An international phase 2 study suggests a novel neurotrophin-3 inhibitor significantly improves pain and function in knee osteoarthritis.
The first attempt at supplementing p75NTR in people with osteoarthritis has yielded positive results.
There is a significant need to novel pharmacological treatments for osteoarthritis. One potential avenue undergoing exploration is the targeting of neurotrophins known to regulate peripheral pain pathways such as nerve growth factor and neurotrophin-3. NT-3 binds to all neurotrophin receptors, including p75NTR, and also has a key role in cartilage and bone metabolism.
Now, the results of a new prospective phase 2 study tests whether targeting excess neurotrophins with p75NTR supplementation could maintain NGF signalling and offer pain relief without unwanted side effects.
“LEVI-04 is a fusion protein comprising two extracellular domains of the human p75NTR coupled to the fragment crystallisable component of human immunoglobulin G1, acting as a stable analogue of the endogenous neurotrophin binding protein, p75NTR,” researchers wrote in The Lancet.
“Our results support the potential of LEVI-04 as a novel treatment for knee osteoarthritis, improving pain and physical function, and reducing disease burden, coupled with an acceptable side effect profile,” researchers concluded in The Lancet.
Adults aged 40-80 years with a history of knee pain on most days for at least three months and radiographically confirmed knee osteoarthritis (Kellgren-Lawrence grade 2 or greater, as per the ACR clinical and radiographic diagnostic criteria) were recruited from 13 clinical research centres in Denmark, Poland, Moldova, the Czech Republic and Hong Kong. They were not allowed to continue using analgesic medications for osteoarthritis during the trial.
Participants were randomised into one of four groups: 0.3mg/kg, 1.0mg/kg or 2.0mg/kg of LEVI-04, or placebo. Treatment was administered monthly for 16 weeks via intravenous infusion, with the primary outcome measure – the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) numerical rating scale (NRS) version 3.1 pain subscale from baseline – being recorded a week after the final infusion.
Five hundred and eighteen participants were included in the intention-to-treat analysis: 130 in each of the 0.3mg/kg and 1.0mg/kg LEVI-04 groups, 129 in the 2.0mg/kg LEVI-04 group and 129 in the placebo group. Most participants were female (56%), while the mean age was 64 years and the mean BMI was 29.8kg/m2. Participants had an average WOMAC pain subscale score of 5.78.
All doses of LEVI-04 resulted in significantly greater reductions in WOMAC pain subscale scores compared to placebo between baseline and week 17: a least squares mean change of -2.77 for participants receiving 0.3mg/kg, -2.87 for participants receiving 1.0mg/kg, -3.05 for participants receiving 2.0mg/kg and -2.26 for participants receiving placebo.
LEVI-04 also led to greater improvements than placebo in secondary outcomes, including WOMAC pain, physical function and stiffness at week 5, WOMAC physical function and stiffness at week 17 as well as Patient Global Assessment scores and performance on the Staircase-Evoked Pain Procedure.
The most commonly reported treatment-emergent adverse events among the three LEVI-04 groups were arthralgia (ranging between 9% and 12%) and nasopharyngitis (5% to 10%). Seven participants reported serious treatment-emergent adverse events, with none occurring in the 0.3mg/kg group.
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In an accompanying editorial, Professor Tonia Vincent, associate director of The Kennedy Institute of Rheumatology at the University of Oxford in the UK, said the results were “very encouraging” and that they “provide hope that neurotrophin targeting in osteoarthritis pain still has a chance to succeed when all hope appeared to have been lost”.
“The trial shows that LEVI-04 is superior to placebo in significantly suppressing osteoarthritis knee pain in a clinically meaningful, part dose-dependent way. This, the authors claim, is due to neutralising effects on NT-3, whose binding affinity to p75NTR is higher than the other neurotrophins in the family, and whose activity in vitro is completely neutralised by soluble p75NTR,” she wrote.
Professor Vincent felt it didn’t matter which neurotrophin is mediating the benefits of LEVI-04.
“LEVI-04 could be advantageous in that it is able to target the activity of several neurotrophins at the same time according to their relative proportions in the damaged tissue. It is also the case that, as p75NTR can bind the proforms of the neurotrophins as well as the fully processed ligands, it might have additional biological effects, yet to be characterised,” she wrote.
“While additional biological explanations are suggested for why NGF neutralisation is associated with rapidly progressive osteoarthritis, it is intuitive that additional joint loading, enabled by effective analgesia, will exacerbate this mechanically driven disease. Ultimately, combining structure modification with pain-modifying treatments may be the optimal way to ensure good long-term outcomes for our patients.”
