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Maxim Jacobs
30 January 2018

Edison KOL Call


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The seventh in our KOL series, Edison sponsors an interview with Dr. Nanette Silverberg, Chief of Pediatric Dermatology at the Mount Sinai Health System. The conversation featured a discussion on emerging Acne and dermatologic treatments.

Call Leader: Great. Thank you, Dr. Silverberg for taking the time for the call. Maybe you can just start by discussing your practice, and your background treating patients with acne.

Doctor: So yes, I am a pediatric and adolescent practitioner, so number one in the pediatric population is eczema. Number two is acne because they’re just volume wise the kids are ... That’s usually how things sort of assess when you look at the studies assessing our intake practice usually. So certainly something that I see on a frequent regular basis, like every day.

Call Leader: Yeah, yeah. I’m in on ... Yeah, I’m sure.

Doctor: Three or four per day would be pretty standard.

Call Leader: Great. And so just to give some background on acne, I know there’s like a gazillion different potential treatments that you can use with your patients, so just how do you decide which treatment to use, or do you have any ones that you like better than others?

Doctor: Well I mean, I participated in acne guidelines developments. It’s standard. Standardly we tend to focus on using as a basis of treatment a retinoid, and a topical retinoid, and benzoyl peroxide. That’s supposed to be the core. But also we have backup options. So we have people who fail those, or people who let’s say are too irritated by the combinations, so we add in maybe a combo antibiotic or Clindamycin in that particular setting. And then we end up adding in other stuff if we have a woman with inflammatory acne who really haven’t responded well to that regimen.

We have a lot of women, older. I have adults too in my practice. The adult women are often have an overlap with rosacea, so those particular individuals have some significant problems responding to the acne regimen we just described because it’s our retinoids are increase irritants, increase penetration of secondary agents, we’re really looking in that particular situation at a self refuting regimen if that’s what you use consistent with as we move onto other agents that per setting which like topical Dapsone which is wonderful on chin acne. We might use topical Metronidazole especially if there’s overlap situation. If it would come to the usage of oral antibiotics at the second tier or oral contraceptives as a second trial to save the latter in females and kind of move on from there.

Call Leader: That was helpful. When you’ve gone through your first line and then the regimens you usually use in failures, how many people after all that are still not responding to treatment and really are clamoring for a new treatment? Do you have a sense of that?

Doctor: I would have to say that teenagers, a lot of them are first coming to me and they’ve had a minimal intervention from the pediatrician. There I can really promote a traditional regimen and it’ll be the first time that they’re using it and I would probably say that two thirds of teenagers are like that.

When it comes to adults, it’s a little bit different. It’s very often the opposite, so I very often have a variation of a 23 or 24 year old woman who doesn’t necessarily desire to go on Accutane and is looking for an alternative. They’ve maybe been offered that standard regimen in the past.
I see a lot of girls who are straight out of college. First, they tell me that they’re looking for something different. That’s a very common entry point into healthcare usage. Some of those women have been undertreated and it’s been very problematic for them in that setting.

Call Leader: One question that I have on getting new treatments for acne. There are a lot of acne trial failures. Do you have any thoughts on why that is?

Doctor: Failures in acne trials?

Call Leader: Yeah, failures in pivotal face Pimtrea, clinical trials for different agents.

Doctor: Looks as though we’ve always had people behind in these particular trials. I consider Epiduo, an excellent drug, 60, 70, 65% maybe of meaning in point, statistically skilled I think. We have drugs that are wonderful but we don’t have our model of acne treatment is not really to use things as monotherapy. That’s the issue. We get these products that are tested as mono therapies. Very often, they’re much more effective in practice because we don’t use them as monotherapy. We use them for combination therapy with other agents and that allows us to achieve a better result. It’s the way that it’s used in the trial. It’s not necessarily real life usage.

Call Leader: I see. Would you suggest to companies that they run combo trials instead?

Doctor: Absolutely. There are trials that have combination therapies. Post marketing combination therapy, so it’s a dearth of trials looking at step therapy. Some of those trials are traditionally incredibly helpful.

I remember a specific trial where there was a usage of Tazarotene. I think it’s the original brand with Minocycline and then at the end of a certain time period, they stopped. They had people randomized to receive Tazarotene alone or Tazarotene with the Min ... long term with the Minocycline like it said. It was really beautiful in the way the study was done, which was really obvious you could maintain yourself without being on oral long term. These kinds of trials are very important for us. It depends on what it is but they’re important for development. We have issues. We really need to develop a better antibiotic stewardship now in all skin care. Any trials that look at ways for us to specifically avoid usage of antibiotics or look at strategies too. Combination strategies are helpful.

None of these drugs hit the market like ... you look at these trials ... I think the original Aczone trial, there was a large enough number that they could separate the effect of the vehicle, but the effective vehicle was actually fairly strong in the original trial. The drug hit the market at a very ... it was a closely how to direct the drugs and we had a lot of people… that want to keep trying alternative products without going on orals. The other thing that hit the market is topical, you will find a user and dermatologist are typically smart about how they incorporate them. You see a lot of people developing really interesting rationales and ultimately that’ll resolve them in a lot of usage long term.

Call Leader: Ok great. The main topic of the call is DRM01 from Dermira, what do you think about them generally or the product generally? What do you think it might fit in the treatment paradigm?

Doctor: I think that issue ... Some people want to go on Accutane to dry their skin out. We have very little to offer people and say they want to dry their skin out. You know, they’re oily, and they want to do something topical. We can do retinoids. Retin-A Micro might have some drying effect because of the long activity and slow release, but generally we don’t have that much to offer people in that respect, and I think that it will have other sort of [inaudible 00:13:01] from OCH. It just absorbs. It’s like makeup in a sense. It absorbs some of the oil production but not necessarily affecting the actual skin and the path we take with it.

We definitely have all kinds of options but not necessarily ... That particular issue is poorly addressed currently in our pharmaceutical options. I think someone like that could really find a strong place in the market. The other thing is there’s clearly ... Let me give you enough background control that when combined with another agent, secondary agents may become more effective. There’s clearly some basis to believe that would be the case because there are four pathogenic mechanisms for acne. One of them happens to be sebaceous gland hyperactivity and overproduction. It’s a conceptual hyperactivity. It’s not really as normal for the age but it’s still hyperactivity and that’s where production contributes to dandruff. It contributes to acne. It contributes for all this. It’s an important feature.

Call Leader: Do you think there’s any safety issues with going out for sebum production or sebaceous gland activity?

Doctor: Do you know what the pregnancy category will be on the drug?

Call Leader: No, not yet.

Doctor: Has the maker given you any fetal rat studies? Is there anything like that in publication? Or any fetal animal studies?

Call Leader: I’m not aware of any but they could exist. Are there any other safety issues besides the sebaceous glands production? I know that ...

Doctor: The four pathogenic mechanisms of acne are excess sebum production, sebum production nourishes the bacteria in the skin causing a bacterial overgrowth and there is a hormonally induced inflammatory blockage of pores. The hormonally induced inflammatory blockage of pores, some of that may have some contributions for ... It may be that one of the sebaceous glands have shrunken and that it may be less of an issue.

It’s possible that this will ... Plus if there’s less oil production, there’ll be less bacteria. It may actually be a feeder mechanism because we consider Accutane the perfect drug and one of it’s main things is that it travels down the sebaceous gland.

Call Leader: In the previous data for DRM01, there was an imbalance. There was actually a lot more colds in the drug arm in the phase two compared to the placebo. There’s theoretically an immune suppression issue. Do you think just in practice, that that would be an issue?

Doctor: What kind of issue? I didn’t understand…

Call Leader: They had more common colds in the drug arm than in the placebo arm. I think it was close to 25 percent, which is relatively high rate.

Doctor: As opposed to what was in the placebo?

Call Leader: I think it was maybe 10 or 12 in the placebo.

Doctor: Interesting, okay. First of all, the company has to have a secondary study on that because it could just be a fluke. You would have just done that one or maybe they decided it wasn’t adequately powered. I could see why that could be potentially the case because we certainly know that these particular products are absorbed into the region, locally. It could be that we’re unaware.
I’ve always felt that sebum production .... When you hit puberty, when you stop…. You have a different activity level. Running through playgrounds and sharing people’s drinks mostly, you have less URI’s in general in that age period. It may be that the application of certain drugs if you’re reducing bacteria on the skin or reducing biotin, all of that may potentially contribute to a change in the flora locally. I do think it’s possible. I just don’t ... It’s hard for me to believe that that’s something that’s concerning in larger series. It’s hard to believe that.

Call Leader: That was helpful. Going back to something you said previously, which was the difference between your adult patients versus your pediatric patients. In the Phase three trial includes adolescents? They weren’t studied previously in the phase two. Do you think that could impact the results?

Doctor: So the adolescents weren’t in the initial trial?

Call Leader: Yeah. Do you think that could impact these results?

Doctor: Could it impact the results? Yeah. The younger you are the more you ... Even the act of touching your face as a teenager is one of the ways that people get you or I. This could impact the results, yeah.

What I would say to a company like that, if they were smart, would produce an age match as opposed to if you’re focused only on global data and there’s not an adequate age matching they have trouble.

Call Leader: That’s very helpful. In the phase two results, they were testing once a day versus twice a day and so they had once a day or twice a day vehicle. Do you think a twice a day vehicle, which is what they have in the Phase three trial, might increase the placebo response?

Doctor: Yes, clearly. Clearly, that would do so but as long as you make a statistical difference in the usage, it really means nothing to us. If the background lies, just as long as it achieves statistical significance because even just a great vehicle ... If it works. If it reduces these so what, we’re going to be happy practitioners using them.

Call Leader: What do you consider a clinically significant benefit in acne both in terms of percent reductions and inflammatory and non?

Doctor: I usually ascribe to the data, the guidelines from the FDA. In clinical practice, the patients will be fairly happy with a 30 to 40 percent reduction in acne if they’re not too severe to start with. If they’re severe, they really need to get more. If they’re moderate to severe, then a 60 to 70 percent reduction to feel satisfied, from our perspective.
That’s just from my clinical experience. I’m not going to say that’s true, globally. I don’t think there’s enough data actually published on that to say that’s the case, but what the actual mark off is. It’s actually a good thought for study.

Call Leader: Just in terms of percentage, you have a two point reduction in IGA scores?

Doctor: I like that the FDA created that. For me, that’s been something that’s very helpful because it’s hard otherwise to figure out how to benchmark acne. I like these acne scores related to counting lesions and then they give these actual numbers. I think that’s a very clever way to put it together because it’s not easy to categorize.

Call Leader: What percent would have to hit that two point reduction in IGA for you to think that’s clinically meaningful?

Doctor: It depends on what the enrollment is. If it’s mild to moderate disease, I personally ... it has to be statistically significant. I don’t really care with the numbers. Virtually, no one reads those numbers, I don’t think. I might be wrong. From my perspective, most of the way people adopt usage of acne skin care products is that companies bring the new product. They explain the mechanism. Maybe people go to a roundtable dinner. They get samples in the office. Somebody comes in and they give him samples and then the patient can decide if it’s working or not.
Sometimes the drugs, they’ll say that if you just happen to give the first couple of patients the drug and it didn’t do a thing in your office. People are going to say I don’t think this thing works.
Sometimes it seems to work great and people will continue their mention of the practice. Some of that has to do with where you practice, who you practice with and whether your patients are fussy about the elegance of the product. In the end, a lot of treatment of acne is an art and we do get people picking things based on their initial rounds of experience or because they need to get something new.

Sometimes drugs are given to individuals who failed many other drugs initially because they may need something new. Sometimes that really does work well and sometimes not as well as you’d wish. Everybody is going to end up using this as long as it’s not a category X. The category X would be harder to sell.

Call Leader: In terms of inflammatory versus non-inflammatory lesions, if they show efficacy against one and not the other. Is that still going to be used? Is that important at all?

Doctor: For us, it’s nicer to have something that works for both but you typically ... When you look at a retinoid and a benzoyl peroxide regimen. The retinoid works largely on non-inflammatory ... It works long term on inflammatory but in the short term, non-inflammatory. The other one works mostly on the inflammatory because of the antibacterial. We are typically mixer and matchers. That shouldn’t be concerning to a dermatologist with experience.

Call Leader: The Dermira trials are relatively small. People are thinking that they’re underpowered. They’re about 350 patients per arm. Some of the other trials ...

Doctor: I don’t think that’s so small.

Call Leader: It’s lower than what some of the other people like Allergen and Galderma have had.

Doctor: For which drugs?

Call Leader: Like the Aczone trials were about a little more than a thousand in each arm.

Doctor: Well, that would concede that there’s high background co-effect on the drug. It needed it. As long as it reached statistical significance, it really doesn’t matter what the size of the trial is.

Call Leader: The size might hurt your ability to hit the statistical significance.

Doctor: If you don’t hit statistical significance, then you have to do a second version of the same trial and combine the two trials. You’ll see that with some of the atopic dermatitis trials.
I like that actually. What’s interesting is that some of the data will vary from site to site in trials because there is statistical variation in response. Sometimes they get things from different ends of the spectrum which still statistically saying. For that particular kind of situation, they have to add more. They have to apply to the FDA to get more. They start smaller because they’re costly trials. I can’t blame people for saying how smaller they are because they’re costly trials. There’s no question but if they reach statistical significance it’s of no account. If they don’t, that’s their issue. They’re stuck. They’ll have to figure out a strategy that the FDA will agree to allow in order to make that reach a statistical level.

Call Leader: In the Phase two trials there was a bit of a complex dose response in that the 4% gel once a day did better than the 7.5% once a day. Do you think that’s an issue or do you think it’s an anomaly of a smaller trial?

Doctor: No, it may be that the efficacy of the product is at a lower level. Conceptually, we always think more is better but it may be that the study status achieved ... Is no different whether you’re at 3% or 10%. Probably the side effects with the irritation lies with the percentages. If one is for a drug company, then that’s actually pretty reasonable because the FDA will look at that and pick the 4%.

I don’t find it that hard. Later on, a lot of times, they look at the higher percentages. It’s a cheaper product to make if you’re using the 4% versus the 7.5%. You do much better off with the drug company.

Call Leader: That’s where it gets a little confusing because in the Phase three they decided to go forward with 5%, which they didn’t have in the Phase two. 5% twice a day. I don’t know if you have any thoughts on that?

Doctor: That is unusual. They have to provide a different concept to the FDA. They’re developing the strike or fail. They have to apply a group of concepts to the FDA. You have to have something quite critical than the 5% twice a day.

I think they’re probably matching Axiom’s percentages. Axiom is either 5% twice a day or 7.5% once a day. They probably made a mistake in the initial trial with the 4%. It’s hard to say. I don’t know what they were thinking on that but they must have the data to support it.

Call Leader: When it comes to the market, do people pay for branded drugs, given that there’s a plethora of generic drugs?

Doctor: Every drug company has to provide coupons and some kind of help and the development of prior authorization. The companies have to work on that when a drug comes to market.

Call Leader: Do you have any thoughts on what price they can charge to get through payers without too much problem?

Doctor: That is a good question. I don’t know. I couldn’t say. I think that if you can make it as a monotherapy and you can show some cost efficacy. You might get a “tier two”. The aim for the drug companies is to get their products into a lower tier. The lower tier of cost because usually tier one, tier two, tier three. Sometimes they’ll go up to tier 8.

Call Leader: Tier 8, that sounds bad.

Doctor: Usually, tier one is going to be a generic. Tier two is going to be a less costly topical. Typically, acne drugs are on tier 3, with a fifty to seventy-five dollar copay. Then the drug company will give a coupon and then they’ll be thirty-five dollar copay.

Call Leader: One question about what is important for you to make treatment decisions. The company didn’t release any before or after pictures from the Phase two. Is that important to you at all? Or are you more interested in numbers and then sampling?

Doctor: You should ask them if they should have at some of the trials, some pictures of before and after because they’re usually included in the marketing. It should be something that they plan to have for marketing purposes even if they haven’t presented them to you.

Call Leader: Do you inject any Botox? Do you use Botox in your practice?

Doctor: I do, actually. I see a lot of adults so I have to. I do a lot actually, if I had to include that. I have a lot of young women. That goes along with the whole process.

Call Leader: There’s a company called Revance that has a long acting Botox. They recently have some data on that. Do you think that’s important to have a long acting Botox? I believe it’s supposed to work for around six months.

Doctor: I think it’s a really nice product, conceptually but they have to come to the market and say what’s distinctive about them. What’s distinctive about them that they should be used as opposed to other drugs?

Call Leader: If they’re longer acting than traditional Botox. I think Botox is supposed to work for two to three months and they’re supposed to work for six months.

Doctor: No, Botox is four to six. The longer you’ve used it, the longer the advocacy persists.

Call Leader: So you don’t think a six month Botox is particularly game changing or distinctive?

Doctor: It could be. It depends. If the results at six months are identical to the results at three months, then I would say that the product has more like a twelve month activity. It’s a longer shelf life. In that setting, you might save yourself with that. It’s my drug of choice because I want to spend less in terms of coming in less frequently. It depends on how it’s positioned.
I’m not totally sure what the plan is with that. I don’t get in touch with the marketing agents much.

Call Leader: Do you have any thoughts on why previous competitors failed. There was Dysport, The Xeomin, that never really made the headway because Allergan has a stranglehold. Do you have any thoughts?

Doctor: Some of it is cost. They price fixed pretty well and it’s very hard for people to figure out what to do with something like Dysport. It was very hard to figure out what the actual conversion rate was. How many units of Botox equals how many units of Dysport? Conceptually, Dysport was a lovely product. But it sort of became….I just don’t think it…It wasn’t…

When you come to market with that kind of stuff, people have a dose in their mind for or a volume in their mind that they use to achieve the effects that they want. If you start shifting that, people are concerned with the markers and ask how to make that equivalent. I can’t say that that’s wrong. I think it’s hard as a physician to start adjusting that all.

Call Leader: Do you also treat psoriasis patients?

Doctor: Yes.

Call Leader: There’s a lot of psoriasis drugs on the market now. There’s always other players in the pipeline. Are there any areas within psoriasis that you would consider to be an unmet need?

Doctor: Yeah. The development of pediatric drugs. Pediatric and adolescents is still unmet. The development of adequate scalp preparations is an unmet need. Development of preparations for sensitive skin areas may be an unmet need. There’s always a unmet need for somebody that’s not ... not so much a biologic. I don’t know that everybody in the universe wants injection.

Call Leader: I see that. One last question. If you include all parts of your practice, what’s making you most excited today?

Doctor: What makes me most excited today? Completing my paperwork. That’s a joke. I love my patients. I love to help them but at the end of the day, when I can close out the list, my stack of col vacs and prior authorizations. There’s something exceptionally gratifying about that.

Call Leader: That’s funny. Is there anything in the pipeline or something that just came out that’s really exciting?

Doctor: It’s clear that the atopic market is going to just take off like crazy in the next five to ten years. There’s a lot of pipelines. It’ll be interesting to see how that sets out.

Call Leader: Great. Thank you so much for your time Dr. Silverberg. This is very helpful.

Doctor: My pleasure. Thanks. Sorry about the phone issues.

Call Leader: No problem at all. Have a great day.

Doctor: Thanks, you too.

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