DENKI

Utilizing the body’s natural pain management system

Dual ENKephalinase Inhibitors (DENKIs), inhibit the two enkephalin-degrading enzymes in order to enhance the body’s natural pain management system.

This means DENKI can provide an alternative, non-addictive, safe, and effective treatment option for pain management.

How it works

1. Enkephalins are released

When there is a painful stimulus, enkephalins are actively secreted where the stimulus originated, as well as all along the involved pain pathways. Enkephalins are opioid peptides produced by the body to relieve pain. They are the most potent physiological pain modulators and act as the body’s own endogenous opioids.

2. NEP and APN degrade enkephalins

Released enkephalins have a short half-life as they are rapidly degraded by two extracellular metalloproteases, Neprilysin (NEP) and Aminopeptidase N (APN), allowing the pain/alarm signal to be transmitted to the brain.

3. DENKI inhibits both NEP and APN

DENKI inhibits both the NEP and APN enzymes thereby increasing local concentrations of enkephalins where they have been secreted.

4. Enkephalins bind to opioid receptors for pain relief

Enkephalins, in addition to binding to the mu receptors, also bind to the delta opioid receptor inducing a transient analgesia or pain relief. Enkephalins are known to produce less side effects than morphine and other opiate drugs, which mainly bind to the mu opioid receptor. This is an additional benefit of DENKIs and another layer of security to the effects of DENKIs.

A novel, non-opioid, ocular pain compound

IACTA is utilizing the benefits of DENKI in ocular applications

DENKI can enhance the power of enkephalins, a key element of the body’s natural pain modulation system, by protecting them from degradation and allowing them to locally increase in concentration. Corneal tissues contain all the elements of the enkephalinergic system which allows DENKI to maximize their effect. This means more relief with less side effects.

IACTA will lead the clinical and commercial development of the world’s first non-opioid drug harnessing endogenous analgesia for the treatment of chronic and acute ocular pain. Analgesic effects were demonstrated in all of our ocular pain and dry eye disease animal models tests.

Based on research and development efforts, DENKI has the potential to be positioned as an ocular analgesia that can also protect the corneal epithelium.

First non-opioid drug harnessing endogenous analgesia for chronic and acute ocular pain
Potential for less adverse effects than conventional treatments

Potential to protect the corneal epithelium
Analgesic effects for ocular pain were demonstrated in animal models testing

IACTA’s expertise in the development of ocular drugs will reveal the full potential of DENKI-based treatments to protect and extend the life of enkephalins expressed locally on the eye surface and work to bring the first dedicated ocular pain treatments to the market and to many suffering patients who currently have no treatment for their pain besides NSAIDs or opiates.

TANJA OUIMET, PhD

CEO of Pharmaleads

DENKI has the potential to transform the treatment of ocular pain, advance patient care, and become one of the most significant scientific innovations for the eye care industry.

TARYN CONWAY

Former Associate Vice President of Marketing, Allergan, Inc.

IACTA’s application of

DENKI

IACTA is applying this technology with a novel mechanism of action to develop drugs that treat diseases in areas of significant unmet medical need.

IC 800

for acute pain relating to ocular neuropathic pain and dry eye

Learn more

IC 805

for chronic pain relating to ocular post-surgical pain management

Learn more

History of

DENKIs development

1975

The enkephalin peptide is discovered

The enkephalin peptide is discovered as the natural ligand for the opioid receptors.
(Hughes et al., Life Sci)
1978

“Enkephalinase” enzymatic activity in the brain discovered

First discovery of an “enkephalinase” enzymatic activity in the brain.
(Malfroy et al., Nature)
1980

First enkephalinase inhibitor is created

Design of Thiorphan, the first inhibitor of enkephalinase activity and demonstration of its anti-nociceptive properties following intra-cerebroventricular injection by JC Schwartz, JM Lecomte, MC Fournie-Zaluski & BP Roques.
(Roques et al., Nature)
1982

Bioprojet is founded

Jean Charles Schwartz and Jeanne Marie Lecomte created Bioprojet, an innovative pharmaceutical company that brought together academic research and industrial pharmaceutical development.
1984

First dual NEP/APN inhibitor shows analgesic activity

Kelatorphan, the first NEP/APN inhibitor, shows intra-cerebroventricular analgesic activity.
(Fournié-Zaluski et al., Eur J Pharmacol)
1987

Approval of an APN inhibitor

Bestatin (ubenimex), an APN/LTA4H inhibitor (with µM affinities) for the treatment of acute myeloid leukemia, is approved in Japan
1988

Potent analgesic effects in humans shown using inhibitors of enkephalin metabolism

Analgesic effects from intrathecal (IT) administration of Thiorphan and Bestatin are shown in patients suffering from intractable cancer pain. The combination of the NEP and APN inhibitors shows to be most effective.
(Meynadier et al., Pain Clinic)
1992

The dual enkephalinase inhibitor, RB101, shows intravenous analgesic activity

RB101, an enkephalinase prodrug inhibitor developed by Bernard P. Roques and M-C Fournié-Zaluski, shows oral analgesic activity following intravenous administration in mice.
(Fournié-Zaluski et al., J Med Chem)
1993

The enkephalinase inhibitor, Tiorfan^®, shows anti-diarrheal activity

Tiorfan^® (racecadotril), a prodrug of Thiorphan, targeting the protection of endogenous enkephalins in the GI system, shows anti-diarrheal activity in healthy volunteers treated with castor oil and is commercialized by Bioprojet.
1998

Aminophosphinic inhibitors are discovered as a new family of dual enkephalinase inhibitors

Aminophosphinic inhibitors show acute and inflammatory pain alleviation after intravenous administration in mice
(Chen et al., PNAS)
2000

Tiorfan^® is commercialized for pediatric use

Bioprojet commercializes a pediatric formulation which treats over 10 million patients per year.
2000

Creation of Pharmaleads

Bernard P. Roques and Marie-Claude Fournié-Zaluski create Pharmaleads, a pharmaceutical company that designs and develops innovative, non-opiate medicines based on dual NEP and APN enkephalinase inhibition for the management of acute and chronic severe pain.
2006

The first bioavailable RB101 analog, PL37, is patented

PL37, a prodrug composed of an APN inhibitor linked by a disulfide bond to the NEP inhibitor Thiorphan, is patented by Pharmaleads.
2008
The first orally bioavailable aminophosphinic prodrug, PL265, is patented

PL265, a new family of Dual ENKephalinase Inhibitors (DENKIs), is patented by Pharmaleads.

First phase 1 SAD for PL37 demonstrates its safety and tolerability.
2011

PL37 study confirms safety and tolerability

Second phase 1 MAD study confirms safety and tolerability profile of PL37 and shows first efficacy results in an evoked pain model in healthy volunteers.
2015

First NEP inhibitor marketed for chronic use

Novartis gets market approval for Entresto (sacubitril + valsartan) for the treatment of systolic heart failure/chronic heart failure. Sacubitril is a NEP inhibitor and the first marketed for chronic use.
2015-2016

PL265 shows efficacy in all ocular pain models and its safety is demonstrated in humans

PL265 demonstrated safety and tolerability in first phase 1 SAD study. Pharmacokinetics (PK) and pharmacodynamics (PD) results from dosing of PL265 in healthy volunteers show good bioavailability and long target engagement (t_1/2 = 13 hours for the only metabolite).
2017

PL37 positioned for acute pain therapeutic indications

PL265 positioned for chronic pain indications

Pharmaleads Clinical Advisory Board validates compiled results from PL37 Phase 2a and PL265 SAD studies and positions PL37 for acute pain therapeutic indications and PL265 for chronic pain indications. PL265 seeks licensing for ocular applications.
2017-2018

PL37 shown effective in acute and chronic migraine

First pre-clinical pharmacology results showing efficacy of PL37 in acute and chronic migraine models.
June 9, 2020

PL37 studied for safety and efficacy in the treatment of headache pain

The French regulatory authority, ANSM, authorizes study into the safety and efficacy of PL37 (400mg) for the treatment of headache pain in episodic migraine.
2020

PL37 and PL265 licensed to IACTA Pharma

PL37 and PL 265 are licensed to IACTA Pharma for the development of ocular treatments.

Read the press release

Dual ENKephalinase Inhibitor

DENKI

Utilizing the body’s natural pain management system

How it works

1. Enkephalins are released

2. NEP and APN degrade enkephalins

3. DENKI inhibits both NEP and APN

4. Enkephalins bind to opioid receptors for pain relief

A novel, non-opioid, ocular pain compound

IACTA is utilizing the benefits of DENKI in ocular applications

TANJA OUIMET, PhD

CEO of Pharmaleads

TARYN CONWAY

Former Associate Vice President of Marketing, Allergan, Inc.

IACTA’s application of

DENKI

IC 800

IC 805

History of

DENKIs development

1975

The enkephalin peptide is discovered

The enkephalin peptide is discovered as the natural ligand for the opioid receptors. (Hughes et al., Life Sci)

1978

“Enkephalinase” enzymatic activity in the brain discovered

First discovery of an “enkephalinase” enzymatic activity in the brain. (Malfroy et al., Nature)

1980

First enkephalinase inhibitor is created

Design of Thiorphan, the first inhibitor of enkephalinase activity and demonstration of its anti-nociceptive properties following intra-cerebroventricular injection by JC Schwartz, JM Lecomte, MC Fournie-Zaluski & BP Roques. (Roques et al., Nature)

1982

Bioprojet is founded

Jean Charles Schwartz and Jeanne Marie Lecomte created Bioprojet, an innovative pharmaceutical company that brought together academic research and industrial pharmaceutical development.

1984

First dual NEP/APN inhibitor shows analgesic activity

Kelatorphan, the first NEP/APN inhibitor, shows intra-cerebroventricular analgesic activity. (Fournié-Zaluski et al., Eur J Pharmacol)

1987

Approval of an APN inhibitor

Bestatin (ubenimex), an APN/LTA4H inhibitor (with µM affinities) for the treatment of acute myeloid leukemia, is approved in Japan

1988

Potent analgesic effects in humans shown using inhibitors of enkephalin metabolism

Analgesic effects from intrathecal (IT) administration of Thiorphan and Bestatin are shown in patients suffering from intractable cancer pain. The combination of the NEP and APN inhibitors shows to be most effective. (Meynadier et al., Pain Clinic)

1992

The dual enkephalinase inhibitor, RB101, shows intravenous analgesic activity

RB101, an enkephalinase prodrug inhibitor developed by Bernard P. Roques and M-C Fournié-Zaluski, shows oral analgesic activity following intravenous administration in mice. (Fournié-Zaluski et al., J Med Chem)

1993

The enkephalinase inhibitor, Tiorfan®, shows anti-diarrheal activity

Tiorfan® (racecadotril), a prodrug of Thiorphan, targeting the protection of endogenous enkephalins in the GI system, shows anti-diarrheal activity in healthy volunteers treated with castor oil and is commercialized by Bioprojet.

1998

Aminophosphinic inhibitors are discovered as a new family of dual enkephalinase inhibitors

Aminophosphinic inhibitors show acute and inflammatory pain alleviation after intravenous administration in mice (Chen et al., PNAS)

2000

Tiorfan® is commercialized for pediatric use

Bioprojet commercializes a pediatric formulation which treats over 10 million patients per year.

2000

Creation of Pharmaleads

Bernard P. Roques and Marie-Claude Fournié-Zaluski create Pharmaleads, a pharmaceutical company that designs and develops innovative, non-opiate medicines based on dual NEP and APN enkephalinase inhibition for the management of acute and chronic severe pain.

2006

The first bioavailable RB101 analog, PL37, is patented

PL37, a prodrug composed of an APN inhibitor linked by a disulfide bond to the NEP inhibitor Thiorphan, is patented by Pharmaleads.

2008

The first orally bioavailable aminophosphinic prodrug, PL265, is patented

PL265, a new family of Dual ENKephalinase Inhibitors (DENKIs), is patented by Pharmaleads. First phase 1 SAD for PL37 demonstrates its safety and tolerability.

2011

PL37 study confirms safety and tolerability

Second phase 1 MAD study confirms safety and tolerability profile of PL37 and shows first efficacy results in an evoked pain model in healthy volunteers.

2015

First NEP inhibitor marketed for chronic use

Novartis gets market approval for Entresto (sacubitril + valsartan) for the treatment of systolic heart failure/chronic heart failure. Sacubitril is a NEP inhibitor and the first marketed for chronic use.

2015-2016

PL265 shows efficacy in all ocular pain models and its safety is demonstrated in humans

PL265 demonstrated safety and tolerability in first phase 1 SAD study. Pharmacokinetics (PK) and pharmacodynamics (PD) results from dosing of PL265 in healthy volunteers show good bioavailability and long target engagement (t1/2 = 13 hours for the only metabolite).

2017

PL37 positioned for acute pain therapeutic indications

PL265 positioned for chronic pain indications

Pharmaleads Clinical Advisory Board validates compiled results from PL37 Phase 2a and PL265 SAD studies and positions PL37 for acute pain therapeutic indications and PL265 for chronic pain indications. PL265 seeks licensing for ocular applications.

2017-2018

PL37 shown effective in acute and chronic migraine

First pre-clinical pharmacology results showing efficacy of PL37 in acute and chronic migraine models.

June 9, 2020

PL37 studied for safety and efficacy in the treatment of headache pain

The enkephalin peptide is discovered as the natural ligand for the opioid receptors.
(Hughes et al., Life Sci)

First discovery of an “enkephalinase” enzymatic activity in the brain.
(Malfroy et al., Nature)

Design of Thiorphan, the first inhibitor of enkephalinase activity and demonstration of its anti-nociceptive properties following intra-cerebroventricular injection by JC Schwartz, JM Lecomte, MC Fournie-Zaluski & BP Roques.
(Roques et al., Nature)

Kelatorphan, the first NEP/APN inhibitor, shows intra-cerebroventricular analgesic activity.
(Fournié-Zaluski et al., Eur J Pharmacol)

Analgesic effects from intrathecal (IT) administration of Thiorphan and Bestatin are shown in patients suffering from intractable cancer pain. The combination of the NEP and APN inhibitors shows to be most effective.
(Meynadier et al., Pain Clinic)

RB101, an enkephalinase prodrug inhibitor developed by Bernard P. Roques and M-C Fournié-Zaluski, shows oral analgesic activity following intravenous administration in mice.
(Fournié-Zaluski et al., J Med Chem)

The enkephalinase inhibitor, Tiorfan^®, shows anti-diarrheal activity

Tiorfan^® (racecadotril), a prodrug of Thiorphan, targeting the protection of endogenous enkephalins in the GI system, shows anti-diarrheal activity in healthy volunteers treated with castor oil and is commercialized by Bioprojet.

Aminophosphinic inhibitors show acute and inflammatory pain alleviation after intravenous administration in mice
(Chen et al., PNAS)

Tiorfan^® is commercialized for pediatric use

PL265, a new family of Dual ENKephalinase Inhibitors (DENKIs), is patented by Pharmaleads.

First phase 1 SAD for PL37 demonstrates its safety and tolerability.

PL265 demonstrated safety and tolerability in first phase 1 SAD study. Pharmacokinetics (PK) and pharmacodynamics (PD) results from dosing of PL265 in healthy volunteers show good bioavailability and long target engagement (t_1/2 = 13 hours for the only metabolite).