` 69
`
`actinic keratoses of the face and scalp. This table lists
`
`
`
`the two pivotal trials. Eight centers in the United States
` participated in each of these studies. After qualifying
`
`
`
`receive either Levulan or vehicle applicators,
` respectively.
`
`for the study, subjects were randomized in a 3:1 ratio to
`
` In our review,
`
`the primary endpoint parameter
`
`was missing, it was considered a failure.
`
`In addition to
`
`
`was based on the percent of subjects who were completely
`
`cleared of all their targeted lesions at Week 8, based on'
` an intent-to-treat population. At Week 8 if an observation7
`
`
`
`the per-subject analysis, a per-lesion evaluation was
`
`
`performed. These analyses were done based on per-protocol
`
`
`
`
`the sponsor has to demonstrate the superiority of
`efficacy,
`
`
` studies separately.
`I will be referring to these studies
`
`
`Next slide, please.
` Study 018, a total of 117 subjects from eight
`
`
` were randomized into the Levulan and 29 into the vehicle
`
`
`centers were enrolled into Study 018, where 88 subjects
`
`instead of intent-to-treat.
`
`In order for this drug product to prove
`
`Levulan solution to its vehicle in each of these two
`
`as Study 018 and 019 throughout this presentation.
`
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`
`
` 7O
` treatment arms in regard to the demographics and baseline
`
`And to answer your question, Dr. Lavin, that's
`
` characteristics of the subjects.
`
`
`showing the distribution of lesions or subjects for face
`
`
`
`and scalp separately.
`I think that was one of your
`
` questions.
`
`DR. LAVIN:
`I asked within face and scalp, not
`
`This table summarizes the results of the
`
`analysis for the primary endpoint variable, which was the
`
` MS. FARR: Next slide, please.
`'
`
`
`v
`
`
`
`
`percentage of subjects who had 100 percent of their lesions
`
`
`
`
`cleared. As is seen in this table, highly significant
`
`results were observed when Levulan was compared to the
`
`
`
` Next slide, please.
`
`vehicle arm relative to the rate of complete clearance.
`
`analysis for the primary endpoint variable for subjects who
`
` This table summarizes the results of the
`
`
`had 75 percent or more of their lesions cleared, and as you
`
`
`
`
`Next slide, please.
` This is Study 019.
`A total of 126 subjects
`
`
`can see in this table, highly significant results were
`
`observed when Levulan was compared to the vehicle arm.
`
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`
`the two treatment arms in regard to the demographics and
`
`Next slide.
`
`relative to the complete clearance.
`
`Next slide, please.
`
`subjects who had 75 percent or more of their lesions
`
`
` 71
` subjects were randomized into the Levulan and 33 into the
`
`
`vehicle arm. No statistical differences were found between
`
`
` baseline characteristics of these subjects.
`
`
`This table summarizes the results of the
` analysis for the primary endpoint variables for subjects
`
` who had 100 percent of their lesions cleared for Study 019.
`
`
`As is shown in this table, highly significant results were
`
`
`observed when Levulan was compared to the vehicle arm
`
`
`
`This table shows the result of the analysis for
`
`cleared for
`
`
`
`Study 019. Again, as we can see, highly
`
`
`
`
`significant results were observed when the two arms were
`
`
`compared to each other.
`
`
`
`the lesion
` analyses were based on per-protocol.
`Now I'm looking at
`
`
`
`
`This is Study
`the total number of lesions of the patients.
` 018.
`A total of 803 lesions were under the study. Of
`
`
`these,
`the data was available for only 784 at Week 8. This
`
`
`Next slide, please.
`
`Now, as I mentioned previously,
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`
`to the vehicle arm.
`
`Now the lesion analysis for Study 019.
`
`A total
`
`of 1,086 lesions were under the study, and of those,
`
`the
`
`
` 72
` significant results were observed when Levulan was compared
`
` Next slide, please.
`
`Thank you.
`
`
`
`
`data was available for 1,066 at Week 8. This table gives
`
`
`the rate of response for these lesions, and, again, as we
`
`
`can see, highly significant results were observed when
`
`Levulan was compared to the vehicle arm.
` Next slide, please.
`The two data
`
`
` lesion counts by gender, age category, which was younger
`
`
` lesions, which was face or scalp. Highly significant
`
`
` Next slide, please.
`
`The results of the analysis of
`Conclusions.
`
`
`
`
`statistically significantly better than vehicle in the
`
`
`
`
`
`efficacy of the two studies, Study 018 and 019, demonstrate
`
`Now,
`
`this is the subset analysis.
`
`sets were merged, and subset analysis was done based on
`
`v
`
`than 60 or 60 and older,
`
`skin type, and the location of the
`
`results were observed in each one of these subcategories.
`
`that Levulan Kerastick topical solution, 20 percent,
`
`is
`
`treatment of multiple actinic keratosis of the face and
`
`scalp.
`
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`
`
`DR. OKUN: This slide shows a flow chart
`
`great deal of information here.
`
`
`
`
`
`bring the mike a little closer?
`
`conscious of that.
`
`It's a little complicated to look at. We'll just take a
`
`
` reflecting the patient outcomes from pooled pivotal trials.
`
`
`
`
`
`few minutes to go over it, because there is actually a
`
` Firstly,
`
`I should mention that the outcomes
`
`
`from the pivotal trials were pooled in this flow chart
` merely for illustrative purposes. This approach is
`
`
`
`
`justifiable because the two trials had identical protocols,
`
`and it's worth noting that the results from the two trialsv
`
`
`
`were not pooled in the review process. Each trial standing
` on its own achieved clinical and statistical significance.
`
`
`
`
`DR. DRAKE: Excuse me. Could I ask you to
`
`
`
`I apologize.
`DR. OKUN:
`I’ll try and be more
`
`
`
`Only two patients in the active treatment arm
`
`
`
`were discontinued due to adverse events experienced during
`
`and three in the vehicle arm were lost to follow-up.
`
`
`
`slide. First of all, clearly the majority of patients who
`
`
`were treated with Levulan experienced 100 percent complete
`
`
`light treatment.
`
`Five others in the active treatment arm
`
`A couple of points suggest themselves from this
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`couple dropping off,
`
`to explain how the numbers add up.
`
`about half had 100 percent complete response by Week 12,
`
`going from here to there.
`
`
` 74
`
`at Week 8 117 are counted as clear, 60 as not clear, with a
`
`
`Most of those who were clear at Week 8 remained clear at
`
`
`Week 12. Of those retreated at Week 8, which is over here,
`
` And when you look in the vehicle
`
`
` arm, obviously, of those treated at Week 0, an extremely
`
`
`
`Next slide.
`~
`
`
`
`This slide shows a table recapitulating the 100V
`
`
`looking not only at all patients, but also the
` subset analysis,
`the patients with face and with scalp
`
`lesions, both at Week 8, as over here, and at follow-up at
`
`Week 12 .
`
`small number were 100 percent completely cleared by Week 8.
`
`percent complete response rate of the pooled pivotal
`
`trials,
`
`
`
`going from 65 percent to 69 percent, and the recurrence of
`
`
`
` Several conclusions suggest themselves from
`
`
`that active treatment is superior to
`this table. Firstly,
` vehicle. Retreatment at Week 8 improves overall efficacy,
`
`
` scalp lesions between Week 8 and Week 12 reduces the scalp
` subset efficacy when you're comparing across those two time
`
`periods. Finally, across both time periods, outcomes for
`
`
`patients with face lesions were superior to outcomes for
`
`
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`
`following slides.
`
`comparing Levulan versus vehicle, and also somewhat better
`
`possible explanation for this might be that percutaneous
`
`penetration of Levulan may be superior in thinner lesions,
`
`thus making treatment more effective in that subset.
`
`V
`
`
` 75
` patients with face lesions fare better is suggested in the
`
`
` Next slide.
` This slide shows the lesion response rate at
` Week 8 from the pooled pivotal trials,
`looking across
` different lesion grades, where Lesion Grade 1 are the
`thinner lesions and Lesion Grade 2 are the thicker ones.
` What you can see is that the lesion response rate is better
`
`
`
`for thinner lesions compared to thicker lesions. One
`
`
`
`
`
`
`
`
`Next slide.
`
`In comparing the distribution of lesion grades
`
`
`
`majority of face lesions are thinner, while the majority of
`
`
`
`
`
`thinner lesions respond better to treatment, it may
`
`
`
`lesions.
`
`
`Next slide.
`
`
`face explains the greater efficacy for patients with face
`
`in the different sites at baseline, it's clear that the
`
`scalp lesions are thicker. Since, as the previous slide
`
`showed,
`
`be that the higher proportion of thinner lesions on the
`
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`IV were treated with Levulan 20 percent solution and
`
`
`
`
` 76
` includes patients enrolled both in Phase II and Phase III
` studies, with Fitzpatrick skin types ranging from I through
`
`
`
`between 6 and 10.9 joules per centimeter squared blue
`
` light. There were additional patients in the Phase II
` studies, but there were 232 who were treated under these
`
`
`conditions. There were no deaths, serious or systemic
` adverse events attributed to treatment which emerged during
` the clinical trials. Transient local cutaneous adverse
`
`'
`
`
`Next slide.
`This slide shows the incidence of adverse
` events in the period between drug application and light
`
`
`reported any sign or symptom. Patients treated with
`
`
`Levulan, about 44 percent reported burning and stinging at
`
` some time point between drug application and light
` treatment, compared to 10 percent of control, and about 13
`
`percent active treatments had edema.
`It is possible that
`
`these symptoms result from inadvertent exposure of the target lesions to ambient light in the time period between
`
`
`drug application and device activation, perhaps thereby
`
`
`'initiating a low-grade photodynamic response.
`The
`
`
`events occurred in most patients.
`
`treatment, and it shows the fraction of patients who
`
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`Next slide.
`
`had edema on at least some of their target lesions,
`
`Fifty—seven percent of the patients
`
`at one time point during this time interval. Dr.
`
`
` directly a dermal irritant.
`
`
`
`This slide shows,
`in the time period during
`
`the fraction of
`and/or 24 hours after light treatment,
` patients who report burning, stinging, or edema at any time
`
`in that interval. One hundred percent of the Levulan-
`treated patients reported at least some degree of burning
`
`or stinging in this time period, compared to about 50
` percent of the controls, and 48 percent of Levulan patients
`
`
`
`compared to 0 vehicle.
`
`
`Next slide.
`
`
`
`
`characterized the burning and stinging as severe at least
`
`
`
` Piacquadio's point is well taken that for the vast majority
`
`
`of patients who reported severe burning or stinging at one
`
`
`they did not necessarily have severe
`
`
`burning and stinging during the entire time period. This
`
`is just the percentage of patients who reported that at
`
`
`
`
`light treatment, and more than 90 percent of the patients
`
`
`burning/stinging usually resolved within 24 hours after
`
`of those time points,
`
`least once during that time interval.
`
`The edema and
`
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`retreatment .
`
`
`
`
`Next slide.
`
`This slide shows adverse events noted longer
`
`than 24 hours after light treatment. Specifically
`
`scaling, crusting, scabbing as these lesions resolve.
`
`the incidence of hypo- and
`
`-
`
`vehicle. What this number refers to is the percentage of
`
`patients who developed hypo— or hyperpigmentation on at
`
`least one target lesion during follow-up after treatment.
`
`This analysis is a little different from the sponsor's
`
`analysis, because they were looking at the per-lesion
`
`likelihood of hypo- or hyperpigmentation, and this refers
`
`hyperpigmentation, which was 27 percent in Levulan and in’V
`
`
`
`
`
`
` discussing the adverse events that developed in more than S
`
`
`
`percent of patients,
`the most common adverse event is
`
`
`_I'd like to make special mention of the prevalence of -- rather,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` to the per-patient likelihood of developing hypo- or
`
`hyperpigmentation on at least one target lesion.
`Other adverse events experienced include
`
`
`itching, more common in Levulan than vehicle, erosions,
`
`
` Next slide.
` Adverse events reported by a smaller percentage
`
`
`wheel/flare, and other non—specified skin disorders.
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`
` 79
`
`vesiculation, pustules, and dysesthesia, and these are all
`
`
`
`
`
`Next slide.
`
` to moderate in intensity and short-lived.
`
`The few patients
`
`
`without evidence of scarring.
`
`
`
`significant laboratory abnormalities following treatment.
`
`V
`
`who developed ulcers on these sites,
`
`the ulcers healed
`
`Next slide.
`
`Laboratory evaluations were, no clinically
`
`more common in Levulan-treated than in vehicle-treated
`
`patients.
`
`Most local cutaneous adverse events were mild
`
`Two percent of Levulan-treated versus no vehicle-treated
`
`
`
`
`
`patients had normal baseline urine ALA levels that became
`
`
`marginally elevated after treatment. This information
`
`should be considered in the context that these marginally
`
`
`
`the baseline urine ALA levels of three of the study
`
`
`participants.
`
`Next slide.
`
`elevated post-treatment urine ALA levels were lower than
`
`the Levulan Kerastick topical
`
` In conclusion,
`
`solution, 20 percent, and blue light treatment effectively
`
`
`
`
`
`
`
`scalp. Adverse events associated with treatment are local,
`
`
`treats non-hyperkeratotic actinic keratoses of the face and
`
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`
`
`the committee.
`
`afternoon where we're now going to open the discussion to
`
`
` intensity, and short-lived.
` DR. DRAKE: Thank you.
` All right. We've now reached the point of the
`
`
`
`
`Dr. Wilkin, do you have any sort of
`
`
`instructions for us? We have the questions you've posed
`
`before us, and would you mind reviewing those so we make
`
`
`sure we try to give you the information that the agency -
`
`
`
`needs?
`
`DR. WILKIN:
` Yes .
`
`
`
`
`
`
`
`DR. DRAKE: Excuse me.
`Just one second.
`
`Henry?
`
`
`
`DR. LIM:
`I have a question of clarification.
` DR. DRAKE: Yes?
`
`
`
`I'm sorry,
`
`come before we go to Dr. Wilkin.
`
`
`
`
`
`
`DR. LIM: Specifically on the device issue --
`
`
`I should have asked for DR.
` DRAKE:
`
`
`
`
`I apologize. You're absolutely right. That should
`that.
`
`
`
`Jon, will you pardon me for just a moment while
`
` I do what I'm supposed to do here?
` Yes, Dr. Lim?
`
`DR. LIM: Specifically on the device issue, I'd
`
`
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`
`I do have a question about how to monitor the
`
`phototherapy clinic are not going to be able to measure
`
`internal meter that comes with it.
`
`So what is the
`
`
` 81
`
`interesting light source with a very reputable light source
`
`manufacturer, which is National Biologics.
`
`
` output of this light source. This light source has a peak
`
`
`at 417. Most of the photometers that are in the regular
`
`
`this, and I don't see in the picture that was provided an
`
`
`recommended maintenance, and how do we know the half-life-
` essentially of these light bulbs? '
`
`MR. FELTEN:
`The phosphor that is used in the
` bulb is specifically designed to put out that wavelength at
`
`
`417 nanometers.
`The company has done lifetime studies
`
`
`goes out as long as 328 treatment cycles, which is long,
`
`
`addressed in one of our questions back to them will be
`
`
`
`
`
`
`
`
` So we would just limit them by how many treatments they
`
`
`could recommend before the bulb should be changed.
`
`
`showing that the life of the bulb, if I remember correctly,
`
`long treatment cycles, and your question that will be
`
`about wavelength, about how to track the life of the bulb,
`
`and it will probably be based, on our recommendation, on
`
`some type of cycles of treatment, because all the treatment
`
`cycles are exactly the same, which would be 1,000 seconds.
`
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`
`
`
`
`
` that wavelength and that output. And they have looked also
`at the stability of these bulbs, and they're stable during
`
`these treatment cycles for at least an hour, maintaining
`
`
`So that
`the output level both in wavelength and in energy.
`
` has been tested.
`
`82
`
`For 1 hour, did you say?
`
`The testing shows that over an
`
` DR. LIM: Thank you.
` DR. DRAKE:
` MR. FELTEN:
`
`hour period of time,
`the bulb stays steady for wavelength-
`
`and energy, Which is --
`
`
`
`
` treatment cycle.
` DR. DRAKE: Right.
`
`DR. DRAKE: Over the period of an hour.
`
`MR. FELTEN: Almost four times longer than the
`
`300—plus cycles before the bulb started to show
`
`did a series of on/off cycles where the bulbs were run,
`
`the
`
` MR. FELTEN: And then what they did is,
`they
`
`
`thing was rested,
`turned back on, out to over 400 cycles,
`
`and all of the machines that they looked at have at least
`
`
` deterioration.
`
`So we will limit their lifetime based on
` that kind of -—
`
`DR. DRAKE:
`On the number of cycles.
` MR. FELTEN: Right.
`
`
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`
` Okay.
`I have Dr. Kilpatrick, and then Dr.
` DiGiovanna.
`
`
`
`
`
`DR. KILPATRICK: Ms. Farr made a comment which
` intrigued me.
`She said that in the subjects randomized to
`treatment, all targeted lesions were treated, which
`
`
`implies, being legalistic,
`
`that some lesions were not
`
`
`
`treated?
`
`
`
`MS. FARR: Well,
`they were supposed to choose
`
`So they’V
`
`So for all these subjects that they had chosen, all these
`
`targeted lesions had been treated, and success was --
`
` -- patients who were entered to the study had between four to 15 lesions. These were the targeted lesions.
`
`
`
`
`
`were treating these lesions -- for example, a subject might
` have had four lesions, another subject might have had 10.
`
`
`
`
` DR. KILPATRICK:
`
`I understand.
`I understand.
`
`
`MS. FARR:
`Go ahead.
`
` DR. KILPATRICK: But your answer is no,
`
`
`there
`
`
`
`
`for treatment by randomization.
`
` DR. DRAKE: Dr. Okun?
`
` MR. FELTEN: Dr. Okun?
`
` DR. OKUN:
`
`
`In fact,
`there were untreated
`
` lesions in the patients who were selected for
`
`
`were no untreated lesions in individuals who were selected
`
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` of course.
`DR. KILPATRICK: Yes,
`
`
`
`It's
`
`
`possible in this protocol for patients, for instance,
`to
`
`
`have more than 15 lesions, and they would have no more than
`
` 15 of those treated.
`
`DR. OKUN: Not supposed to be treated.
`
` DR. DRAKE: Okay. Dr. DiGiovanna?
`
`
`KILPATRICK:
`
`
`DR.
`May I pursue this, please?
`
`
`I'm sorry, Dr. Kilpatrick. .DR. DRAKE:
`
`
`DR. KILPATRICK: And may I be a little bit
`
`
`
`~ p
`
`edantic?
`
`DR. DRAKE: Yes, sir.
`
`
`
`DR. KILPATRICK: Donald Minland published a
`
`text called "Elementary Medical Statistics" back in the
`
`
`19605,
`in which he makes a big distinction between sampling
`
`
` units that are randomized -- here in this case, subjects --
`
`you,
`
`units and measurement units, and sampling units are those
`
`measurement units in this case would be the lesions, and
`
`I think, very properly have focused on the subject
`
`analysis per subject, but subsequent to that we get into
`
`
`lesion analysis, and then analysis by different lesion
`
`
`I don't think it
`grades. And while I'm being pedantic,
`makes any difference, but there are other possible
`
`
`
`explanations for differences between lesion grades in terms
`
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`
`So I'm just being pedantic.
`
`I don't think it's
`
`right point to
`
`about as good --
`
`T
`
`
` grades in different patients.
`
`
`
`a big issue.
`Thank you.
`
`Thank you, Madam Chair.
`
`
`
`DR. DRAKE: You're very welcome.
`
`
`
`
`
`
`I'm sorry.Dr. McGuire? Now Dr. DiGiovanna.
`
` DR. DiGIOVANNA:
`I'm not certain I'm at the
` ask this, because I'm not certain it's a
`
` point of clarification, but I think that this is probably‘
`
`
`
`
`
`
`
`
`DR. DiGIOVANNA: This is a junctional sort of
` question, and you might be able to clarify this quickly.
`
` But what focused me on it was the last part of the FDA's
`
`
`
`were not serious, mild to moderate in intensity, and short-
`
`
`
`lived. My understanding of this compound,
`from what I have
` in the literature that was given to us,
`is that it does
` cause oxidative damage to DNA. My understanding is that
`
`
`lesions in a way that to a large extent partially treats
`
`those lesions.
`
`
` what we are doing here is attempting to treat premalignant
`
`DR. DRAKE: That's okay. We've started moving
`
`on anyway.
`
`Go ahead.
`
`presentation that the adverse events associated with this
`
`FRIEDMAN & ASSOCIATES. COURT REPORTERS
`(301)881-8132
`
`
`
`specific mutations that have been identified in skin
`
`those mutations are very clearly associated with the
`
`premalignant lesions and exposing those lesions to agents
`
`that damage DNA and are not totally eradicating those
`
`in is the long-term development of malignancy in the areas
`
`that have been treated.
`
`
` 86
` over the last 5 to 10 years, enough to know that there are
`
`
`
`cancers and in precancers, and that the accumulation of
`
`
`
`development of malignancy, and the concern that I would
` have here is that if one is taking a large number of
`
`
`
` lesions,
`
`then the adverse event that I would be interested
`
`
`
`
` And if I'm not correCt that that should be what
` I'm concerned about, can you explain to me why? And if I
`
`
`am correct,
`then what sort of studies would be done to
`
`
`who are at a high risk?
` DR. DRAKE:
`
`
`
`from time to time I may ask if you have something pertinent
`
`to add to that.
`
`follow,
`
`to monitor for that outcome in these individuals
`
`even though the company has completed your presentation,
`
`I would ask Dr. Okun, and also,
`
` So, Dr. Okun, may you address that question
`
`
`
`
`
`
`
`DR. OKUN: Well,
`I think answering that
`
`
`FRIEDMAN & ASSOCIATES, COURT REPORTERS
`(301) 881-8132
`
`
`
`You know,
`
`I understand your concerns, Dr.
`
`considerably longer than that time period.
`
`So in fact at-
`
`v
`
`this juncture, based on what has been submitted from the
`
`
`
`
`
`
`DiGiovanna. First of all,
`just to clarify,
`in the
` conclusions we said that the adverse effects are short-
`
`
`lived, and it perhaps would be more precise to say the
`
`
`adverse events that were observed were short-lived. As was
`
`
`discussed in the protocol outline, patients were not
`
`
`A period in
`followed for a period longer than 3 months.
`
`
`
`which in humans carcinogenicity would be observed would be
`
`
`
`
`
`there is follow-up for no longer than
`studies for this NDA,
`
`
`
`The issues that you raised that are potentially
`
` of concern would,
`I suppose, need to be addressed in terms
`
`of having longer-term follow—up on patients who are being
`
`
`
`
`whether they are having a higher rate of carcinogenic
`
`
`progression.
`
`
`Now, again, one consideration in this sort of
`
`
`study design is, obviously, we're dealing with a study
`
`
`population where there is already underlying risk of skin
`
`
`carcinogenesis, given the enrollment criteria by which
`
`they're enrolled.
`So special attention needs to be paid in
`
`
`the conclusion of those 3 months.
`
`treated with this modality to test the hypothesis about
`
`FRIEDMAN & ASSOCIATES, COURT REPORTERS
`(301) 881-8132
`
`
`
`to separate a theoretical or potential signal from the ALA
`
`as opposed to the endogenous signal from these folks
`
`
`
`adverse events indicates that 3 percent of,
`
`I think,
`
`the
`
`
`
`is it possible
`
`
` 88
`
`
`
`
`because of their pre-existing solar history exposure.
`
`
`DR. KILPATRICK: Martin, Table G-lo of the
`
`
`
`
`patients had carcinoma of the skin. Again,
`
` that the photodynamic therapy was a causal agent in this?
`
`DR. OKUN: These were cancers that were
` diagnosed before or during --
`
`
`
`comment on this issue.
` DR. LIM: Yes,
`
`
`levels. One is that the mechanism of action of this
`
`
`topical ALA is through the generation of protoporphyrin,
`
`
`
`DR. KILPATRICK: Okay.
`
`Thank you.
`
`7
`
`
`
`DR. DRAKE: Dr. Lim,
`
`I think you might have a
`
`DiGiovanna's questions.
`
`I think one can look at it on two
`
`just to try to address Dr.
`
`solar band, it would go the exitus state,
`
`would interact with the oxygen molecule to form the singlet
`
`oxygen.
`
`The site of action primarily is in the cell
`
`membrane, so it would cause lysis of the cell.
`
`I don't
`
`think we can completely answer the question and the concern
`
`which, upon exposure to the active spectrum, which is a
`
`the exitus state
`
`
`
`
`
`
`
`
`
`that you raised, specifically DNA damage.
`It primarily is
`
`
`FRIEDMAN & ASSOCIATES, COURT REPORTERS
`(301) 881-8132
`
`
`
`
` 89
`
`
`Number two is that the other therapies for --
`
`
`the 5-FU specifically,
`I'm not sure if you know it doesn't
`
` damage DNA either.
`
`thirdly, as was mentioned before,
`
`there is a very large cohort of patients with
`
`nature where they have tremendously elevated levels of
`
`to a lesser extent in the plasma, and to my knowledge,
`
`there is no report that those patients as a group have a
`
`-
`
`7
`
`and I believe she can confirm that.
`
`is in the audience,
`
` And then,
`
`
`
`erythropoietic protoporphyria, which is an experiment in
`
`
`
`protoporphyrin in the skin as well as in the red cell, and
`
`
`
`
`
`
`
`higher incidence of skin cancer. Dr. Poh-Fitzpatrick, who
` has followed a large group of patients,
`
`
` DR. DiGIOVANNA:
`
`
`Can I just respond to that?
` DR. DRAKE: Yes, but I was going to ask Dr.
`
`
` DR. DiGIOVANNA: You are correct that if you
`
`
`generate enough toxic oxygen species and other toxic
`
`
`that you kill the cell, and I don't have a problem
`
`
`
`
`with that. You can do that with cryotherapy, and you can
`
`
`do that with a number of other agents.
`
`
`with the inadequate treatment of the premalignant lesion,
`
`
`Maureen Poh-Fitzpatrick to comment,
`
`too.
`
`So, John, go
`
`ahead, and then let Maureen have a say.
`
`agents,
`
`I have a problem
`
`FRIEDMAN & ASSOCIATES. COURT REPORTERS
`(301)881-8132
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`
`
`destroyed early on.
`
`
` have sustained one hit of a two-hit-leads-to-cancer
` hypothesis, and then the remaining cells,
`some have
`
`sustained an additional amount of DNA damage.
`
`
`I did consider the point that you were talking
`
`
`about,
`that there are a lot of people who are walking
`
`around who have had high levels of these compounds for many
`they may have the sustained exposure to —-
` years; however,
`
` I don't know what the incidence of actinic keratosis in
` that population is, but it very well may be that those
`
`
`lesions occur at a lower level because they're totally
`
`
`
`I think the concern here is really the partial
`
`
`treatment of lesions.
`I think if you can destroy the
`
`
`premalignant lesions, you remove the problem.
`If you
`
`
`partially treat it with an agent that causes DNA damage,
`
` you've raised a different scenario, and you've taken
`
`someone who has a predisposition to cancer -- for example,
`
`an individual analogy would be someone who has a nevoid
`
`
`
`
` additional exposure to a DNA-toxic agent will increase
`
`
` But, as pointed out,
`I think one
`
`
`basal cell carcinoma syndrome, and they have a number of
`
`cells —— all of their cells have one hit already, and
`
`their risk.
`
`FRIEDMAN & ASSOCIATES. COURT REPORTERS
`(301) 881-8132
`
`
`
`because cryotherapy doesn't necessarily cause selective DNA
`
`I don't think that's true,
`
` treat actinic keratoses.
`
`
`DR. DiGIOVANNA:
`
` damage.
`
`I mean, if I'm wrong,
`It destroys the cells.
`
`
`please tell me, but I think these are --
`
`you're clearly disturbing, perturbing the barrier function,
`
`DR. DiGIOVANNA: Usually cryotherapy is a
`
`timely isolated event, and I don't know of liquid nitrogen
`
`being a DNA specifically damaging agent,
`
`
`
`DR. LIM:
`I'm not sure about that.
`
`
`
`
`DR. DRAKE:
`I'm not sure about that, because
`
`
`and if these people go out and get more UVA exposure, how-
` do you know you're not subjecting them to additional DNA
`
`
`
`damage? Because you've perturbed the natural protective
`
`barrier that might have been there before you froze them.
`
`
`
`like reactive
` oxygen species are.
`
`DR. DRAKE: There are two people who still want
`
` to respond to this particular thing.
`
`
`
`
`
`
`All right.
` already asked, and Rob wants to respond.
`
` I'm Maureen Poh-
`
`DR. POH-FITZPATRICK:
`
`
`Joe, yours isn't in response to this,
`
`is it?
`
`I'm going to ask Maureen, whom I
`
`So, Dr. Maureen Poh-Fitzpatrick, welcome.
`
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`(301)881—8132
`
`
`
`
` 92
` Columbia University, and clinical professor of dermatology
` at the University of Tennessee.
`
`patients with protoporphyria for 20 to 30 years, and in
`
`those patients, combined with the data from Dr. Micheline
`
`in about 153
`
`some of whom are now
`
`octogenarians,
`
`our databases and one with actinic keratosis.
`
`
`
` I've had the opportunity to follow a cohort of
`
`
`
`
`
`
`Matthews-Ross from the Harvard Medical School,
`
`
`patients with this disease,
` there were no skin cancers tabulated from
`
`
`
`
`Now, whether that means that these people never7
`
`therefore, go out in the sun so, they're protected, that's
`
`
`
`a possibility. And the other possibility is that indeed
`
`there is some kind of low-grade protective effect from the
`
`porphyrin in the skin, although there is absolutely no data
`
`
`
`these people haven‘t
`
`
`keratosis for some reason, and they're certainly not at
`high risk of having a genetic predisposition through some
`
`other gene -- of having a PS3 mutation, for instance -- and
`
`then having this protoporphyrin alongside over a lifetime
`
`
`doing whatever concurrent damage it may do.
`
`So these are the data that I can sort of throw
`
`
`to support that at all.
`
`So in point of fact,
`
`gotten skin cancers and they haven't gotten actinic
`
`
`
`
`
`IREDMAN&AfimCMTELGXRTRHDKHRS
`(301)881-8132
`
`
`
` DR. DRAKE:
` And Rob?
`
`Thank you.
`
`DR. STERN:
`
`I think if you look at the
`
`progression of carcinogenesis in actinic keratosis or sun-
`
`damaged skin,
`
`On the other hand,
`
`I think the point that John
`
`alluded to is, what are the effects of incomplete
`
`7
`
`treatment, and what was disturbing to me was that even with
`
`
`
`
`
`
`mechanisms going on here of carcinogenesis and you consider
` this 1,000-second hit, even if there are cells that do
`
`survive and they're DNA damaged, compared to the overall
`
`
`
`the biologic insult in terms of the
` likelihood of leading to cancer is likely to be trivial, on
` the one hand.
`
`
`
`
`
`
`
`
`the non-responders getting a second treatment 4 weeks after
`
`
`the initial prime endpoint,
`8 weeks, on the lesions that at
`
`
`least in the people who get them -- elderly men are
`
` considered higher-risk lesions in terms of progression to
`
`carcinogenesis, all on the basis of clinical data,
`
`likelihood of metastasizing -- in fact the clearance rate
` went down even 4 weeks after the initial time, and these
`
`
`
`
`
`time with the data we have in terms of scalp lesions?
`I
`
`
`are in selected, pretty thin lesions.
`
`My concern is,
`
`is this really ready for prime
`
`FRIEDMAN & ASSOCIATES. COURT REPORTERS
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`
`
`
`that outweigh further clearances with an additional
`
`
` 94
` have real doubts about is this really safe and efficacious
` for scalp lesions if you have recurrences within 4 weeks
`
`
` therapy.
`
`DR. DRAKE:
`John,
`thank you.
`It's a good
`
`
`
`question, and where you might want to think about this is
`
`
`in Question 4 in terms of thinking about what studies might
`
`
`be done to continue to answer this very important question
` you've just asked.
`
`
`
`I mean,
`I don't disagree with you in ‘
`
`
`terms of -- we must think about it, if nothing else just 7
`
`
`
`
`
` Dr. McGuire?
`
`looking at the PUVA data over a long period of time.
`
`must be thought about.
`
`So it
`
`
`DR. McGUIRE:
`I had a couple of points. One,
`
`unless I misunderstand the data,
`there appears to be no
`
`
`
`
`
`
`selectivity between normal skin and lesional skin. That
` is,
`the duration of fluorescence and the intensity of
` fluorescence are the same. And I assume that that means
`
` same as it is in the actinic keratoses.
`
`If I'm wrong about
` that, I'd like to hear about it.
`
`
`
`to me is the one that Dr. Okun said was a little bit busy,
`
`
`that the toxicity in non-lesional skin will be about the
`
`But the piece of data that is most concerning
`
`
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