US 20170274071A1 ( 19) United States (12 ) Patent Application Publication (10 ) Pub. No. : US 2017/ 0274071 A1 AGRAWAL ( 43 ) Pub . Date : Sep . 28 , 2017 ( 54 ) COMPOSITIONS AND METHODS FOR (52 ) U .S . CI. TREATING CROHN ' S DISEASE AND CPC . .. A61K 39 / 39533 ( 2013 .01 ) ; A23C 9 / 123 RELATED CONDITIONS AND INFECTIONS (2013 .01 ) ; AIK 2039 /505 (2013 .01 ) ( 57 ) ABSTRACT ( 71 ) Applicant: CENTRE FOR DIGESTIVE In alternative embodiments , the invention provides a “ triple DISEASES , New South Wales (NSW ) combination ” therapy for treating , ameliorating and prevent (AU ) ing Crohn ' s Disease (or Crohn syndrome, terminal or distal ileitis or regional enteritis ) or related disorders and condi (72 ) Inventor : Gaurav AGRAWAL , Manly ( AU ) tions in mammals , such as paratuberculosis in mammals , or Johne ' s disease , including genetically - predisposed and (21 ) Appl. No. : 15 /483 , 702 chronic disorders , where the microbial or bacterial flora of the bowel is at least one causative or symptom -producing ( 22 ) Filed : Apr . 10 , 2017 factor ; and compositions for practicing same. In alternative embodiments , methods and compositions of the invention comprise or comprise use of therapies , medications , formu Related U . S . Application Data lations and pharmaceuticals comprising active agents that (63 ) Continuation of application No . 14 / 405 , 384 , filed on can suppress or eradicate the microbiota super- infection that Dec . 3 , 2014 , now Pat. No . 9 ,616 , 121 , filed as appli causes Crohn ' s Disease or paratuberculosis infection in cation No. PCT/ AU2013 /000587 on Jun . 4 , 2013 . mammals . In alternative embodiments , the methods and uses of the invention for treating , ameliorating and preventing ( 30 ) Foreign Application Priority Data Crohn ' s Disease and complications of Crohn ' s Disease , or related disorders and conditions in mammals , such as para Jun. 4 , 2012 (AU ) .. 2012902307 tuberculosis in mammals , or Johne ' s disease , comprises administration to an individual (human or mammal ) in need thereof : ( 1 ) an anti - TNFa composition , or a composition Publication Classification capable of down -modulating TNFa activity ; ( 2 ) a Hyper (51 ) Int. Cl. baric Oxygen Treatment, or HBOT; and ( 3 ) an anti- Myco A61K 39 /395 ( 2006 .01 ) bacterium avium sub species paratuberculosis MAP( ) ( an A23C 9 / 123 ( 2006 . 01 ) anti -MAP ) agent, composition or therapy. Pre triple therapy . Multiple fistulae Patent Application Publication Sep . 28 , 2017 US 2017 / 0274071 A1 FIG . 1 FIG . 2 Pre triple therapy. Multiple fistulae Completely healed mucosa Post tx FIG . 3 FIG . 4 Pre tx , Recto vaginal fistula Completely healed mucosa Post tx US 2017 /0274071 A1 Sep . 28 , 2017 COMPOSITIONS AND METHODS FOR heal Crohn ' s disease successfully , however healing time can TREATING CROHN ' S DISEASE AND be delayed and may take quite a few weeks or months even RELATED CONDITIONS AND INFECTIONS to induce remission . Anti -MAP Therapy can be slower in acting . When combined with immunosuppressants , such as CROSS -REFERENCE TO RELATED azathioprine or 6 -mercapto -purine , antibiotics do not work APPLICATIONS as they could in Crohn ' s disease possibly due to the [0001 ] This United States Utility patent application is a inhibition of the endogenous immunity . continuation of U . S . Utility patent application Ser . No . 14 / 405, 384 , filed Dec . 3 , 2014 (now pending) , which claims SUMMARY benefit of priority to and is a $ 371 national phase of Patent [0005 ] In alternative embodiments , the invention provides Cooperation Treaty Application Number PCT /AU2013 / methods , treatments or " triple combination " therapies , for 000587 , having an international filing date of Jun . 4 , 2013 , treating , ameliorating and /or preventing a Crohn ' s Disease , which claims benefit of priority to Australian Patent Appli or a complication of a Crohn ' s Disease , or a Crohn ' s cation Serial Number 2012902307, filed Jun . 4 , 2012 . The Disease -related fistulae , or related disorders and conditions aforementioned applications are expressly incorporated by in mammals , such as paratuberculosis in mammals , or reference in their entirety and for all purposes . Johne ' s disease , comprising administration to an individual, a mammal, or a patient in need thereof: TECHNICAL FIELD [0006 ] ( 1 ) an anti - TNFa composition or drug , or a [ 0002 ] This invention generally relates to medicine and composition or a drug capable of down -modulating or gastroenterology, pharmacology and microbiology . In alter down- regulating a TNFa activity ; native embodiments , the invention provides a “ triple com [0007 ] ( 2 ) a Hyperbaric Oxygen Treatment, or HBOT, bination ” therapy for treating , ameliorating and preventing or the medical use of oxygen at a level higher than Crohn ' s Disease ( or Crohn syndrome, terminal or distal atmospheric pressure ; and ileitis or regional enteritis ) or related disorders and condi [ 0008 ] ( 3 ) an anti -Mycobacterium avium sub species tions in mammals , such as paratuberculosis in mammals , or paratuberculosis (MAP ) ( also called M . paratubercu Johne ' s disease , including genetically -predisposed and losis or M . avium ssp .) ( an anti- MAP ) agent, compo chronic disorders , where the microbial or bacterial flora of sition , drug or therapy. the bowel is at least one causative or symptom -producing [0009 ] In alternative embodiments of the methods , treat factor; and compositions for practicing same. In alternative ments or “ triple combination ” therapies of the invention : embodiments , methods and compositions of the invention [0010 ] ( a ) the TNFa activity comprises causing an comprise or comprise use of therapies, medications, formu autophagy or an apoptosis in a cell; lations and pharmaceuticals comprising active agents that [ 0011 ] ( b ) the anti- TNFa composition or drug , or the can suppress or eradicate the microbiota super - infection that composition or drug capable of down -modulating or down causes Crohn ' s Disease or paratuberculosis infection in regulating a TNFa activity, comprises a protein , a peptide or mammals . In alternative embodiments , the methods and uses an antibody capable of specifically binding to a TNFa or a of the invention for treating, ameliorating and preventing TNFa - receptor or TNFa downstream effector; Crohn ' s Disease and complications of Crohn ' s Disease, or [ 0012 ] ( c ) the method , treatment or “ triple combination ” related disorders and conditions in mammals, such as para therapy of ( b ) , wherein antibody is or comprises : an inflix tuberculosis in mammals , or Johne ' s disease , comprises imab or a REMICADETM ( Janssen Biotech , Inc . ) ; an adali administration to an individual (human or mammal) in need mumab or a HUMIRATM ( Abbvie , North Chicago , Ill . ) ; a thereof: ( 1 ) an anti - TNFa composition , or a composition certolizumab , certolizumab pegol or a CIMZIATM , a goli capable of down -modulating TNFa activity ; ( 2 ) a Hyper mumab or a SIMPONITM ; a basiliximab or a SIMULECTTM ; baric Oxygen Treatment, or HBOT; and ( 3 ) an anti -Myco a daclizumab or a ZENAPAXTM ; an omalizumab or a bacterium avium sub species paratuberculosis (MAP ) (an XOLAIRTM ; or, any combination thereof; anti -MAP ) agent , composition or therapy . [0013 ] ( d ) the Hyperbaric Oxygen Treatment or the medi cal use of oxygen at a level higher than atmospheric pres BACKGROUND sure , comprises use or administration of: [0003 ] Crohn ' s disease is a chronic inflammatory condi [ 0014 ] a pressure of about 100 % oxygen , tion most likely caused by some form of infection . The most [0015 ] between about 90 % and 100 % oxygen , likely infective agent is Mycobacterium avium sub species [0016 ] oxygen at about 2 . 5 atm absolute, or between about paratuberculosis (MAP ) . Other infective agents that may 2 and 3 atm absolute , or cause Crohn ' s disease are Mycobacterium tuberculosis [0017 ] oxygen for about 90 minutes or for between about indistinguishable from Crohn ' s disease ; Entamoeba his 1 hour and 2 hours per session or treatment, or tolytica , Escherichia coli, Yersinia enterocolitica & atypical [0018 ] any combination thereof; Campylobacter species . Current therapies aim at reduction [00191 ( e ) the anti -Mycobacterium avium sub species of inflammation but there is an emerging trend to treat the paratuberculosis (MAP ) agent, composition , drug or underlying infection . therapy, comprises administration of : [ 0004 ) Infliximab can suppress a particular segment of the 10020 ] ( 1 ) a macrolide antibiotic ; immune system and exert similar effects in suppressing [0021 ] ( 2 ) a rifabutin and a macrolide antibiotic ; inflammation as azathioprine , 6 -mercapto -purine , Metho [ 0022 ] ( 3 ) a rifabutin or a MYCOBUTINTM , a trexate and Prednisone . Infliximab can have antimicrobial macrolide antibiotic , and a clofazimine ; activity against MAP and MAP containing bacteria . Anti [0023 ] ( 4 ) a combination of a rifabutin , a clarithromycin mycobacterium paratuberculosis ( Anti- MAP ) therapy can and a clofazimine or a LAMPRENETM ; US 2017 /0274071 A1 Sep . 28 , 2017 [ 0024 ] (5 ) any of ( 1 ) to ( 4 ) , wherein the macrolide [ 0043 ] (h ) the anti -MAP agent, composition , drug or antibiotic is or comprises: therapy of ( 3 ) is administered before, during, or after , or in [0025 ] a clarithromycin , or a TRUCLARTM , between sessions of, the Hyperbaric Oxygen Treatment, or CRIXANTM CLARITTTM CLARACTM , HBOT, or the medical use of oxygen at a level higher than