TONIX PHARMACEUTICALS HOLDING CORP. 8-K

Exhibit 99.02

 

 

 

Combined blockade of CD154 and CD28 co - stimulation pathways attenuates pathogenic alloimmunity and prolongs survival in cynomolgus cardiac allografts K. Kinoshita 1 , A. Maenaka 1 , Z. A. Habibabady 1 , M. Ma 1 , V. L. Diaz 1 , I. Ileka 1 , T. Zhang 2 , N. O'Neill 2 , I. A. Rosales 3 , S. Fogarty 4 , P. Maguire 4 , B. Daugherty 4 , S. Lederman 4 , U. Meier - Kriesche 5 ,N. Poirier 6 , A. Azimzadeh 1 , R. N. Pierson III 1 1 Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, 2 Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, 3 Department of Pathology, MGH, Boston, MA, 4 Tonix Pharmaceuticals, Inc., Chatham, NJ, 5 Veloxis Pharmaceuticals, Cary, NC, 6 OSE Immunotherapeutics , Nantes, France KK has no financial relationships with commercial interests to disclose. SF, BD, and SL are Tonix employees, PM is a Tonix consultant, UMK is Veloxs employee, and NP is OSE employee. This work was supported by Tonix through a Sponsored Research Agreement.

 
 

hu5c8  1 st generation anti - CD154 mAb prolonged graft survival in NHP Tx model ( h eart /Kidney/ Islets /skin)  Major thrombotic events in the clinical trial hu5c8 m Ab forms immune complexes with soluble - CD154 via Fc γ RIIa crosslinked s CD154:hu5c8 via Fc γ RIIa a ctivates platelets Background  2nd generation aCD154 reduced efficacy Aglycosyl IgG1 aCD154 Ab (NHP allo islet) FcgR silenced aCD154 domain Ab (NHP allo kidney) ( Ferrant et al 2004) (Kim et al 2016) (Robles - Carrillo L et al 2010)

 
 

hu5c8 Fab Region Fc γ RIIa - modulated Fc region Mutated Fc γ R IIa - binding region ( prevents IC ) FcRn - binding region ( preserve efficacy ) *TNX - 1500 is an investigational new biologic and has not been approved for any indication  3 rd generation: Fc - modified aCD154 mAb TNX - 1500 reduced binding to Fc γ RIIa and retained FcRn binding. ( prevents IC ) ( preserved efficacy ) TNX - 1500:  CD154 IgG4 with retained hu5c8 Fab

 
 

Costimulation Blockade: a CD154 NHP Heart Allograft Survival was significantly prolonged with standard dose TNX - 1500 ( stTNX ) vs low - dose ( loTNX ) > 265 (116 - 305) 99 (35 - 183) 88 (58 - 146) Rejection after cessation of stTNX treatment Explant of beating graft P<0.05 for all comparisons against stTNX Miura et al, AJT 2023 0 30 60 90 120 150180 210240 270300 330 0 20 40 60 80 100 Post-Transplant (Day) G r a f t s u r v i v a l ( % ) stTNX loTNX loTNX+MMF Median survival ( range )

 
 

Platelet activation with hu5c8+soluble CD154 is not seen with TNX - 1500

 
 

 TNX - 1500 S afe , Effective at 20 mg/kg wee kly (Standard Dose) Equivalent to 5c8 at 20 mg/kg monthly (Low Dose) Miura et al, AJT 2023 Heart Tx model in NHP study Poirier et al, Sci Trans Med 2012 Kidney Tx model in NHP study  VEL - 101 (FR 104): anti - CD28 PEGylated monovalent Fab molecule Safe, Effective at 5 or 10 mg/kg weekly  Synergy between VEL - 101 and TNX - 1500 or 5c8 explored with TNX - 1500/5c8 at 20 mg/kg monthly (‘Low Dose’)RK0

 
 

or 5 - 10 mg/kg Twice weekly 5 - 1 0 mg/kg Weekly x2, then Bi - weekly Rx stopped at 90 - 180d Protocol Biopsies Rx stopped at 90 - 400d Low - dose  CD154 5c8 or TNX - 1500 VEL - 101 Anti - CD154 monoRx ‘Low Dose’ Anti - CD28 monoRx Anti - CD154 + Anti - CD28 hu5c8 TNX VEL - 101 TNX +VEL - 101 5c8 +VEL - 101 Methods – Cyno Hetero Heart AlloTx

 
 

5c8 VEL - 101 5c8+VEL - 101 On treatment, stopped d90 5c8+VEL - 101 (extended) On dual treatment, 5c8 stopped d90 On VEL - 101 monoRx 0 30 60 90 120 150 180 0 50 100 Survival proportions: Survival of Allograft Survival (censored) Time (day) P r o b a b i l i t y o f S u r v i v a l hu5c8 FR104 (5 or 10 mg/kg) hu5c8+FR104 (5 or 10) * * * (n=9) (n=7) (n=7) (n=5) Euthanized by protocol for unexplained weight loss * Vel - 101+5c8 prevented graft loss during Rx period Vel - 101 monoRx after dual Rx ‘induction’ prolonged graft survival Results

 
 

loTNX loTNX+VEL - 101 On treatment On VEL - 104 monoRx * * * Euthanasia with beating graft (surgical complication, unexplained weight loss) * (n=4) (n=3) Vel - 101+TNX prevented graft loss during Rx period Vel - 101 monoRx after dual Rx ‘induction’ prolonged graft survival No alloantibody, generally low ISHLT ACR and CAV scores

 
 

loTNX loTNX +VEL - 101 5c8 +VEL - 101 hu5c8 VEL - 101 Anti - donor IgG Anti - donor IgM 0/5 0/5 2/4 (MHC I + II) 1/4 (MHC I + II) 2/7 (MHC I + II) 2/7 (MHC I) 0/5 0/5 0/3 0/3 TNX - 1500 or hu5c8 with VEL - 101 inhibited alloantibody elaboration, class switching *NB: Assay in older h5c8 studies was less sensitive than in contemporary VEL/TNX studies

 
 

Biopsy/Explant<d45 d45<Bx/Ex<d90 d90<Bx/Ex<d180 After off Rx 0 1 2 3 I S H L T S c o r e NA NA NA loTNX loTNX +VEL - 101 5c8 +VEL - 101 hu5c8 VEL - 101 VEL - 101 with either 5c8 or loTNX reduced ISHLT ACR score

 
 

Biopsy/Explant<d45 d45<Bx/Ex<d90 d90<Bx/Ex<d180 After off Rx 0 1 2 3 C A V S c o r e NA NA NA loTNX loTNX +VEL - 101 5c8 +VEL - 101 hu5c8 VEL - 101 VEL - 101 with 5c8 reduced CAV score F urther study of TNX+VEL - 101 is warranted

 
 

 TNX - 1500 efficacy is similar to hu5c8 parent molecule in NHP study - No procoagulant phenotype - Well tolerated: no increase in viral infections or PTLD   CD154 with  CD28 has synergistic effects  durable protection from pathogenic allo - immunity  promising for clinical translation. Conclusions RK0

 
 

 Pierson and Cooper lab Dr Richard N. Pierson III Dr David K. Cooper Shannon Pratts Zahra Abady Akihiro Maenaka Madelyn Ma Victoria Lynn Diaz Ikechukwu Ileka Maho Terashita Gweneth Eliza Lavalla Shuhei Miura Franzi Pollok Gannon McGrath Ryan Chaban Thank you!  Kawai lab Dr Tatsuo Kawai Ryo Otsuka Ahmad Karadagi Toshihide Tomosugi Andrea Yanulevich Grace Lassiter Ashley D'Attilio  Madsen lab Dr Joren C. Madsen Jane M. O Cynthia L. Miller James T. Nawalaniec Samantha M. Landino  Markmann lab Dr James F. Markmann Rudy Matheson Olivia Bourgeois Katsuhiro Tomofuji Daniel Cloonan Taylor M. Coe  Pathology team Dr Robert B. Colvin Ivy A. Rosales  Knight surgery Michael J. Duggan Jessica Marie Burke Anet T. Calisir Nelson Marquez Eli Smith Erin B. Marx Carolyn B. Wike Nicholas M. Deluca  CCM Joanne Morris Desiree N. Meuse Diane Chen Timothy Jones Stephen M. McElroy Lauren Marie Romero