News today of yet another company in the courts fighting against Galderma for the right to make Generic Oracea.

Amneal Pharmaceuticals, based in Gujarat, India, a producer of generic pharmaceuticals, has submitted an Abbreviated New Drug Application to the FDA. By doing so, Amneal Pharmaecuticals are seeking permission to market delayed release doxycycline 40mg for oral administration in the treatment of rosacea.

Galderma is claiming that the three patents 7,749,532, 7,232,572 and 7,211,267 protect it from competing manufacturers of Oracea.

It is War Out There!

Amneal now joins Mylan Pharmaceuticals, Impax and Lupin in a quest to crack their share of the lucrative Oracea market – thought to be as much as $260m for 2011.

Haven’t We Been Here Before?

We know from the dispute between Mylan Pharmaceuticals and Galderma that only the U.S. Patent No. 7,749,532, the so-called Chang Patent ("Once Daily Formulation of Tetracyclines," issued July 6, 2010), is a valid patent held that my protect Galderma from generics.

Is this more Bad News?

As I said back in August, I fear that worst possible outcome for rosacea sufferers believing that Oracea is too expensive, will be a ruling that the patent protecting Oracea won’t expire until 2027.

Amneal joining the fight is really only a good sign if Mylan is able to negotiate a deal with Galderma in the favor of rosacea sufferers.

Court Report

Patent Docs: Court Report

Galderma Laboratories Inc. et al.v. Amneal Pharmaceuticals LLC et al.
Filed November 8, 2011 in the District Court of Delaware

• Plaintiffs:  Galderma Laboratories Inc.; Galderma Laboratories LP; Supernus Pharmaceuticals Inc.
• Defendants:  Amneal Pharmaceuticals LLC; Amneal Pharmaceuticals Co (I) Pvt Ltd.

Infringement of U.S. Patent Nos. 7,749,532 ("Once Daily Formulation of Tetracyclines," issued July 6, 2010), 7,232,572 ("Methods of Treating Rosacea," issued June 19, 2007), and 7,211,267 ("Methods of Treating Acne" issued May 1, 2007) following a Paragraph IV certification as part of Amneal’s filing of an ANDA to manufacture a generic version of Galderma’s Oracea (doxycyline delayed release capsules, used to treat inflammatory lesions of rosacea).

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A recently posted proposed Clinical Trial has me thinking that Galderma wants to be able to market Oracea as a product to Maintain Rosacea Remission.

First Some History

In 1998, Archives of Dermatology published a much quoted paper Topical Metronidazole Maintains Remissions of Rosacea. (the PDF of the full paper is available online). The premise of the research was that for a majority of subjects studied, once rosacea symptoms (specifically their papules and pustules) were brought under control with oral tetracycline and topical metronidazole combined, the remission of symptoms could be maintained by the use of metrogel alone.

The 1998 study was funded by Galderma and the distinguished list of authors included academics and consultants paid by Galderma.

Note that Metrogel 1% was launched in the US in 2005, well after the 1998 trial that used Metrogel 0.75%, which at that stage was still protected by Galderma’s patents.

Oracea Maintains Remission?

This new trial will attempt to prove that Oracea is also capable of keeping the papules and pustules of rosacea at bay, once they have first been brought under control when treated in combination with Metrogel 1%.

The trial will also be able to confirm the safety of Oracea when used for a period of up to 1 year. Which pharmaceutical company wouldn’t want to be able to promote their profitable drug as effective and safe for such a long period?

Should this trial succeed Galderma will be able to market Oracea in new ways in the future.

Clinical Trial NCT01426269

Evaluation of Relapse, Efficacy and Safety of Long-term Treatment With Oracea vs Placebo After 12 Weeks of Oracea and MetroGel 1%

The purpose of this study is to assess relapse, efficacy and safety in subjects with rosacea during long-term treatment with either Oracea® or placebo, after an initial 12-week regimen of Oracea® and MetroGel® 1%.

Detailed Description:

Adult subjects with moderate to severe papulopustular rosacea will receive Oracea and MetroGel 1% once daily during phase 1 (baseline to week 12) of the study.

Subjects will be eligible to enter phase 2 of the study based upon improvements in the Investigator’s Global Assessment (IGA) score.

During phase 2, subjects will receive either Oracea or placebo once daily for up to an additional 40 weeks. Subjects who relapse during phase 2 will be discontinued from the study.

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As part of the proceedings Mylan looked at the on-going Oracea sales and projected that Galderma can expect to receive around $260 million in 2011.

MYLAN PHARMACEUTICALS INC., v.  GALDERMA LABORATORIES, L.P.; et. al.

Mylan projected that Oracea’s brand dollars for the period of January 2011  through December 2011  would be approximately $258.1  million.

Oracea’s sales growth was listed as

• 2007: $43 million
• 2008: $80.4 million
• 2009: $155.3 million
• 2010: $236.7 million

Obviously a highly successful product for Galderma.

As I noted recently, the battle still has some way to go. As neither Galderma nor Mylan prevailed with all of their claims, further arguments are required from each party.

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Another step in the ongoing battle between Galderma and Mylan over the right to manufacture generic Oracea.

A judge has declared that Mylan infringes 1 of the patents that protects Oracea from generic copies.

Some History

In July 2010, Mylan was banned from selling generic Oracea, despite having regulatory approval, pending the outcome of the litigation between Galderma and Mylan.

The Result

Finding no clear winner, Judge Stark has declared that only 1 of the 4 claimed patents are infringed by Mylan Pharmaceuticals.

Both sides are to submit further arguments, though, because the only patent that was found to be violated was in fact only granted AFTER that July 2010 order.

Mylan was hoping to obtain a declaration that its generic formulation of Oracea does not violate any of the “valid claims” of the newly issue Patent 7,749,532. Sadly for those wanting access to cheaper Oracea, this is not the case.

U.S. Patent No. 7,749,532, the so-called Chang Patent ("Once Daily Formulation of Tetracyclines," issued July 6, 2010), is licensed to Galderma.

Some Encouragement

In an encouraging move to others that might want to sell generic Oracea (Impax and Lupin for eg.), Judge Stark ruled that two of the other patents were invalid because they aren’t different enough to earlier inventions. Further the third claimed patent, relating to dosage forms was rules as uninfringed.

Mylan Violated Patent for Acne-Drug Oracea, Judge Rules

By Steven Church – Aug 27, 2011 6:55 AM GMT+0800

Mylan Pharmaceuticals Inc., a generic drugmaker, violated one of four patents related to the acne drug Oracea, a judge ruled.

U.S. District Judge Leonard P. Stark in Wilmington, Delaware said today he’ll wait to decide whether to bar Mylan from selling a generic version of Oracea, as requested by Galderma Laboratories LP. A temporary ban will remain in place, Stark ruled.

“Galderma is entitled to some relief,” Stark wrote in his opinion. Still, he said, he will delay imposing any permanent restrictions on Mylan until after hearing from both sides “given that neither party prevailed in the entirety of its position.”

Mylan has regulatory approval to sell the medicine, which is used to treat acne rosacea and is known by its active ingredient doxycycline monohydrate. In July 2010, Stark ordered Mylan not enter the market for the drug until he ruled on Galderma’s patent-infringement claims.

Galderma is seeking an extension of that order until the patent expires in 2027

What Does it All Mean?

Well it means we still have to wait to see what sort of `relief’ will be granted to Galderma once further arguments are considered.

The worst possible outcome for rosacea sufferers believing that Oracea is too expensive, will be an extension of the ban until the patent expires in 2027.

Stay tuned, this battle isn’t over yet.

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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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The last we heard from Impax Laboratories was in late 2009 when they had filed an Abbreviated New Drug  Application (ANDA 91-447) to produce a generic version of Oracea.

A recent filing in  Delaware shows Galderma attempting to block the production of Generic Oracea by invoking the protection of Patent 7,749,532. Galderma claim that this patent, the so-called 532 Chang Patent, formally issued July 6, 2010 (after Oracea was released to the market) protects their intellectual property from generic copies.

Impax are following in the footsteps of Mylan Pharmaceuticals, and are hoping to show that this patent is invalid. Mylan are further along in their battle against Galderma, but no doubt Impax will also benefit from any decision that might enable the creation of generic Oracea.

Can Only Be Good News

This can only be good news for rosacea sufferers, especially those who cannot afford Oracea. The good news only eventuates if Impax are successful of course.

Even with full insurance cover, Oracea can be out of the reach of many.

Note that Oracea and Metrogel is available for FREE for low income no insurance.

Legal Filing

Galderma Laboratories Inc. et al. v. Impax Laboratories Inc

1:11-cv-00477; filed May 26, 2011 in the District Court of Delaware

• Plaintiffs:  Galderma Laboratories Inc.; Galderma Laboratories LP; Supernus Pharmaceuticals Inc.
• Defendant:  Impax Laboratories Inc.

Infringement of U.S. Patent No. 7,749,532 ("Once Daily Formulation of Tetracyclines," issued July 6, 2010), licensed to Galderma, following a Paragraph IV certification as part of Impax’s filing of an ANDA to manufacture a generic version of Galderma’s Oracea® (doxycyline delayed release capsules, used to treat inflammatory lesions of rosacea).

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The trial is scheduled to involve 170 participants at multiple centres. If you are able to attend the Los Angeles clinic as detailed below, you will be compensated and may even end up receiving free Oracea during the trial.

From Pearl E Grimes, M.D. Clinical Trials

Do you suffer from Rosacea?

Dr. Pearl E. Grimes, Medical Director of the Vitiligo & Pigmentation Institute of Southern California, is nationally and internationally recognized for her research work. The institute is conducting a clinical study for rosacea.

If you are between the ages of 18 and 70 and have a red face with at least 5 but no more than 40 papules and/or pustules, you may be eligible to participate in this study. Involvement in this study may last up to 13 weeks.

All qualified participants will receive all study-related care and either oral medication or placebo at no cost, and will be compensated for time, participation and travel.

Are you interested?

If you are interested, please contact:
Kali Ghazali, CRC
Vitiligo & Pigmentation Institute of Southern California
5670 Wilshire Blvd, Suite 650
Los Angeles, CA 90036
t: (323) 467-4389 ext 6
e: Research@pearlgrimesmd.com

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I have been watching for a while to see for any developments in the legal proceedings between Mylan and Galderma. These proceedings will determine whether Mylan is allowed to sell Generic Oracea. This is of interest to many rosacea sufferers who consider that Oracea is too expensive.

Previously it seems that Generic Oracea may be available as soon as First Quarter 2011. Now we learn that legal proceedings are only scheduled to begin in earnest on July 5, 2011.

Mylan Pharmaceuticals is pushing to be allowed to sell Generic Oracea, and have been joined in this request by two other companies; Impax Laboratories and Lupin Pharmaceuticals. Clearly there is potential to make a lot of money in this market.

Mylan is hoping to obtain a declaration that its generic formulation of Oracea does not violate any of the “valid claims” of the newly issue Patent 7,749,532. This patent granted and thus added to Galderma’s war chest after Oracea was released to the market.

Mylan Pharmaceuticals vs. Galderma Laboratories and Supernus Pharmaecuticals

The two cases have been consolidated for purposes of trial, which is scheduled to being July 5, 2011.

All of the patents – the Ashley patents, the Amin patents and the Chang patent are directed toward using antibiotics for purposes other than treating bacterial infection.

The patents-in-suit, therefore, teach doxycycline dosages that are below a certain level, in order to prevent antibiotic resistances that accompanies the use of antibiotics at higher dosages for longer time frames.

If you think new drug development is slow, then also consider the law, that moves kind of slow too !

So Why This Update Now?

This particularly enthralling court document, dated March 24, 2011, was devoted to whether the `532 Chang’ patent should be construed to mean the singular or plural form for the language plasma concentration or plasma concentrations.  The judgement of the court declared that the plural form would be the way forward.

No wonder this stuff takes a year and an age (and a lot of dollars).

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Whilst the trial only directly mentions LL-37 and MMP I would expect other well known markers to be measured as well.

If the researchers include markers that can be proven to be indicative of rosacea disease, and these markers show a statistical difference compared to placebo participants, then this study could then lead to something important regarding the progression of rosacea.

Evaluation of Rosacea-related Inflammatory Biochemical Markers in Adult Skin When Treated With Oracea  vs Placebo

The objective of this study is to determine the clinical effects of doxycycline 40 mg (30 mg immediate release and 10 mg delayed release beads) capsules (Oracea) as compared to placebo in the skin of adults with papulopustular rosacea and to identify a correlation, if any, with rosacea-related inflammatory markers.

Mean change from baseline to week 12 in biochemical markers of rosacea and expression in skin samples. A biological marker is a substance used as an indicator of a biological state such as rosacea. Biochemical markers are serine protease activity and expression, metalloprotease activity and expression, and production of leucine leucine-37 [LL-37] peptide.

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Late last year Galderma generated quite a lot of publicity in the lead up to the release of the Phase 4 trials of Oracea.

Phase IV trials typically try to replicate the efficacy and safety of drugs seen in Phase III trials, but on a much larger scale. Phase IV trials are conducted after a drug is already generally available.  Physicians typically use the Phase IV results to build confidence in prescribing a particular medicine.

The ORCA study was able to confirm that the majority of sufferers of the papules and pustules of rosacea were clear or near-clear after 12 weeks of being on Oracea. The redness associated with the rosacea lesions was also similarly reduced after 12 weeks.

Now, The journal Cutis has posted the papers that describe the details of the Oracea Phase 4 trial online. You can read the full text of these papers online for free.

The supplement contains the 3 papers listed below and an introduction. Download the PDF for the full details.

The ORCA (Oracea for Rosacea: A Community-Based Assessment) Trial: A Large-Scale, Phase 4 Trial in Papulopustular Rosacea

VOL. 86 NO. 5S[i] NOVEMBER 2010

An Open-Label, Community-Based, 12-Week Assessment of the Effectiveness and Safety of Monotherapy With Doxycycline 40 mg
(30-mg Immediate-Release and 10-mg Delayed-Release Beads), Guy F. Webster, MD, PhD

Rosacea is a common inflammatory disorder of the skin of middle-aged and older adults. A unique 40-mg formulation of doxycycline (30-mg immediate-release and 10-mg delayed-release beads) developed for its anti-inflammatory properties is the only US Food and Drug Administration–approved oral medication for the disorder.
This report describes the results of the Oracea for Rosacea: A Community-Based Assessment (ORCA) trial, a phase 4 trial of the 40-mg formulation as monotherapy in adults with mild to severe papulopustular rosacea. A total of 1197 participants were enrolled in the monotherapy arm of the 12-week open-label study at 271 community-based investigational sites.

The primary outcome measure was a change in the 5-point investigator global assessment (IGA) score from baseline to end point (week 12). Secondary outcome measures included change in the 5-point clinician erythema assessment (CEA) score from baseline to end point, IGA success, and adverse events (AEs). 

The monotherapy per-protocol (PP) population was selected a priori as the primary analysis population and safety assessments were performed on all participants who received at least 1 dose of the study drug. In the PP population of 826 monotherapy participants who completed the trial, approximately 75% of participants with mild to severe rosacea at baseline were clear or near clear by week 12 according to IGA scores.

Furthermore, approximately 75% of participants had CEA scores reflecting none or mild erythema after 12 weeks. In the safety population of 1196 participants, treatment-related AEs were reported in 6.7% of participants that were mainly mild or moderate in severity.

Adverse events that occurred in more than 1% of the safety population included diarrhoea (1.2%), nausea (1.3%), and headache (1.0%). The incidence of fungal and yeast infections was 0.4%. The results of the ORCA trial support the effectiveness and safety of the 40-mg formulation of doxycycline in patients with papulopustular rosacea.

Effectiveness and Safety of Doxycycline 40 mg (30-mg Immediate-Release and 10-mg Delayed-Release Beads) Once Daily as Add-on Therapy to Existing Topical Regimens for the Treatment of Papulopustular Rosacea: Results From a Community-Based Trial, James Q. Del Rosso, DO

Rosacea is a prevalent inflammatory skin disorder that affects approximately 16 million individuals in the United States. Although its exact etiology is unknown, basic science, histologic evidence, and clinical evidence suggest that it is inflammatory in nature.

In this 12-week, open-label, multicenter, community-based, phase 4 trial, we evaluated the anti-inflammatory effects of once daily subantimicrobial-dose doxycycline 40 mg (30-mg immediate-release and 10-mg delayed release beads) in participants with papulopustular rosacea (PPR) who were receiving topical therapy (metronidazole, azelaic acid, and/or sodium sulfacetamide–sulfur) at the time of the study entry but whose rosacea symptoms were still present.

The primary outcome measure was the change in the investigator global assessment (IGA) score from baseline to end of study (week 12). Secondary outcome measures were changes from baseline to end of study in the clinician erythema assessment (CEA) score, treatment responders (IGA score of clear, near clear), and safety.
After week 12, 75.7% of participants in the per-protocol (PP) population had IGA scores of clear or near clear. In addition, there were significant differences in the distribution of baseline and week 12 IGA scores in the PP group (P=.0012). At week 12, most participants (63.6%) had mild CEA scores; the distribution was significantly different from baseline (P=.0407). Only 7% of participants had treatment-related adverse events (AEs), mostly mild or moderate in severity.

Thus the 40-mg formulation of doxycycline proved to be effective and well-tolerated in a real-world setting in participants with rosacea who were receiving topical therapy but still experiencing symptoms.

A Community-Based Study of the Effectiveness of Doxycycline 40 mg (30-mg Immediate-Release and 10-mg Delayed-Release Beads) on Quality of Life and Satisfaction With Treatment in Participants With Rosacea, Hilary E. Baldwin, MD

Changes to the skin of the face in patients with rosacea have the potential to substantially impair multiple domains of quality of life (QOL); however, the number of publications providing evidence for this topic is limited.

This 12-week, open-label, community-based, phase 4 trial of 1421 participants is the largest study of the disease to date. It explores the effects of mild to severe rosacea and its treatment on QOL.

Participants were treated with doxycycline 40 mg (30-mg immediate-release and 10-mg delayed-release beads) as monotherapy or add-on treatment to existing topical therapy.  This article examines QOL issues in the primary analysis population consisting of 966 participants who completed the trial without a major protocol violation. Quality of life was assessed at baseline and study end (week 12) with the RosaQoL , a validated 21 -question instrument.

Participant and investigator satisfaction with treatment also were evaluated. In the monotherapy group, the mean RosaQoL score was 3.3 at baseline and 2.8 at end of study. In the add-on therapy group, the mean RosaQoL score was 3.2 at baseline and 2.8 at end of study. The improvement in QOL was both clinically and statistically significant (P=.0001) and was similar in both monotherapy and add-on therapy groups.

Most participants expressed satisfaction with treatment and approximately 90% of the community-based investigators reported that they were likely or very likely to continue prescribing this formulation. The study demonstrates that the impaired QOL in patients with rosacea can be substantially improved during a 3-month period by once-daily treatment with the anti-inflammatory activity of subantimicrobial-dose doxycycline

Supported by an educational grant from Galderma Laboratories, L.P. It seems reasonable to me that because this research is funded externally to the journal, the full text of the papers can be made available for free.

The Elephant in the room

Whilst this data confirms that Oracea can continue as a mainstream rosacea treatment, the spectre of the impending availability of generic Oracea also hangs over this product’s long term profit making ability.

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