting NGF clinical studies, with greater safeguards in place, since it felt that the benefits of enhanced pain relief outweighed the potential risks of this new class of compounds. The FDA has not yet indicated whether it will accept the recommendation of the Advisory Committee or impose additional requirements on study sponsors.
What makes the Lane paper a must-read?
Well, it is a game-changer. We have spent the last 30 to 40 years working on COX-1 and COX-2 inhibitors, and nothing came up to a level of efficacy like what was seen with tanezumab. This paper throws out a challenge to all of us in terms of what we need to do—it says, this is what is possible; this is where we need to go.
The Lane study on tanezumab was also a well-designed study. I often have been disappointed by the way that poorly designed clinical trials have had a significant impact on the way people think about certain drugs or mechanisms. I’m always excited when somebody has a really thoughtfully designed trial that comes to a crisp conclusion about what the efficacy of a drug is going to be. That’s why I point out Nancy Lane’s article.
I’m happy that, when the FDA put the anti-NGF trials on hold, there was one group of patients that it did not restrict from continuing treatment: patients with bone cancer pain. This is what had attracted my attention to NGF when I first saw the basic biology of NGF inhibitors in animal studies more than eight years ago. This was a unique opportunity to develop highly active compounds that could treat a type of pain—bone cancer pain—for which nothing else was successful.
Are there any other papers that you’re keen on?
I think everybody needs to read the Declaration of Montreal, which was published in the journal Pain in 2011 [Cousins and Lynch, 2011]. It says that access to pain management is a fundamental human right.
There’s also a good paper that appeared last year by a group from Canada, talking about movement-evoked pain versus pain at rest, and the importance from a clinical perspective of measuring pain during motion [Srikandarajah and Gilron, 2011]. Pain during motion has been missed in a lot of clinical trials. My perspective is that you need to look at a range of pain endpoints as well as other quality-of-life endpoints. I know this feeling is shared by the FDA, and it means that we need clinical trials designed to measure these endpoints.
Henrik Kehlet [Copenhagen University Hospital, Rigshospitalet, Denmark] wrote a short editorial on that study, talking about assessment of postoperative pain [Kehlet and Dahl, 2011]. I’ve collaborated with Kehlet on clinical trials in the past, and I’ve been very influenced by a lot of his thinking. I have been amazed by his use of multimodal analgesic techniques for postoperative pain, meaning that you use multiple strategies to reduce pain at the source in addition to altering how the brain and the rest of the body respond to and interpret pain. I also recommend two other recent papers by Kehlet and colleagues: an editorial on persistent postsurgical pain in the journal Anesthesiology [Kehlet and Rathmell, 2010] and a review on postoperative pain management in Expert Opinion on Pharmacotherapy [Dahl et al., 2010].
Pain researchers are often frustrated by how few drugs succeed in clinical trials, but you sound quite positive about the future.
I am really and honestly optimistic about the future in pain medicine. I’ve had the opportunity to be innovative in my career, and to get several innovative medicines on the market. However, the fundamental reason for which I got into this field is still here today: Patients continue to have pain. What are we going to do that’s different, and better, so that we can address the different types of pain that individual patients have? And how can we do this with greater safety? That’s my challenge, still. I keep the lives of individual patients in mind.
We’ll end on that note. Thank you for speaking with us.
PRF Related Content:
News: FDA Gives the Green Light to Restart NGF Antibody Trials (13 Mar 2012)
View William Schmidt's profile on Pain Research Forum (requires member log in)
Other Forum Interviews:
Pain and Its Control: A Conversation with Allan Basbaum (6 June 2012)