News today that the giant pharmaceutical company Novartis International is buying Fougera Pharmaceuticals.

Fougera is known to rosacea sufferers through the availability of generic metronidazole 0.75%. Fougera will brings its specialty in generics to Sandoz, the generics division of Novartis.

Who is Novartis?

Novartis was previously the manufacturer of Elidel (Pimecrolimus cream 1%).

Novartis are also trialling BFH772 for the redness of rosacea (NCT01449591). BFH772 is also being trialled for Psoriasis (NCT00987870).

BFH772 appears to be a metrondizaole variant of some sort, perhaps a genuine competitor to Metrogel 1%.

Hopefully this further signals Novartis as a company willing to invest in treatments for rosacea.

Press Release

Novartis to Buy Fougera Pharmaceuticals for $1.5 Billion

BY MICHAEL J. DE LA MERCED

Novartis International agreed on Wednesday to buy Fougera Pharmaceuticals, a maker of generic skin care medicine, for $1.525 billion in cash. The move would make the company the biggest manufacturer in the field.

It is the latest round of consolidation in the health care industry, a sector that has had a number of deals over recent weeks.

Under the terms of the deal, Fougera will be folded into Sandoz, the generics division of Novartis. The acquisition would give Novartis a leading position in generic treatments for ailments like acne, eczema and rosacea. The combined business will have an estimated $620 million in annual global sales, mostly in the United States.

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From my high school organic chemistry it seems to me that Ivermectin and Metrondizole are in fact chemically akin to cousins.

I started to think about this because of the huge investment being undertaken by Galderma in developing a 1% Ivermectin Cream for Rosacea.

Why would Galderma believe so much in an anti-parasitic?

Is the message that demodex is so rampant in all rosacea sufferers that an anti-parasitic is to become de rigueur?

Well I’m no fan of the `Demodex Is the Root of Rosacea’ theory so it got me to thinking about what is really happening here.

Thinking Out Loud

So, could it be possible that both Metronidazole and Ivermectin are actually related chemically.

Calling Organic Chemists

If you are an Organic Chemist please feel free to help me out here. Is it correct to say that as both Ivermectin and Metrondizole are `Nitro-5-imidazoles’ then they will exhibit similar properties?

I’m sure if I kept looking I could find more compelling chemical structure images. Below you can at least see the carbon ring with a NO2 hanging off it and something that could be similar hanging off Nitrogen at position 5.

Metronidazole

Metronidazole belongs to a group of nitro-5-imidazole and is active mainly against anaerobic microorganisms.

My one sentence summary of how Metronidazole works is “metronidazole breaks down into a substance that kills the DNA of the cells of some particular bacteria and protozoa”.

Chemically,metronidazole is 2-methyl-5-nitro-1H-imidazole-1-ethanol. The molecular formula is C6H9N3O3 and molecular weight is 171.16.

Ivermectin

Ivermectin is a part of a larger chemical family known as the nitro-5-imidazoles which, alternatively, has been termed the 13-deoxy ivermectin aglycones. The nitro-5-imidazole family of molecules includes invermectin, ivermectin, avermectin, moxidecion and various derivatives thereof.

Speculate Away

Experts please chime in below !!

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A large study looking at a treatment for the papules and pustules of rosacea is looking to recruit participants right across the US and Canada.

A web site just for this study has been created at www.pprstudy.com (Papulo – Pustular – Rosacea Study). On the site you can use your ZIP code to see if there is a study location close to you.

As there is such a good overlap with study locations this publicity push looks to be for Trial NCT01493687.

Study  NCT01493687 is for Galderma’s mysterious CD5024 1% Cream and involves 45 locations and around 1360 participants.

My guess is that CD5024 is 1% Metrocream – seems reasonable that as the trial wants to compare against the “competition” in Finacea, the concentration is 1%, it is a Phase III trial, and the target is the papules and pustules of rosacea.

[update:] CD5024 is Ivermectin

I now believe that CD5024 is not Metronidazole. I speculated last year that Galderma might be looking at at topical Ivermectin preparations - Topical Ivermectin + Metrogel from Galderma and this page from the NHS UK seems to offer a clue as well – New Drugs Online – Ivermectin.

So I will go out on a limb and say that CD5024 is Topical Ivermectin 1%. Good news – rosacea sufferers might shortly have a new treatment available to them.

Do Let Us Know

Please do let us know in the comments below if you can confirm CD5024 is Ivermectin based, or if you get to be involved in the trials, how it goes.

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Taro Pharmaceuticals in fact already markets a generic form of Metrogel – Metronidazole Gel USP, 0.75%

When the patent covering Metrogel 0.75% expired, Galderma changed the formulation, increased the concentration of metronidazole to 1% and now produces the best-known rosacea treatment, Metrogel 1%.

This is good news for rosacea suffers, who can only benefit from competition in the rosacea treatment staples market. Often rosacea sufferers come away from their first visit to the doctor and pharmacist with one thought – Why is this Metrogel so expensive?

Trial CT01513863 is listed to compare Taro Pharmaceutical’s Generic Metronidazole 1% Gel with Galderma’s Metrogel 1% (and also placebo).

Clinical Trial NCT01513863

A Therapeutic Equivalence Study of Two Metronidazole 1%Topical Gel Treatments for Patients With Rosacea (MTZG)

A Randomized, Double-Blind, Placebo Controlled, Parallel Design, Multi-Site Clinical Study to Compare the Bioequivalence of Two Metronidazole 1% Topical Gel Formulations in Patients With Moderate to Severe Rosacea

Arm 1

Metronidazole Topical Gel 1%: Experimental

Intervention: Drug: Metronidazole Topical Gel 1%

Arm 2

Metronidazole Topical Gel 1% (Metrogel ): Active Comparator

Intervention: Drug: Metronidazole Topical Gel 1% (Metrogel)

Arm 3

Placebo: Placebo Comparator

Intervention: Drug: Placebo

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Galderma have announced that Metrogel 1% will now be available in a 55gm Pump. Galderma are citing the benefits of a better looking dispenser, minimizing waste, easier compliance with prescribing instructions and “facilitating product handling”. Galderma received FDA approval for Metrogel 1% Pump in October 2011.

Metrogel 1% Pump is now available on prescription in pharmacies across the U.S.

As we know, the Metronidazole market is awash with choices; Metrogel 1%, Rozex, Metrolotion, Metrocream and Noritate – and now Metrogel 1% Pump.

Galderma Announces Availability of New Metrogel(R) 1% Pump Dispenser for the Treatment of Papulopustular Rosacea

Pump Delivery Provides Consistent Dosing, Minimizes Waste and May Help Increase Patient Compliance

FORT WORTH, TX–(Marketwire -01/17/12)- Galderma Laboratories, L.P. today announced the availability of a new pump dispenser design for MetroGel® (metronidazole) Gel, 1%, the most powerful strength of topical metronidazole available in a gel to treat the inflammatory lesions (bumps and blemishes) associated with rosacea. The MetroGel® 1% Pump, which the U.S. Food and Drug Administration approved in October 2011, is now available by prescription to patients in pharmacies nationwide.

Results from a new survey of 207 physician-diagnosed rosacea patients, ages 25 to 65, found 69 percent of patients prefer a pump over a tube. Patients in the survey also felt the pump was more aesthetically pleasing and reported the pump delivery facilitates product handling and storage and minimizes waste. Additionally, patients thought the pump delivery would help them to follow their doctor’s instructions on product usage.

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Galderma has another rosacea-targeted treatment, until now undisclosed, in the final stages of approval. Hey – how come no one told me?

Could it be possible that the rosacea heavyweight Galderma has kept a new product so secret?

What is this CD5024?

Just what exactly is this CD5024 1% Cream? Galderma always give code names to their in-development products, why has no one noticed this new code so far?

I can’t find many clues, but my guess is that CD5024 is a 1% cream formulation of metronidazole.

Read on to see why my guess is that we can pretty much ignore CD5024 as being something new and innovative.

Two Clinical Trials Posted

I was first alerted to the new product CD5024 when two new clinical trials were posted at clinicaltrials.gov. Both of these are Phase 3 Trials, suggesting that the product was in the latter stages of product development.

• Trial NCT01493947 is a Phase 3 trial comparing CD5024 to Metronidazole 0.75% for 16+36 weeks.
• Trial NCT01493687 is a Phase 3 trial proving CD5024 works better than placebo after 12 weeks, for the papules and pustules of rosacea. A further 40 weeks to prove that CD5024 is as safe as Finacea.

So it seems a reasonable guess that as the trials want to compare against Finacea, the concentration is 1% and the target is the papules and pustules of rosacea, that CD5024 is merely metronidazole.

Another reference to CD5024 was from 2006 in an Australian trial. Perhaps this is another hint – Metronidazole in a 1% formulation is not available in Australia, so perhaps this shows that Galderma is preparing a Metrocream 1% for a wide market.

Do We Need Another Metro Sibling?

If I am correct, and CD5024 is merely MetroCream 1%, it will be joining a pretty crowded metronidazole market. Even though you can find Metrogel 1%, Metrogel 0.75%, Metrocream, Metrolotion, Noritate and even Metronidazole with sunscreen, some research suggests that it doesn’t actually matter which you choose, they all work much same. Marketing gone mad? I would suggest so.

Your Thoughts

Do you have any more information about CD5024? Please let us know in the comments below or drop me an email to david AT rosacea-support.org. Thanks.

[Update:] I now believer that CD5024 is Ivermectin Cream 1%. See Uk Medicines Information New Drugs Online for confirmation.

Related Articles

Galderma has a long history with topical metronidazole products, starting with Metrogel 0.75%, then adding Metrolotion and Metrocream, and when the patent on the 0.7% Metrogel expired, Galderma created Metrogel 1%.

Past research seems to suggest that it matters little whether you use Metrogel, Metrolotion, Metrocream or Noritate. Further it seems to not matter whether you use these products once or twice per day.

As far as foam based rosacea treatments are concerned, we learnt in 2009 that a clinical trial would investigate whether a foam based form of Finacea was safe and effective.

The foam being patented is described as a “stable, metronidazole-based oil-in-water emulsion expandable into a topically applicable foam having a firm, creamy and light consistency” and is claimed to have improved release-penetration capacity.

METRONIDAZOLE-BASED DERMATOLOGICAL FOAM AND EMULSIONS FOR THE PRODUCTION THEREOF

Oil-in-water emulsions expandable into stable foams having diminished inhibitor of skin breathing and useful for the treatment of dermatological conditions/afflictions, e.g., rosacea, advantageously contain:

(a) 72% to 76% of water;
(b) 0.1% to 5% of a gelling agent for the aqueous phase of the emulsion;
(c) 0.75% to 2% of metronidazole;
(d) 5% to 10% of mineral oil;
(e) 0.5% to 10% of a surfactant;
(f) 0.5% to 5% of a fatty acid;
(g) 0% to 4% of a metronidazole absorption promoter (c); and
(h) 0.1% to 5% of a preservative selected from the group consisting of methylparaben, propylparaben, phenoxyethanol and mixtures thereof.

Domain Name

Galderma have owned the domain name metrofoam.com since 2004, which currently just redirects to Galderma.com.

Can You Get Excited?

Does the thought of being able to get your Metronidazole dose from a foam do anything for you?

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This review looked at the published results of 58 trials to note bias and construct a high level summary of the results.

No Surprises Here

It will come as little surprise that the well known treatments Metrogel, Finacea and Oracea were found to be effective. These prescription based treatments from Galderma and Intendis have seen high levels of investment in research and development and indeed marketing specifically as rosacea treatments.

What is a Cochrane Review

From The Cochrane Collaboration: Cochrane Reviews are designed to facilitate the choices that doctors, patients, policy makers and others face in health care. Most Cochrane Reviews are based on randomized controlled trials, but other types of evidence may also be taken into account, if appropriate.

What Bias?

The Cochrane Review attempts to identify any bias that may have affected the outcome of the trials reviewed.

Many levels of bias are possible; are the participants truly randomly selected, representative of the population, truly blinded to the treatments?, are outcomes fairly reported? what about exclusions and attrition rates ?

Any one of these sorts of bias can cause the results of a trial to be questioned. As is the usual case with these large systematic reviews, high or unclear levels of bias were present in the clinical trials.

Clinical Trials without any bias are hard to achieve and seem to be quite rare.

Effective and evidence-based management strategies for rosacea: summary of a Cochrane systematic review, Br J Dermatol. 2011 Jun 21, van Zuuren EJ, Kramer SF, Carter BR, Graber MA, Fedorowicz Z.

Background: Rosacea is a common chronic skin disease affecting the face. There are numerous treatment options, but it is unclear which are the most effective.

Objective: To assess the evidence for the efficacy and safety of treatments for rosacea.

Methods: Searches included the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index, and Ongoing Trials Registers (updated February 2011). Randomized controlled trials in people with moderate to severe rosacea were included.

Results: Fifty-eight trials, including 27 from the original review, comprising 6,633 participants were included in this updated review. Interventions included topical metronidazole, oral antibiotics, topical azelaic cream or gel, topical benzoyl peroxide and/or combined with topical antibiotics, sulphacetamide/sulphur, and others. There was some evidence that topical metronidazole and azelaic acid were more effective than placebo. Two trials indicated that doxycycline 40 mg was more effective than placebo. There was no statistically significant difference in effectiveness between doxycycline 40 mg and 100 mg and with evidence of less adverse effects. One study reported that cyclosporine ophthalmic emulsion was significantly more effective than artificial tears for treating ocular rosacea.

Conclusions: Although the majority of included studies were assessed as being at high or unclear risk of bias, there was some evidence to support the effectiveness of topical metronidazole, azelaic acid, and doxycycline (40 mg) in the treatment of moderate to severe rosacea, and cyclosporine 0.05% ophthalmic emulsion for ocular rosacea. Further well-designed, adequately-powered randomised controlled trials are required.

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Recent research is highlighting just how important are all of the ingredients in a topical preparation.

The benefits to your skin from the vehicle components help explain why one might even obtain relief from vehicle-only preparations. For example if you are on a clinical trial that is blinded. Particularly if your skincare regime is not supporting the functions of your skin, the vehicle carrying the active ingredient in a topical may itself be worth using.

This further reinforces the argument that a gentle (and supportive) skincare regime is important for rosacea sufferers.

Of course mixing your own topicals is not an easy task, so mostly we are limited to the formulations that have been made for us by the pharmaceutical companies.

As a refresher here is a listing of ingredients of the most popular rosacea topicals. As you can see it is not an easy task to discover just from the listing whether a topical is going to be a winner for you.

Metrogel Ingredients

METROGEL (metronidazole gel), 1% is an aqueous gel; each gram contains 10 mg of metronidazole in a base of betadex, edetate disodium, hydroxyethyl cellulose, methylparaben, niacinamide, phenoxyethanol, propylene glycol,propylparaben and purified water.

Finacea Ingredients

Each gram of Finacea contains 0.15g (15%) micronized azelaic acid in a gel base. It also contains 0.1% benzoic acid, propylene glycol, polysorbate 80, lecithin, polyacrylic acid, triglycerides (medium chain), sodium hydroxide, disodium edetate and purified water.

Plexion Ingredients

Each gram of Plexion® (sodium sulfacetamide USP 10% and sulfur USP 5%) Topical Suspension contains 100 mg of Sodium Sulfacetamide USP and 50 mg of Sulfur USP in a suspension containing: Purified Water USP, Propylene Glycol USP, Isopropyl Myristate NF, Light Mineral Oil NF, Polysorbate 60, Sorbitan Monostearate NF, Cetyl Alcohol NF, Hydrogenated Coco-Glycerides, Stearyl Alcohol NF, Fragrances, Benzyl Alcohol NF, Glyceryl Stearate (and) PEG-100 Stearate, Dimethicone NF, Zinc Ricinoleate, Xanthan Gum NF, Edetate Disodium USP, and Sodium Thiosulfate USP.

Klaron Ingredients

Each mL of Klaron (sodium sulfacetamide lotion) Lotion, 10% contains 100 mg of sodium sulfacetamide in a vehicle consisting of purified water; propylene glycol; lauramide DEA (and) diethanolamine; polyethylene glycol 400, monolaurate; hydroxyethyl cellulose; sodium chloride; sodium metabisulfite; methylparaben; xanthan gum; EDTA and simethicone.

Research Abstracts

Topical rosacea therapy: the importance of vehicles for efficacy, tolerability and compliance, J Drugs Dermatol. 2011 Jun 1;10(6):627-33, Jackson JM, Pelle M.

Many topical medications are available for the treatment of papulopustular rosacea. While treatments contain metronidazole, azelaic acid, or sodium sulfacetamide-sulfur as the active ingredient, the composition of the vehicle formulations varies widely.

These vehicles come in gels, creams, lotions and foams; some ingredients are common to many vehicles, while some vehicles contain unique ingredients designed to optimize skin penetration and delivery of the active drug to its target.

Vehicles can also influence tolerability, which is always a concern in patients with heightened skin sensitivity, and compliance, which is typically lower for topical treatments than oral treatments.

Ideally, the vehicle of any rosacea treatment should enhance drug delivery, be non irritating and be easy to use. Ingredients that help repair barrier function are also desirable. This review will focus on the key components of the vehicles from the most commonly used topical therapies for papulopustular rosacea and how vehicle formulations influence the delivery of active ingredient, skin barrier repair, tolerability and compliance.

Further related research;

THE IMPORTANCE OF VEHICLE IN ACNE THERAPY

Emil A. Tanghetti, MD, Chair, A Supplement to Skin & Allergy News,

Skin Disease Education Foundation’s 29th Annual Hawaii Dermatology Seminar, a continuing medical education program, March 18-24, 2005, in Maui, Hawaii. 

Physicians attempting to balance aggressive acne treatment with tolerability stress the importance of restoring hydration of the stratum corneum. Research demonstrating the stratum corneum’s pivotal role in drug delivery has sparked renewed interest in this topic.

Many common conditions directly and indirectly affect barrier function.  For example, atopic dermatitis, psoriasis, and acne affect barrier function directly through the impact of the inflammatory process on epidermal growth and maturation. Medications used to treat a number of conditions indirectly disrupt barrier function.  Topical retinoids—the mainstay of acne treatment—change and disrupt barrier function.

Several signs and symptoms characterize damage to the epidermal barrier.  Dryness and peeling occur when the water content of the stratum corneum falls below 10%.  This creates a damaged and leaky epidermis that may lead to overabsorption of topical medications and products, causing even more barrier damage.

Summary

Restoring and maintaining barrier function is critical for outcomes in patients with dermatologic diseases.  For optimal hydration, a vehicle that is both occlusive and humectant is ideal.  The addition of moisturizers such as dimethicone and glycerin to acne treatment products helps maintain barrier function and will provide better outcomes. This is particularly important when topical retinoids are included in the therapeutic regimen. For comedonal acne, combination products containing moisturizers may be effective first-line agents. Finally, clinicians should consider the vehicle prior to prescribing or recommending any products to patients with acne.

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Once you have been diagnosed with rosacea, everyone naturally wants to know What is the best treatment for rosacea?

Wouldn’t it be great if there was a simple answer to this question that satisfied everyone who has rosacea!

Hopefully it doesn’t come as a surprise to find out that there is no known panacea for rosacea.

This high level paper from The Journal of Family Practice seeks to summarise the available published research into rosacea treatments. Thus the treatments being labelled `best’ by this study are only ever going to be the ones that have been proven by years of research and development and real life testing.

What I’m trying to warm you up to is the idea that you should only ever expect to see the well known prescription topical and systemic treatments emerge from these sorts of studies.

Clinical Inquiries: What is the most effective treatment for acne rosacea?

J Fam Pract. 2011 Feb;60(2):108a-c., May D, Kelsberg G, Safranek S.

Topical metronidazole and azelaic acid are equally effective for the papulopustular lesions of acne rosacea, although metronidazole is better tolerated. Oral doxycycline, tetracycline, and metronidazole are also effective, but not enough evidence exists to determine whether one is more effective than another or more effective than topical therapy (strength of recommendation [SOR]: A, systematic review and individual randomized controlled trials [RCTs]).

Some evidence supports a benefit for topical sodium sulfacetamide with sulfur, and benzoyl peroxide (SOR: B, small single RCTs).

Pulsed-light and laser therapy may improve the erythema and telangiectasias associated with acne rosacea (SOR: C, case series).

All patients with acne rosacea should use sunscreen and emollients, and avoid skin irritants (SOR: C, expert opinion)

Recommendations

The American Acne and Rosacea Society guidelines state that good evidence supports topical treatments—metronidazole,
azelaic acid, and sulfacetamide/sulfur—as well as anti-inflammatory doses of oral doxycycline.

The guidelines also list other topical and oral antibiotic treatments, but cite low-quality evidence for their efficacy and concerns about the emergence of antibiotic resistance. They advise appropriate skin care, including gentle cleansers, moisturizers, and sun protection.    

Full Article PDF: What is the most effective treatment for acne rosacea?

Best Topical Therapy

Topical Metronidazole (Metrogel) and Azelaic Acid (Finacea) are indicated as being better than placebo, but “the studies
were generally weak because of poor methodology and reporting, small sample sizes, and lack of quality-of-life measures.”

Overall Metrogel is better tolerated than Finacea.

Best Systemic Therapy

Oral Metronidazole (Flagyl) and Oral Tetracycline as well as anti-inflammatory dose oral doxycycline (Periostat/Oracea) have been found to be effective.

Best Therapy for Redness

The best therapy for redness and broken blood vessels was found to be pulsed light therapy, laser therapy and photodynamic therapy with red light. No great surprises there.

Other Tips

“They advise appropriate skin care, including gentle cleansers, moisturizers and sun protection”. That is good advice we should all heed.

Can YOU Answer This Question?

Perhaps this paper won’t happily satisfy everyone’s quest for rosacea relief, but maybe you can.

You meet a newly diagnosed rosacea sufferer who is distressed. You have memories of being there yourself. What advice will you give them – what do you think is the best treatment for rosacea?

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