John Markman, MD, on Subcutaneous Tanezumab vs Tramadol or Placebo for Chronic Low Back Pain

In this podcast, Dr Markman discusses promising findings from a large phase 3 trial comparing subcutaneous tanezumab, a monoclonal antibody with a novel mechanism of action, vs tramadol and placebo among patients with chronic low back pain and history of inadequate response or intolerance to standard-of-care analgesics. This study was featured in the 2020 American Academy of Neurology Science Highlights.

Additional Resources:

• Markman J, Bolash R, McAlindon T, et al. Subcutaneous tanezumab versus tramadol for chronic low back pain: efficacy and safety results from a 56-week phase 3 study with a 24-week follow up period (306). Neurology. 2020;94(15 suppl.). https://n.neurology.org/content/94/15_Supplement/306
• Markman J, Bolash R, McAlindon T, et al. Subcutaneous tanezumab versus tramadol in patients with chronic low back pain: 16-week efficacy and safety results from a phase 3 study (305). Neurology. 2020;94(15 suppl.). https://n.neurology.org/content/94/15_Supplement/305
• Markman D, Bolash R, McAlindon T, et al. Tanezumab for chronic low back pain: a randomized, double-blind, placebo- and active-controlled, phase 3 study of efficacy and safety. Pain. Published online May 19, 2020. https://journals.lww.com/pain/Abstract/9000/Tanezumab_for_chronic_low_back_pain__a_randomized,.98400.aspx

John Markman, MD, is a professor in the Department of Neurosurgery and Neurology and director of the Translational Pain Research Program in the Neuromedicine Pain Management Division at the University of Rochester Medical Center in Rochester, New York.

Disclosures: Dr Markman has served on an advisory board for Clexio Biosciences, Flexion Therapeutics, Quark Pharmaceuticals, Quartet Medicine, Collegium Pharmaceutical, Purdue Pharma, Biogen, Novartis, Aptinyx, Nektar, Greenwich Bioscience, Allergan, Grünenthal, Eli Lilly and Company, Depomed, Janssen Pharmaceuticals, Teva Pharmaceutical Industries, KemPharm, Abbott Laboratories, Plasma Surgical, Chromocell, Convergence Pharmaceuticals, Inspirion, Pfizer, Sanofi, Daiichi Sankyo, Greenwich Bioscience, SK Lifescience, and Trevena; has served as a consultant to Trigemina, Editas Medicine, and Plasma Surgical; has equity in YellowBlack Corp; and has served on data safety monitoring boards for Novartis and Allergan.

TRANSCRIPT:

Christina Vogt: Hello everyone, and welcome back to another podcast. I’m Christina Vogt, associate editor of the Consultant360 Specialty Network. Today, I’m joined by Dr John Markman, who is a professor in the Departments of Neurology and Neurosurgery at the University of Rochester Medical Center in Rochester, New York. Thank you for joining me today, Dr Markman.

Dr Markman: Christina, thanks for having me.

Christina Vogt: Today, we’ll be discussing his recent study, “Subcutaneous Tanezumab Versus Tramadol for Chronic Low Back Pain: Efficacy and Safety Results from a 56-Week Phase 3 Study with a 24-Week Follow Up Period,” which was recently published in Neurology.

So first, what prompted you to conduct this study comparing these 2 drugs among patients with chronic low back pain and history of inadequate response or intolerance to standard-of-care analgesics?

Dr Markman: Well, as you probably know, chronic low back pain is the number one cause of disability worldwide and a leading reason for folks to seek medical care. And, the reality is that there's an enormous, unmet need for non-opioid drugs to treat chronic pain. Opioids are one of the leading classes of drugs to treat chronic pain. The other would be anti-inflammatory medications like ibuprofen or naproxen.

So, the prompt for this study is a global search on behalf of investigators really around the world to try and find drugs which reduce the intensity of low back pain that don't require one of those 2 classes of drugs, and this study is particularly interesting because it is the longest and largest analgesic clinical trial ever conducted in chronic low back pain, screening over 6000 patients and conducted in 8 countries at 191 sites. And again, this is also interesting because it's a novel mechanism of action in terms of how this drug works compared to those other 2 classes I mentioned. And it's also an interesting trial because it's an antibody, the protein that blocks nerve growth factor protein that circulates in the blood. And so, this antibody is given once every 2 months.

And, the other interesting aspect of this study is that, you know, this drug not only has to be given very infrequently, but also has a series of trials that have already been conducted with an intravenous formulation. This formulation is subcutaneous, a small injection underneath the skin, the thigh, or the abdomen. But previously, there was a study conducted, a phase 2 study, using an IV formulation. So, this is the first study using the subcutaneous formulation. So again, this is part of a broader search for non-opioid drugs, and it's a very large trial that was conducted in eight countries.

Christina Vogt: Your study found that improvements in pain and function with tanezumab were maintained long-term, but were not significantly better than tramadol at week 56. What do these findings mean for the treatment landscape for chronic low back pain that doesn’t respond to standard-of-care therapies?

Dr Markman: Well, I think it's important to realize a couple things. First and foremost, this was an efficacy trial, a trial designed to compare the act of therapy, which is tanezumab, this antibody to nerve growth factor, to placebo. And the reason for that is, this is a phase 3 registration trial seeking regulatory approval or FDA approval. So, the design of the trial is really focused on week 16 here, or 4 months of treatment after 2 doses of the medication. So, that's the primary endpoint of the study.

The extension phase, which you were describing just a moment ago, is largely designed to evaluate questions of safety, and in this case safety with respect to one specific type of complication, but it has to do with joints. So, I think the first key point here is that the trial is positive at 10 mg, the higher of the 2 doses studied here, at week 16, which shows separation from placebo at that time point. So, in considering the trial, I think the first point to be made is it’s a positive trial, given that at the primary study endpoint, there is a separation from placebo.

To your point, there is an active comparator in this study, both through week 16 and week 56. And the reality is that tramadol does not separate from placebo. It's not superior to placebo. In this study, there are several design reasons that might explain why tramadol which is, you know, is commonly used for chronic low back pain, did not fare as well in this study as it has in some prior ones.

And one might be the fact that you mentioned earlier, that patients enrolled in this study were quote “difficult to treat,” quote, meaning they have not had response to 3 classes of medication previously, and the mechanism of action of a lot of the drugs which they may have previously not responded to overlap with that of tramadol, so that might explain why the patients studied here might not have been particularly responsive to tramadol whereas, you know, in other studies with low back pain populations. There has been benefit with that drug.

Christina Vogt: What direction should future research take now after this study?

Dr Markman: Well, I think the next steps here are to understand which patients among those with chronic low back pain would be most likely to benefit from this therapy with the lowest amount of risk. As I mentioned earlier, it's a 10-mg dose which separated from placebo here. So, I think one place to begin is to understand whether there can be a lower dose used in a group of patients with chronic low back pain of them who may respond at that dose, because the risk of having a joint problem is clearly related to dose in important ways.

It's notable here that patients were not allowed to have significant baseline signs of osteoarthritis by imaging or by exam or history, and they were also not allowed to be treated with a concurrent NSAID medication. And so, I think one next step would be to identify patients who could have responded at a lower dose to further reduce the risk of any joint safety issues with this class of medication.

Christina Vogt: And lastly, what key takeaways do you hope to leave with neurologists on this topic?

Dr Markman: Well, I think this is particularly exciting because it is the first antibody treatment for chronic low back pain, number one. Number two, it has a novel mechanism of action, which has been studied for the past 60 to 70 years but has never really been fully demonstrated in a pivotal trial, which is to reduce sensitization, meaning the lowering of no susceptive thresholds for patients with chronic pain, and that's been amply demonstrated here, not only in phase 2 studies, but now in a large global phase 3 study. It's also been demonstrated in osteoarthritis. So, this supports the idea that the nervous system is importantly involved in modulating pain intensity and that by targeting that modulation, you can reduce pain intensity, and that really has not been demonstrated as a class previously. So, I think that's particularly exciting here.

I think it's also important because this drug does not have the side effects that people are most concerned about, neurologists are most concerned about, with anti-inflammatory medications with regard to cardiovascular disease or with regard to addiction or sedation with opioids. So again, this has a different side effect profile, which may be of interest to neurologists because they're looking for alternatives for patients with pain that don't involve opioid mechanisms or anti-inflammatories.

And I think, lastly, you know, again, it's important because chronic low back pain has such a staggering, unmet need, and this is only one form of low back pain syndrome, the axial musculoskeletal form. And so, I think that, obviously, this raises the question about whether other chronic low back pain syndromes may be responsive to this strategy to reduce peripheral sensitization or other ones going forward.

Christina Vogt: Thanks again for joining me today, Dr Markman.

Dr Markman: It was really my pleasure. Thanks for the great questions.