A recent press release teases rosacea sufferers that a topical foaming form of minocycline might become a new treatment.

The trial results promoted in the press release are for a condition called Impetigo, a bacterial skin infection.

Minocycline, as a member of the tetracycline family may offer some anti-inflammatory benefit to rosacea sufferers, but the question remains as to whether this benefit can be seen via a topical application. Minocycline is an unstable chemical and thus far has only been suitable as a systemic treatment – topical treatments have not been readily available.

Foamix Minocycline and Rosacea

We learnt in 2010 that a Phase II clinical trial was underway to examine whether a topical form of minocycline could help with rosacea. This trial NCT01134991 is due to complete in March 2012.

Foamix Impetigo Press Release

Foamix’s Minocycline Foam – 100% Effective in Impetigo Phase II Clinical Trial With No Side Effects – 80% Improved Significantly After 3 Days of Treatment

REHOVOT, Israel, March 14, 2012 /PRNewswire via COMTEX/ — Foamix, a clinical stage specialty pharmaceutical company, announced today the successful completion of the Phase II clinical trial of Minocycline foam in Impetigo patients. Minocycline Foam has shown to be highly effective against bacteria, including some multi-drug resistant strains (such as MRSA).

…

"These results are excellent; especially considering this study is the first to treat patients with topical Minocycline. The results confirm the efficacy of our Minocycline Foam in skin infections. It is also significant that our Minocycline Foam was well-tolerated and that there was no evidence of clinical safety concerns since one of the persistent barriers to the development of new classes of antibiotics has been the issue of patient safety," commented Dov Tamarkin, Foamix CEO. "We intend to aggressively pursue the development of our Minocycline Foam as a first-line treatment for a range of skin conditions, including Acne, Rosacea, Impetigo and other skin infections."

Key Features of Foamix’s Minocycline Foam

Minocycline is an extremely unstable compound, which currently exists only in oral dosage forms. Foamix successfully developed a stable, patient-friendly topical foam containing up to 4% Minocycline.

The topical administration of Minocycline Foam provides concentrated drug delivery to the infected lesion site, and leads to rapid cure, whilst avoiding the side effects common in the oral Minocycline treatment.

With a twice daily application, Minocycline Foam can lead to better patient compliance compared with other treatment options.

Foam is a user friendly dosage form which spreads evenly and absorbs easily without rubbing. This offers a great advantage when treating open wounds especially in small children.

Related Articles

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In contrast to the ongoing disputes over generic Oracea, the makers of the low-dose minocycline Solodyn, Medicis have entered into a joint development and sales agreement with Lupin Pharmaceuticals.

Solodyn is a form of Minocycline, a member of the tetracycline famaily, available in 8 strengths, prescribed based primarily on your weight.

Solodyn tablets are available in 45 mg, 55 mg, 65 mg, 80 mg, 90 mg, 105 mg, 115 mg, and 135 mg.

Officially, Soldyn is indicated to treat the inflammatory lesions of non-nodular moderate to severe acne vulgaris.

Medicis are known to rosacea sufferers as the manufacturers of Ziana and Plexion.

The Agreement

This agreement allows Medicis and Lupin to set aside the legal wrangling over the patents that are said to protect Solodyn, and allow Lupin to progressively manufacture Generic Solodyn. Additionally the two companies will work together to further develop the market for generic versions of Solodyn.

Lupin vs. Galderma

We also know from other court filings that Lupin Pharmaceuticals, along with Mylan and Impax Laboratories are all fighting for the right to manufacture Generic Oracea. Galderma is engaged in an extended dispute, using the Oracea Patents to attempt to stop others from manufacturing a cheaper version of Oracea.

This is Good News

This sort of agreement is good news for those who would like access to Solodyn, but at a more affordable price.

Rosacea Sufferers can only hope that Galderma would consider a similar agreement over Oracea. Too much to expect? Maybe so.

Medicis and Lupin Settle Solodyn Infringement Dispute; Agree to Drug Development Collaboration

Medicis has entered into multiple agreements with Lupin over the acne drug Solodyn, allowing the generic drugmaker to enter the market prior to the expiration of Medicis’ patents.

In a separate agreement, Medicis agreed to join Lupin in a drug development collaboration worth an initial $20 million to the generic company.

Medicis claimed Lupin infringed U.S. Patent Nos. 5,908,838 and 7,790,705 by seeking to manufacture a generic version of Solodyn before the patents expire.  The ’838 patent covers a slow-dissolving form of tetracycline, a class of oral antibiotics commonly used to treat acne.  When tetracycline dissolves too rapidly after being swallowed, the incidence and severity of side effects such as vertigo, dizziness, and blurred vision can increase.  The ’705 patent relates to methods of administering the dosages.

On July 21, Judge J. Frederick Motz signed off on a consent judgment that permanently enjoined Lupin from selling generic Solodyn except under the terms of a separate licensing agreement.  The licensing agreement allows Lupin to sell a generic version of Solodyn in various different doses prior to the expiration of the patents.  Under the agreement, Lupin can move ahead with 45mg, 90mg, and 135-milligram doses in November, the 65mg and 115milligram doses in February 2018, and the 55mg, 80mg, and 105milligram doses in February 2019. 

Under certain conditions that were not disclosed, Lupin could begin making the generic earlier.

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Documents recently filed in the Mylan vs. Galderma patent litigation reveal that Mylan Pharmaceuticals continues to argue that it should be allowed to manufacture generic Oracea. This ongoing battle is known as the “Oracea Patent Litigation”.

If you are interested to see how generic pharma takes on big pharma to get a bite of the rosacea prescription market, read on!

This legal battle has been ongoing for several years. Rosacea News covered Galderma’s legal proceedings against Mylan in March 2009. Mylan has filed  for and as we now know, received approval for an Abbreviated New Drug Application (ANDA) for Doxycycline Delayed-release (DR) Capsules USP, 40 mg. This filing was challenged in court by Galderma.

Mylan are now seeking to prove that a particular patent 7,749,532, is invalid and thus their application to manufacture generic Oracea should proceed as it won’t violate this invalid patent.

We can learn a few interesting facts from court documents filed by Mylan Pharmaceuticals.

• Patent 7,749,532, also known as the Chang Patent, is assigned to Supernus Pharmaceuticals and contains terms relating to Oracea such as “an immediate release (IR) portion comprising a drug, wherein the drug consists of about 30 mg doxycycline; (ii) a delayed release (DR) portion comprising a drug, wherein the drug consists of about 10 mg doxycycline”. Galderma has licensed this patent from Supernus and is paying license fees (so far $2m has been disclosed) based on the sales of Oracea.
• Mylan wants the Chang patent (only  issued on July 6, 2010) to be declared invalid so that Galderma cannot use it to stop them releasing generic Oracea.
• Mylan first applied to be allowed to manufacture Generic Oracea in October 2008.
• Galderma has listed patents 7,211,267, 5,789,395 and 5,919,775 (Ashley and Amin patents) as proscriptive to their drug Oracea. Mylan says that these patents are “later-listed” compared to their application for an abbreviated new drug application.
• Galderma says that their sales of Oracea would be “devastated” if a generic version was to become available.
• In November 2009 the FDA denied Galderma’s request to stop Mylan’s Abbreviated New Drug Application saying that Oracea is an old antibiotic.
• Galderma are concerned that if it leaks out that Mylan is about to release Generic Oracea it will seriously affect the market in the period until the court case is finally settled.
• Mylan has received final approval from the FDA for generic Oracea.
• The next court date in this process is February 14-18, 2011.

So What Does This All Mean?

Speculation earlier in the year suggested that Generic Oracea may become available as soon as the first quarter of 2011. That speculation continues to look possible if the February 2011 trial proves successful for Mylan. Great news for everyone who thinks that Oracea is too expensive.

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• Is Oracea different to 50mg doxycycline ?

A previous published study instigated by Collagenex (now owned by Galderma) showed that 100mg doxycycline was no better than oracea in treating the papules and pustules of rosacea.

What would be really interesting, though, would be to see a double blind study comparing 50mg a day of generic doxycyline with Oracea. I doubt that Galderma would be at interested in the this sort of comparison, but perhaps one of the manufacturers of generic doxycycline should undertake such a trial.

Galderma holds up to 6 patents related to Oracea, so we can expect that it will be may years before  generic oracea becomes available. Pharmaceutical companies that want to make generic oracea will have to wait until all of the patents lapse.

This paper additionally calls for further trials of metronidazole vs. oral tetracyclines. Now that is something for which I think we already have enough published, light weight papers.

The role of tetracyclines in rosacea, Am J Clin Dermatol. 2010;11(2):79-87

There is a great deal of evidence to support the use of tetracycline and doxycycline in the treatment of papulopustular rosacea. Nevertheless, these agents have shared and unique adverse effects and relative contraindications.

Recently, subantimicrobial-dose doxycycline was demonstrated to be an effective treatment for rosacea, due to its inherent anti-inflammatory properties.

Furthermore, subantimicrobial-dose doxycycline has a more preferable tolerability profile and a lower occurrence of bacterial resistance than traditional-dose doxycycline.

To further elucidate the role of tetracycline agents in rosacea, clinical trials that compare these agents with each other as well as with other effective rosacea treatments are called for. Adherence studies comparing oral tetracycline treatment with topical metronidazole treatment may also enhance clinical decision making.

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We learnt in 2007 that tetracyclines have anti-inflammatory actions:  “Tetracyclines are known to exhibit multiple significant anti-inflammatory actions … the mechanisms of this anti-inflammatory activity, such as inhibition of chemotaxis, granuloma formation, and protease.”

Further, back in in 2006 we learnt that tetracyclines help rosacea via their anti-inflammatory effects – “More recently, biologic actions affecting inflammation, proteolysis, angiogenesis, apoptosis, metal chelation, ionophoresis, and bone metabolism have been researched.”.

More related research from 2006: how do tetracyclines help rosacea ?

“Thus the therapeutic effect of tetracyclines in acne may at least in part be due to reduction in neutrophilic chemotaxis as well as their inhibitory effect on proinflammatory cytokines and MMP-9.

…

The anti-inflammatory effects of tetracyclines already mentioned may explain, at least in part, their beneficial effects in rosacea. Inhibition of angiogenes  may be a contributory factor in the therapeutic effect of tetracyclines in this group of disorders. Features that favor angiogenesis may contribute to the telangiectasia of rosacea. These include protease-triggered release of angiogenetic factors stored in the extracellular matrix, release of inhibition of endothelial factors, and release of angiogenic factors from activated macrophages.”

So the following abstract hardly seems to be moving us forward in rosacea research ;

Tetracycline Actions Relevant to Rosacea Treatment, Skin Pharmacol Physiol. 2009 Sep 25;22(6):287-294

Until today, the pathogenesis of rosacea is not known in detail. Yet in recent years evidence has been accumulating that rosacea with its common symptoms such as inflammatory lesions, erythema, telangiectasia, phymatous changes, and ocular symptoms is of inflammatory nature. Tetracycline derivatives like doxycycline successfully used in the treatment of skin diseases like acne and rosacea seem to inhibit different inflammatory pathways involved in the pathogenesis by various modes of action. Although data for skin diseases are relatively scanty, the following modes of action of tetracyclines seem to be most relevant for an effective treatment of acne and rosacea: inhibition of matrix metalloproteinases, downmodulation of cytokines, inhibition of cell movement and proliferation, inhibition of granuloma formation, inhibition of reactive oxygen species, nitric oxide, and angiogenesis, whereas inhibition of phospholipase A2 seems to be of lower importance. The role of the saprophytic mite Demodex folliculorum remains to be clarified. Additional studies are necessary to further elucidate how tetracyclines work in rosacea treatment.

Oh well, all rosacea specific research is welcomed and seeing rosacea researchers from around the world get papers published is a good thing for all rosacea sufferers.

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If you have trouble swallowing tablets, here is an official FDA sanctioned tip. Open the tablet and sprinkle the delayed release pellets on to a spoonful of applesauce. This is a good option for anyone who finds swallowing the capsule difficult.

This advice is only given for the 100mg and 75mg delayed release formulations of doryx which contain specially coated pellets of doxycycline hyclate. A clinical trial confirmed that the absorption of doxycycline is comparable when the table is taken whole or sprinkled on applesauce, both with and without water.

From Daily Med, Current Medical Information, Doryx (doxycycline hyclate) Tablet, Delayed Release

DORYX Tablets contain specially coated pellets of doxycycline hyclate, a broad-spectrum antibiotic synthetically derived from oxytetracycline, in a delayed-release formulation for oral administration.

Sprinkling the Tablet on Applesauce

Doryx Tablets may also be administered by carefully breaking up the tablet and sprinkling the tablet contents (delayed release pellets) on a spoonful of applesauce. The delayed release pellets must not be crushed or damaged when breaking up the tablet. Any loss of pellets in the transfer would prevent using the dose. The applesauce/Doryx mixture should be swallowed immediately without chewing and may be followed by a glass of water if desired. The applesauce should not be hot, and it should be soft enough to be swallowed without chewing. In the event that a prepared dose of applesauce/Doryx tablet cannot be taken immediately, the mixture should be discarded and not stored for later use.

The FDA has also issued instructions on how to prepare 100mg tablets of doxycycline (in an emergency), for children and adults who cannot swallow pills. See Mixing Doxycycline Hyclate 100mg Tables with Food. This method crushes a tablet into 4 teaspoons of water and then combines this with 3 teaspoons of milk, or chocolate milk or chocolate pudding or apple juice + sugar.

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I came across the following graph in a recent presentation at the recent AAD meeting and figured it was interesting enough to highlight it here.

The following graph, sourced from Collagenex (who sell Oracea), shows the blood plasma concentration of doxycycline after taking Oracea compared to 50mg once a day of generic doxycycline. The horizontal axis stretches out to 24 hours post dosage. The vertical axis is in nano-grams per milli-litre (ng/mL).

The horizontal grey line is labelled anti-microbial threshold is listed here as a concentration of 1000 nano grams/mL (i.e. 1.0µg/mL). This value of 1 microgram per millilitre is considered to be the concentration at which doxycycline is able to affect bacteria i.e. have an anti-bacterial effect.

The two inverted curves show the amount of doxycycline that is present in the blood over a 24 hour period. The top grey curve is for 50mg of generic doxycycline and the bottom green curve is for Oracea.

I read this graph to suggest that Oracea is able to maintain a sustained release of the active ingredient doxycycline without venturing into anti-microbial territory. The advantage of a delayed release product is that Oracea can offer the `area under the concentration-by-time curve’ delivery, but at sub-antimicrobial dosage over 24 hours.

That is, Oracea can deliver a dosage of doxycycline that can give measurable results, but keep the concentration of doxycycline in your blood low enough to reduce potential problems associated with antibiotics.

(click image for larger view)

*16 healthy adult subjects, per arm; mean weight 75 kg

† Measured at 7 days

Data on file, CollaGenex Pharmaceuticals, Inc.

What is happening here ?

We do know that antibiotics have non-antibiotic properties. Recent research has found biologic actions affecting inflammation, proteolysis, angiogenesis, apoptosis, metal chelation, ionophoresis, and bone metabolism. Thus a whole new range of clinical applications are being investigated. So it does appear that taking a low dose, or even a sub-antibiotic dose of antibiotics can have real clinical benefits.

A Cheaper Alternative ?

As Oracea is a new prescription product it can be quite expensive, especially if you don’t have comprehensive insurance coverage. One possible alternative you could discuss with your doctor is 50mg a day of generic doxycycline. Whilst this dosage won’t have exactly the same profile in your blood, the benefits and side effects are likely to be  close. See your doctor for a better opinion.

I doubt whether we will ever see a trial to prove that the benefits and side effects of Oracea and 50mg of doxycycline are comparable. Therefore it seems unlikely that one can say either way whether the above graph shows an important distinction between the two treatments.

Does it really matter that 50mg a day of doxycycline ventures above the anti-microbial threshold for a couple of hours a day, or that the overall dosage delivered is around twice for the generic ? These are questions that can’t be answered at this stage.

As with all systemic treatments, both Oracea and a low dose of doxycycline can cause unwanted side effects so the supervision of your doctor is important.

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Some interesting comments from KUNC commentator Dr. Marc Ringel via a NPR segment. He raises two points that are worth discussing. Firstly is Oracea really any better than generic doxycycline and secondly what does it say about the pharmaceutical industry (and insurance companies – ed) that a repackaged old product  can be so expensive ?

Galderma would say that Oracea is sub-antimicrobial and 50mg doxycycline is a low-dose antibiotic. The distinction is that Oracea will maintain a blood serum level less than 1000 nano grams/mL (i.e. 1.0µg/mL) for the 24 hours post ingestion. 50mg of doxycycline will result in a blood serum level above the `antimicrobial threshold’ of 1.0µg/mL. This can potentially lead to side effects such as antibiotic resistance, abdominal upsets etc., although the amount by which this threshold is exceeded is still relatively small.

At best I would say that the pharmacological benefits of Oracea over 50mg generic doxycycline are are still up for debate.

As to the cost of Oracea, Galderma of course has shareholders like every large pharmaceutical company. Marketing to both health providers and directly to consumers make sense to gain the largest market share possible. Given that they are so few treatments directly targeted at rosacea sufferers it is clear why Galderma wants patients to ask for Oracea by name and for Oracea to be strongly associated as a front line rosacea treatment.

By way of comparison, in Australia pharmaceutical companies are prohibited from marketing prescription brand names directly to the public. Advertisements usually end with a request to ask your doctor for more information. This reduces the pressure doctors feel to prescribe a particular product but may also result in less consumer choice and involvement in their treatment.

In the end, for those with good insurance cover this whole topic is pretty moot as Oracea will be affordable. Additionally those who cannot afford Oracea have a cheap viable alternative in 50 mg of generic doxycycline once a day. See your doctor for more information.

KUNC: The Big Zit Rip-off, Marc Ringel

GREELEY, CO (2009-05-18) Most agree that something needs to be done to overhaul America’s healthcare system. But leave it to KUNC commentator Dr. Marc Ringel to illustrate the problem – through something as small and innocuous as a pimple.

Or you can buy Oracea, a brand-name doxycycline marketed by Galderma Laboratories. Oracea will set you back over $200 a month if you purchase it in this country or about $150 if you shop online and make your buy from a Canadian outfit. To be sure, the dosage of Oracea is 40mg, making it, like the baby bear’s porridge, just right.
…

I cannot imagine, though, how the extra 10 mg in a 50 mg generic doxycycline capsule could cause close to the distress that too-hot or too-cold porridge did to Goldilocks. Nor do I see how Oracea would work better than the plain vanilla generic except, perhaps, for an enhanced placebo effect generated by spending so much money on a product marketed especially to this affliction. A person might figure that such an exorbitantly expensive brand name would just have to work better.

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Warner Chilcott Limited calls itself a “specialty pharmaceutical company, that engages in the development, manufacture, marketing, and sale of branded prescription pharmaceutical products in women’s healthcare and dermatology segments primarily in the United States”.

In the WCRX 2007 Annual Report we find ;

WC3035. In July 2007, we entered into an agreement with Paratek under which we acquired certain rights to novel tetracyclines under development for the treatment of acne and rosacea. Currently, we are working with Paratek to select a lead compound for development.

The 2009 annual report notes that a lead compound is currently in preclinical development.

Warner Chilcott own patents for and manufactures Doryx delayed release tablets for 75mg, 100mg and 150mg. WCRX claim that “DORYX Delayed-Release Tablets contain unique enteric-coated pellets of doxycycline hyclate. DORYX is the only enteric-coated pelletized doxycycline.”

We’ve seen novel antibiotics under development for rosacea in recent years. Collagenex, now owned by Galderma, was developing a “tetracycline which has no antibacterial activities but is a pure play anti-inflammatory, and it’s being targeted for the treatment of acne.” The product was called Incyclinide. This formulation of tetracycline was shelved as a rosacea treatment when it was discovered that a 40mg dose causes photo-toxicity and also trial participants who were give the Incyclinide did not demonstrate a greater reduction in papules and pustules compared to patients on the placebo.

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A recent investor presentation from Collagenex shows some interesting insights into how Collagenex are promoting Oracea.

Oracea is promoted as safe and effective for long term use. It was reported that the average duration of Oracea therapy is 4 months, compared to an average of 2.5 months for other rosacea prescriptions.

52% of Oracea prescriptions are refills – the presentation suggests that this is a high refill rate thus implying high patient satisfaction.

Of the 14 million adults in the US who have rosacea, only 1.4 million currently seek treatment. The current value of rosacea prescriptions is greater than $500m a year – leading to the implication that the rosacea treatment market has plenty of room for growth. The dermatology market as a whole is presented as a $8.9 billion opportunity.

Collagenex are holding up to 6 patents relating to Oracea. These patents cover Oracea’s method of use, mechanism of action and pharmacokinetic profile (i.e. how it is absorbed and acts over time).

Their aim is to generate 85% of rosacea prescriptions by targeting 5,600 dermatologists. Collagenex need to market Oracea effectively as they have a some good competition from generic doxycycline (50mg a day). As I’ve mentioned before we should thank Collagenex for proving that low dose doxycycline is an effective and safe treatment for the papules and pustules of rosacea.

From my reading of their graphs, Oracea is now selling over 1.2 millions units a month.

Your turn to write something: How much are you paying for a month of Oracea ? Were you convinced to try it by your doctor and has it worked ? Have you been able to try generic doxycycline as an alternative ? Please let us know in the comments below.

Related Articles:

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