JohnnySeville
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Guys...
In my never ending travels on the web I have come across an interesting study. I find no note of this on this site, so I am presenting it for your evaluation. Read it well and draw your own conclusions.
************************************************************
TU-2100 - A Novel Topical Sebostatic Preparation
Tamarkin Pharmaceutical Innovation (2 February 2000)
Author: Dov Tamarkin, Ph.D.
ABSTRACT
There is currently no topical therapy to influence the production of sebum and thus, the treatment of oily skin and seborrhea still remains an unmet need. TU-2100 is a novel pro-drug, composed of azelaic acid and ethyl salicylate, which was designed to penetrate the pilosebaceous unit and control sebum production. In effort to test the safety and efficacy of this agent, TU-2100 10% lotion was applied twice daily for 8 weeks to the face of ten women with oily skin. Sebum excretion rates declined by 30-44%, reaching normal levels within 8 weeks of treatment in all study volunteers. Notably, neither skin irritation, nor systemic adverse reactions were noted throughout the study.
Hence, TU-2100 is an effective sebum control agent, making it a useful treatment for oily skin and seborrhea. Moreover, due to its combined sebostatic and comedolytic properties, TU-2100 is also effective treatment for acne, as revealed in our subsequent trials.
INTRODUCTION
The biology of the pilosebaceous unit has attracted the attention of numerous investigators on account of its involvement in important skin functions, including hair growth and sebum excretion. Malfunctioning of the pilosebaceous unit is the cause of common skin disorders, such as acne, seborrhea, dandruff, androgenic alopecia and hirsutism. Androgen metabolism plays an important role in the control of both sebum excretion rate (SER) and keratinization patterns in the pilosebaceous unit. The enzyme 5-a -testosterone reductase is responsible for the conversion of testosterone to dihydrotestosterone (DHT), and DHT is known to modulate both keratin formation and sebum production.1,2,3 Reducing sebum excretion is not an easy task. In his recent review, titled "Therapy For Acne Vulgaris", J. Leyden stated: "No topical therapies influence the production of sebum".4 Indeed, clinical studies with various topical anti-acne medications, including tretinoin and other retinoids, benzoyl peroxide and azelaic acid did not reveal any significant reduction of SER in acne and seborrhea - prone subjects.5,6,7,8 Topical application of the antiandrogen, inocoterone acetate did not reduce sebum excretion either.9 Other androgen antagonists, spironolactone and17-a -propylmesterolone, produced a significant reduction in SER, which occurred 12 weeks after the initiation of topical treatment.10,11 Interestingly, oral 13-cis-retinoic acid (accutan) and oral 9-cis-retinoic acid profoundly suppressed sebum excretion, with a long-lasting residual effect,12,13,14 whereas oral tretinoin did not.15
TU-2100 (Nonanedioic acid, bis[(2-(ethoxycarbonyl)phenyl] ester) is a novel dual-action pro-drug, composed of azelaic acid and ethyl salicylate. Both pro-drug components possess anti-acne properties, however, due to their hydrophilic character, they barely penetrate the skin and thus, their therapeutic benefits are limited. By contrast, TU-2100 is highly lipophylic and readily penetrates the follicle. Non-specific esterases in the skin hydrolyze this pro-drug and liberate its components to exert their effects inside their target site of action. Consequently, azelaic acid may then act via its 5-a -reductase inhibiting property (hitherto revealed only in vitro)16,17 and exert its keratolytic and antibacterial effects.17 Salicylic acid contributes to the therapeutic effect by its keratolytic and anti-inflammatory properties. In vivo studies, using the rabbit ear model, revealed that this agent was comedolytic, without the skin irritation which is typical to other potent anti-acne medications, such as Retin A®.18 In vitro studies have demonstrated that TU-2100 inhibits keratinocyte proliferation, thus supporting the in vivo results. The above-mentioned observations led us to initiate human studies, aimed to assess the safety of topically applied TU-2100 and to evaluate its effect on sebum excretion.
MATERIALS AND METHODS
The present exploratory human study was carried out at S.K.I.N., Incorporated, Conshohocken, Pennsylvania and the principal investigator was Dr. Albert M Kligman. Ten adult female volunteers, mean age of 33 years (range 25-46), with oily facial skin were enrolled in this exploratory study. They were free of dermatoses and were not receiving any prescribed drugs. After signing an Informed Consent form, they were instructed to apply TU-2100 10% (dissolved in ethanol-PEG 400, 9:1) twice daily to the forehead and cheeks. The volume applied was adjusted to an approximate amount 2 mg/cm2. They were also told not to apply the test lotion during a 24 hr-period preceding scheduled clinic visits on the 4th and 8th week of the study. Safety evaluations were based on detection of potential skin irritation, as well as clinical chemistry and hematological parameters at study termination. Sebum excretion levels were assessed on the central forehead and nasolabial region of the cheek (sebum-test sites) at baseline and on the 4th and 8th week of the study, using the Sebutape® technique as previously described.19
RESULTS AND CONCLUSION
No clinically significant deviations from the normal values of serum chemistry and hematology were observed after eight weeks of treatment. There was no skin irritation. Neither changes in skin infrastructure, nor skin dryness, redness or peeling were noted during the 8-week period.
In all volunteers, baseline sebum excretion levels on the forehead were higher than those detected on the nasolabial area of the cheek. Baseline SER measurements indicated oily to very-oily forehead skin and oily skin at the nasolabial region of the cheek (% Areas covered by spots = 8.4 ± 1.1 and 6.2 ± 0.4, respectively). Mean sebum excretion rates after 4 weeks of repeated TU-2100 10% application, declined 33% (forehead) and 26% (cheek) and reached normal values in all the participants. Following 8 weeks of treatment, SER was 56% and 70% of the baseline values at the forehead and cheek, respectively (Figure 1). These decreases in sebum excretion rate were statistically significant at a 95% confidence level and with p values of <0.01 in both the forehead and cheek (ANOVA, Dunnett Multiple Comparison).
In light of the results of this exploratory study, the following conclusions were drawn: 1) TU-2100 can normalize sebum excretion, making it useful in the treatment of oily skin and seborrhea. 2) Based on the effect of TU-2100 on sebum excretion and in light of its comedolytic and anti-inflammatory properties, it is reasonable to conclude that TU-2100 may be effective in the treatment of acne vulgaris.
Further controlled studies are underway, to establish the therapeutic effect of TU-2100 in seborrhea, acne, psoriasis and possibly other disorders of the pilosebaceous unit
*************************************************************
Tamarkin Pharmaceutical Innovation (TPI), a young pharmaceutical company, has done a remarkable job in going from establishment to successful Phase II clinical results for its lead compound, a topical treatment for acne and related skin disorders, in only three years.
The company was founded in 1998 by Dr. Dov Tamarkin and Dr. Arie Giniger, both with long experience in skin treatment. Dr. Tamarkin, who is the inventor of the technology, brings along a resume that includes R&D management at biomedical startups as well as management of Teva’s drug development programs in the fields of dermatology and infectious diseases and R&D management at Portman Pharmaceuticals.
“I reproduced my experiences as R&D manager at Elad Ventures, and in senior R&D management positions at Portman Pharmaceuticals and Teva, in order to build TPI in both cost and time effective manners. TPI attained development milestones quickly and on a small budget, reaching the current phase of development on less than $2 million, Tamarkin said.
The company has completed initial phase II clinical trials at Belgian hospitals for TU-2100, a proprietary compound that is actually a combination of two lesser known acne treatments, salicylic acid and azelaic acid. Individually, these compounds have minimal efficacy in fighting acne, which is estimated to effect about 95 percent of American young adults and represents a $1 billion treatment market. However, TPI’s synthesis of the two compounds into what the company terms a “Dual Action Pro-drug†has resulted in a treatment that has demonstrated superior efficacy to Retin A, the current gold standard. In an initial 42-person study, it has been shown to act faster and diminish more acne lesions than retin A, while causing no irritation or other side effects.
According to Tamarkin, the efficacy of TU-2100 lies in its ability to attack all the causes of acne, through a series of mechanisms that are not yet fully understood. At the root of acne is a process by which testosterone is converted to DHT, a hormone which causes sebum overproduction, especially at adolescence. A cascade of effects result, which include the creation of keratin plugs that block pores and prevent the release of sebum. This in turn promotes the proliferation of bacteria within the system, and the inflammation that results in visible acne. Current acne treatments, which include benzoyl peroxide for cases of mild to medium severity, and systemic treatments such as Roche’s Roaccutane, are only somewhat effective, and cause side effects including dry skin and increased photosensitivity. Potential side effects for Roaccutane are so severe that the FDA requires patients to sign their consent before taking the medication.
Tamarkin believes that TU-2100’s efficacy and safety are assisted by the fact that the molecule dissolves only in oil, and therefore penetrates very effectively into the sebaceous glands of the skin, where it is the first topical treatment to have shown the ability to inhibit excess sebum production, while not penetrating as deeply as the blood stream itself.
“In 1997, prior to founding the company, I had the compound tested by Dr. Albert Kligman at the University of Pennsylvania, who invented the use of retin A as an acne treatment,†Tamarkin said. “The study showed that sebum production was inhibited by 30 to 40 percent. The result was not to dry the skin, but to normalize, and normalization is ultimately what one looks for.â€
“Additionally, because the molecule is extremely hydrophobic, it does not penetrate to the lower layers of skin and into the circulatory system. TU-2100 could not be detected in the blood of individuals involved in the Phase II trials, which is a great relief from the point of view of FDA approval,†Tamarkin said.
TPI recently entered a licensing agreement with Istituto Biochimico Italiano Giovanni Lorenzini (IBI), an Italian pharmaceutical company, for the mutual development of TU-2100 as a topical anti-acne medication. Under terms of the agreement, IBI will conduct a multi-center Phase IIb clinical study in several centers in Europe, the purpose of which will be to collect further safety and dosage information in advance of Phase III trials which the company hope to initiate by the end of 2002.
“We see the total development cost of TU-2100 to be in the range of $12 to $20 million, however our working assumption is that most of this cost will be covered by partners, of which IBI is the first,†Tamarkin said. “Our strategy is to have one good partner in the US, and partners in Europe sufficient to cover the continent. Our partners will be able to promote development of the product and bring it to market in the most effective way.â€
Tamarkin expects to market TU-2100 initially as a prescription medication for acne, shifting to an over-the-counter (OTC) formulation in three to five years. “It isn’t likely that the FDA will approve of TU-2100 as an OTC treatment initially, since it will want to collect additional post-marketing safety data first, and this is only possible while TU-2100 is a prescription medication,†he said.
Tamarkin stressed that the company is developing a platform of compounds for the treatment of skin disorders, as well as additional indications including baldness and psoriasis. The connection to baldness comes from TU-2100’s conceivable ability to inhibit the conversion of testosterone into DHT, the hormone known to cause excess sebum secretion, but which is also curiously responsible for the growth of hair on all parts of the body except for the head, where it actually inhibits hair growth for reasons yet to be understood. “Our objective is to develop additional molecules on the same platform, as well as new platforms, which we’ll take into the proof of concept and initial clinical trials stages,†Tamarkin said.
Investment in the company to date has been from private Israeli investors, as well as founders Tamarkin and Giniger. The company is currently seeking a new round of funding, and has entered negotiations with foreign institutional investors to provide the amount of capital needed to fund the company going forward. Tamarkin said that the company has applied for patents in all relevant markets. A broad patent covering the company’s compounds and all potential uses in humans was issued in the US in January of this year.
Further details about the Tamarkincan be viewed at their Pharmalicensing profile here.
and you can visit their licensing opportunity profile for TU-2100 - Anti Acne Topical Medication here.
To make any comments on this article, or to ask a question of the author, please contact the
*************************************************************
http://www.tamarkin.co.il/Pharmaceutical.asp
http://pharmalicensing.com/articles/dis ... 86fc914957
http://pharmalicensing.com/articles/dis ... bfd9e8ee9b
In my never ending travels on the web I have come across an interesting study. I find no note of this on this site, so I am presenting it for your evaluation. Read it well and draw your own conclusions.
************************************************************
TU-2100 - A Novel Topical Sebostatic Preparation
Tamarkin Pharmaceutical Innovation (2 February 2000)
Author: Dov Tamarkin, Ph.D.
ABSTRACT
There is currently no topical therapy to influence the production of sebum and thus, the treatment of oily skin and seborrhea still remains an unmet need. TU-2100 is a novel pro-drug, composed of azelaic acid and ethyl salicylate, which was designed to penetrate the pilosebaceous unit and control sebum production. In effort to test the safety and efficacy of this agent, TU-2100 10% lotion was applied twice daily for 8 weeks to the face of ten women with oily skin. Sebum excretion rates declined by 30-44%, reaching normal levels within 8 weeks of treatment in all study volunteers. Notably, neither skin irritation, nor systemic adverse reactions were noted throughout the study.
Hence, TU-2100 is an effective sebum control agent, making it a useful treatment for oily skin and seborrhea. Moreover, due to its combined sebostatic and comedolytic properties, TU-2100 is also effective treatment for acne, as revealed in our subsequent trials.
INTRODUCTION
The biology of the pilosebaceous unit has attracted the attention of numerous investigators on account of its involvement in important skin functions, including hair growth and sebum excretion. Malfunctioning of the pilosebaceous unit is the cause of common skin disorders, such as acne, seborrhea, dandruff, androgenic alopecia and hirsutism. Androgen metabolism plays an important role in the control of both sebum excretion rate (SER) and keratinization patterns in the pilosebaceous unit. The enzyme 5-a -testosterone reductase is responsible for the conversion of testosterone to dihydrotestosterone (DHT), and DHT is known to modulate both keratin formation and sebum production.1,2,3 Reducing sebum excretion is not an easy task. In his recent review, titled "Therapy For Acne Vulgaris", J. Leyden stated: "No topical therapies influence the production of sebum".4 Indeed, clinical studies with various topical anti-acne medications, including tretinoin and other retinoids, benzoyl peroxide and azelaic acid did not reveal any significant reduction of SER in acne and seborrhea - prone subjects.5,6,7,8 Topical application of the antiandrogen, inocoterone acetate did not reduce sebum excretion either.9 Other androgen antagonists, spironolactone and17-a -propylmesterolone, produced a significant reduction in SER, which occurred 12 weeks after the initiation of topical treatment.10,11 Interestingly, oral 13-cis-retinoic acid (accutan) and oral 9-cis-retinoic acid profoundly suppressed sebum excretion, with a long-lasting residual effect,12,13,14 whereas oral tretinoin did not.15
TU-2100 (Nonanedioic acid, bis[(2-(ethoxycarbonyl)phenyl] ester) is a novel dual-action pro-drug, composed of azelaic acid and ethyl salicylate. Both pro-drug components possess anti-acne properties, however, due to their hydrophilic character, they barely penetrate the skin and thus, their therapeutic benefits are limited. By contrast, TU-2100 is highly lipophylic and readily penetrates the follicle. Non-specific esterases in the skin hydrolyze this pro-drug and liberate its components to exert their effects inside their target site of action. Consequently, azelaic acid may then act via its 5-a -reductase inhibiting property (hitherto revealed only in vitro)16,17 and exert its keratolytic and antibacterial effects.17 Salicylic acid contributes to the therapeutic effect by its keratolytic and anti-inflammatory properties. In vivo studies, using the rabbit ear model, revealed that this agent was comedolytic, without the skin irritation which is typical to other potent anti-acne medications, such as Retin A®.18 In vitro studies have demonstrated that TU-2100 inhibits keratinocyte proliferation, thus supporting the in vivo results. The above-mentioned observations led us to initiate human studies, aimed to assess the safety of topically applied TU-2100 and to evaluate its effect on sebum excretion.
MATERIALS AND METHODS
The present exploratory human study was carried out at S.K.I.N., Incorporated, Conshohocken, Pennsylvania and the principal investigator was Dr. Albert M Kligman. Ten adult female volunteers, mean age of 33 years (range 25-46), with oily facial skin were enrolled in this exploratory study. They were free of dermatoses and were not receiving any prescribed drugs. After signing an Informed Consent form, they were instructed to apply TU-2100 10% (dissolved in ethanol-PEG 400, 9:1) twice daily to the forehead and cheeks. The volume applied was adjusted to an approximate amount 2 mg/cm2. They were also told not to apply the test lotion during a 24 hr-period preceding scheduled clinic visits on the 4th and 8th week of the study. Safety evaluations were based on detection of potential skin irritation, as well as clinical chemistry and hematological parameters at study termination. Sebum excretion levels were assessed on the central forehead and nasolabial region of the cheek (sebum-test sites) at baseline and on the 4th and 8th week of the study, using the Sebutape® technique as previously described.19
RESULTS AND CONCLUSION
No clinically significant deviations from the normal values of serum chemistry and hematology were observed after eight weeks of treatment. There was no skin irritation. Neither changes in skin infrastructure, nor skin dryness, redness or peeling were noted during the 8-week period.
In all volunteers, baseline sebum excretion levels on the forehead were higher than those detected on the nasolabial area of the cheek. Baseline SER measurements indicated oily to very-oily forehead skin and oily skin at the nasolabial region of the cheek (% Areas covered by spots = 8.4 ± 1.1 and 6.2 ± 0.4, respectively). Mean sebum excretion rates after 4 weeks of repeated TU-2100 10% application, declined 33% (forehead) and 26% (cheek) and reached normal values in all the participants. Following 8 weeks of treatment, SER was 56% and 70% of the baseline values at the forehead and cheek, respectively (Figure 1). These decreases in sebum excretion rate were statistically significant at a 95% confidence level and with p values of <0.01 in both the forehead and cheek (ANOVA, Dunnett Multiple Comparison).
In light of the results of this exploratory study, the following conclusions were drawn: 1) TU-2100 can normalize sebum excretion, making it useful in the treatment of oily skin and seborrhea. 2) Based on the effect of TU-2100 on sebum excretion and in light of its comedolytic and anti-inflammatory properties, it is reasonable to conclude that TU-2100 may be effective in the treatment of acne vulgaris.
Further controlled studies are underway, to establish the therapeutic effect of TU-2100 in seborrhea, acne, psoriasis and possibly other disorders of the pilosebaceous unit
*************************************************************
Tamarkin Pharmaceutical Innovation (TPI), a young pharmaceutical company, has done a remarkable job in going from establishment to successful Phase II clinical results for its lead compound, a topical treatment for acne and related skin disorders, in only three years.
The company was founded in 1998 by Dr. Dov Tamarkin and Dr. Arie Giniger, both with long experience in skin treatment. Dr. Tamarkin, who is the inventor of the technology, brings along a resume that includes R&D management at biomedical startups as well as management of Teva’s drug development programs in the fields of dermatology and infectious diseases and R&D management at Portman Pharmaceuticals.
“I reproduced my experiences as R&D manager at Elad Ventures, and in senior R&D management positions at Portman Pharmaceuticals and Teva, in order to build TPI in both cost and time effective manners. TPI attained development milestones quickly and on a small budget, reaching the current phase of development on less than $2 million, Tamarkin said.
The company has completed initial phase II clinical trials at Belgian hospitals for TU-2100, a proprietary compound that is actually a combination of two lesser known acne treatments, salicylic acid and azelaic acid. Individually, these compounds have minimal efficacy in fighting acne, which is estimated to effect about 95 percent of American young adults and represents a $1 billion treatment market. However, TPI’s synthesis of the two compounds into what the company terms a “Dual Action Pro-drug†has resulted in a treatment that has demonstrated superior efficacy to Retin A, the current gold standard. In an initial 42-person study, it has been shown to act faster and diminish more acne lesions than retin A, while causing no irritation or other side effects.
According to Tamarkin, the efficacy of TU-2100 lies in its ability to attack all the causes of acne, through a series of mechanisms that are not yet fully understood. At the root of acne is a process by which testosterone is converted to DHT, a hormone which causes sebum overproduction, especially at adolescence. A cascade of effects result, which include the creation of keratin plugs that block pores and prevent the release of sebum. This in turn promotes the proliferation of bacteria within the system, and the inflammation that results in visible acne. Current acne treatments, which include benzoyl peroxide for cases of mild to medium severity, and systemic treatments such as Roche’s Roaccutane, are only somewhat effective, and cause side effects including dry skin and increased photosensitivity. Potential side effects for Roaccutane are so severe that the FDA requires patients to sign their consent before taking the medication.
Tamarkin believes that TU-2100’s efficacy and safety are assisted by the fact that the molecule dissolves only in oil, and therefore penetrates very effectively into the sebaceous glands of the skin, where it is the first topical treatment to have shown the ability to inhibit excess sebum production, while not penetrating as deeply as the blood stream itself.
“In 1997, prior to founding the company, I had the compound tested by Dr. Albert Kligman at the University of Pennsylvania, who invented the use of retin A as an acne treatment,†Tamarkin said. “The study showed that sebum production was inhibited by 30 to 40 percent. The result was not to dry the skin, but to normalize, and normalization is ultimately what one looks for.â€
“Additionally, because the molecule is extremely hydrophobic, it does not penetrate to the lower layers of skin and into the circulatory system. TU-2100 could not be detected in the blood of individuals involved in the Phase II trials, which is a great relief from the point of view of FDA approval,†Tamarkin said.
TPI recently entered a licensing agreement with Istituto Biochimico Italiano Giovanni Lorenzini (IBI), an Italian pharmaceutical company, for the mutual development of TU-2100 as a topical anti-acne medication. Under terms of the agreement, IBI will conduct a multi-center Phase IIb clinical study in several centers in Europe, the purpose of which will be to collect further safety and dosage information in advance of Phase III trials which the company hope to initiate by the end of 2002.
“We see the total development cost of TU-2100 to be in the range of $12 to $20 million, however our working assumption is that most of this cost will be covered by partners, of which IBI is the first,†Tamarkin said. “Our strategy is to have one good partner in the US, and partners in Europe sufficient to cover the continent. Our partners will be able to promote development of the product and bring it to market in the most effective way.â€
Tamarkin expects to market TU-2100 initially as a prescription medication for acne, shifting to an over-the-counter (OTC) formulation in three to five years. “It isn’t likely that the FDA will approve of TU-2100 as an OTC treatment initially, since it will want to collect additional post-marketing safety data first, and this is only possible while TU-2100 is a prescription medication,†he said.
Tamarkin stressed that the company is developing a platform of compounds for the treatment of skin disorders, as well as additional indications including baldness and psoriasis. The connection to baldness comes from TU-2100’s conceivable ability to inhibit the conversion of testosterone into DHT, the hormone known to cause excess sebum secretion, but which is also curiously responsible for the growth of hair on all parts of the body except for the head, where it actually inhibits hair growth for reasons yet to be understood. “Our objective is to develop additional molecules on the same platform, as well as new platforms, which we’ll take into the proof of concept and initial clinical trials stages,†Tamarkin said.
Investment in the company to date has been from private Israeli investors, as well as founders Tamarkin and Giniger. The company is currently seeking a new round of funding, and has entered negotiations with foreign institutional investors to provide the amount of capital needed to fund the company going forward. Tamarkin said that the company has applied for patents in all relevant markets. A broad patent covering the company’s compounds and all potential uses in humans was issued in the US in January of this year.
Further details about the Tamarkincan be viewed at their Pharmalicensing profile here.
and you can visit their licensing opportunity profile for TU-2100 - Anti Acne Topical Medication here.
To make any comments on this article, or to ask a question of the author, please contact the
*************************************************************
http://www.tamarkin.co.il/Pharmaceutical.asp
http://pharmalicensing.com/articles/dis ... 86fc914957
http://pharmalicensing.com/articles/dis ... bfd9e8ee9b
