Natural  Pain  Medica/ons   Nadurel  Pharma  Inc   November  ,  2012   ©  CuraPhyte  Technologies  Inc  

Droxanol   •  Drug  Class:   –  NSAID  /  COX  inhibitor  

•  Key  clinical  advantage  :   –  Safety  profile:    no  side  effects  typical  of  a   conven/onal  COX  inhibitor*    

*  Not  observed  in  more  than  20  clinical  trials  and  post-­‐marke7ng  surveillance.   ©  CuraPhyte  Technologies  Inc  

Pavosic   •  Drug  Class:   –  Opioid  &  5-­‐HT1A  +  5-­‐HT7   –  Analgesic  +  HypnoIc/sedaIve  

•  Key  clinical  advantage:   –  Safety  profile:   •  No  addic/on/physical  dependence     •  High  tolerability  versus  conven/onal  narco/cs.  

©  CuraPhyte  Technologies  Inc  

Plant  Tradi/onal  Medicine  

Devil’s  claw  (Harpagophytum  procumbens)   •  South   African   plant   recognized   for   its   anI-­‐inflammatory   properIes.   •  AcIve  part  of  the  plant  is  the  dried  secondary  roots.     •  An  anI-­‐inflammatory,  anIrheumaIc  and  analgesic  remedy.     •  Doses*  range  from  0.6  to  9  grams  of  the  dried  root  daily  (or  the   equivalent  in  the  form  of  a  dried  extract).   Droxanol: Equivalent to 3744 mg dried root per tablet (23.4 mg harpagoside per tablet)

*  Doses  considered  safe  by  regulatory  agencies  around  the  world.   ©  CuraPhyte  Technologies  Inc  

Plant  Tradi/onal  Medicine  

Devil’s  claw  (Harpagophytum  procumbens)   •  The  iridoid  glycoside,  harpagoside,  linked  to  its  anI-­‐inflammatory  and   analgesic  benefits.   •  PD  &  PK  -­‐  3  studies  in  human  volunteers*:   –  RelaIon  between  serum  harpagoside  levels  and  the  inhibiIon  of   leukotriene  biosynthesis.   –  Maximum  levels  of  plasma  harpagoside  reached  a\er  1.3  to  2.5   hours.     •  A  linear  relaIonship  between  dose  and  the  first  maximal   concentraIon  (Cmax)  or  area  under  the  curve  (AUC).   –  Harpagoside  eliminaIon  half-­‐life  has  been  reported  as  5.6  hours.   *  Clin  Pharmacol  Ther.  2001  May;69(5):356-­‐64.   ©  CuraPhyte  Technologies  Inc  

Plant  Scien/fic  Evidence  

Devil’s  claw  (Harpagophytum  procumbens)   •  Enteric  coa/ng  required:   –  Studies  demonstrated  loss  of  anI-­‐inflammatory   effects  by  oral  administraIon   –  Dose-­‐dependent  effects  observed  with   intraperitoneal  and  intraduodenal  administraIon   –  Enteric  coaIng  -­‐  protecIon  of  efficacy  demonstrated   –  Droxanol  has  an  enteric  coa/ng  that  conforms  to   USP  standards.   ©  CuraPhyte  Technologies  Inc  

Plant  Scien/fic  Evidence  

Devil’s  claw  (Harpagophytum  procumbens)  

InhibiIon  of  Cyclo  Oxygenase  2  

Assists  the  extracellular  matrix     construcIon  (synthesis  of  GAGs)  

Synthesis  of  hyaluronic  acid   (human  chondrocytes)  

Iridoids (harpagosides) interact with Arachidonic Acid metabolism pathways: • Action on eicosanoids synthesis • Action on cyclo-oxygenase, lipoxygenase and NO synthetase • Action on TNFa liberation • Action on Cys-LT synthetis • Action on enzymes responsible for collagen degradation ©  CuraPhyte  Technologies  Inc  

Manufacturer’s in-house data.

Plant  Scien/fic  Evidence  

Devil’s  claw  (Harpagophytum  procumbens)   •  Over 23 clinical trials in patients with OA, RA or low back pain. Double-blind-RCT: 6 trials –  Articular pain; 2 g root/day (n=89; 2 mnths Rx) –  Knee or hip OA (n=122; 4 mnths Rx) –  Active Controlled: Harpadol (2.6 g/day) vs 100 mg Diacerhein - knee or hip OA (n=122; 4 mnths Rx) –  Active Controlled: Doloteffin (60 mg harpagoside/day) vs 12.5 mg Vioxx - low back pain (n=44; 6 wks Rx) –  Pain of back, shoulder & neck (n=63; 4 wks Rx) –  Active Controlled: phenybutazone (300mg/day D1-4; 200mg/day D5-28) (n=50; 28 days Rx)

Placebo-RCT: 7 trials –  –  –  – 

1 trial: osteoarthritis (n=46; 20 wks Rx) 1 trial: arthritis (n=50; 3 wks Rx) 2 trials: low back (n=197 & 118; 4 wks Rx) 3 trials: rheumatic conditions (n=100 each; 30-days Rx) ©  CuraPhyte  Technologies  Inc  

Plant  Scien/fic  Evidence  

Devil’s  claw  (Harpagophytum  procumbens)   –  Observational post-marketing trial: 4 trials •  N=250 (104-low back, 85 knee OA, 61 hip OA); 8wks Rx •  N=675 (OA, spondylarthropathies, fibromyalgic); 8wks Rx •  N=630 arthritis conditions; 6mnths Rx •  N=13 arthritic symptoms; 6wks Rx –  Uncontrolled –Open-label trial: 3 trials+ •  75 patients – hip, knee OA -12-weeks •  130 patients – chronic back – 6-months •  102 patients – acute low back - 6-months

©  CuraPhyte  Technologies  Inc  

Plant  Scien/fic  Evidence  

Devil’s  claw  (Harpagophytum  procumbens)   •  According  to  UpToDate  (www.uptodate.com):   –  "Devil's  claw  reportedly  improves  joint  mobility  and   reduces  pain  and  swelling  in  arthriIs."   –  "It  may  be  more  effecIve  for  osteoarthriIs  as   compared  to  rheumatoid  arthriIs."   –  "It  may  be  more  effecIve  for  chronic,  rather  than   acute,  arthriIs  symptoms."  

*UpToDate®  is  an  evidence-­‐based  clinical  decision  support    system  authored  by  physicians     ©  CuraPhyte  Technologies  Inc  

Plant  Scien/fic  Evidence  

Devil’s  claw  (Harpagophytum  procumbens)   •  "There  is  a  growing  body  of  scien7fic  evidence  

sugges7ng  that  devil's  claw  is  safe  and  beneficial  in  the   short-­‐term  management  of  pain  related  to   degenera7ve  joint  disease  or  osteoarthri7s.  It  may  be   equally  effec*ve  as  drug  therapies,  such  as  non-­‐ steroidal  an7  inflammatory  drugs  (or  may  allow  for   dose  reduc*ons  or  cessa*on  of  these  drugs  in  some   pa7ents).“  –  Natural  Standard  database*  

*Natural  Standard  is  imparIal;  not  supported  by  any  interest  group,  professional  organizaIon  or  product  manufacturer.   ©  CuraPhyte  Technologies  Inc  

Plant  Scien/fic  Evidence  

Devil’s  claw  (Harpagophytum  procumbens)   •  Double-blind, randomized, multicentre clinical study: –  Harpadol (6 capsules/day; 2610 mg/day). Droxanol: Equivalent to 3744 •  9.5mg harpagoside/capsule (57 mg/day). mg dried root per tablet (23.4 mg •  435 mg powdered cryoground Harpagophytum harpagoside per tablet) procumbens. –  Diacerhein 100 mg/day –  Rx 4 months; 122 patients OA knee and hip. –  Evaluations: •  pain & functional disability: 10 cm horizontal VAS. •  severity of OA: Lequesne's index. ©  CuraPhyte  Technologies  Inc  

Plant  Scien/fic  Evidence  

Devil’s  claw  (Harpagophytum  procumbens)   •  Double-blind, randomized, multicentre clinical study (contd):

–  Results: •  Spontaneous pain = significant improvement; no difference between groups. •  Progressive & significant ↓ Lequesne functional index; no statistical difference. •  End of trial: –  Harpadol significantly less NSAIDs and antalgic drugs. –  Frequency of AE was significantly lower in Harpadol group. –  Most frequent AE = diarrhea, occurring in 8.1% and 26.7% of Harpadol and diacerhein patients respectively. ©  CuraPhyte  Technologies  Inc  

Plant  Scien/fic  Evidence  

Devil’s  claw  (Harpagophytum  procumbens)   Droxanol: •  Double-blind clinical study: Equivalent to 3744 –  89 patients with articular pain received 670mg of mg dried root per devil's claw three times daily (total of 2010 mg dried tablet (23.4 mg root) for 2 months. harpagoside per tablet) –  Results: •  Significant decrease in severity of pain and a significant increase in spinal and cofexomoral mobility in the experimental group. •  No side effects or changes in safety parameters were observed.

–  Lecomte  A  and  Costa  JP.  Harpagophytum  dans  l'arthrose:   Etude  en  double  insu  contre  placebo.  Le  Magazine   1992;15:27-­‐30. ©  CuraPhyte  Technologies  Inc  

Plant  Scien/fic  Evidence  

Devil’s  claw  (Harpagophytum  procumbens)   •  Placebo-controlled clinical study: –  50  arthriIc  paIents  receiving  devil's  claw,  two  capsules  of   400mg  three  Imes  daily  for  3  weeks   –  StaIsIcally  significant  decrease  in  severity  of  pain  was   measured,  with  more  frequent  improvements  in  moderate   cases  compared  to  more  severe  cases.   –  Guyader  M.  Les  plantes  anIrhumaIsmales.  Etude  historique  et  pharmacologique,   et  etude  clinique  du  nebulisat  d'Harpagohytum  procumbens  DC  chez  50  paIents   arthrosiques  suivis  en  service  hospitalier  [DissertaIon].  Universite  Pierre  et  Marie   Curie,  1984.

©  CuraPhyte  Technologies  Inc  

Plant  Scien/fic  Evidence  

Devil’s  claw  (Harpagophytum  procumbens)   •  20-week, Randomized, Placebo controlled study: Droxanol: –  46 patients with OA hip. –  Two tablets per day (extract equivalent to 2400 mg dried root, or placebo tablets. –  Both groups also received identical, stepwise-reduced daily doses of ibuprofen: 800mg daily for the first 8 weeks, 400mg daily for a further 8 weeks, and none during the last four weeks of the study. –  Efficacy: WOMAC index. –  Frerick  H,  Biller  A,  and  Schmidt  U.  Stufenschema  bei   Coxarthrose.  Der  Kassenarzt  2001;5(34):41.

©  CuraPhyte  Technologies  Inc  

Equivalent to 3744 mg dried root per tablet (23.4 mg harpagoside per tablet)

Plant  Scien/fic  Evidence  

Devil’s  claw  (Harpagophytum  procumbens)   •  20-week, Randomized, Placebo controlled study (contd): –  WOMAC: •  Scores decreased in both groups over the study period, despite the reduced dose of ibuprofen. •  Sub-scores for stiffness, pain and dysfunction decreased similarly in both groups. –  In final ibuprofen-free period: •  Increase of 20% or less in the pain score was considered a clinically relevant response rate: –  71% of devil's claw patients –  41% of placebo patients (p=0.04). •  52% of patients in the devil's claw group, compared to 36% in the placebo group, were able to complete the study without using rescue therapy during the ibuprofen-free period. ©  CuraPhyte  Technologies  Inc  

Plant  Scien/fic  Evidence  

Devil’s  claw  (Harpagophytum  procumbens)   •  Randomized, Placebo controlled clinical study: –  100  paIents  suffering  from  various  rheumaIc  pain   Droxanol: syndromes   Equivalent to 3744 –  2460mg  Harpagophytum  extract  (equivalent  to     mg dried root per          4920  mg  dried  root  (30mg  harpagoside)  per  day)  or   tablet (23.4 mg harpagoside per          placebo.     tablet) –  Aber  30  days:   •  Number  of  paIents  with  moderate  pain:   –  6  in  Harpag  group  and  32  in  the  placebo  group.  

•  Only  1  in  Harpag  group  with  severe  pain  vs  9  in   placebo.     •  AE  2  paIents  (harpag  group:  diarrhea;  placebo:  mild   gastriIs). ©  CuraPhyte  Technologies  Inc  

Plant  Scien/fic  Evidence  

Devil’s  claw  (Harpagophytum  procumbens)   Droxanol: •  Observational postmarketing study: Equivalent to 3744 –  Total of 250 patients enrolled (227 completed): mg dried root per •  104 patients low back pain tablet (23.4 mg harpagoside per •  85 patients arthritic knee pain tablet) •  61 patients arthritic hip pain –  Doloteffin® (60mg harpagoside) daily for 8 weeks. –  Outcome measures: •  Arhus low back pain index, •  WOMAC index, •  German version of the HAQ, •  Unvalidated measures (total pain index, three score index, the patient's global assessment of the effectiveness of treatment). ©  CuraPhyte  Technologies  Inc  

Plant  Scien/fic  Evidence  

Devil’s  claw  (Harpagophytum  procumbens)   •  Observational postmarketing study (contd): •  Multivariable analysis results: –  Improvement greater when the initial pain and disability score was high. –  older patients improved less than younger, –  Hip group improved more than back group, –  Improvement in knee group less readily differentiated from back group. –  Patients with back pain who required NSAIDs during the 8 weeks: •  used significantly more NSAIDs per patient than patients in the other two groups, but that requirement also declined more with time. –  About 10% of the patients suffered from minor AE possibly attributable to Doloteffin. –  Between 50% and 70% of the patients benefitted from Doloteffin with few adverse effects (primarily gastrointestinal). ©  CuraPhyte  Technologies  Inc  

Plant  Scien/fic  Evidence  

Devil’s  claw  (Harpagophytum  procumbens)   Droxanol:

•  8-Week Open-Label study:

Equivalent to 3744 –  130  paIents  non-­‐radiaIng  chronic  back  pain  (>6  months)   mg dried root per –  480mg  of  devil's  claw  root  dry  extract  BID  (equivalent  4800  mg     tablet (23.4 mg            dry  root  daily).     harpagoside per tablet) –  Rescue  medicaIon  (paracetamol)  available  1st  4  weeks.     –  Results:   •  MulI-­‐dimensional  pain  scale  and  the  Arhus  back  pain  index   decreased  significantly  (p