Imagine living with excruciating pain that prevents you from walking or doing the things most of us take for granted. We all experience pain, and 50 million people cope with chronic, debilitating pain. The market for pain therapies is estimated at $74 billion. And yet, investment in new pain and addiction treatments is falling short of what is needed, according to a new BIO report, which shows a 44% decrease in clinical drug programs for pain over the past five years. Our guests on this episode talk about the challenges of living with and treating pain, as well as research and development on new, non-addictive and safer pain therapies.
Imagine living with excruciating pain that prevents you from walking or doing the things most of us take for granted. We all experience pain, and 50 million people cope with chronic, debilitating pain. The market for pain therapies is estimated at $74 billion. And yet, investment in new pain and addiction treatments is falling short of what is needed, according to a new BIO report, which shows a 44% decrease in clinical drug programs for pain over the past five years. Our guests on this episode talk about the challenges of living with and treating pain, as well as research and development on new, non-addictive and safer pain therapies.
Rachel King (00:06):
All of us at some point experienced pain, right? It may be the result of an injury, the aftermath of surgery, or just pushing our bodies during exercise. We all experienced pain differently.
Cindy Steinberg (00:23):
Chronic Pain devastates people's lives. You can't sleep, you can't take care of your family. You can't socialize with friends, and really curtails your enjoyment of life and leads to really immeasurable suffering. There is a dearth of effective options, particularly for severe pain, and especially since opioids have largely been removed from the table.
Rachel King (00:49):
Imagine it, you can't get up from a chair without feeling excruciating pain. You can't go for a walk. You can't do a number of things that most of us take for granted. Maybe you don't have to imagine it because you're among the 50 million people in the United States who experience pain every day. Will there ever be safe and effective treatments for pain? We explore that question today. I'm Rachel King, and you're listening to I Am BIO.
(01:36):
There are immense challenges to developing better therapies for pain, and anyone who's paying attention can tell you that the need is great. Today, our guest will talk about these challenges and the hope for finding effective, safe and non-addictive alternatives for addressing pain. In this episode, our guests include one of the authors of a bio report on the state of innovation and pain addiction treatments. We also talk with a leading policy advocate for people who live with chronic pain, as well as leaders of two biotech companies developing new treatments. Our first guest is a leading expert in pain.
Cindy Steinberg (02:13):
I am Cindy Steinberg, Director of Policy and Advocacy for the US Pain Foundation.
Rachel King (02:18):
Cindy explains the debilitating reality of chronic pain.
Cindy Steinberg (02:22):
Pain is the number one reason why Americans go to their doctor and is the number one reason for disability, both globally and nationally. With chronic pain, people don't really understand how devastating it really is to people's lives. I often describe it like being trapped in your body 24/7 with no way of getting out.
Rachel King (02:51):
The US pain foundation runs a network of support groups for pain sufferers. Their goal is to improve pain care and understanding of how chronic pain affects people's lives. Here's Cindy talking about her work and the challenge of insufficient pain therapies.
Cindy Steinberg (03:06):
I've run a support group for pain sufferers for 22 years. And in those 22 years, so many people have come to my group with common conditions like arthritis or cancer or neuropathy. And then with uncommon conditions that I had almost never heard of before until I ran my group like Ehlers-Danlos and Behcet's Syndrome and Marfan Syndrome and trigeminal neuralgia and vulvodynia and many others. And during all this time, for at least the past decade, there have been no new treatments, no new breakthroughs for chronic pain except for one condition and that is migraine. We question the morality of torturing prisoners, individual prisoners as well we should, but we allow millions of Americans to live in this kind of relentless torture 24/7. And there needs to be much more done about it because people suffer a great deal and can't find help.
Rachel King (04:14):
And what is being done? BIO recently published a report on the status of research, development and investment in pain and addiction. The main takeaway, the pipeline for pain therapies has decreased 44% compared to five years ago. Our next guest explains.
David Thomas (04:32):
I am David Thomas, the Senior Vice President of Research and analysis at BIO.
Rachel King (04:37):
Dave and his BIO colleague, Chad Wessel, co-authored this year's report.
David Thomas (04:42):
BIO is publishing its first report that is actually a look back at where we've come in the last five years since our original publication on this topic. So what we found five years later, is that we've had a significant reduction in the number of drug programs that are in the pain, clinical pipeline back in 2017. We had 220 programs that were in the clinic from phase one all the way to submission to the FDA. Today, we have 124, those are finding in this report that we have seen a 44% reduction in the total number of programs. So of those 220 original programs, 77% of those are no longer around. That was the top line finding which was very startling to us.
Rachel King (05:32):
The report finds that venture capital and R&D are much more heavily invested in other areas such as oncology. Dave continues.
David Thomas (05:40):
You have platforms like CRISPR, or other cell therapy strategies, and even some of the antibody strategies that are perfect for addressing some of those targets in cancer and rare disease. Pain is not necessarily genetic disease, there are a couple of rare diseases within pain that are genetic, but by and large, the majority of the population isn't experiencing pain due to some genetic abnormality. And so those other platforms that tend to be very targeted for a genetic mutation, they aren't as useful here in the pain space. So we can't use all of the tools that we have in some of the other biotechnology arenas.
Rachel King (06:23):
One reason pain treatments are more difficult to develop is the size of the affected population.
David Thomas (06:29):
So to develop a drug for a large population requires larger clinical trials. Therefore, it costs more money than some of the rare disease or some of the oncology indications.
Rachel King (06:40):
Another reason is the amazing complexity of the human brain.
David Thomas (06:46):
For the most part, pain is very difficult because you're targeting the brain. So you have to have a compound, typically, that will go through the blood brain barrier. And that's more amenable to small molecules and other areas like in psychiatric disorders, depression for example, and others, it has been very difficult to develop these drugs. So we have always been advocates of more brain research. So early stage research to understand the biochemical basis of pain, and to identify new targets that can help to spawn new discoveries for drugs that will be useful in that paradigm.
Rachel King (07:25):
Dave says government policies also play a role.
David Thomas (07:28):
There are also solutions that BIO advocates for on the regulatory front and that is, for example, to have clear definitions of how to achieve an expedited development pathway through the FDA to help identify new biomarkers that can be used in clinical trials and how to potentially run innovative clinical trial designs, and maybe use real world evidence, patient reported outcomes data for those trials. So those are some of the things that can help on the regulatory front.
Rachel King (07:58):
Unfortunately, government policy is going in the wrong direction. The recently passed Inflation Reduction Act is likely to result in even fewer drug programs for pain.
David Thomas (08:17):
This Inflation Reduction Act, which is going to move fairly quickly this year into what I see as a biasing of investment and company management towards biologics versus small molecules, and the pipeline for pain and addiction is 85% Small molecules right now. So again, in order to penetrate the brain, it's a lot easier to do that if you have a small molecule. And now we have a law in place that's going to be basically biasing and favoring biologics over small molecules. Secondly, there is a provision within the Inflation Reduction Act that will disincentivize investors once again, that have invested in companies that have worked with the government. So in the Inflation Reduction Act, there is a clause where the government's fair price assessment can be influenced by the fact that a company has actually received funding from the government.
(09:11):
So that's a second hurdle that the Inflation Reduction Act has placed on this particular segment of the industry. And then lastly, you have the orphan indication issue where a company that has maybe developed a drug molecule for a rare pain indication, like a small fiber neuropathy, if they wanted to pursue that for another indication within pain, they are going to be disincentivized to do that, because they would no longer be exempt from the drug price controls that are going to be implemented by the government. So I think for those three reasons, the Inflation Reduction Act could actually harm the pain and addiction space even further, which already is now showing some of the worst success rates in the entire industry.
Rachel King (10:01):
One particularly startling finding in the BIO report was the small percentage of new pain therapies that make it to phase three clinical trials.
David Thomas (10:09):
We found that phase three was amazingly low, just well below the averages where most disease areas have the least a 50/50 chance of a phase three success, oftentimes closer to 66%. In pain, it was 21%. So it's basically one in five molecules that are novel or making it from phase three to FDA filing for marketing approval.
Rachel King (10:42):
Dave does not paint an optimistic picture for patients who will need to find new ways to manage their pain. Hopefully this report will sound the alarm and the government and other stakeholders will respond. When we come back from a break, we'll talk with two companies that are defying the odds and making exciting progress on new pain therapies.
(11:15):
Are you interested in hearing more fascinating stories like this one? Check out bio.news. Bio.News is a daily news website exploring the intersection of biotech innovation and US and international policy. With new content daily, Bio.News has you covered on the latest in biotech. Visit now by typing bio.news into your browser.
(11:48):
Despite the many challenges we've discussed, we found some pharmaceutical companies that are working on innovative solutions to pain. We talked with two of them.
Paul Negulescu (11:57):
I am Paul Negulescu, Senior Vice President and Disease Area Executive for the Pain Program at Vertex Pharmaceuticals.
Hernan Bazan (12:05):
My name is Hernan Bazan. I'm the CEO and co-founder of South Rampart Pharma. I'm also the Endowed John Ochsner Professor of Cardiovascular Innovation at the Ochsner in New Orleans.
Rachel King (12:15):
In a space where so few companies reach phase three clinical trials. Our next guest, Paul Negulescu of Vertex, describes his company's technology and how it achieved this important milestone.
Paul Negulescu (12:29):
The VX548 is a sodium channel inhibitor. It is a selective sodium channel inhibitor, and it targets a sodium channel called Nav1.8, which is present on our sensory nerves, and very important in the transmission of pain signals. The story behind this medicine is that a couple of decades ago, basic researchers discovered that there were specific sodium channels expressed on our sensory nerves, one of which is Nav1.8. And in addition, learned that there were human mutations in Nav1.8 that were associated with increased pain. So from those basic research studies, we believed that Nav1.8 could be a relevant target to treat human pain.
(13:18):
Our role in the biotechnology industry is to translate discoveries like this into effective medicines for people. So what we had to do was develop assays for this target, develop chemistries to test inhibitors and optimize those inhibitors to be selective for the Nav1.8 compared to all the other Navs in our body, and then develop those in clinical studies to show whether they were safe or effective. And we are now at the last stage of clinical development prior to approval for this approach. So we've taken the basic science, applied it to discovery of a drug, and are testing the drug in clinical studies, with the aim to ultimately take it to patients.
Rachel King (14:03):
Rather than being a replacement for current pain drugs, Paul says Vertex's medication would fall into a whole new category.
Paul Negulescu (14:10):
These sorts of inhibitors would constitute a new category of pain medication in the sense that it's neither an anti-inflammatory like an NSAID which affects the signals that actually go into your nerve to tell you that you've been injured, nor does it affect the central nervous system processing, like the opioids, which have general euphoric effects that can lead to the addiction. So it's a new class of medication that affects just the sensory nerves. And that's why we're really excited about it because it fills a gap that we have in our ability to treat pain.
Rachel King (14:46):
Vertex is excited and optimistic about the company's learnings from the phase two clinical trials.
Paul Negulescu (15:01):
So the most exciting thing about 548 so far, based on what we've learned in the clinic, is that this molecule has been well tolerated in healthy volunteers, and has been effective in treating pain. That is a big deal, because a lot of compounds that enter clinical development for pain never get that far, they can show safety issues early on, or they may just not be effective. So we're very excited to be able to take this mechanism and this compound through those two stages. And again, we are in the third stage, the biggest and largest study for this compounds so far prior to filing for approval with the FDA.
(15:41):
So we're really excited about how far this has gotten. It's the first truly selective sodium channel inhibitor to get this far through the drug development process. And if it continues on the path that it's on, it will be the first selective sodium channel inhibitor to treat pain. The other thing that we're excited about regarding VX-548 is that it has been granted breakthrough therapy designation for moderate to severe acute pain. And I think this reflects the FDA's recognition for the potential of this medicine as a significant advance.
Rachel King (16:14):
As Paul indicates, and as BIO's Pain and Addiction Report finds, few pain treatments get that far. In fact, most new pain medicines don't make it past phase one. Paul describes the challenge companies face in developing new pain medicines.
Paul Negulescu (16:30):
It all rolls up to the fact that there's a very high bar for the development of a new pain medicine. So I think it might dissuade many from entering the field because of the high bar. And in the sodium channel field, specifically, which has been an active area of research for the last two decades, since we learned that these sodium channels, specifically associated with the sensory nerves, might be good targets is that it's very difficult to find very selective molecules, we have nine sodium channels expressed in our body of this type. And they do all kinds of things to support our body functions, including in the brain, in the heart, all through the body, they have important functions.
(17:14):
So targeting the Nav1.8 which is specifically expressed on the sensory nerve, and not hitting any of those other channels has been very difficult from a drug discovery perspective. And we've been working on this problem for over 20 years, trying to understand what is unique about the Nav1.8 channel that we could target so that our drug would act on that channel and not the others. So there's sort of a general high bar in the field, for new medicines, you do have the additional consideration that the drug could be taken by many, many people. And we all know that different people metabolize and respond to drugs differently. And so as part of our safety assessment, as part of our ability to assess the safety and convenience of the medication, we factor that into the design of the drug.
Rachel King (18:15):
Paul explains that another challenge is the amount of time it can take to research and develop a new treatment for pain.
Paul Negulescu (18:22):
We actually had to invent new technologies in the laboratory, because these are very difficult channels to study. They open for a very brief time, just a few milliseconds, and then they snapshot. And it's very difficult in an assay, in a lab test to catch that channel in the act, and to catch your drug working on that channel. So it took us about a decade just to get that part worked out, like how are we going to study that channel in a relevant context? And then we have to do the chemistry, develop the compounds, find the compounds that work best, advance them into clinical studies. I think you can see how that adds up to a very big investment over time without a guarantee of success until you're very far down the road.
(19:10):
We've been working on this challenge for over 20 years at Vertex. And I think what I have really appreciated about working here at Vertex is the chance to work on this type of problem for so long, because it is a difficult one, but it's also one worth solving. And many times I think in our industry, what happens is people just run out of steam, you just can't work on something long enough to solve the problem. And I hope this is an example of where persistence pays off, and very glad to have had the chance to do that at Vertex.
Rachel King (19:45):
Paul says drug developers cannot do it alone. As the saying goes, it takes a village for innovation to work and make advances that people need.
Paul Negulescu (19:55):
We can't do this alone. Bringing a new medicine forward in this field of pain will require collaboration, not just from Vertex and other companies that are trying to advance innovations in this space, but partnering with policymakers, with patient advocacy groups, with medical community itself, to evolve our thinking about pain, how we treat it, and make sure that people have access to these medicines when they become available.
Rachel King (20:29):
Paul has been inspired to continue his work because of the impact it could have for pain sufferers.
Paul Negulescu (20:35):
The journeys of a pain patient are very difficult. They often get moved around from one part of the medical system to another, they don't really have a place they can go to get treatment for their pain. And when we started to get clinical results from VX-548 in our pain studies, I was amazed by how many people at Vertex came up to me and said, "You know, I haven't told people this but I have chronic pain. I am really excited about what we are doing because I can see this medicine may be helping me as someone who works at Vertex." So just the ubiquity of it is really overwhelming at times, and I think has been very inspiring to our team.
Rachel King (21:23):
Another company isn't far behind Vertex with a new pain therapy now in phase one clinical trials. South Rampart Pharma CEO, Hernan Bazan, explains how the company's replacement for acetaminophen and ibuprofen could offer patients a pain treatment that is safer than what is currently available.
Hernan Bazan (21:42):
Our lead acid SRP-001, it works similarly in the brain as acetaminophen, which is Tylenol, yet it lacks the liver toxicity and we know the two mechanisms of action of how it lacks a liver toxicity that acetaminophen Tylenol has. It is not an NSAID, it is not Advil ibuprofen, it is not that type of a medicine and therefore by not being that type of a drug, it avoids the kidney toxicity that's inherent to Advil ibuprofen and chronic or high doses. And obviously the other large differentiator is that it's not an opioid, it's novel, non-opioid, therefore, it lacks abuse potential.
Rachel King (22:16):
Hernan is optimistic that his small molecule alternative will eventually be on the market. He shares what South Rampart has learned from its phase one clinical trial.
Hernan Bazan (22:26):
What we know from the way it works, and what we've observed in the current phase one human trial is that it gets rapidly absorbed. And this is based on the pharmacokinetics and pharmacodynamics, the PK, PD, how it's absorbed and distributed in the body. And it's rapidly absorbed, and there's a very high peak within an hour, and then it gets distributed in a way that it has a fairly favorable half-life for more chronic conditions. So we have a strategy of using an oral formulation that we've developed for an acute pain model, particularly for example, to test in a future phase two after subjects have wisdom teeth pulled or third molar extractions, because that's an acute pain model, as well as for chronic pain because of the long half-life.
Rachel King (23:13):
South Rampart Pharmaceuticals worked with Louisiana State University and received a grant from the National Institutes of Health. The company's progress demonstrates how collaboration with academia and government can help bring new treatments to market.
Hernan Bazan (23:29):
The NIH Grant is absolutely pivotal. So this is done through the NINDS, the Neurological Disorders and Stroke and what's called the HEAL program, H-E-A-L. The Helping To End Addiction Long-term. It's a program that NIH started in 2018. I'm grateful for the program's financial, scientific and commercialization support. It's not just the funds, it's also... There's a lot of intrapreneurship and commercialization support. And it's really an essential start towards the pain relief innovation. It's interesting though, the government alone in my opinion, cannot bear the cost of developing and commercializing innovative pain medicines. But I think overall progress towards a safer pain treatment will only come from an all hands deck approach from all of these parties, the government, the NIH, the academic community, and also strategics and pharmaceutical companies as well as the finance community. And if they're all committed towards a safer treatment of pain, I think that's the way that novel promising technologies can move forward.
Rachel King (24:28):
We need more breakthroughs in the pain pipeline. BIO's report shows that investment in pain and addiction remains disproportionate to the gravity of the societal problem. With continued commitment by researchers, advocates and drug developers like our guests, we can develop the new therapies that patients desperately need. I want to thank Cindy, Dave, Paul and Hernan for talking about the challenges of treating pain and the exciting potential of new developments. Thanks to all of you for tuning in. Make sure to subscribe, rate and review this podcast and follow us on Twitter, Facebook and LinkedIn @IAmBiotech and subscribe to Good Day BIO at bio.org/goodday. This episode was developed by executive producer Theresa Brady, then producers Lynne Finnerty, and Rob Gutnikoff. It was engineered and mixed by Jay Goodman with the music created by Luke Smith and Sam Brady.