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PHE377: A novel clinical-stage TRPV1 antagonistdevoid of “class” side effects for the treatment ofchronic pain syndromes Summary of the Opportunity
PharmEste wishes to identify a partner for development and commercialization of the New Molecular Entity (NME), PHE377, an innovative
TRPV1 antagonist, which successfully completed a Phase Ib proof-of-principle clinical study in 2012. In this study, PHE377 demonstrated a
highly safe profile being devoid of unwanted “class” side-effect on body temperature and heat perception as well as positive pharmacodynamic
profile as assessed on agonist (capsaicin)-induced neurogenic flare. Furthermore, encouraging initial results following mechanical-evoked
stimulation in naïve as well as UVB-irradiated skins were obtained following PHE377 oral daily dosing in healthy subjects. The compound’s
clinical and pre-clinical data support the potential for its development as a new treatment for chronic pain syndromes with different etiologies.
PHE377 is the most advanced proprietary orally available TRPV1 antagonist fully developed by PharmEste. In addition, a structurally different
TRPV1 antagonist, namely: PHE575, currently in pre-clinical stage of development is proposed as back-up strategy.
Neuropathic pain is a result of damage to or dysfunction of either the peripheral or central nervous system. Most often chronic pain isconsequent to traumatic lesion, metabolic dysfunction i.e. diabetic neuropathy or infection. Current treatments of choice for chronic pain involvesthe use of anticonvulsants i.e. gabapentin, pregabalin, the anti-depressant, duloxetine or opioids. However this remains a therapeutic area inwhich there is still a large unmet medical need.
The transient receptor potential vanilloid 1 (TRPV1) channel is a member of the TRP superfamily of structurally related, non-selective cationchannels activated by capsaicin, the pungent component of chili peppers. TRPV1 channels have many different roles in both physiologicalconditions (i.e. transfer of thermo- and mechano-inputs) as well as pathological states including neurogenic inflammation and thus, persistentpain making TRPV1 an interesting new target for the development of novel therapeutic strategies for this highly social impact disorder.
Despite the large effort devoted to search TRPV1 antagonists, clinical stage competitors have failed to progress because of their unforeseenadverse effects including hyperthermia and impaired noxious heat perception that increases the risk of scalding injury in treated patients.
PHE377 has the potential to offer broadened and increased clinical benefit over current treatments due to
its unique ability to potently and selectively block TRPV1 receptors without affecting body temperature and
heat perception. Pre-clinical and clinical phase1b studies are consistent with this assumption.

Pre-clinical pharmacology
• PHE377 is an highly potent and selective TRPV1 antagonist as it block agonist (capsaicin)-induced Ca++ influx in isolated rodent dorsal root ganglia neurons and Figure 1. PHE377 inhibits
• PHE377 exerts dose-dependent “on-target” activity following oral treatment when tested against agonist (capsaicin)-induced pain (see Figure 1).
• PHE377 is an effective anti-hyperalgesic drug following Vehicle ipsilateral
acute and sub-chronic oral treatment in neuropathic and Vehicle contralateral
PHE377 (30 µmol/kg, po) ipsilateral
inflammatory pain models including chronic constriction PHE377 (10 µmol/kg, po) ipsilateral
injury (CCI, see Figure 2), Streptozotocin (STZ)-induced Gabapentin (292 µmol/kg) ipsilateral
diabetic neuropathy and Complete Freud’s Adjuvant Figure 2. PHE377 inhibits
• PHE377 is virtually devoid of unwanted “class” effect on body temperature (Figure 3) and heat perception in rodents (see Figure 4). Similar results were obtained in dogs further confirming the lack of unwanted side effects To explore this partnering opportunity, please contact:
Via Ariosto 21 - 20092 – Bresso, Milan - Italy Tel : +39 (0) 2 66524254; Mobile: +39 (0) 3492421468; e-mail: Vehicle ( n=15)
PHE377 (100 µmol/kg, po n = 9)
PHE377 (10 µmol/kg, po n=8)
PHE377 (30 µmol/kg, po n=8)
Figure 3. PHE377 does not affect rectal temperature
Figure 4. PHE377 does not affect heat perception
in naïve rats at relevant pharmacological doses in naïve rats at relevant pharmacological doses Clinical data
• PHE377 completed three Phase I studies testing safety, tolerability, pharmacokinetics as well as food interaction.
Most recently PHE377 successfully completed a Phase Ib PoP study, namely: placebo-controlled, multiple dose study in 36 healthy male subjects.
• PHE377 is very well tolerated (no significant AEs related to treatment) • PHE377, differently from clinically discontinued TRPV1 antagonists, does not increase body temperature and does not impair HPPT and HPTT on naive skin.
• PHE377 shows “on target“ activity, namely: TRPV1 antagonistic activity on agonist (Capsaicin)-induced neurogenic • Encouraging results on pain perception following mechanical stimulation (MPPT) Pre-clinical toxicology
- Genotoxicity , phototoxicity standard battery tests were successfully completed.
Patent position
- PHE377 is covered by composition of matter granted PCT patent. Additional patent applications covering novel, second generation TRPV1 antagonists have also been filed Future development
The completed Ph1b study of PHE377 assessed safety, tolerability, pharmacodynamics and pharmacokinetics.
significant progress in the clinical data required to support PHE377 product profile. Future studies intended for the advancement of PHE377 will
include new formulation and a proof-of-concept Phase II study in a target population experiencing Chronic pain with different etiology.
PharmEste has an additional proprietary TRPV1 antagonist, PHE575, currently in pre-clinical stage of development. PHE575, a
compound with further improved potency and efficacy yet retaining similar safety profile as PHE377 is proposed as back-up.
PHE575 belongs to a new series of compounds with independent IP coverage.

- PharmEste is private biopharmaceutical company focused on the discovery and development of Transient Receptor Potential (TRP) therapeutics for the treatment of neuropathic pain, and other TRP-mediated diseases. - The Company brings together a validated technology platform along with and an experienced multidisciplinary management team supported by an outstanding international advisory board. - Resources are focused on the advancement of PHE377, a TRPV1 antagonist developed for the relief of signs and symptoms of chronic pain. - Company’s pipeline also includes, PHE575, a second generation TRPV1 antagonist, currently in preclinical development and a discovery program on TRPA1 antagonists where several promising New drug candidates for pain and other TRP-mediated diseases have been identified. - Website : To explore this partnering opportunity, please contact:
Via Ariosto 21 - 20092 – Bresso, Milan - Italy Tel : +39 (0) 2 66524254; Mobile: +39 (0) 3492421468. e-mail:


Edital de tomada de preÇos nº 05/2006

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