Effect of Time Since Trauma on Response to TNX 102 SL* (Cyclobenzaprine Sublingual Tablets) in Military Related PTSD: Results of Two Double Blind Randomized Placebo Controlled StudiesGregory Sullivan, MD , R Michael Gend

Effect of Time Since

Trauma on Response to TNX 102 SL* (Cyclobenzaprine Sublingual Tablets) in Military Related PTSD: Results of Two Double Blind Randomized

Placebo Controlled StudiesGregory Sullivan, MD , R Michael Gendreau, MD, PhD , Judy Gendreau, MD , Ashild Peters, RN , Perry Peters

, Amy Forst , Jean Engels, MS , Seth Lederman, MD(1)Tonix Pharmaceuticals, Inc., New York, NY 10022; Gendreau Consulting, Poway,

CA 92064; Engels Statistical Consulting, Minneapolis, MN 55044*TNX-102 SL is an investigational new drug and has not been approved

for any indicationTable 2. Participant Demographics and CharacteristicsThe ON/OT/NT- subgroup had a numerically lower decrease

- ( 1.8 points; p=0.523). However, as seen in Figure 3, in P201 sustained remission rates (CAPS-5 total <11 at both Week 8

& 12), were similar between the ON/OT/NT+ and - subgroups. In P301, the ON/OT/NT+ subgroup had an improvement in CAPS-5 of

-5.5 points (p=0.010), relative to the mITT population BDI-II=Beck Depression Inventory-II; CAPS-5=Clinician-Administered PTSD

Scale for DSM-5; MADRS= Montgomery- change of -1.0 point (p=0.602). The P301 ON/OT/NT- subgroup did not improve, with a change

in CAPS-5 of +1.5 points sberg Depression Rating Scale; NA=not applicable - scale not administered in designated

study (p=0.505). In P301 the ON/OT/NT+ group appears to correlate with treatment response in the = 9 year subsample (-13.4 Table

5. P301 CGI I, PGIC, SDS & PROMIS SD Results for points), but not in the > 9 year subsample (-0.6 points). The lack of

response in the > 9 year subsample that was ON/OT/NT+ Table 3. P301 Study Primary Analysis mITT Population Weeks 4 and 12 mITT

Population and =9 Year Subsample indicates treatment response could not simply be due to an unblinding effect (caused by the sublingual

formulation) as this subgroup would be expected to show a treatment response. Together, these findings support the interpretation

that ON/OT/NT events did not account for the observed responses to TNX 5.6 mg in the P201 mITT population or the P301 = 9 year

subgroup. DISCUSSION AND CONCLUSIONSPosttraumatic stress disorder (PTSD) is complex with clear evidence that it has a dynamic

pathophysiology which CGI-I=Clinical Global Impressions - Improvement scale; PGIC, Patient Global Impression of Change scale;

PROMIS SD=Patient-Reported Outcome Measures Information System Sleep Disturbance; SDS=Sheehan Disability Scale changes over time.

Treatment responsiveness over the Table 6. Adverse Events in P201 & P301 (at =5% in TNX Groups) course of the disease may

vary with different (SUDs) within 6 pharmacological classes, and may also differ between PTSD months; lifetime from combat versus

other types of trauma (Figure 4). US bipolar, psychotic, epidemiologic study suggests a quarter to a third of PTSD obsessive-

remits within 1(st)year of symptom onset, another third compulsive, or remits over the next 4-5 years, and, in over a third, PTSD

antisocial personality persists for many years.(10)A comparable pattern of PTSD disorders. Table 1 lists CAPS-5=Clinician-Administered

PTSD Scale; LS=least squares; MCFB=mean change from baseline; SE=standard error persistence beyond 6 years is observed in OEF/OIF

service differences between members.(11)Several longitudinal studies of diverse PTSD Table 4. P301 Study Subsamples on CAPS =9

& >9 Years Since Trauma samples have defined a similar trajectory pattern of early P201 and P301. *no values in a row for

either study means the AE in the active group(s) in the study at a rate of <5% rapid remitters, slower remitters, and a non-remitting

group with persistent PTSD in 17-40%.(12-15)SSRIs have been RESULTS Safety shown to be effective in civilian samples with mean

times P201 enrolled 245 participants (modified Intent-To-Treat [mITT]= 231). In the primary There were no serious and unexpected

adverse events (AEs) in since trauma of 15 years or more,(6-8)and one trial reported analysis using MMRM, TNX 2.8 mg did not separate

significantly from PBO at Week 12 P301 or P201. The AEs observed in both studies (Table 6) were a treatment by time-since-trauma

interaction suggesting (p=0.259). TNX 5.6 mg showed a strong trend for difference from PBO (MMRM, comparable and also consistent

with the experience in prior greater response to paroxetine in those with index trauma p=0.053; effect size [ES]=0.36), and in

the sensitivity analysis MMRM with multiple studies in fibromyalgia. Observed systemic AEs were consistent greater than 5 years

prior.(9)In contrast, a similar pattern as imputation (MI), p=0.031. Also, at Week 12, TNX 5.6 mg had more Clinical Global with

those described in approved oral cyclobenzaprine product seen with TNX may be extrapolated from prazosin studies, Impressions

- Improvement (CGI-I) responders (63%, p=0.041, logistic regression) labels. Similar severity and incidence of oral hypoaesthesia

which improved sleep and global measures in active duty compared to PBO (45%), and greater improvement on Patient Global Impression

of (tongue/mouth numbness) is reported across studies (37% in military close to combat trauma,(4)but had no effect in Change and

the social and work domains of the Sheehan Disability Scale (SDS) (MMRM, P301; 36% in P201) for TNX 5.6 mg. veterans mostly >9

years out (~70%)(3)Comparison of the all p=0.05). Retrospective subgroup analysis of P201 subjects with baseline CAPS-5 =33--

P301 and P201 studies points to a differential treatment a threshold comparable to that used in precedent studies with older CAPS

versions and Retrospective Analyses of Participants with Administration effect with TNX in a military sample based on time since

was the threshold used in the Phase 3 study P301, demonstrated improvement of TNX Site Reactions trauma, with greater effect within

9 years of the index 5.6 mg over PBO at Week 12 by -6.8 points with ES=0.53 (MMRM, p=0.013). TNX is a sublingual tablet that rapidly

disintegrates in the mouth CAPS-5=Clinician-Administered PTSD Scale; Diff=least squares mean difference; LS=least squares; MCFB=mean

change trauma. It is not clear how SSRIs would behave in military from baseline and results in transmucosal absorption of cyclobenzaprine.

sample closer to trauma, although one study described a P301 had 274 randomized participants (mITT=252) for the interim analysis.

Table 2 treatment non-responsive, meaning no improvement on TNX-5.6 mg at Week Some local administration site reactions that occurred

in TNX better response to fluoxetine among combat veterans in Europe with relatively short time since trauma.(1)provides the demographic

and baseline characteristics for both studies. The two studies 12 (numerical increase in CAPS-5 of +1.8 points, p=0.509). The

lack of response treated groups more than placebo include oral numbness (ON, - The Phase 3 P301 study differed from the Phase

2 P201 study because median time since index trauma in the P301 TNX were comparable on most characteristics, although it is notable

that median time since to TNX in the > 9 year group was attributable to a high placebo response at oral hypoaesthesia), oral

tingling (OT, oral paraesthesia) and 5.6 mg group was 9.5 years, whereas it was only 6 years in P201 index trauma in the P301

TNX 5.6 mg group was approximately 1.5 times (Figure 1) as Week 12 (least squares mean change from baseline -14.1 points). noticeable

taste (NT). ON events are typically mild and transient - The =9 year subgroup of the P301 study essentially replicated the

results of the P201 mITT TNX 5.6 mg group long (9.5 years) as in the P201 TNX 5.6 mg group (6 years). As shown in Table 3, the

P301 In Table 5, the results of the P301 mITT population and the P301 =9 year (typically <60 min) and rarely lead to discontinuation.

ON/OT/NT - Time since index trauma is important in the treatment response, as in is more difficult to demonstrate a response

in primary analysis at Week 12 was not significant (LS mean [standard error] difference -1.0 subsample are presented for the key

secondary measures of CGI-I and SDS, and experiences were not elicited systematically and may have had those with >9 years

since trauma [1.88], p=0.60, MMRM with MI), yet, there was notable separation from placebo on the the PGIC and PROMIS SD for Week

4 and Week 12. None of these fours variable reporting. ON/OT/NT events are episodic and observed - The TNX treatment-responsive

phase of PTSD may correspond to the "remitting" phase of Kessler et al. (10)(see Figure 4). primary at Week 4 - (

3.6 [1.51], p=0.019). Several retrospective analyses were performed measures differed from placebo at Week 8 in the =9 year subsample

(data not infrequently. ON adverse event rate also has been consistent - The P301 and P201 studies help to advance the clinical

development of TNX-102 SL, i.e. future studies will focus on to better understand how to design future studies and identify the

potential group of shown). Note that for the =9 subsample, all four measures showed a p-value across studies. participants with

more recent trauma (=9 years) responders. <0.05 at the Week 12 endpoint, indicating possible global recovery, functional To

investigate the possibility of ON/OT/NT events for potential - Treatment response with TNX in P301 decreases over time since

trauma (lack of separation from PBO), suggesting recovery, and improved sleep quality after 12 weeks of treatment compared unblinding,

individuals were grouped as either having military service members and veterans with PTSD >9 years are transitioning from a

treatment responsive state to a non-with placebo. Similar results were seen in P201 with the mITT TNX 5.6 mg experienced ON/OT/NT

event or not (+ or -). In P201 and P301, Retrospective Analysis on Time since Trauma responsive state and emphasizes the urgency

for early diagnosis and treatment for PTSD, especially military-related group. experiencing ON/OT/NT event(s) seems to correlate

with PTSD The median time since trauma in P301 was approximately 9 years. When P301 Figure 2 shows the levels of remission (CAPS-5

<11) in P301 that was sustained treatment effect based on some post hoc analyses, but not Citations: (1)Martenyi et al. J Clin

Psychiatry 2002;63:199-206.(2)Friedman et al. J Clin Psychiatry 2007;68:711-720. (3)Raskind et al. NEJM 2018;378:507-517. (4)Raskind

et al. Am J participants are divided into two subsamples (Table 4), one with index trauma within 9 at both Weeks 8 and 12 in the

P301 =9 year subsample next to the comparable others. In P201, the TNX 5.6 mg ON/OT/NT+ subgroup had an Psychiatry 2013;170:1003-1010.

(5)Shalev et al. Arch Gen Psychiatry 2012;69:166-176. (6)Davidson et al. Arch Gen Psychiatry 2001;58:485-492. (7)Brady et al.

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Week 12 of -5.9 points, p=0.039). In contrast, those in the > 9 year group were studies although formal comparisons between

studies may not be feasible. points (p=0.053).