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Positive Results for TNX-102 SL in Phase 3 RELIEF Trial
On December 7, 2020, Tonix Pharmaceuticals Holding Corp. (NASDAQ:TNXP) announced positive topline results for the Phase 3 RELIEF trial of TNX-102 SL 5.6 mg in patients with fibromyalgia (NCT04172831). This was a randomized, double blind, placebo controlled trial that enrolled 503 participants at 39 centers in the U.S. In September 2020, the company announced that at the interim analysis the independent data monitoring committee (IDMC) made the non-binding recommendation that the trial continue to completion with the addition of 210 participants to the original sample size of 470 participants, which is the maximum number of participants that could be added under the interim statistical analysis plan. The company decided at the time to complete the trial with the 503 enrolled participants.
The following graph shows the results for the primary efficacy endpoint of the trial, the mean change from baseline in weekly averages of the daily diary pain numerical rating scale (NRS) scores. At week 14, participants on TNX-102 SL had a LS mean change from baseline of -1.9 units compared to -1.5 units for participants on placebo (P=0.01). The graph shows that a statistically significant separation between TNX-102 SL-treated and placebo-treated participants appears intermittently at Week 5, Week 8, and Week 10 and continues consistently from Week 12 to Week 14.
The analysis of the efficacy endpoints involved a sequential test procedure being applied to the primary endpoint and six key secondary endpoints such that each endpoint had to meet statistical significance (P<0.0452) in order for the subsequent endpoints to be considered statistically significant. As explained above, the primary endpoint was statistically significant. The key secondary endpoints examined, in sequential order, were:
1) Patient Global Impression of Change (PGIC)
2) FIQ-R symptom domain score
3) FIQ-R function domain score
4) PROMIS sleep disturbance instrument T-score
5) PROMIS fatigue instrument T-score
6) Daily diary NRS assessment of sleep quality
The PGIC analysis was not statistically significant (37.5% vs. 29.4%; P=0.058), thus due to the sequential test waterfall, the rest of the secondary endpoints could only be considered nominally significant at best even though all of the P values were <0.0452, as shown in the following table.
What is interesting about the PGIC results is that in two prior studies of TNX-102 SL 2.8 mg in fibromyalgia patients, PGIC was statistically significant in both. One explanation for the lack of significance in PGIC in the RELIEF trial could be due to the fact that the trial took place during the COVID-19 pandemic. Since PGIC is not particular to fibromyalgia symptoms, the current environment of uneasiness and uncertainty for everyone may have affected the PGIC results.
In regards to safety, TNX-102 SL was well tolerated similarly to what had been shown previously in the Phase 2 BESTFIT and Phase 3 AFFIRM trials, which both tested TNX-102 SL at 2.8 mg daily. Similar numbers of participants in the TNX-102 SL and placebo arms finished the 14-week dosing period (82.3% vs. 83.5%). The most common adverse events for the TNX-102 SL group were focused on administration site reactions, including tongue/mouth numbness, tongue/mouth pain/discomfort, taste impairment, and tongue/mouth tingling. The only systemic adverse event that occurred in ≥5% of patients was somnolence/sedation at 5.6% in the TNX-102 SL arm. This is consistent with known side effects of cyclobenzaprine, however the rate (5.6%) was lower than reported in previous trials of TNX-102 SL.
We were very glad to see the positive results from the Phase 3 RELIEF trial. The company had previously failed a Phase 3 trial in fibromyalgia with TNX-102 SL 2.8 mg, however the 5.6 mg dose delivered a successful outcome with no apparent difference in the AE profile, in fact systemic AEs such as somnolence were lower in the RELIEF trial than in previous trials. We look forward to updates on enrollment of the RALLY trial and we anticipate results from an interim analysis in the second quarter of 2021 and topline results in the fourth quarter of 2021. Based on the positive results from the RELIEF trial we have raised our probability of approval for TNX-102 SL in fibromyalgia to 70%, which has increased our valuation to $3.50.
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