Re: Repost from Dr. Pilcher

May 24, 2002

I'm genuinely not looking to give you a hard time, Dr. Pilcher, and I

certainly don't mean to put you on the defensive. I appreciate the

added information, and I hope my feedback is useful to you, as

reflections of a typical physician hoping that a safe, effective

lotion will be found to help rosaceans.

ly, your data appears less impressive when the control group is

included. According to your stats, the control group 6/10 (60%)

improved, compared to 13/18 (72%) of the Quadrinone group -- not a

huge difference. In fact, it seems those two people who dropped out

are what gave you the statistical edge; if those two subjects are

included -- not unreasonable, since without an explanation we can

assume they weren't thrilled with the product -- the percent of

improved drops to essentially the same percentage as the control

group: 13/20 (65%).

You data suggests that those rosaceans who improved in the control

group did so at a greater rate when Quadrinone was included, but it

doesn't appear that the addition of Quadrinone significantly

increased the number of people who were helped. It's hard to tell,

because the groups are relatively small, and your statistical

analysis is (appropriately) based on the difference between improved

subjects, not the differences in the number of improved subjects.

Your study begs the question: was it Quadrinone alone, or its

presence in concert with other anti-inflammatory agents in your

control lotion, that made the statistical difference for those who

were already inclined to show an improvement?

We disagree over the definition of independent study. By independent,

I am not advocating multi-center studies per se, but for studies

where the researcher has NO relationship whatsoever to the company or

product. Dr. Draelos's consulting firm was hired by your company, and

presumably she was paid for her services. Of course you didn't " pay

her off, " but we can't ignore the reputation these services have in

general, for designing research that puts their client's products in

the best possible light, to showcase strengths while minimizing

limitations.

I was surprised that you said, " The scale used by Dr. Draelos in this

study reflects the limitations of claims we can make. " That sounds

like an admission of my concerns, of studies designed to match a

company's expectations, rather than objectively define and measure a

product.

I was also surprised by your comments regarding a cure. No one who

understands rosacea believes that an anti-inflammatory agent -- OTC

or by prescription -- would CURE rosacea. Would you really present

Quadrinone as a curative agent were it not for limitations of claims?

Still, good selection of parameters would permit you to convincingly

demonstrate a REMISSION of relevent symptoms, even 100% remission.

Unfortunately, your study parameters don't reflect rosacean symptoms -

- rather than peeling, uneven skin tone, or dermatitis, one might

expect categories for mild-moderate inflammatory rosacea on blinded

patients' self-assessment of changes in burning or itching, or

counting changes in the number of papules/pustules, or changes in

flushing in addition to erythema (which can be due to vascular

flushing or increased inflammation). On rereading, I see Dr. Draelos

used the same parameters she used to assess eczema. So it's not

surprising that the parameters don't fit rosacea well.

Your control lotion ingredients are very interesting. Thank you for

sharing them. We've been discussing topical niacinamide in this

group; presumably your lotion contains 4% niacinamide? Are you aware

of clinical studies supporting the use of topical niacinamide in

inflammatory or allergic dermatitis (or, dare to dream, in rosacea)?

Is it fair to say that Quadrinone is probably more active against

inflammation in the epidermis (such as in eczema) than in the dermis

(such as in rosacea)? Have you considered that those rosaceans with

elements of eczema or other conditions with epidermal inflammation

improve out of proportion to pure rosaceans, whose inflammation is

characteristically dermal in origan?

I gather you aren't able to share with us the range and extent of UV

protection, (or did you miss that question)?

However your product is ultimately received, I don't believe this

discussion is moot. For me, it brings up important issues in research

and in how products are presented to the public -- and gives me a

rare (and very appreciated!) opportunity to discuss these issues with

someone like yourself. I also hope it helps you and your company to

hear the thoughts of a physician, a free " focus group " impression.

I truly appreciate your time and information. I hope you feel your

time was well-spent. Have a nice holiday weekend.

Marjorie

Marjorie Lazoff, MD

> I'm sure this is meant for the group:

>

> -=-=-=-=

>

> Hopefully I can finally put to rest the criticisms and concerns

> voiced here regarding the manner in which our cea clinical

study

> results were presented. I have posted an updated version of the

study

> that includes data obtained from the control group as well as

> additional graphs showing comparisons of the severity scores at the

> beginning and end (4 weeks) in both the control and Dramatic Relief

> treated groups. And to head certain concerns off at the pass, this

is

> all of the data- not just a portion of it.

>

> Some explanation is due. For a currently unknown reason, the

document

> that has been circulating (the original study document for which we

> have been criticized) did not include the control data. Rather than

> continue to say that indeed our study was blinded and controlled we

> have now uploaded the document that includes this information. It

is

> posted in the files section of this forum under the name " Cutanix

> cea Clinical Study " and is available for your perusal.

>

> The control lotion used in our study was the Dramatic Relief lotion

> minus Quadrinone. Patients in the active group received Dramatic

> Relief Lotion with Quadrinone (1%). I am sure there will be further

> questions regarding this study and will be happy to address them.

>

> >Here's the problem I still see: even as a private communication to

a

> > lay person, the study said absolutely nothing about a control

cream

> or

> > control subjects (and it's not easy to imagine where these would

> fit

> > in); it described Dr. Draelos as assessing the scores herself;

and

> > the scale as described sounds imperfect as a tool for assessing

> > rosacea, much less for assessing changes in an objective manner.

>

> Hopefully, I have taken care of your concerns regarding control

> subjects and control cream used in the study. Dr. Draelos did

indeed

> assess and score the patients herself- after all she is the

> physician. The scale used by Dr. Draelos in this study reflects the

> limitations of claims we can make. We are not a pharmaceutical

> company per se in that Dramatic Relief is not to be marketed as a

> prescription drug. It will be sold as a cosmeceutical that one can

> purchase OTC. As such, we are unable to make specific claims about

> CURING rosacea and are limited to claiming that Dramatic Relief

will

> treat symptoms associated with the disease. The parameters Dr.

> Draelos used in her assessment directly reflect just that- 1)

> erythema, 2) desquamation (peeling), 3) uneven skin tone, and 4)

> dermatitis. How are her assessments less than objective? She was

> blinded to who received control or active until after the

completion

> of the study.

>

> > I recognize these criticisms are directed at an unofficial

> > presentation of the data. Still, I presume it was an accurate

> > description. You must agree that, as presented to us, it is not

> > accurate to describe Dr. Draelos' study as blinded and

controlled.

>

> > I remain skeptical of company-sponsored conference presentations

> and

> > studies, no matter how well-credentialled the researcher may be.

I

> > know why most physician-researchers participate in these types of

> > studies

>

> Perhaps your most troubling comment is in regards to Dr. Draelos

> herself and to the fact that we are not performing our studies in

an

> independent manner. Dr. Draelos is in no way directly affiliated

with

> Cutanix and has not received any direct benefit from these studies

> (cash or stock). She runs an INDEPENDENT contract clinical testing

> service named Dermatology Consulting Services in High Point, North

> Carolina that we decided to use for our clinical studies. To infer

> that she has gained monetarily from some sort of under the table

> arrangement in exchange for favorable clinical results is simply

> ridiculous. I urge you to go to her web site and view her

curriculum

> vitae (http://zdraelos.dermdex.net/). Perhaps the clinical services

> she has provided for other companies such as Procter & Gamble, S.C.

> and Sons, Colgate – Palmolive,

> Schick, Neutrogena, Glaxo Pharmaceuticals, Ortho Pharmaceuticals,

> Merck Pharmaceuticals, Allergan, Collagen Corporation, and

> Worldwide Consumer Products, Galderma, Pharmacia and others

> have been biased as well. If Dr. Lazoff, when she says " independent

> studies " means a multi-center university trial, I am afraid she

will

> never be satisfied with Cutanix. Our R&D budget will simply not

> afford that luxury.

>

> I can assure you that we are not marketing zinc oxide. Quadrinone

has

> been shown to inhibit the production of a number of inflammatory

> cytokines and chemokines produced by keratinocytes, dermal

> fibroblasts, T-Cells, and monocytes in response to inflammatory

> inducers such as chemical irritants, ultraviolet light,

> lipopolysacharride, and interleukin-1. Although I cannot comment

> specifically on exactly what Quadrinone is, I can tell you the rest

> of the ingredients that compose Dramatic Relief (I promised this in

> my initial post). They are as they will appear on the product label:

>

> Water (aqua)

> Propylene Glycol

> Glycerin

> Glyceryl Stearate (and) PEG 100 Stearate

> Simmondsia Chinensis (Jojoba) Seed Oil

> Isocetyl Stearate

> Ethoxydiglycol

> Paraffinum Liquidum

> Isostearyl Palmitate

> Niacinamide

> Glycereth -7

> Isocetyl Alcohol

> PEG-7 Glyceryl Cocoate

> Polyacrylamide (and) C13-14 Isoparaffin (and) Laureth-7

> Quadrinone

> Cetyl Ricinoleate

> Phenoxyethanol (and) Methylparaben (and) Ethylparaben (and)

> Butylparaben (and)

> Propylparaben (and) Isobutylparaben

> Polysorbate-20

>

> I'll end here by saying I'm open to further questions. Cutanix's

goal

> is to provide products that are effective in treating the symptoms

> associated with many dermatologic conditions. I was convinced

enough

> in their mission and the results I obtained in my own lab with

their

> compounds that I left my tenure track assistant professor position

at

> a nationally renown medical school (UT Southwestern in Dallas,

Texas)

> to join them. As Dr. Lazoff stated, only time will tell. If the

> lotion truly works as we have seen in our clinical studies, then

this

> discussion is a moot point.

>

> K. Pilcher, Ph.D.

> Director of Research

> Cutanix Corporation

May 25, 2002

I would urge you to look at the degree of improvement between control

and treated groups rather than looking solely at numbers of those

that improved. We fully agree that the control group did show

improvement- in fact, it simply bolsters our confidence that we have

a highly moisturizing lotion that aids in the treatment of symptoms

such as desquamation. We have seen this consistently in our eczema

studies as well. Your point is well taken about dermal vs. epidermal

inflammation. We have found in our Franz cell analyses that we are

able to obtain biologically active amounts of compound in the dermis

of human skin. So I personally believe that any effects in the

epidermis will also be seen in the dermis as well.

If there were no limitations on claims why would we claim to have a

cure if it didn't cure rosacea? I hope that you see we are not making

those types of claims. In fact, all we have said since the firs post

is that it helps in improving symptoms. I don't want to sound

defensive and am truly trying to keep an open mind. Please forgive me

if I feel just a little grilled over the coals J.

The sunscreen effect you refer to is due to the molecular structure

of Quadrinone. It was discovered in one of our initial UV studies

that it had the ability to absorb UVR. In the very first clinical

study performed by Cutanix patients were pre-dosed with the lotion

prior to UV exposure. Naturally, the data came back incredibly

positive and we were extremely pleased. Then we decided to test for

UV absorbing capacity and indeed Quadrinone in a 5% lotion had an spf

of 8-9. We have since looked at 2% and 1% lotions and for those the

spf is around 3-4 and 1-2, respectively. In all of our subsequent

clinical studies we have post-dosed the subjects with control or

active lotions after UV treatment to prevent skewing our data with

the natural sunscreen characteristics of the molecule. In those

studies Quadrinone effectively inhibit UV-induced erythema.

It seems as though we are bound to disagree on much and I hope that

none of our debate has been taken personally. Although, I have to

admit that it has been hard for me at times. All that our company

asks is that you give us a shot and see if the product works in your

case. Cheers to all in this group- you are why I do what I do.

Pilcher

May 25, 2002