GLG News by Sunil Dhawan, MD

Implications:  This article is important in that it describes a growing trend among dermatologists to offer a higher level of "customer service" for their cash paying cosmetic patients. This has contributed in a small way to the long waits for non cosmetic dermatology patients to be able to see a dermatologist. A larger cause of the long waits is the small number of dermatologists being trained, and many of them working less than a full schedule. As the waits become longer and access more difficult, many dermatologists will opt out of managed care plans and move toward a cash/fee for service practice. This trend is already beginning. Also many primary care physicians are also offering ancillary procedures, and access for their patients may also become limited, which has more serious implications.

Analysis: Companies that offer cosmetic products will do well, especially those with products requiring repeated purchasing such as fillers and toxins. These include Allergan, Medicis, and soon Stiefel , Ortho- Neutrogena, and Mentor. Other comnpanies such as Galderma and Graceway, etc., which have a predominant focus on medical dermatology, will also do well, because of the breadth of their product offerings, and the lack of managed care issues in regards to access to their products.

Implications: This article is important in that it describes a worrying trend for branded  pharmaceutical companies. As copays for branded products go up and the patients economic status worsens, the use of these drugs will fall. This may be especially true for medications in dermatology, where the perceived need may be less than that for a cardiac drug. The pipelines in dermatology are smaller due to high drug development costs, and limited means to recover them, because the market is smaller than that for other conditions. Many of our patients are complaining about difficulty in getting insurers to cover their branded products, and copays and requests for prior authorizations have increased exponentially. A positive factor is that many of the products in dermatology still enjoy several years of patent protection.

Analysis: The companies that will be most affected by this slowdown would be the branded manufacturers like Medicis, Allergan, Galderma, Stiefel, etc.  Most have products that are patent protected for the moment, and have copay assistance plans, so that the impact will be reduced.

Implications: This article is important in that it confirms a commonly used method in clinical dermatology practice. Namely that of using Protopic for longer term maintenance to prevent flares, and to act as a topical steroid sparing agent. This has been done since the introduction of Protopic, and among dermatologists there are no significant safety concerns over its long term use. Elidel, from Novartis, should also be studied, though it is commonly acknowledged to be a weaker topical immunomodulator, albeit better tolerated.

Analysis: The company most positively affected will be Astellas, the makers of Protopic. Protopic sales did not decrease to the same degree as those of Elidel, when the FDA warnings came out, because it was being used by dermatologists, who were more comfortable with immunomodulators. Elidel was more commonly used by primary care physicians who were not as familiar or as comfortable.

Other companies that may be affected would be the makers of branded low potency topical steroids used in atopic dermatitis such as Skin Medica (Desonate prodcut) and Stiefel ( Verdeso product). The effect would not be great as these products are still the first line branded agents used in childhood atopic dermatitis.

Implications: This article is important because it describes a growing concern that is not well known to the investment community or the public. Due to increased pressure from the generic companies, the FDA, and the public many companies are finding new uses for older medications. This is very true in dermatology and other smaller specialties where the cost of new drug development is higher than many smaller companies can support. Unfortunately this strategy, while good for keeping the bottom line high initially, will eventually hurt these same companies because the alternative uses will run out, and newer medications will be needed. Both strategies are needed in order to ensure a good pipeline of medications both old and new.

Analysis:   The companies in dermatology with good drug development programs, using both older and newly developed medications include Stiefel, Galderma,and to a lesser extent Medicis and Allergan. The rest,by and large, are smaller and are looking to get new uses out of older compounds, ar acquiring new technologies. Internal drug development is difficult and costly for these smaller companies.

Implications: This article is important because it outlines the rationale and benefits of the new collagen based filler from Ortho-Neutrogena/ Johnson and Johnson. This filler appears to last at least 6 months, and does not require pre testing as other collagen based fillers have needed in the past. The fact that this filler has been used overseas is reassuring. The remaining products will have some increased competition, though both Restylane/ Perlane ( Medicis),  Juvederm (Allergan), and Radiesse( Bioform) do last longer than 6 months, and have few if any significant side effects as well. Pricing as well as positive patient and physician experience will dictate if this product will be successful in this increasingly crowded market. This product will do better if it had been brought to market earlier.

Analysis: Allergan ( Juvederm ), Medicis( Restylane/ Perlane), and Bioform ( Radiesse) will have increased competition initially as patients and physicians will begin to try this product.  Incentivizing physicians to use the product with favorable pricing strategies and extensive training opportunities are a must The release of this product into a competitive market will make more difficult to be successful, unless there are several compelling reasons to use it  Pricing, favorable patient and physician response, and longevity will dictate success. These factors need to be made clear rapidly or the product will get lost in the increasing number of fillers that are being released.

Implications: This article is important in that, for the most part , it describes a basic therapeutic regimen for adolescent acne patients. The only error is describing the inflamed lesions as "infections." Acne is predominantly an inflammatory condition, not an infectious one, though a bacteria is involved in creating inflammation. I prescribe a retinoid such as tretinoin- Retin A, Differin, Ziana, or Tazorac to "unclog the blocked oil gland. For inflammation I use a topical clindamycin, or combination products such as Duac,etc. Oral antibiotics like tetracycline, doxycycline ( Doryx), minocycline ( Solodyn), are added. Finally Isotretinoin ( Accutane) is used fpor more severe or resistant cases. Oral contraceptives such as Yaz can be used in females.  The new Allergan aquisition ,Aczone, offers promise as the first non antibiotic topical anti inflammatory agent. Lasers/IPL and home based devices  have not been found to offer enough or sustained relief.

Analysis: Companies that have significant products in acne are Stiefel ( Duac, Evoclin, and Brevoxyl), Skin Medica( Neo Benz Micro), Galderma ( Differin), Medicis ( Ziana, Solodyn), Allergan ( Tazorac, Aczone), Warner- Chilcott ( Doryx). These will all benefit from increased use of their products with educational articles such as these. This is especially true for articles targeted to primary care doctors and physician assistants/ nurse practitioners who are increasingly taking care of even the most severe acne patients.

Again the laser/ IPL /home based devices do not  currently offer sustained or enough relief . Future resarch will beneficial in this area.

Implications: This article is important in that this acquisition is the first new product for Allergan's dermatology division in several years. This is also the first novel molecule in 5-7 years that has been released. The issues of having to get blood tests with this topical agent have been solved. The obvious paring of this antiinflammtory with Allergan's Tazorac retinoid product will drive sales of both products.

Analysis:   The release of Aczone should be beneficial for Allergan's dermatology division, and also drive sales of its companion product- Tazorac. This is also the first new antiinflammatory product for acne in several years, and Allergan can capitalize on this as well. Several new products from other companies for acne will impact sales, but these will not be available until next year.

Implications: This article is important in that it is a good summary of the current knowledge and treatment methods for atopic dermatitis for pediatricians. It is needed in that this condition is inadequately treated, and a periodic refresher is needed for all physicians. Both pharmacologic and non pharmacologic methods are discussed.

Analysis: The companies whose products will be impacted positively include branded and non- branded manufacturers of topical steroids for children ( Skin Medica, Triax, Pharmaderm, Coria, Taro, Ranbaxy etc.), and Astellas and Novartis ,the makers of the topical immunomodulators. This article may be used by those manufacturers who have a pediatric sales force such as Skin Medica in collaboration with Galderma, Astellas, and Novartis.

Implications: This article is important in that it makes the public aware that they should avoid all unlicensed persons who re injecting any substance into their bodies. These especially include those injecting silicone mixtures. The public will become more aware and should have more confidence in licensed practitioners who are injecting FDA approved materials such as Restylane, Perlane, Juvederm Ultra, Radiesse, etc. It is unlikely that this event will adversely impact the field. This is especially true in light of the previous illegal injection of Botox by an unlicensed person, and that this had minimal effect on the volume of Botox injected.

Analysis: It is unlikely that Allergan, Medicis, or Bioform will be adversely affected, due to the reasons outlined above.

Implications:  This article is important in that it lays to rest a misconception that long term repeated use of Botox ( Allergan) leads to decreased efficacy. Efficacy was maintained, and no neutralizing antibodies were found to Botox. This will reassure most users of Botox, and patients as well.

Analysis:   This will have a positive impact on Allergan's product Botox, and potentially on its future competitor, Reloxin, from Medicis. However, Reloxin has not been approved and no  similar efficacy studies have been done with this product to date.

Implications:  This article is important in that it defined the incidence of serious skin reactions to the three common TNF antagonists- Enbrel, Humira, and Remicade. The incidence is relatively low in comparison to the numbers of patients treated. Any foreign protein has the potential for eliciting these reactions, and these reports are to be expected. The reactions range from the milder Erythema Multiforme to the more serious Toxic Epidermal Necrolysis. The reactions are more common in female patients receiving these products for rheumatoid arthritis.

Analysis: It is doubtful that this report will have any significant effect on the three companies that manufacture the three TNF antagonists- Amgen, Abbott, or Centocor. The incidence of these reactions is low and these reactions have been reported with multiple agents in the past and are not unique to these products.

Implications: Anacor's recent release of the data from their phase 2a study of AN 2728  for psoriasis were encouraging.  Over 69% actively treated plaques of psoriasis improved versus only 6% of placebo treated plaques. The study was limited by the short duration- only 28 days versus up to 16 weeks for other trials, the limited number of patients- usually even phase 2 trials have a larger number of patients, and the use of the same patient for both active and placebo ointments. Also the strict definition of "improvement" was not given. A larger and longer study, with separate actively treated and placebo treated patients is needed. Also the use of standard criteria for psoriasis grading such as Pasi score reduction , reduction in psoriasis disease activity, or investigator global assesment will be important.

Analysis:   If the larger studies are positive then this compound, AN 2728 will offer a novel compound for treating psoriasis that is non steroid based. The only other competitors in this area of non steroid based compounds for psoriasis are Dovonex ( Waner- Chilcott) and Tazorac ( Allergan). This would offer a valuable addition to what we have available now and could even be used in combination with steroid compounds.

Implications:  This article is important in that it is one of the first to confirm what is  a widely held belief among many dematologists who treat many patients with psoriasis. Specifically that these patients suffer a higher rate of cardiovascular diseases, depression, malignancy, etc. This makes perfect sense as the immune system in these patients is activated and in essence there is a chronic state of inflammation throughout the body. This could lead to blood vessel damage in various organs such as the heart, etc.,  and to cardiac events. Chronic inflammation can also increase the risk of malignancy, and any chronic potentially debilitating disease like psoriasis has a significantly higher incidence of depression.

Analysis:    Since psoriasis is a systemic immune disease that is manifested in the skin, a product that reduces systemic inflammation in these patients may have benefit in reduction of these other comorbidities. The most obvious of these would be the biologics such as Enbrel, Hunira, Remicade, etc. A long term study would be helpful in following these patients to see if these agents do indeed reduce the incidence of cardiac events, malignancy, depression, etc.

Implications: Centocors new product- Ustekinumab /CNTO 1275 had impressive results in the recent PHOENIX trials and the application is under review at the FDA. The PASI score reductions are superior to the exiting agents such as Enbrel and Humira, and are comparable to those of the other Centocor product- Remicade which has to be given by infusion as opposed to subcutaneously. The subcutaneous method is preferred for patient convenience as an infusion requires a visit to the physicians' office. Also the adverse event rate was not high when compared to other biologic agents and the low drop out rate indicates that the serious adverse events were low.

Analysis:  When this product gets approved the other competitors- Enbrel from Amgen and Humira from Abbott will have stiff competition if the impressive results hold up in regular use, with minimal side effects such as infections, etc. The injection frequency of every 12 weeks is significant advantage over the weekly and twice monthly injections required by the other agents.

Implications: This article is important in that this is an under served market. Current scar reduction products are only modestly effective, or not effective at all. An agent which has a "70% "reported reduction in scar appearance,is safe, and only has to be used a few times has a large market and will be successful. The scientific rationale behind this product is sound. A phase 3 trial in the US would be useful.

Analysis: There are no real competitors for this product except Mederma by Merz pharmaceuticals and that is an OTC product. This would be the first scar reduction prescription product that has undergone rigorous phase 2/3 trials. A US trial would be useful. There may be wider implications in treating difficult scars like keloids, etc.  A successful phase 3 trial in multiple scar types would bode very well for this product and company.

Implications: This new delivery system from Phosphagenics for enhancing absorption and reducing irritation will have moderate effect on the retinoid market. Retinoic Acid use has been in decline not so much because of irritation, but because of the introduction of more efficacious retinoids like Tazorac and Differin 0.3%. The trial size was limited, and a larger trial is a good initial step. Efficacy will generally be less than that for the other retinoids.

Analysis: The use of the proprietary delivery system by Phosphagenics for retinoic acid is a good initial step. However a better market may be topical steroids and other anti inflammatory agents for which the market may be also larger, as well as other retinoids which would benefit from enhanced penetration. Retinoic acid was chosen as it has lost patent protection 7-8 years ago, and Tazorac and Differin are still protected. This technology may have more benefit if it is licensed to other companies as a novel drug delivery system.  

Implications: The recent FDA warning on Botox is unlikely to limit the cosmetic use of the product because the dose is relatively low. The warning only applies to significantly  higher doses in patients with neuromuscular conditions like cerebral palsy. Serious adverse events like allergic reactions are very rare with the cosmetic use of Botox and its analogues.

Analysis: This will temporarily adversely impact the public image and stock price of the major manufacturers of Botox and its analogues like Allergan. Over the next few weeks this will fade from the public view and it is unlikely that a "black box warning" will be generated by the FDA for the cosmetic use of the product. Other companies with future products like Medicis will not be affected as their products have not been approved yet.

Implications: Botox is  highly effective cosmetic product, albeit not long lasting. Patient satisfaction is high, and the cost is still not prohibitive. However the predictable and not always justified increases in price have forced many physicians to eagerly await the newer agents. The include products from Medicis, Mentor, and the topical Botox from Revance and the nerve ablative technology from GFX corp. Once these are released then Botox market share will suffer unless price is adjusted to be more competitive.

Analysis: It will be interesting to see the market share of Botox once the competitors are released. Most authorities agree that there will be a price adjustment from Allergan to retain sales and be competitive. The other toxins will also need extensive marketing efforts in order to penetrate the market, and there may be consolidation among the various companies.

Implications: This study will expand the use of Enbrel in newer populations. this is important in that Humira just received approval for adults, and the market has become more competitive. This is good news for children with severe resistant psoriasis.

Analysis:  This will have a positive impact on sales of Enbrel as this is the only biologic studied in the pediatric age group. the impetus is now on the other companies like Abbott and Centocor to do the same.

Implications:  The new Centecor psoriasis product, Ustekinumab, is impressive in its efficacy. The PASI 75 reduction is equal or surpasses Remicade, the current leader in efficacy in psoriasis. This product has the advantage of being a self administered injection at home, rather than a prolonged IV injection at the office or hospital. This product will offer stiff competition to Amgen's Enbrel, and Abbott's Humira.

Analysis:   The release of this powerful product will benefit Centocor sales in a significant way, probably exceeding current sales of Remicade, their other psoriasis product. Amgen and Abbott will see a potential decline or lack of growth in their product sales.