On Oct. 31, 2018 Tonix Pharmaceuticals (TNXP) announced that "it plans to start a new Phase 3 trial of Tonmya® for the treatment of posttraumatic stress disorder (PTSD) in the first quarter of 2019,...".
Previously, Tonix has completed a phase 2 trial, AtEase (P201), and started a phase 3 trial, HONOR (P301), which was stopped after the interim analysis "due to inadequate separation from placebo on the primary endpoint at week 12", as announced on July 27, 2018.
Seth Lederman, the CEO, commented in the Oct 31, 2018 PR,
“Results from our Phase 3 HONOR study strengthened the design of the new Phase 3 study,... We believe the innovative design features of this new Phase 3 study will expedite the development of Tonmya for PTSD." [emphasis added]
The CEO's optimistic comments compel me to re-evaluate whether or not my earlier bullish thesis (a high risk/high reward, speculative BUY) is still valid.
HONOR interim results
HONOR was a randomized, placebo-controlled trial in military-related PTSD. Its primary efficacy endpoint was the difference in the 12-week mean change from the baseline in the CAPS-5 scores (a standard for measuring the severity of PTSD symptoms) between the Tonmya 5.6mg group and the placebo group.
The higher the CAPS-5 score, the more severe PTSD symptoms are.
Likewise, a greater decrease in CAPS-5 score means a greater improvement in PTSD symptoms.
Graph 1 below shows the results from the interim data of HONOR.
Graph1 (Source: Tonix November 2018 Presentation, slide 35; Orange highlight by Author)
It shows that HONOR's interim data did not meet the primary end point. At week 12, there was insufficient separation between the Tonmya 5.6mg group and the placebo group, with no statistically significant difference.
AtEase post-hoc analysis
With the results shown in Graph 1, it is hard to imagine how anybody would have a bullish thesis prior to HONOR interim analysis on July 27, 2018.
To understand how, one needs to go back to see a post-hoc analysis of the modified intention-to-treat population, CAPS-5≥ 33 (HONOR's patients; a subgroup in AtEase), as shown in Graph 2.
Graph 2 (Source: Tonix July 2018 Presentation, slide 22; Orange highlight by Author).
There are three points to note here:
- This is a post-hoc analysis of a subgroup in AtEase.
- The blue line shows the results of this subgroup using Tonmya 5.6mg* in patients with entry CAPS-5 ≥33*
(* the changes designed for HONOR based on this post-hoc analysis).
- The blue line shows statistically significant results at all the time points measured in AtEase (i.e. week 2, 4, 8, 12).
In other words, the blue line in Graph 1 (HONOR) was designed to repeat the blue line in Graph 2 (AtEase sub-group), especially at week 12, the primary efficacy point.
And this was the basis of a bullish thesis! That was until the July 27, 2018 PR.
HONOR post-hoc analysis
Since HONOR's interim data did not repeat the results of the AtEase subgroup, Tonix has conducted another post-hoc analysis and identified a new sub-group (patients who experienced an index trauma within 9 years or TST, Time-Since-Trauma, ≤ 9 years).
Graph 3 below shows the results of this new sub-group in HONOR.
Graph 3 (Source: Tonix Nov 2018 Presentation, slide 35)
Again, three points to note here:
- This is also a post-hoc analysis of a subgroup in HONOR.
- The blue line shows the results of this subgroup using Tonmya 5.6mg* in patients with entry CAPS-5≥ 33*
(* the changes designed for HONOR based on AtEase post-hoc analysis)
- The blue line shows statistically significant results, at weeks 4 and 12, but not at week 8.
So can the HONOR post-hoc analysis support a bullish thesis, as the AtEase post-hoc analysis supported a bullish thesis?
Can HONOR post-hoc analysis support a bullish thesis?
Graph 4 below shows the interim data of HONOR in the whole group (Graph 1) and the results of a subgroup from HONOR post-hoc analysis (Graph 3) side by side.
Two points to note here:
- The blue lines (the TNX-102 SL 5.6mg groups) are almost identical, i.e. Tonmya performs no better (or worse) in the TST ≤ 9 yrs subgroup than in the whole group.
- The red lines (the placebo groups), however, are quite different, i.e. the placebo effect is markedly smaller in the subgroup (graph on the right) than in the whole group (graph on the left).
In summary, the better results seen at weeks 4 and 12 in HONOR post-hoc analysis (Graph 3, on the right) is due to smaller changes in the placebo subgroup, and not greater efficacy (treatment effect) in the treatment subgroup.
[Update 11/07/2018: The section entitled 'Problems with the data behind Graph 1 and 3' has been removed after contact with TNXP management.]
'Innovative Design' in Tonix's next phase 3 study
Based on a post-hoc analysis of HONOR's interim data, the company has proposed, and the FDA has accepted, 'several new design features into the new Phase 3 study' as indicated in the Oct 31, 2018 PR.
[Update 11/09/2018: After an update on 11/07/2018, there are no longer Table 1 & 2 in this article (i.e. HONOR's interim data as reported in the slide 30 and 40 of Tonix November 2018 presentation). Where it used to say 'data from the Table 1 and Table 2' is now replaced with 'HONOR's interim data' in the first sentence of this section.]
These new design features are:
- 'restricting enrollment of study participants to individuals with PTSD who experienced an index trauma within nine years of screening.'
- including 'study participants who have experienced civilian traumas, in addition to inclusion of those with military-related traumas.'
- 'the CAPS-5 primary end point will be assessed at week 4 instead of at week 12.'
It should be obvious to most why these feature are new. Nevertheless, let me state again for emphasis.
- The inclusion criteria of AtEase and HONOR was baseline CAPS-5 score, and not TST (Time-since-Trauma).
- Tonix's two prior PTSD trials enrolled only military-related PTSD patients, and did not include civilian PTSD patients.
- For both AtEase and HONOR, the CAPS-5 primary end point was assessed at week 12, and not at week 4.
How do these new features affect the probability of success for Tonix's next trial?
Firstly, Tonmya did not show a greater efficacy in TST ≤9 years subgroup. Instead the better results at week 4 and 12 were due to changes in the placebo data for this subgroup. Therefore, the relevancy or advantage of this new entry criteria (TST ≤9 years) is unknown.
Secondly, in military-related PTSD, both AtEase and HONOR did not meet the pre-specified primary end point, but only found better results in post-hoc analysis of a subgroup (not in the trials' intend-to-treat patients or modified ITT population). Adding civilian PTSD patients adds significant risks to Tonix's already-complex-and-hard-to-succeed military-related PTSD trial, as the company had never studied civilian PTSD before.
Lastly, changing the efficacy end point assessment to week 4 from week 12 is the only change which makes sense, based on HONOR interim data and AtEase post-hoc analysis. This change should be positive, as CAPS-5 will remain as an entry criteria in the next trial, in addition to the new TST criteria (see slide 46, Tonix November 2018 presentation).
[Update 11/07/2018: I corrected an earlier inaccuracy that only the new TST will be the entry criteria for the next trial. I also update the affected discussion in the conclusion].
Limited data on improved sleep quality to support Tonmya's Mechanism of Action for PTSD efficacy
Considering Tonmya's stated mechanism of action is to target sleep quality as a means to facilitate a better recovery from PTSD (i.e. better sleep quality --> better processing of memories related to trauma --> improvement in PTSD symptoms --> decreasing CAPS-5 score), Tonix reported very limited data on improved sleep quality to support/confirm the effectiveness of this approach.
There are, in my views, at least two possible explanation for this lack of emphasis on the data of sleep quality improvement:
- Tonmya may not improve the sleep quality of military-related PTSD patients effectively; or
- Even if Tonmya succeeds in #1, it has not then translated to a clinically meaningful reduction of PTSD symptoms (i.e. there is no correlation between improved sleep quality and decrease in CAPS-5 score) to date in Tonix's PTSD trials.
It is very possible that PTSD is too complex a serious condition with multiple significant variables, heterogeneous patient population, for a treatment like Tonmya with an indirect mechanism of action to prove its efficacy conclusively and successfully.
I asked earlier: Can HONOR's post-hoc analysis support a bullish thesis?
For me, the answer is a NO, as Tonyma did not appear to work better in the subgroup than in the whole group (i.e. the relevancy or advantage of the new entry criteria is unknown).
Can one be optimistic about the 'innovative design features' in expediting Tonmya's development in PTSD, like Tonix's CEO?
Two out of three new features add significant risks and there is only one new feature that is positive. Therefore the answer is also a NO.
I don't think that a bullish thesis in Tonix is valid going forwards, as Tonmya for PTSD is the most advanced drug candidate for this company. Another phase 3 trial failure will likely devastate the company beyond the point of no return.
Thanks very much for reading. On a personal note, I'm very sorry to have reached such a conclusion in my re-evaluation. Nevertheless I feel it would be wrong not to write this update, given my past bullish coverage on Tonix. Please do NOT base your investment decision on this (or other) SA articles alone, but consider them as intended--a help for your own DD. All the best!
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