Trial Breathes New Life Into Neurotrophins as Target in Osteoarthritis

An investigational infusion drug provided more pain relief for patients with osteoarthritis (OA) of the knee than did placebo in a 17-week, phase II clinical trial, researchers said.

Pain scores as rated with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) fell by half in patients receiving the agent, called LEVI-04, at various doses, according to Philip Conaghan, MBBS, PhD, of the University of Leeds in England, and colleagues.

As is often the case in pain-drug trials, WOMAC scores (rated 0-10 for pain) also improved substantially in the placebo group. Still, between-group differences at week 17 were statistically significant at all LEVI-04 dosage levels, Conaghan’s team reported in The Lancet:

• LEVI-04 0.3 mg/kg vs placebo: -0.51 (95% CI -0.96 to -0.07)
• LEVI-04 1.0 mg/kg vs placebo: -0.62 (95% CI -1.07 to -0.17)
• LEVI-04 2.0 mg/kg vs placebo: -0.79 (95% CI -1.24 to -0.35)

And importantly, no patients appeared to develop rapidly progressing OA, an adverse effect that sank another once-promising drug targeting the same pathways several years ago.

That led Tonia Vincent, PhD, of the University of Oxford in England, to express cautious optimism in an accompanying editorial.

“These results are very encouraging,” she wrote, “and provide hope that neurotrophin targeting in osteoarthritis pain still has a chance to succeed when all hope appeared to have been lost.”

That was an allusion to tanezumab, a monoclonal antibody targeting nerve growth factor (NGF), a member of the broader neurotrophin family, which Eli Lilly and Pfizer brought to the FDA in 2020, only to have it shot down by an agency advisory committee. Clinical holds were placed on the drug’s phase II and phase III trials after a few patients developed rapidly progressing OA; while they eventually were completed, the FDA and its European counterpart determined that tanezumab’s benefits (compared with existing analgesics) weren’t great enough to outweigh the extra risks.

That was thought to spell the end of drugs targeting neurotrophin pathways, but the British firm Levicept pressed ahead with its differently designed product LEVI-04. Conaghan and colleagues described it as “a fusion protein comprising two extracellular domains of the human p75NTR coupled to the fragment crystallizable component of human immunoglobulin G1, acting as a stable analogue of the endogenous neurotrophin binding protein, p75NTR.” The latter acts as a receptor for NGF and other neurotrophins. But while NGF has a range of effects beyond pain signalling, including regulatory roles in bone and cartilage metabolism, LEVI-04’s effects are more narrowly focused on pain transmission than those of anti-NGF antibodies like tanezumab, the authors explained.

Study Details

Conaghan and colleagues randomized 518 patients from four European countries and Hong Kong with knee OA in equal numbers to receive infusions of placebo or LEVI-04 at one of three doses, given monthly through week 16. WOMAC scores for pain, function, and stiffness were calculated at weeks 5 (after two doses) and week 17 (four doses). Radiographic analyses were performed at baseline and week 20; adverse effects were tracked to week 30.

Mean patient age was about 64 and a little over half the sample were women. WOMAC pain scores in the target knee at baseline averaged 5.74-5.82 in the four study arms; scores in the contralateral knee were about 2 points lower. Half the sample had joint degeneration at baseline rated as Kellgren-Lawrence grade 3 in the target knee, and about 30% were at grade 4.

Mean WOMAC pain scores declined by 2.18-2.43 points as of week 5 in the three LEVI-04 arms, compared with a 1.57-point decrease with placebo (all P<0.05). By week 17, the change from baseline stood at -2.77 to -3.05 with the active drug, versus -2.26 in the placebo group.

Similar results were seen for WOMAC function and stiffness scores, all greater with LEVI-04 though with a still-substantial improvement compared with placebo.

Treatment-emergent adverse events occurred at similar rates in all four study arms, and nothing stood out as clearly more common with LEVI-04 at any dose. A few cases of rapidly progressing OA were seen — two with the middle dose, one with the high dose, and one in the placebo group — but these only reflected joint-space narrowing without actual destruction.

Still, in her editorial, Vincent noted that 4 months of dosing is not enough for adequate judgment on the risk for rapidly progressing OA. “[T]his was a short study and the study team selected their patient population carefully. For instance, they excluded those with changes on joint imaging that appeared, from retrospective analyses of the anti-NGF trials, to be associated with increased risk of rapidly progressive osteoarthritis, such as large bone cysts.”

This was not necessarily a study flaw, she added, but “may be a pragmatic approach worth considering for all new analgesic trials in osteoarthritis.” As well, the underlying cause of sudden rapid OA progression isn’t well known but could actually stem from effective pain relief, encouraging patients to resume high-load activities that their joint tissues can no longer withstand, Vincent offered.

Another question for future studies is whether the degree of pain relief seen in the trial is clinically significant. In 2020, another study led by Conaghan addressed the question of what degree of WOMAC pain score change is meaningful for patients. It indicated that scores must improve by at least 0.8 points to be clinically meaningful.

In the current study, this standard was met easily when looking only at change from baseline in the three LEVI-04 dosage groups, but it never reached it when compared with placebo.

Levicept has not yet started a phase III trial, but has announced plans to do so.