The aim of this trial is show which strength is the most suitable for general use. Trial participants will be using one of 4 different strengths: 0.07%, 0.18%, %0.50 or effectively %0 contained in the gel vehicle. This trial should be completed by the end of the year, paving the way for an eagerly anticipated FDA approval in 2010.

Rosacea News previously found a patent application listing the full ingredients for Sansrosa, which included a mention of the active ingredient Brimonidine tartrate at a concentration of 0.18%. This trial suggests that Galderma is now also interested in a almost 3 times as strong version of %0.50.

The trial details again confirm that Sansrosa is to be applied once per day and that benefits can be expected for up to 12 hours after application. The patent related to the Sanrosa product itself suggested that typical usage was 1-4 times per day.

Galderma is looking for 112 participants, and the register suggests that residents of Pennsylvania, Texas, Virginia  and Arkansas are eligible. Please do post below if you get to be a part of this final phase of testing.

Galderma acquired the Sansrosa product through their acquisition of Collagenex. Rosacea News has been following this product for several years now, since Collagenex first started talking about a new product COL-118, in 2006. It appears that Galderma is approaching the final hurdle before being able to ask the FDA for permission to sell their product. It has been a long slow process, but it is encouraging to see this potential redness treatment reaching the end of the approvals process.

Read more of my extensive coverage of Sansrosa News.

Dose-Finding Study of CD07805/47 Topical Gel in Subjects With Erythematotelangiectatic Rosacea

This is a randomized, double-blind, parallel-group, vehicle-controlled, dose-finding study to investigate the pharmacodynamics and the safety of three dosages of CD07805/47 topical gel (0.07%, 0.18%, and 0.50%), after a single application in subjects with a clinical diagnosis of stable moderate to severe erythematotelangiectatic rosacea. Subjects will be randomized in a 1:1:1:1 ratio to receive either one of three CD07805/47 topical gel concentrations (0.07%, 0.18%, or 0.50%) or Vehicle Gel. All subjects will be treated with a single application (once daily dosing for one day) of study medication.

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The article mentions the positive results from the “most recent research” on Brimonidine ;

In the most recent research, a double-blind study for Galderma, a 1 g application of 0.18 percent COL-118 facial gel (1.8 mg brimonidine) was administered topically in the morning; a second, four hours later. The erythema began decreasing within an hour, and the results lasted most of the day.

Almost suggesting that the real success of Sansrosa is it’s placebo effect are the following comments ;

Dr. Leyden describes the redness as significantly reduced when the brimonidine is applied, and he says that patients are thrilled with the results.

"They’re ecstatic. They know the result isn’t permanent and will wear off in a matter of hours, but just the fact that redness can be controlled is more than what they have had," Dr. Leyden tells Dermatology Times.

While there is no medical reason for the preparation to have a lasting effect on a patient’s basic rosacea erythema, Dr. Leyden says some improvement can often be seen in that baseline redness.

"It may be because stress is one of the contributing factors in rosacea. Once the patient knows there is a way to reduce the redness, they worry less about a flare-up, and the base redness decreases as a result," he says.

Whilst is it fine to state that the method of operation is unknown, claiming a drug’s success is psychological is a little concerning. Whilst the placebo effect is well known and somewhat understood, it naturally doesn’t form any solid basis for a product’s success. One has to ask whether the product will be universally successful across the population if an important part of the treatment is the belief that it will work. Having said all this, it might just be a throw away line, as indeed double-blind placebo-controlled trials are designed to prove that the active agent is effective.

Moving on to discuss Oxymetazoline, the article quotes Dr. Shanlen and covers information that is well known to readers of Rosacea News (oxymetazoline may be good for 2 years).

Dr. Baumann cautions about the topical use of Afrin;

"I would caution patients with rosacea not to go out and apply straight Afrin on their skin. Afrin contains several ingredients that can be irritating. But the ingredients used in Afrin do show signs of offering a breakthrough in rosacea treatment in the future," she says.

We also know from the Feb. 2008 meeting of the AAD that oxymetazoline is effective for up to 6 hours after application, and that no negative side effects have been seen after 3 months usage.

Dr. Shanlen holds a patent on the usage of oxymetazoline to treat rosacea.

This DermatologyTimes article is in addition to some encouraging publicity at the recent AAD Meeting in SFO, which also highlighted Oxymetazoline as a treatment for rosacea.

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Those following the development of sansrosa closely will be encouraged by this patent application; making this new treatment seem one step closer to being available.

Brimonidine Compositions for Treating Erythema, United States Patent Application 20090061020

The present invention is directed to a pharmaceutical composition including brimonidine tartrate in an amount from about 0.17 percent by weight to about 0.19 percent by weight in a pharmaceutically acceptable carrier such as a gel or cream. The invention also relates to a method of treating erythema in a patient with rosacea by administering the composition of the invention to the site of erythema on the skin of the patient.

More extracts:

A composition wherein the gel comprises water, a gelling agent, a skin-penetrating agent (propylene glycol), a moisturizer (glycerin), a preservative (methylparaben or phenoxyethanol), a gelling agent (Carbomer 934P), a protective agent (titanium dioxide), a carrier to have a pH of about 5 to about 7.5 (sodium or potassium hydroxide)

A composition wherein the gel comprises water, a carbomer, propylene glycol, glycerin, methylparaben, phenoxyethanol, glycerin, titanium dioxide and a sufficient amount of base to cause the carrier to have a minimum pH of about 6.2 and a maximum pH of about 6.8 when the gel is diluted by a factor of ten.

Later on we can see the relative amounts of each component.

Gel Formulation

The Phase 2 studies used a composition similar to the above gel formulation. Three strengths were used for the trials – 0.02%, 0.07% and 0.20% brimonidine tartrate. The placebo of course contained no brimonidine tartrate. A strong benefit in reduction of erythema was seen in the mid and high doses.

Cream Formulation

Dosage

We can also see that `Typically, one to four applications per day are recommended during the term of treatment.’

Do you see anything you don’t like ? Anything interesting or of concern given your own experience with topicals ?

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We know from patent filings that the active ingredient in the in-development sansrosa product is brimonidine tartrate. This is also the active ingredient in Alphagan P, a treatment for glaucoma.

Alphagan P 0.1%, is known as an alpha2-adrenergic receptor agonist, and is used to lower intraocular pressure and reduce ocular hypertension. Around 10-20% of users of Alphagan P experience adverse side effects including conjunctivitis, swelling of the conjuctiva and itchiness of the eye. Extreme caution is advised in patients with cardiovascular disease.

Sansrosa, also known by its in-house name COL-118, is based on brimonidine tartrate, and is in the process of being assessed by the FDA and it believed to be scheduled to start Phase 3 trials in early 2009.

A recently published paper has shed some light on the method of operation of brimonidine tartrate. This could be interesting to rosacea sufferers, especially those investigating the link between nerve mediated flushing and rosacea. Could the active ingredient also help rosacea sufferers by protecting against nerve damage in your skin ? This is a question that I think is worth investigating.

After topical instillation, brimonidine reduces intraocular pressure within 1 hour, and the peak effect occurs at 2–3 hours after dosing. Preclinical trials have shown that brimonidine has neuroprotective effects in animal models of optic nerve damage. Neuroprotection has been investigated as a therapeutic approach for neurodegenerative conditions including stroke, spinal cord injury, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and Alzheimer’s disease.

Interestingly, systemic administration of brimonidine, which does not reduce Intraocular Pressure, is also neuroprotective.

Clinical efficacy and neuroprotective effects of brimonidine in the management of glaucoma and ocular hypertension

Abstract: Elevated intraocular pressure (IOP) is a signifi cant risk factor for the development and progression of glaucomatous optic neuropathy, but increasingly we appreciate that non-pressure dependent factors, are key to our understanding of the pathophysiology of these neurodegenerative diseases, that target the retinal ganglion cell. As we try to expand therapy beyond IOP control, medications are being assessed for their neuroprotective abilities. Brimonidine is an effective ocular hypotensive treatment both as a fi rst and second line agent, in the management of glaucoma and ocular hypertension. Brimonidine tartrate 0.2% is generally safe and well tolerated, with its safety profi le further enhanced in the altered formulation brimonidine-Purite™ 0.1%. Beyond brimonidine’s pressure lowering capacity, laboratory and early clinical evidence supports its neuroprotective potential. We await validation of this in human clinical trials. 

Keywords: brimonidine, neuroprotection, clinical effectiveness, tolerability

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One article talks about how Galderma/Collagenex is excited about new possible drugs. It doesn’t directly name the Sansrosa product, but it does have a little note that it `likely won’t be available for several years’. If that is a direct quote from Dr. Schlessinger, a long term investigator from Galderma/Collagenex then that will be discouraging news for many.

Now on trial: New rosacea medications hold promise for future

One of the medications being studied by scientists at Galderma Laboratories acts as a vasoconstrictor. A topical gel, it decreases redness around the area for up to 12 hours, a considerable increase over current treatments. The compound has shown very dramatic results and is beneficial for people with significant rosacea, according to Dr. Schlessinger.

Although initial trials have been conducted, the product likely will not be available for several years.

Collagenex had an excellent Public Relations engine and were normally very quick to release any official news about upcoming products – especially one would imagine if that might effect investors’ view of the company. Since Galderma purchased Collagenex, the Collagenex web site has morphed into a Galderma corporate site, and subsequently lost a lot of the bleeding edge information about Sansrosa. This would be as expected, now that the much smaller operations of Collagenex, and indeed SansRosa Pharmaceutical Development have been merged into Galderma.

The latest official information from Galderma was that they `anticipate completing the study in the third quarter of 2008 and commencing our Phase III clinical trials before the end of 2008’ (Sansrosa Phase 3 Delayed until END of 2008).

We know that in May 2008 details of the commencement of the additional Phase 2 trials were posted on clinicaltrials.gov, and shortly later the trial was listed as completed. Apart from that, we are still waiting for more official news. While we wait, we are left wondering if the Phase 2 trials didn’t go well, or if it is just the  wheels of bigpharma drug development processes turning slowly.

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The dermatology news sheet Dermatology Times has published an item to their web site about the emerging use of oxymetazoline to treat the redness and flushing associated with rosacea. This article draws from the Nov. 2007 paper that introduced us to the possibility of treating rosacea with oxymetazoline.

We also know from the Feb. 2008 meeting of the AAD that oxymetazoline is effective for up to 6 hours after application, and that no negative side effects have been seen after 3 months usage. Further comments here in the DT article extends the apparent `durable’ treatment period to 2 years. Note that this successful long term avoidance of rebound whilst using oxymetazoline refers to just one patient.

Dr. Shanler notes that loss of effectiveness and rebound dilation is a problem associated with the use of intranasal use of oxymetazoline.

Oxymetazoline is classified as a alpha-1 Adregenic Receptor Agonist, whereas COL-118/Sansrosa is a alpha-2 Adregenic Receptor Agonist. According to this DT article oxymetazoline is “also partially selective for the alpha 2a receptor.”

The paper’s authors are both corporate officers of Aspect Pharmaceuticals, who are now planning more formal studies to evaluate rosacea friendly formulations of oxymetazoline and other alpha-1 adrenergic agonists to treat the redness and flushing of rosacea.

From: Taking the red out of rosacea: Topical alpha-1-adrenergic receptor agonist shows promise

Limited experience in a small number of patients indicates that the erythema and flushing associated with rosacea may be safely and successfully treated with topical application of a selective alpha 1-adrenergic receptor agonist, such as oxymetazoline, researchers say.

…

"The results achieved with topical oxymetazoline are exciting, but very early, and they need to be confirmed through more rigorous studies," Dr. Shanler tells Dermatology Times.

Patient responses to topical oxymetazoline were based on direct clinical assessment and review of high-resolution digital photographs taken pretreatment at one, two to three and 24 hours post application, and then again after longer-term treatment. The evaluations showed topical oxymetazoline had a rapid effect in reducing erythema.

With continued treatment, which extended up to two years in one patient, the responses remained durable, with no evidence of tachyphylaxis, rebound or adverse events.

"Loss of efficacy due to receptor desensitization and rebound vasodilation is a problem associated with use of intranasal oxymetazoline and other imidazoline- and amine-class nasal decongestants.

"There is some laboratory evidence that the potential for receptor desensitization varies depending on the agonist’s selectivity for different alpha-adrenoreceptor subtypes and its duration of action. This may be a consideration in the development of a dermatologic medication that will provide optimal efficacy with minimal risks," Dr. Shanler says.

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The Clinical Trial register is showing details for the bio-availabilty trial for COL-118/Sansrosa. This Phase 2 trial aims to compare the amount of the active ingredient that is bio-available when the newly formulated gel is used on rosacea skin, and when used as eye drops.

This announcement appears to be the extra trial asked for by the FDA who are concerned that rosacea skin may allow more systemic absorption than non rosacea skin. The side effects of Brimonidine when it gets into your blood are extremely dangerous. Even though the Phase 1 trials of COL-118 showed that healthy volunteers did not have measurable quantities of the active ingredient, diseased rosacea skin may allow more of the Brimonidine to enter the blood stream.

The bit that is new in this trial is that all of the participants will have moderate to severe erythematous rosacea and use the brimonidine ophthalmic solution. The group will be split randomly such that 1/2 will use the new Sansrosa Gel and 1/2 will use the inactive vehicle. The amount of the active ingredient in the blood plasma will be compared between the 2 groups. For the product to proceed to the next step, there will need to be no measurable difference.

The larger scale Phase 3 safety trials have been delayed until after this Phase 2 trial is completed in September this year.

From Systemic Bioavailability Study Of Col-118 Administered Topically as a 0.18 % Facial Gel And Brimonidine Ophthalmic Solution 0.2%

Primary Outcome Measures:
To assess the relative bioavailability of 0.18% COL-118 facial gel and 0.2% brimonidine ophthalmic solution under conditions of maximum use in patients with moderate to severe erythematous rosacea.

Secondary Outcome Measures:
To evaluate the safety of COL-118 administered topically as a facial gel in male and female subjects with moderate to severe erythematous rosacea

…

Detailed Description:

A double-blind, randomized, 2-way crossover, safety, pharmacokinetic/-dynamic (PK/PD) study of 0.18% COL-118 facial gel and 0.2% brimonidine ophthalmic solution administered in male and female patients with moderate to severe erythematous rosacea.

Twenty male and female subjects with moderate to severe erythematous rosacea will be randomized into 2 groups of 10 subjects.

Each group will be randomized to receive 2 treatments (Treatments A and B, in Sequence 1: A/B or Sequence 2: B/A), as follows:

Treatment A: One 1-g application of 0.18% COL-118 facial gel (1.8 mg brimonidine) administered topically plus one drop of Advanced Eye Relief™ in each eye, once in the morning. 1 g of 0.18% COL-118 facial gel is reapplied once after four hours;

Treatment B: One 1-g application of COL-118 facial gel vehicle (0.0 mg brimonidine tartrate) administered topically plus one drop of 0.2% brimonidine ophthalmic solution (0.1 mg brimonidine tartrate/drop) in each eye. Four hours after the first application 1-g of COL-118 facial gel vehicle (0.0 mg brimonidine) is administered topically.

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According to the just published earnings call, Collagenex have been asked to undertake a additional Phase 2 study before commencing Phase 3. These additional studies will take several months, delaying the start of Phase 3. Collagenex are still hopeful of commencing Phase 3 studies some time before the end of 2008.

These additional studies are to confirm that the diseased rosacea skin does not allow more of the active ingredient to absorbed into the blood, compared to healthy volunteers. The Phase 1 trials showed that healthy volunteers did not have measurable quantities in their blood plasma.

From CollaGenex Pharmaceuticals Q4 2007 Earnings Call Transcript

Prior to starting the Phase III studies, the FDA has requested that we do a small additional Phase II study, which we anticipate will enroll about 20 patients and take several months to complete. The purpose of this study is to augment data from a Phase I bioavailability study that we conducted — that showed that administration of COL-118 to the skin of healthy volunteers did not yield measurable levels of 118 in plasma.

As a safety precaution, FDA has requested that we repeat this study in rosacea patients to demonstrate that plasma levels of COL-118 are not increased in patients with the disease skin of rosacea. We anticipate completing the study in the third quarter of 2008 and commencing our Phase III clinical trials before the end of 2008.

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Man: “I realize that it’s an in-class, COL-118, it’s kind of difficult to work out the economics of the opportunity. Now, the fact that it’s kind of an instant gratification therapy, it’s something you put on, the erythema disappears, and it persists over time, and presumably there’s also a therapeutic effect over time. Is there any kind of rebound effect, do the receptors get burnt out where people cannot use it for an extended period of time, because you kind of think that given the product profile that they will, and that might have a significant impact on how much you ultimately sell. “

Mr. Stewart: “In studies we’ve done so far, we have seen no rebound effect. When the drug was used successfully for over 11 years within opthomics, there was no perceived rebound effect. One of the things that excites us about this is that it has a fast onset of action, and that it can be used incomitantly with the patient. Given that and the historical safety record of the drug, we don’t anticipate any rebound. If there were, they would show up in the Phase 3 long-term safety studies that we’re about to do.”

The next meeting with the FDA to discuss COL-118 Phase 3 trials will be in the “first half of March.”  Mr. Stewart also stated the Quarter 4 and Year 2007 company conference call would be March 12.  Stay tuned for more info…

This poster abstract is an update to the paper that was published in Archives of Dermatology in 2007 and was covered by Rosacea News as Sansrosa’s sister to enter redness race. This now expanded abstract suggests that oxymetazoline is effective for up to 6 hours after application and no side effects have been seen after 3 months usage. Oxymetazoline is a related compound to that which forms the basis for the sansrosa product. As I previously noted, this is good news for rosacea sufferers as it means there may well be a choice between 2 topicals that can help address the redness and flushing of rosacea.

Poster Abstracts, American Academy of Dermatology 66th Annual Meeting, February 1–5, 2008, San Antonio, Texas. Supplement to the JAAD, Feb 2008, Volume 58, Number 2.

Poster Abstract P400, Successful treatment of the erythema and flushing of rosacea using a topically applied selective α1 adrenergic receptor agonist, oxymetazoline, Stuart Shanler, MD, Las Cruces Dermatology, Las Cruces, NM, United States, Andrew Ondo, MD, Las Cruces Dermatology, Las Cruces, NM, United States.

Background: Rosacea is a common chronic cutaneous disorder affecting more than 40 million people worldwide. Type I, or Erythematotelangiectatic rosacea (ETR), is the subtype of rosacea characterized by frequent episodes of transient facial
erythema (flushing) and/or persistent erythema, and may be accompanied by facial edema, burning, or stinging. ETR in general responds poorly to treatment and there are no effective topical therapies directed towards the erythema and telangiectasias.
While rosacea remains a disorder of uncertain etiology and pathogenesis, the abnormal flushing and persistent erythema have usually been theorized to arise from a progressive dysregulation of the cutaneous vasomotor response resulting in an abnormal and persistent dilation of facial blood vessels. The mechanism of such ‘‘dysregulation’’ has never been elucidated. The regulation of the cutaneous circulation is extremely complex and activation of adrenergic receptors (adrenoceptors) present on vascular smooth muscle may result in vasoactive changes that are difficult to predict. Recent studies, however, have demonstrated that the contraction of peripheral vascular smooth muscle is primarily mediated by α1A and α1D adrenoceptor subtypes, and certain experimental models indicate several α2 receptors may play a role as well.

Objective: An attempt to treat ETR using topically applied oxymetazoline, an overthe-counter drug known to be a potent selective α1A and partially selective α2A adrenoceptor agonist—a potent vasoconstrictor—was undertaken.

Methods: A commercially available preparation ofoxymetazoline 0.05% solution was applied once daily to the faces of 4 patients with ETR. Clinical evaluation and high resolution digital photographs were performed pre treatment, 1, 3, and 24 hours after a single application and 1 and 3 months after initiating once daily application.

Results: All 4 patients showed clinical improvement in the erythema, marked decrease in the erythematous flares (flushing), relief from the stinging/burning, and no adverse effects. The effect was noted within 1 hour of drug application, lasted more than 6 hours, and was maintained at 3-month follow-up.

Conclusion: We propose that the erythema and flushing of ETR may be caused by an abnormal expression, function, distribution, or responsiveness of a adrenoceptors, likely of an α1 subtype, and that ETR may be successfully treated by the topical application of agonists selective for these receptors, such as oxymetazoline.

Commercial support: None identified.

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DISCUSS: add a comment below or discuss this news item in the Non Prescription Topicals forum.