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Neurotrophin Regulating Drugs to Help Knee OA Pain: What Could Go Wrong?

Published on Dec 30, 2022

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Should we use drugs that regulate critical receptors or instead focus on things that amp up repair? Today I’ll dive deep into a new drug class now being tested that I call neurotrophin regulators. Let’s dive in.

Why Do this Review?

As the Chief Medical Officer (CMO) for Regenexx, it’s my job to know what’s out there well before the average physician knows it’s there. For example, yesterday, I got a text from one of our network providers about a new bone marrow aspiration device on the market. While it’s new to many, it came on my radar in 2019 when we tested it with patients. I hoped it would increase the stem cell numbers we could draw during a bone marrow aspiration. However, our internal lab testing showed that it didn’t perform well, and it was also much more invasive and painful for patients.

The same holds with these new neurotrophin-regulating drugs. They aren’t even on the market yet, but it’s my job to know what they are, how they work, and whether they could help our network physicians treat chronic arthritic knee pain long before any physician gets detailed and sold by a sales rep.

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Pharma 101

If you want to create a new drug, a really easy way to do that is just to take an existing drug class and reswizzle it. That’s what Oxycontin was, which is made from a decades-old drug called oxycodone. If you’re creating a brand new drug class, you can usually bet the farm on something that blocks a critical receptor or pathway in the body. Today we’ll focus on that kind of drug.

Before we go there, let’s review what a receptor does. A cell receptor is like a lock on the surface of that structure that is activated by a specific key. That key is a protein, and when I say “activated,” that could mean anything from a signal to grow more cells to a message that says, “it’s time to self-destruct.” There are thousands of different cell surface receptors that are all usually involved in many different critical body functions.

Neurotrophins

Neurotrophins are proteins that regulate nerve repair and maintenance. Nerve Growth Factor (NGF) is the most well-known of the four mammalian neurotrophins. This substance is produced by your body to regulate the growth, maintenance, proliferation, and survival of nerves. However, NGF is involved in all sorts of processes, including the immune system, ovulation, and pain (1-3). It’s also present in platelet-rich plasma and is believed to be one mechanism by which that substance can help stimulate nerve repair (4).

Blocking NGF to reduce the number of overgrown nerves in a chronically injured area has been postulated as a way that arthritis pain could be treated (5). However, doing that with antibodies against NGF comes with side effects, as one would imagine. From the above-cited paper:

“While anti-NGF therapy has been shown to be efficacious in OA, safety concerns led to the US FDA hold on all clinical testing in 2010. These were based on reports of rapidly progressive OA and of osteonecrosis (ON) among patients who had received anti-NGF therapy, including involvement of joints without known OA.”

Why did these NGF blockers lead to a rapid progression of knee arthritis? Because NGF is involved in adapting cartilage and bone to heavier loads (6). Block NGF and increase your walking because you feel no knee pain, and your body can no longer increase the strength of your cartilage or bones to accommodate the increased loads from all those extra steps.

Fusion Protein Therapy for Chronic Knee Pain

This new drug class of neurotrophin-modulating drugs came on my radar through a UK news article on an ongoing clinical trial of a drug that could be infused once a month to help knee arthritis pain. Some Internet research turned up a company in the UK that put out a press release in 2017 about this drug candidate. From the release (7):

“LEVI-04 is a proprietary p75 neurotrophin receptor fusion protein (p75NTR-Fc) being developed by Levicept as a once-a-month injectable for the treatment of osteoarthritis and chronic pain. It modulates the nerve growth factor (NGF) pathway, clinically proven to provide effective analgesia.”

First, what the heck is a fusion protein? This is a protein made by fusing two genes.

Second, what does the p75 neurotrophin receptor do? It’s where NGF and the other neurotrophins BDNF, NT-3, and NT-4 bind to the nerve cell.

Third, what do these neurotrophins do? While they all regulate nerve cell growth, repair, and maintenance, they also have many other functions that interact with many key body functions. For example, BDNF is essential for learning and memory (8). NT-3 is also involved in learning and memory by regulating the building of new neuronal connections (9). See a trend here? The neurotrophins aren’t just focused on creating new nerves involved in chronic pain but also key things like memory.

Fourth, what exactly is p75NTR-Fc? Levicept owns the patent on this artificial (not naturally occurring) molecule created in the lab (10).

How Does the Company Claim that p75NTR-Fc Works?

The concept is that excess neurotrophins are present in chronic pain states and that p75NTR-Fc binds them. It apparently doesn’t block the neurotrophins involved in cartilage repair, reportedly fixing the problem associated with the anti-NGF antibodies discussed above that lead to the rapid progression of arthritis and osteonecrosis.

This is from the patent:

“p75NTR(NBP)-Fc fusion protein achieves efficacy in the treatment of pain or a symptom of pain by effecting the functional activity of the aforementioned neurotrophins, (defined as modulating or up or down regulating the functional activity of the neurotrophins) NGF, BDNF, NT3 or NT4/5, for example the functional activity of the aforementioned neurotrophins resulting from their interaction with their respective receptors.”

So basically, p75NTR(NBP)-Fc changes the ability of the four neurotrophins (NGF, BDNF, NT-3, and NT-4) to activate their respective receptors.

What Could Go Wrong?

Here’s my big concern. These four neurotrophins are involved in everything from immune responses to ovulation to memory and learning. This new drug class aims to change how they interact with their receptors, with the goal of reducing pain. If the drug were confined to the knee and injected there, it might have minimal side effects on the immune system, reproduction, and memory. But the drug is an IV infusion. Hence, who knows how it impacts these systems? While its clinical trial is designed to detect some of these problems, it’s the long-term impacts that crop up long after FDA approval that scare me (11).

The Sledgehammer vs. The Toolbox

I also have a conceptual problem with drugs given to control pain, as every single one on the market now, based on my clinical experience, has big-time side effects. I call these drugs the sledgehammer as they all interfere with one or more critical receptors or chemical pathways in the body that are involved with pain and other things. It’s the last part of that sentence that causes the problem, as the “other things” are other critical body systems.

The toolbox in this example is represented by orthobiologics designed to increase repair. This is a very different concept from blocking a receptor. The goal here isn’t to negatively impact the “other things” but to target these substances with image-guided injections directly into the area needing repair, thus reducing the negative impacts on the body as a whole. In other words, if we’re going to invent new artificial drugs to treat pain, they should amp up repair and NOT block critical receptors.

The upshot? I wasn’t sure where this journey into these new neurotrophin-regulating drugs would take me. However, as I always say, this blog is as much a way for me to keep up with what’s new as a way to educate patients. So now we’re both educated on what’s coming down the pike over the next few years, so when I get a text three years from now about the fantastic new p75NTR(NBP)-Fc drug for knee arthritis, I’ll have already been there and done that!

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References:

(1) Lambiase A, Bracci-Laudiero L, Bonini S, Bonini S, Starace G, D’Elios MM, De Carli M, Aloe L. Human CD4+ T cell clones produce and release nerve growth factor and express high-affinity nerve growth factor receptors. J Allergy Clin Immunol. 1997 Sep;100(3):408-14. doi: 10.1016/s0091-6749(97)70256-2. PMID: 9314355.

(2) Reis C, Chambel S, Ferreira A, Cruz CD. Involvement of nerve growth factor (NGF) in chronic neuropathic pain – a systematic review. Rev Neurosci. 2022 Jul 7. doi: 10.1515/revneuro-2022-0037. Epub ahead of print. PMID: 35792932.

(3) Ratto MH, Leduc YA, Valderrama XP, van Straaten KE, Delbaere LT, Pierson RA, Adams GP. The nerve of ovulation-inducing factor in semen. Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):15042-7. doi: 10.1073/pnas.1206273109. Epub 2012 Aug 20. PMID: 22908303; PMCID: PMC3443178.

(4) Zheng C, Zhu Q, Liu X, Huang X, He C, Jiang L, Quan D, Zhou X, Zhu Z. Effect of platelet-rich plasma (PRP) concentration on proliferation, neurotrophic function and migration of Schwann cells in vitro. J Tissue Eng Regen Med. 2016 May;10(5):428-36. doi: 10.1002/term.1756. Epub 2013 May 31. PMID: 23723151.

(5) Miller RE, Block JA, Malfait AM. Nerve growth factor blockade for the management of osteoarthritis pain: what can we learn from clinical trials and preclinical models? Curr Opin Rheumatol. 2017 Jan;29(1):110-118. doi: 10.1097/BOR.0000000000000354. PMID: 27672741; PMCID: PMC5436144.

(6) Tomlinson RE, Li Z, Li Z, Minichiello L, Riddle RC, Venkatesan A, Clemens TL. NGF-TrkA signaling in sensory nerves is required for skeletal adaptation to mechanical loads in mice. Proc Natl Acad Sci U S A. 2017 May 2;114(18):E3632-E3641. doi: 10.1073/pnas.1701054114. Epub 2017 Apr 17. PMID: 28416686; PMCID: PMC5422802.

(7) Levicept. Levicept Starts First-in-Human Phase I Trial of LEVI-04, A Novel Fusion Protein Therapy for Chronic Pain. https://www.b3cnewswire.com/201709141635/levicept-starts-first-in-human-phase-i-trial-of-levi-04-a-novel-fusion-protein-therapy-for-chronic-pain.html Accessed 12/30/22

(8) Bathina S, Das UN. Brain-derived neurotrophic factor and its clinical implications. Arch Med Sci. 2015 Dec 10;11(6):1164-78. doi: 10.5114/aoms.2015.56342. Epub 2015 Dec 11. PMID: 26788077; PMCID: PMC4697050.

(9) Shimazu K, Zhao M, Sakata K, Akbarian S, Bates B, Jaenisch R, Lu B. NT-3 facilitates hippocampal plasticity and learning and memory by regulating neurogenesis. Learn Mem. 2006 May-Jun;13(3):307-15. doi: 10.1101/lm.76006. Epub 2006 May 16. PMID: 16705139; PMCID: PMC1475811.

(10) USPTO. P75ntr -fc fusion protein. https://patents.google.com/patent/WO2016146841A1/en. Accessed 12/30/22.

(11) ClinicalTrials.gov. Clinical Trial to Evaluate the Efficacy and Safety of LEVI-04 in Patients With Osteoarthritis of the Knee. https://clinicaltrials.gov/ct2/show/NCT05618782 Accessed 12/30/22