TPTX » Topics » NGX267 and NGX292-Muscarinic Receptor Agonists

This excerpt taken from the TPTX DEF 14A filed Jun 19, 2009.

NGX267 and NGX292—Muscarinic Receptor Agonists

We in-licensed NGX267 and NGX292 from Life Science Research Israel, or LSRI, in 2004. NGX267 is a clinical stage product candidate for the treatment of xerostomia secondary to Sjogren’s syndrome. NGX292 is a structurally similar backup compound to NGX267.

Mechanism of Action

NGX267 is a partial muscarinic receptor agonist with functionally specific M1 and M3 receptor activity, with greater activity on the M1 receptors than the M3 receptors. When muscarinic agonists stimulate the M1 and M3 receptors, they produce cholinergically-mediated side effects such as salivation, sweating, and tearing. The cholinergic system mediates both salivary flow and the sweating response, but there are some differences in the muscarinic subtypes involved. Salivary flow involves both M1 and M3 receptors, but the sweating response is primarily mediated by the M3 receptors.

 

4


Table of Contents

Xerostomia

Xerostomia, or dry mouth, may be caused by an underlying disease such as Sjogren’s syndrome or may also result from medical treatments such as radiation therapy to the head or neck. In two Phase I trials and a Phase II trial, NGX267 has been shown to stimulate the M1 and M3 receptors and, depending on dose, produce salivation, sweating and tearing. We believe that we have identified a therapeutic dose range for NGX267 that will alleviate complaints of dry mouth without producing unpleasant or intolerable side effects such as excessive sweating. There are currently only two prescription medications for the treatment of xerostomia. Both of these medications have side effects and may not be suitable for all sufferers of dry mouth.

Clinical Development Status

We have completed three Phase I clinical trials and one Phase II trial of NGX267. In the first Phase I trial, we identified the maximum tolerated single dose of NGX267 as 35 mg in healthy young adult males. All doses up to and including 35 mg were well tolerated by the subjects and there were no reports of clinically significant adverse events. In the second Phase I trial, we confirmed the safety and tolerability of a single dose of NGX267 up to 15 mg in a healthy elderly population. In addition, at 15 mg, statistically significant increases in salivary flow were demonstrated for NGX267 in comparison to placebo in the study.

We have also completed a multiple dose Phase I clinical trial of NGX267 in healthy adult males. Subjects received either a 10 mg, 20 mg, 30 mg or 35 mg dose of NGX267 once-daily for each of four consecutive days. NGX267 was safe and well tolerated in the trial with no clinically significant adverse events. In the study, statistically significant increases in peak and total salivary flow were demonstrated for NGX267 in comparison to placebo and these effects were maintained over four days of dosing.

In December 2008 we announced positive results from a 26 patient Phase II trial evaluating three doses of NGX267 as a treatment for xerostomia, or dry mouth, in patients with Sjögren’s syndrome. NGX267 met the primary endpoint of a statistically significant increase in salivary flow production compared to placebo at all three doses: 10 mg, 15 mg, and 20 mg. These doses were safe and well tolerated with few reports of excessive sweating and gastrointestinal complaints. The clinical trial was a randomized, double-blind, placebo-controlled design and enrolled 26 patients. Using a cross-over design, each patient received a once-daily oral dose of placebo, 10 mg, 15 mg or 20 mg of NGX267 in four distinct treatment periods. We will need to secure additional funding in order to pursue the Phase II clinical development of NGX267 for the potential treatment of xerostomia.

These excerpts taken from the TPTX 10-K filed Mar 27, 2009.

NGX267 and NGX292—Muscarinic Receptor Agonists

We in-licensed NGX267 and NGX292 from Life Science Research Israel, or LSRI, in 2004. NGX267 is a clinical stage product candidate for the treatment of xerostomia secondary to Sjogren’s syndrome. NGX292 is a structurally similar backup compound to NGX267.

Mechanism of Action

NGX267 is a partial muscarinic receptor agonist with functionally specific M1 and M3 receptor activity, with greater activity on the M1 receptors than the M3 receptors. When muscarinic agonists stimulate the M1 and M3 receptors, they produce cholinergically-mediated side effects such as salivation, sweating, and tearing. The cholinergic system mediates both salivary flow and the sweating response, but there are some differences in the muscarinic subtypes involved. Salivary flow involves both M1 and M3 receptors, but the sweating response is primarily mediated by the M3 receptors.

 

4


Table of Contents

Xerostomia

Xerostomia, or dry mouth, may be caused by an underlying disease such as Sjogren’s syndrome or may also result from medical treatments such as radiation therapy to the head or neck. In two Phase I trials and a Phase II trial, NGX267 has been shown to stimulate the M1 and M3 receptors and, depending on dose, produce salivation, sweating and tearing. We believe that we have identified a therapeutic dose range for NGX267 that will alleviate complaints of dry mouth without producing unpleasant or intolerable side effects such as excessive sweating. There are currently only two prescription medications for the treatment of xerostomia. Both of these medications have side effects and may not be suitable for all sufferers of dry mouth.

Clinical Development Status

We have completed three Phase I clinical trials and one Phase II trial of NGX267. In the first Phase I trial, we identified the maximum tolerated single dose of NGX267 as 35 mg in healthy young adult males. All doses up to and including 35 mg were well tolerated by the subjects and there were no reports of clinically significant adverse events. In the second Phase I trial, we confirmed the safety and tolerability of a single dose of NGX267 up to 15 mg in a healthy elderly population. In addition, at 15 mg, statistically significant increases in salivary flow were demonstrated for NGX267 in comparison to placebo in the study.

We have also completed a multiple dose Phase I clinical trial of NGX267 in healthy adult males. Subjects received either a 10 mg, 20 mg, 30 mg or 35 mg dose of NGX267 once-daily for each of four consecutive days. NGX267 was safe and well tolerated in the trial with no clinically significant adverse events. In the study, statistically significant increases in peak and total salivary flow were demonstrated for NGX267 in comparison to placebo and these effects were maintained over four days of dosing.

In December 2008 we announced positive results from a 26 patient Phase II trial evaluating three doses of NGX267 as a treatment for xerostomia, or dry mouth, in patients with Sjögren’s syndrome. NGX267 met the primary endpoint of a statistically significant increase in salivary flow production compared to placebo at all three doses: 10 mg, 15 mg, and 20 mg. These doses were safe and well tolerated with few reports of excessive sweating and gastrointestinal complaints. The clinical trial was a randomized, double-blind, placebo-controlled design and enrolled 26 patients. Using a cross-over design, each patient received a once-daily oral dose of placebo, 10 mg, 15 mg or 20 mg of NGX267 in four distinct treatment periods. We will need to secure additional funding in order to pursue the Phase II clinical development of NGX267 for the potential treatment of xerostomia.

NGX267 and
NGX292—Muscarinic Receptor Agonists

We in-licensed NGX267 and NGX292 from Life Science Research Israel, or LSRI, in 2004.
NGX267 is a clinical stage product candidate for the treatment of xerostomia secondary to Sjogren’s syndrome. NGX292 is a structurally similar backup compound to NGX267.

STYLE="margin-top:18px;margin-bottom:0px; text-indent:4%">Mechanism of Action

NGX267 is a
partial muscarinic receptor agonist with functionally specific M1 and M3 receptor activity, with greater activity on the M1 receptors than the M3 receptors. When muscarinic agonists stimulate the M1 and M3 receptors, they produce
cholinergically-mediated side effects such as salivation, sweating, and tearing. The cholinergic system mediates both salivary flow and the sweating response, but there are some differences in the muscarinic subtypes involved. Salivary flow involves
both M1 and M3 receptors, but the sweating response is primarily mediated by the M3 receptors.

 


4







Table of Contents


Xerostomia

FACE="Times New Roman" SIZE="2">Xerostomia, or dry mouth, may be caused by an underlying disease such as Sjogren’s syndrome or may also result from medical treatments such as radiation therapy to the head or neck. In two Phase I trials and
a Phase II trial, NGX267 has been shown to stimulate the M1 and M3 receptors and, depending on dose, produce salivation, sweating and tearing. We believe that we have identified a therapeutic dose range for NGX267 that will alleviate complaints of
dry mouth without producing unpleasant or intolerable side effects such as excessive sweating. There are currently only two prescription medications for the treatment of xerostomia. Both of these medications have side effects and may not be suitable
for all sufferers of dry mouth.

Clinical Development Status

STYLE="margin-top:6px;margin-bottom:0px; text-indent:4%">We have completed three Phase I clinical trials and one Phase II trial of NGX267. In the first Phase I trial, we identified the maximum tolerated
single dose of NGX267 as 35 mg in healthy young adult males. All doses up to and including 35 mg were well tolerated by the subjects and there were no reports of clinically significant adverse events. In the second Phase I trial, we confirmed the
safety and tolerability of a single dose of NGX267 up to 15 mg in a healthy elderly population. In addition, at 15 mg, statistically significant increases in salivary flow were demonstrated for NGX267 in comparison to placebo in the study.

We have also completed a multiple dose Phase I clinical trial of NGX267 in healthy adult males. Subjects received either a 10 mg, 20
mg, 30 mg or 35 mg dose of NGX267 once-daily for each of four consecutive days. NGX267 was safe and well tolerated in the trial with no clinically significant adverse events. In the study, statistically significant increases in peak and total
salivary flow were demonstrated for NGX267 in comparison to placebo and these effects were maintained over four days of dosing.

In
December 2008 we announced positive results from a 26 patient Phase II trial evaluating three doses of NGX267 as a treatment for xerostomia, or dry mouth, in patients with Sjögren’s syndrome. NGX267 met the primary endpoint of a
statistically significant increase in salivary flow production compared to placebo at all three doses: 10 mg, 15 mg, and 20 mg. These doses were safe and well tolerated with few reports of excessive sweating and gastrointestinal complaints. The
clinical trial was a randomized, double-blind, placebo-controlled design and enrolled 26 patients. Using a cross-over design, each patient received a once-daily oral dose of placebo, 10 mg, 15 mg or 20 mg of NGX267 in four distinct treatment
periods. We will need to secure additional funding in order to pursue the Phase II clinical development of NGX267 for the potential treatment of xerostomia.

SIZE="2">Our Gamma-secretase Modulator Drug Discovery Program

We have
identified two distinct series of compounds that modulate the gamma-secretase enzyme and may have potential as a treatment for Alzheimer’s disease. These gamma-secretase modulator, or GSM, compounds reduce the brain levels of
42, a toxic peptide, or protein, found in the brain of Alzheimer’s disease patients, while maintaining the overall balance of Aß
in the brain. They do this by influencing the enzyme to make shorter, less toxic Aß peptides at the expense of the longer, toxic Aß
42
peptide. Because GSM compounds allow the gamma-secretase enzyme to perform its normal functions on other substrates, it is believed they will likely not have some of the side effects associated with the first generation compounds that fully
inhibited enzyme function. We are currently attempting to sell this program.

These excerpts taken from the TPTX 10-K filed Mar 31, 2008.

NGX267 and NGX292—Muscarinic Receptor Agonists

        We in-licensed NGX267 and NGX292 from Life Science Research Israel, or LSRI, in 2004. NGX267 is currently in Phase II clinical development for xerostomia secondary to Sjogren's syndrome. NGX292 is structurally similar to NGX267 and is currently in preclinical testing.

    Mechanism of Action

        There is extensive data validating the rationale for using muscarinic receptor agonists in the symptomatic treatment of cognitive impairment. This rationale, based on the cholinergic hypothesis of learning and memory, links disturbances in acetylcholine function with changes in cognition. Many of the currently approved treatments for symptomatic improvement of Alzheimer's disease are based on this cholinergic hypothesis. NGX267, a partial muscarinic receptor agonist with functionally specific M1 receptor activity, mimics the action of acetylcholine by stimulating the M1 receptors. In animal models NGX267 has been shown to be effective in improving cognitive deficits in learning and memory.

        In addition to improving cognition, a second mechanism of action, the reduction of Aß42, also supported by preclinical data, suggests that NGX267 may be effective as a treatment to delay the onset or to slow the progression of Alzheimer's disease. It has also long been hypothesized that the cause of Alzheimer's disease lies in the build up of protein deposits, referred to as amyloid plaques, in the brain. The plaques are largely comprised of aggregations of a peptide referred to as amyloid ß, or Aß, peptide. A specific Aß peptide, Aß42, is thought to play a significant role in the cause of Alzheimer's disease. In transgenic mice, a specific testing model where the animals have characteristics of Alzheimer's disease, NGX267 has been shown to reduce Aß42 and to prevent the formation of amyloid plaques. NGX292 has demonstrated a biological profile similar to the profile of NGX267.

    Xerostomia

        Xerostomia, or dry mouth, may be caused by an underlying disease such as Sjogren's syndrome or may also result from medical treatments such as radiation therapy to the head or neck. In evaluating NGX267 as a treatment for xerostomia, we are leveraging a known biological effect of muscarinic receptor agonists. Similar to acetylcholine, when muscarinic agonists stimulate the M1 receptor, they produce cholinergically-mediated side effects such as salivation, sweating, and tearing. In two Phase I trials, NGX267 has been shown to stimulate the M1 receptor and, depending on dose, produce these side effects. We believe that we have identified a therapeutic dose range for NGX267 that will alleviate

5


complaints of dry mouth without producing unpleasant or intolerable side effects such as excessive sweating. There are currently only two prescription medications for the treatment of xerostomia. Both of these medications have side effects and may not be suitable for all sufferers of dry mouth.

    Alzheimer's Disease and CIAS

        There are currently no approved products to treat the underlying cause of Alzheimer's disease or to modify the progression of the disease. All of the approved products, as well as many of the compounds under development for Alzheimer's disease, treat or intend to treat only the signs and symptoms of Alzheimer's disease. With regard to CIAS, an emerging approach to improving the functional ability of patients with schizophrenia is to develop therapies that will improve their cognitive impairment. There are no current approved therapies for CIAS. Because impairments in memory and learning have been demonstrated in both Alzheimer's disease patients and schizophrenic patients, we believe that there is a strong rationale to develop NGX267 as a treatment for Alzheimer's disease as well as CIAS.

    Clinical Development Status

        We have completed three Phase I clinical trials of NGX267. In the first trial, we identified the maximum tolerated single dose of NGX267 as 35 mg in healthy young adult males. All doses up to and including 35 mg were well tolerated by the subjects and there were no reports of clinically significant adverse events. In the second trial, we confirmed the safety and tolerability of a single dose of NGX267 up to 15 mg in a healthy elderly population. In addition, at 15mg, statistically significant increases in salivary flow were demonstrated for NGX267 in comparison to placebo in the study.

        We have also completed a multiple dose Phase I clinical trial of NGX267 in healthy adult males. Subjects received either a 10, 20 30 or 35 mg dose of NGX267 once-daily for each of four consecutive days. NGX267 was safe and well tolerated in the trial with no clinically significant adverse events. In the study, statistically significant increases in peak and total salivary flow were demonstrated for NGX267 in comparison to placebo and these effects were maintained over four days of dosing.

        In March 2008 we initiated a Phase II clinical trial of NGX267 in patients suffering from xerostomia secondary to Sjogren's syndrome. The clinical trial is a randomized, double-blind, placebo-controlled design and will enroll 24 patients. Using a cross-over design, each patient will receive a once-daily oral dose of placebo, 10 mg, 15 mg and 20 mg of NGX267 in four distinct treatment periods. We have no plans to initiate any clinical trials of NGX267 in Alzheimer's disease or CIAS in 2008.

NGX267 and NGX292—Muscarinic Receptor Agonists



        We in-licensed NGX267 and NGX292 from Life Science Research Israel, or LSRI, in 2004. NGX267 is currently in Phase II clinical development for
xerostomia secondary to Sjogren's syndrome. NGX292 is structurally similar to NGX267 and is currently in preclinical testing.





    Mechanism of Action





        There is extensive data validating the rationale for using muscarinic receptor agonists in the symptomatic treatment of cognitive impairment. This rationale,
based on the cholinergic hypothesis of learning and memory, links disturbances in acetylcholine function with changes in cognition. Many of the currently approved treatments for symptomatic
improvement of Alzheimer's disease are based on this cholinergic hypothesis. NGX267, a partial muscarinic receptor agonist with functionally specific M1 receptor activity, mimics the action of
acetylcholine by stimulating the M1 receptors. In animal models NGX267 has been shown to be effective in improving cognitive deficits in learning and memory.




        In
addition to improving cognition, a second mechanism of action, the reduction of Aß42, also supported by preclinical data, suggests that NGX267 may be effective
as a treatment to delay the onset or to slow the progression of Alzheimer's disease. It has also long been hypothesized that the cause of Alzheimer's disease lies in the build up of protein deposits,
referred to as amyloid plaques, in the brain. The plaques are largely comprised of aggregations of a peptide referred to as amyloid ß, or Aß, peptide. A specific Aß
peptide, Aß42, is thought to play a significant role in the cause of Alzheimer's disease. In transgenic mice, a specific testing model where the animals have characteristics of
Alzheimer's disease, NGX267 has been shown to reduce Aß42 and to prevent the formation of amyloid plaques. NGX292 has demonstrated a biological profile similar to the profile
of NGX267.





    Xerostomia





        Xerostomia, or dry mouth, may be caused by an underlying disease such as Sjogren's syndrome or may also result from medical treatments such as radiation therapy
to the head or neck. In evaluating NGX267 as a treatment for xerostomia, we are leveraging a known biological effect of muscarinic receptor agonists. Similar to acetylcholine, when muscarinic agonists
stimulate the M1 receptor, they produce cholinergically-mediated side effects such as salivation, sweating, and tearing. In two Phase I trials, NGX267 has been shown to stimulate the M1
receptor and, depending on dose, produce these side effects. We believe that we have identified a therapeutic dose range for NGX267 that will alleviate



5









complaints
of dry mouth without producing unpleasant or intolerable side effects such as excessive sweating. There are currently only two prescription medications for the treatment of xerostomia. Both
of these medications have side effects and may not be suitable for all sufferers of dry mouth.





    Alzheimer's Disease and CIAS





        There are currently no approved products to treat the underlying cause of Alzheimer's disease or to modify the progression of the disease. All of the approved
products, as well as many of the compounds under development for Alzheimer's disease, treat or intend to treat only the signs and symptoms of Alzheimer's disease. With regard to CIAS, an emerging
approach to improving the functional ability of patients with schizophrenia is to develop therapies that will improve their cognitive impairment. There are no current approved therapies for CIAS.
Because impairments in memory and learning have been demonstrated in both Alzheimer's disease patients and schizophrenic patients, we believe that there is a strong rationale to develop NGX267 as a
treatment for Alzheimer's disease as well as CIAS.





    Clinical Development Status





        We have completed three Phase I clinical trials of NGX267. In the first trial, we identified the maximum tolerated single dose of NGX267 as 35 mg in
healthy young adult males. All doses up to and including 35 mg were well tolerated by the subjects and there were no reports of clinically significant adverse events. In the second trial, we confirmed
the safety and tolerability of a single dose of NGX267 up to 15 mg in a healthy elderly population. In addition, at 15mg, statistically significant increases in salivary flow were demonstrated for
NGX267 in comparison to placebo in the study.



        We
have also completed a multiple dose Phase I clinical trial of NGX267 in healthy adult males. Subjects received either a 10, 20 30 or 35 mg dose of NGX267 once-daily for each of
four consecutive days. NGX267 was safe and well tolerated in the trial with no clinically significant adverse events. In the study, statistically significant increases in peak and total salivary flow
were demonstrated for NGX267 in comparison to placebo and these effects were maintained over four days of dosing.




        In
March 2008 we initiated a Phase II clinical trial of NGX267 in patients suffering from xerostomia secondary to Sjogren's syndrome. The clinical trial is a randomized,
double-blind, placebo-controlled design and will enroll 24 patients. Using a cross-over design, each patient will receive a once-daily oral dose of placebo, 10 mg, 15 mg and 20
mg of NGX267 in four distinct treatment periods. We have no plans to initiate any clinical trials of NGX267 in Alzheimer's disease or CIAS in 2008.



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