Please introduce yourself and tell us what you do
I’m a neurointerventionalist at Massachusetts General Hospital and a professor at Harvard Medical School. Clinically, I’m focused full-time on spine and neurointerventional work. My journey with spine care started back in 1997, when we performed the first vertebroplasty in New England. That experience launched a deep interest in spinal interventions, especially in patients suffering from Low Back Pain. Over the years, I’ve served as President of the Society of Neurointerventional Surgery, the American Society of Spine Radiology, and I’ve been actively involved with the pain community as a board member and Fellow of the American Society of Interventional Pain Physicians.
What challenges do patients and medical specialists with moderate to severe back pain face?
Chronic Low Back Pain (cLBP) is an enormous problem. Millions of people suffer from it, and it impacts not just their ability to work or perform daily activities, but also affects caregivers, employers, and entire health systems. One of the biggest challenges is that there are so many different types of pain – radicular, discogenic, vertebrogenic, facet-related – and therapies are often used in a manner that doesn’t get at the root cause of the pain, potentially leading to sub-optimal outcomes.
How do patients with Modic changes and moderate to severe back pain differ from other patients?
That’s a great question, and it really gets at the evolution of how we understand back pain. In the late 1980s, Mike Modic and colleagues published a foundational paper in Radiology that introduced a classification system for vertebral endplate changes seen on MRI. At that time, MRI was new and slow, just doing a couple of sequences could take over an hour. Radiologists were frequently flagging signal changes in the vertebral bodies with phrases like, “can’t rule out discitis or osteomyelitis,” which triggered unnecessary concern and repeat imaging.
To solve this, the Modic system was proposed:
Modic Type 1: Edema
Modic Type 2: Fatty replacement
Modic Type 3: Sclerosis
Initially, the main purpose was to help radiologists consider the possibility that these changes did not require further workup or imaging to rule out infection. For decades, Modic changes were considered radiologic artifacts – background noise. But that changed and over time, we began to understand that Modic Type 1 and 2 changes are not incidental. They correlate with a specific kind of pain – what we now call vertebrogenic pain, which arises from the endplates and is transmitted via the basivertebral nerve. This type of pain is different, it’s anterior, midline, mechanical pain. Patients often say things like “Doc, it really hurts when I tie my shoes before I go running” or “I used to love gardening, but I can’t do it anymore.” It hurts when they bend forward, when they change positions, or even after sitting still for too long. This isn’t radicular pain shooting down the leg, it’s deep, dull, central Low Back Pain – an entirely different phenotype.
The key point is that this specific pain type has a radiographic biomarker – Modic Type 1 and 2 changes – which makes it unique in the world of back pain, where so often we treat lesions that lack a specific radiographic biomarker. That’s what makes this patient group different: they not only have a well-defined clinical presentation but also an imaging signature that correlates with an identifiable and now treatable pathophysiology.
How prevalent is moderate to severe cLBP – in your practice and in general?
cLBP is incredibly common. It’s one of the most pervasive and costly health issues we face. In my practice, which is heavily focused on spine care, I see it constantly, but that’s not unique to me. If you look around almost any workplace, whether it’s clinicians wearing lead, office staff at desks, or people in physically demanding jobs, you’ll find people suffering from it. It affects tens of millions of people in the U.S. alone and is one of the leading causes of disability worldwide. The cost burden is enormous, not just in direct healthcare spending, but in lost productivity and quality of life. It’s everywhere, and because it’s so varied in cause and presentation, it’s often difficult to treat effectively, which is why precision targeted therapies are so needed.
Can you describe the current landscape of treatment for cLBP?
It’s a bit like looking at a map of a city where everyone’s trying to get to the same destination – pain relief – but they’re all taking different routes. For patients with vertebrogenic or disco vertebrogenic pain, the most exciting advancement has been basivertebral nerve ablation (BVNA). This has solid randomised control trials support, including a sham-controlled study, and is the fastest-growing ablative procedure in the space. There are also biological agents being injected into discs, some aim to bolster structure, others aim to regenerate, but many still lack the high-level evidence I personally look for before introducing them into my practice. We’re also seeing early work on combination therapies: ablation for vertebral components, injection for discal pathology. I think we’re moving toward a model where multiple targeted treatments coexist to address different pain generators.
What are the limitations of existing treatments, particularly injection therapy and surgery?
This is where I want to be precise. These treatments aren’t in competition; they’re just addressing different pain sources. Take surgery, it’s often excellent for structural issues causing nerve compression, like herniated discs leading to sciatica, but for axial non-radicular back pain most spine surgeons I know are reluctant to operate because the outcomes aren’t great.
With injections, some are diagnostic, some are therapeutic. Medial branch blocks can help with facet pain, epidurals can be used for radiculopathy, but for vertebrogenic pain, pain from the endplate and basivertebral nerve, those treatments don’t really hit the target. So, there’s a large cohort of patients for whom existing options aren’t ideal, which is why therapies like BVNA or potentially PP353 are so important.
What are other innovations have you seen for cLBP and how do you see PP353 in comparison?
There have been quite a few innovations in the cLBP space, especially when it comes to pain coming from the vertebral endplates and the disc, what we now refer to as the disco vertebrogenic complex. One of the biggest advancements is BVNA as mentioned which has strong clinical trial data behind it and has quickly become one of the most performed procedures for patients with Modic changes and cLBP axial pain. We are also seeing increased interest in biologic treatments for the disc itself. These include stem cells, hydrogels, and other agents aimed at regenerating or supporting disc tissue. Some doctors are using them already, but I would say the level of evidence is still catching up, so I have not brought them into my own practice just yet.
PP353 is something different, and in my view, very exciting. What makes it potentially unique is that it goes after what could be the underlying pathology in certain patients.The idea is that some people may have a chronic low-grade infection inside the disc. Not an obvious infection like discitis or osteomyelitis, but a slow-burning infection that became walled off years ago and has been causing inflammation and pain ever since. This infection may be what leads to Modic changes on MRI and to the symptoms of axial back pain.
If that idea is correct, then delivering the right kind of antibiotic directly into the disc could treat the infection and stop the pain at its source. That is not a simple thing to do. The disc is a relatively avascular area, so standard antibiotics would not work well and PP353 was designed to address that challenge. If this turns out to be effective, it would be a major shift. It would be like when doctors realized that H. pylori cause ulcers; that discovery changed the way we treat a common condition. PP353 has the potential to do the same thing for a select group of patients with cLBP. It is not just another pain treatment; it could be a treatment for the cause itself.
If Phase III studies demonstrate similar results to the initial clinical trial, how do you see this impacting clinical practice?
If the Phase III trial results are positive, I think the implications would be game changing. We would likely have clear proof that this theory of chronic smouldering infection in the disc is valid. This idea, which I believe came out of northern Europe, suggests that low-grade bacteria can become walled off in the disc over time. These bugs are not causing an active infection in the way we think of discitis or osteomyelitis, but they may be triggering inflammation that leads to Modic changes and chronic pain. This theory has been around for a while, but it has never been a formal part of treatment algorithms. If PP353 demonstrates success in treating this condition, it would allow us to rethink how we approach cLBP. Instead of focusing on symptoms, we would have a way to target the cause for a specific group of patients. That alone would mark a major shift in our clinical mindset.
In practice, I think PP353 would fit into the care pathway for patients who have chronic axial back pain that has lasted more than six months, have failed conservative therapies, and show Modic type changes on MRI. In those cases, this treatment could be offered early, as a foundational intervention. For some patients it might be curative, for others it might work best when followed by additional treatments like BVNA or disc support procedures, although the biggest change would be at a deeper level in that we would be redefining a portion of back pain as something that is not just mechanical or degenerative but infectious in origin. That would fundamentally change how we think, diagnose, and treat.
What difference could this make to patients that you see?
If this treatment works as we hope, the difference for patients could be profound. It would give us a way to treat the actual cause of pain in a subset of people with cLBP rather than just managing their symptoms. That alone could change lives. Think about when it was discovered that H. pylori was the cause of duodenal ulcer disease. Before that, patients, at times, required surgery to treat these ulcers … I remember learning about those surgeries in medical school. I have not investigated the exact numbers, but I suspect those procedures are now uncommon. That discovery changed the entire model of care though even with that discovery, other therapies did not disappear. We still have drugs like omeprazole and cimetidine and all the other antacid or acid-suppressing medications and there remains a massive industry around them. The same will be true here, I do not believe that a successful treatment, even one as promising as this, will wipe out everything else we do. In fact, I would argue the opposite. When patients improve, they are often motivated to improve even further. Even if this antibiotic injection resolves the infection and reduces or eliminates the primary pain, the spine may still have secondary problems from years of degeneration. That is where other treatments like BVNA or disc procedures might still play a role. The potential is big, and this drug could be disruptive in the best way if it gives us a chance to treat the source of the problem. But it does not mean we stop using the other tools in our toolkit, it just means we start from a stronger place.
What other medical specialists would use PP353?
While I am a neurointerventionalist and came into spine care through procedures like vertebroplasty, I do not think this treatment would be limited to people in my field, we are a relatively small group. I believe the bulk of adoption would come from pain physicians, which is a diverse and growing specialty. That includes anaesthesiologists, physical medicine and rehabilitation doctors, radiologists, and even some emergency physicians who have moved into the pain space. I could also see some minimally invasive spine surgeons becoming interested, especially those who have already been active in disc-based procedures. Infectious disease doctors might have the expertise around antibiotics, but they are not typically trained to perform disc injections, so their involvement would likely be consultative rather than procedural.
The main factor will be the practice pattern. Some physicians already perform disc injections and have the setup and patient population to support this. Geography will also play a role as in some regions, certain specialties are more dominant than others in spine care. Overall if the treatment proves effective, I do not believe we will have a shortage of qualified physicians ready to deliver it.
How easily would PP353 fit into the current treatment practices for cLBP in the US?
From a technical standpoint, PP353 would fit quite easily into existing practices. There are already many physicians who have the skills and equipment to perform targeted disc injections, so the actual procedure itself is something we already know how to do. Where things get more complicated is in how disruptive this treatment might be as it challenges the current way we think about cLBP. For years, we have approached it as a degenerative or mechanical problem but now we are talking about infection as a cause. That requires a mental shift for clinicians. I think what will happen is that early adopters will begin using it and sharing results. Over time, more doctors will take notice and become interested, but it will take strategic education and outreach. Just publishing a study and getting approval will not be enough, the people behind this treatment will need to make sure that physicians understand the science and know how to identify the right patients. Once that happens, I believe adoption will grow quickly.
This is a non-opioid treatment and targets the cause of the pain. How important is this?
This is incredibly important. For years, opioids were used as a primary tool to manage cLBP. That approach has led to a lot of harm and I was raising concerns about opioid overuse long before it was part of the mainstream conversation. Back then, talking about interventional alternatives instead of opioids was not a popular position to take. Now we all recognize that the costs of that overuse have been enormous, both to patients and to society. I would say at best opioids cover the symptoms of the disease, and that is at best. They do not treat the underlying problem and when patients are on them for months or even years, as is often the case with cLBP, the risks and downsides only grow.
If PP353 can get to the underlying cause and thereby diminish or take away the need for opioids, then that is not just a benefit of the treatment, it is part of the success story, and I am confident that will be embraced by the medical community once the treatment becomes more widely available. We have needed better options in this space for a long time and a non-opioid therapy that also targets the source of the pain would be a major advancement.
Can you summarise the potential of PP353 for patients?
What excites me about PP353 is that it offers a real opportunity to get at the potential cause of cLBP. In many situations, we are only treating the symptoms, patients cycle through physical therapy, medications, injections and sometimes even surgery but often without real lasting relief. That is because we have not always been able to identify or treat the true source of the pain.
So, what do I think is important? I think if this drug turns out to work, and if it is proven through a well-designed phase III trial, then it would be a game changer. Those are big ifs, but if the theory holds, we would be looking at a treatment that precisely targets the cause of the disease rather than just managing its effects and that has implications that go far beyond the exam room. Whether you are a provider, a caregiver, or a patient, the idea of treating the actual cause of chronic back pain is something everyone can understand. We are not just offering another temporary fix; we are talking about potentially changing the course of the disease for certain patients. That kind of precision is rare in spine care. If PP353 can deliver on its promise, it could completely shift how we think about and treat a significant group of patients who have been living with pain for far too long.
There have been many turning points in medicine. One that stands out is the introduction of antibiotics, which changed infections from life-threatening conditions to something treatable. Another is more personal to my field: when vertebroplasty was first introduced, it allowed us to help patients who were told to wait months in pain while their fractures healed. Suddenly, we could relieve that pain in a single session, that changed how we thought about spine care.
PP353 has the potential to do something similar for a certain kind of back pain. What makes it so important is that it does not just manage the pain, it aims to treat the actual cause. That is what we mean when we talk about precision care. If this drug works the way we hope it does, we will be able to identify the specific patients who are suffering because of a low-grade infection inside the disc and treat that infection directly.
For someone who does not have a medical background, think of it like this. If you have a fire in your kitchen, you want to put it out at the source. You do not want to just open a window and let the smoke escape. That is the difference, we are not just masking the symptoms. We are going after what is fuelling the pain and when you do that everything changes.
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