JOURNAL OF AEROSOL MEDICINE
`Volume 16, Number 2, 2003
`© Mary Ann Liebert, Inc.
`Pp. 175–182
`
`Bolus Inhalation of rhDNase with the AERx System
`in Subjects with Cystic Fibrosis
`
`DAVID GELLER, M.D.,1 JOHN THIPPHAWONG, M.D.,2 BABATUNDE OTULANA, M.D.,2
`DANIEL CAPLAN, M.D.,3 DAWN ERICSON, M.D.,4 LAURA MILGRAM, M.D.,5
`JERRY OKIKAWA, B.S., R.R.T,2 JOANNE QUAN, M.D.,6
`and C. MICHAEL BOWMAN, M.D., Ph.D.7
`
`ABSTRACT
`
`Inhaled recombinant human deoxyribonuclease (rhDNase) delivered by nebulizer improves
`pulmonary function and reduces the rate of pulmonary exacerbations in cystic fibrosis sub-
`jects. Standard jet nebulizers are relatively inefficient and require a delivery time of 10–20
`min. We conducted an open-label, proof-of-concept study to evaluate whether bolus inhala-
`tion of rhDNase with a more efficient delivery system was safe and effective in cystic fibro-
`sis subjects. The AERx system used for this study aerosolized 1.35 mg of rhDNase in three
`inhalations at a single sitting. The predicted AERx lung dose was approximately 0.68 mg, a
`dose consistent with lung doses of rhDNase given by jet nebulizer. In our 16 subjects with
`cystic fibrosis, a mean relative increase in FEV1 of 7.8% (p # 0.001) was observed after 15 days
`of bolus delivery of rhDNase with the AERx system. The safety profile of rhDNase given as
`a bolus was similar to that observed with traditional nebulizer delivery. This study demon-
`strated that bolus inhalation of rhDNase was feasible, reasonably well-tolerated, and associ-
`ated with improvement in pulmonary function in this small group of cystic fibrosis subjects.
`
`Key words: AERx, nebulizer, aerosol, rhDNase, cystic fibrosis
`
`INTRODUCTION
`
`CYSTIC FIBROSIS (CF) is a chronic disease char-
`
`acterized by persistent airway obstruction as-
`sociated with accumulation of viscous purulent
`airway secretions, recurrent infectious exacerba-
`tions and progressive deterioration in lung func-
`tion.1 The increased viscosity of airway secretions
`in CF subjects is due in part to the presence of
`
`numerous polymorphonuclear neutrophils and
`their degradation products, including DNA,
`which aggregates in large fibrils that greatly in-
`crease sputum viscosity.1 Cleaving the large
`DNA strands with bovine pancreatic dornase al-
`pha was shown to reduce the viscosity of infected
`sputum in vitro over 50 years ago, and was ef-
`fective when inhaled by subjects with lung infec-
`tions.2–6 However, adverse reactions to the
`
`1The Nemours Children’s Clinic, Orlando, Florida.
`2Aradigm Corporation, Hayward, California.
`3Emory University, Atlanta, Georgia.
`4Children’s Hospital, Boston, Massachusetts.
`5Rainbow Babies and Children’s Hospital, Cleveland, Ohio.
`6Genentech, Inc., South San Francisco, California.
`7Medical University of South Carolina, Charleston, South Carolina.
`
`175
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`

`Nase, Pulmozyme®, Genentech, South San Fran-
`cisco, CA) is a 260—amino acid glycoprotein,
`cloned and expressed in a genetically engineered
`Chinese hamster ovary cell line that selectively
`cleaves extracellular DNA.7 A double-blind,
`placebo-controlled study of 968 CF subjects8
`showed that by giving 2.5 mg of thNase with a
`Hudson-T nebulizer a-Iudson Respiratory Care,
`Temecula, CA), the risk of respiratory exacerba-
`tions was reduced by 28% (daily dose) and 37%
`(twice daily dose). In addition, mean relative
`FEVl increased by 7.9% and 9.0% after 7 days of
`treatment with thNase 2.5 mg once or twice
`daily, respectively. Improvement in FEV1 was
`maintained at 5.8% and 5.6%, respectively, over
`the ensuing 23 weeks of treatment. Since thNase
`was approved for use in 1993, it is widely used
`in CF subjects of all severities.9
`RhDNase1s approved for use with specific neb-
`ulizer/ compressor combinations shownin clini-
`cal trials to effectively deliver the drug. These sys-
`tems include the Acorn II (Marquest Products,
`Eaglewood, CO) with the Pulmo-Aide compres-
`sor (DeVilbiss Health Care, Inc., Somerset, PA),
`the PARI LC JetTM nebulizer with ProNeb com-
`pressor (Pari, Richmond, VA)10 and recently the
`SideStream nebulizer with MobilAire compressor
`(Invacare Corporation, Elyria, OH).11
`Although the safety and efficacy of thNase
`delivered with nebulizers systems have been clin-
`ically demonstrated, these systems present cer-
`tain disadvantages for subjects such as lack of
`portability, low proportion of respirable particles,
`low delivery efficiency, and protracted delivery
`times. Including set up and cleaning, the time cost
`
`chodilators, and antibiotics, with total treatment
`
`time exceeding 2 h per day for some. Clearly more
`efficient delivery methods are required to reduce
`the time burden of taking multiple inhaled drugs
`in CF patients.
`There are nebulizer/ compressor systems avail-
`able that reduce the administration time of th-
`
`Nase for the convenience of CF subjects. For ex-
`ample,
`two studies showed the SideStream
`nebulizer coupled with a powerful compressor
`reduced the delivery time and maintained effi-
`cacy.“'12 Whether taking a further step and de-
`livering thNase by bolus inhalation could be
`safe and effective was unknown.
`
`The AERx® System is under development for
`the pulmonary delivery, via oral inhalation, of
`aerosolized liquid formulations of various small
`and large molecules. The AERx System is a
`drug/ device combination (a ”drug product”)
`consisting of a hand-held, microprocessor-con-
`trolled device capable of aerosolizing a liquid for-
`mulation of drug filled into disposable unit-dose
`blisters incorporating single-use nozzles (dosage
`forms) through which the drug solution is ex-
`truded to form a fine aerosol. The AERx System
`uses no propellants (Fig. 1).
`The AERx device contains aerosol generation
`hardware and electronics associated with breath
`
`actuation and automatic compliance monitoring.
`The AERx System has been designed to assist
`subjects in remembering and complying with in-
`structions for use. Features include the following:
`
`0 Breath actuated; delivery of an aerosol ”bolus"
`when the optimal
`inspiratory flow rate is
`
`disposable
`mouthpiece
`
`
`
`
`
`blister /
`strip exit
`
`dosing lights
`
`LCD display
`
`data pon
`
`FIG. 1. AERx thNase system.
`
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`Page 2
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`

`BOLUS INHALATION OF rhDNase
`
`achieved within a preprogrammed inspired
`volume range
` Visual cues for the subject to inhale deeply
`within the optimum range of inspiratory flow
`rates
` A timer for the breath-holding maneuver
`
`The AERx System has been used for the oral pul-
`monary delivery of insulin,13 morphine,14 fen-
`tanyl,15 and numerous other compounds.
`The AERx system generates an aerosol with
`more than 90% of the particles in the 2–3-mm
`range. Conventional nebulizers typically have a
`delivery efficiency of only 10–20%.16 In a previ-
`ous scintigraphic study17 of inhaled rhDNase, the
`nebulizers delivered 0.16–0.78 mg of the 2.5-mg
`loaded dose into the lung. This represents a de-
`livery efficiency of only 6–31%. The AERx system
`typically delivers 50–70% of the loaded drug dose
`to the lung. The AERx system used in this study
`when tested in vitro was predicted to deliver a
`lung dose of rhDNase equivalent to that of a jet
`nebulizer in only three inhalations at a single ses-
`sion, compared to the 10 min or more required
`by most nebulizers. The dose for this study (1.35
`mg loaded dose; 0.68 mg estimated lung dose)
`was selected to target the high end of the nebu-
`lizer lung-delivery range.
`The purpose of this study was to evaluate the
`feasibility of bolus inhalation of rhDNase via the
`AERx system in cystic fibrosis subjects.
`
`MATERIALS AND METHODS
`
`This was a multicenter, open-label study con-
`sisting of three phases: screening and washout,
`treatment, and post-treatment follow-up. Sub-
`jects already using Pulmozyme were screened,
`then withdrawn from Pulmozyme treatment for
`14 days prior to study treatment. Subjects not pre-
`viously using Pulmozyme were screened three
`days prior to study treatment. Subjects received
`rhDNase with the AERx System for 15 days. Sub-
`jects were seen in the clinic for safety and efficacy
`evaluation on treatment days 1, 2, 8, 11, and 15.
`On these study-visit days, the subjects took their
`dose of rhDNase in the clinic. They also per-
`formed pulmonary function tests before and 30
`min after the dose to detect any bronchospasm
`that might be caused by bolus drug administra-
`tion. Subjects returned to clinic 2 weeks after the
`final dose for pulmonary function tests. As part
`
`177
`
`of the safety evaluation, all subjects had a blood
`sample for anti-rhDNase antibodies collected
`prior to the first dose and 4 weeks after the last
`dose.
`Subjects with a confirmed diagnosis of cystic
`fibrosis were recruited from five sites across the
`United States. The study protocol was approved
`at each institution’s human subjects Institutional
`Review Board. Informed consent was obtained
`from all subjects and/or from their guardians if
`the subject was ,18 years of age. Subjects were
`screened within 14 days prior to any other study
`procedure. Screening procedures included a com-
`plete physical exam, medical history, and a re-
`view of inclusion and exclusion criteria.
`Eligible subjects met the following inclusion
`criteria: (1) ages 8–19 years; (2) either using rhD-
`Nase or not using rhDNase for a minimum of 3
`months prior to the study; (3) FEV1 of 25–75% of
`predicted values, and an FVC of $1.5 L; and (4)
`able to perform reproducible spirometry maneu-
`vers in accordance with American Thoracic Soci-
`ety Guidelines.18 An FVC of 1.5 L was necessary
`for the subject to inhale the complete drug dose
`from the AERx device.
`Subjects were excluded from the study if they:
`(1) used an investigational product within the 28
`days of enrollment; (2) used inhaled tobramycin
`within 3 months of enrollment19; (3) had a qual-
`itative change in inhaled antibiotic, bronchodila-
`tor, or steroid regimen within 14 days of enroll-
`ment; (4) were hospitalized within 14 days of
`enrollment; or (5) were pregnant. Females of child
`bearing potential were required to have a preg-
`nancy test at screening and to use an effective
`method of birth control for the expected duration
`of the study. Subjects were required to demon-
`strate proficient use of the AERx device prior to
`taking it home.
`Each AERx dosage blister contained 0.45 mg of
`rhDNase in 45 mL solution. The daily dose of
`AERx rhDNase in this study consisted of three
`inhalations (1.35 mg total loaded dose, or 0.45 mg
`loaded dose per inhalation) taken over 1–2 min
`at a single session. Assuming a 50% delivery ef-
`ficiency, the AERx System was expected to de-
`liver approximately 0.68 mg of rhDNase to the
`lung.
`All efficacy assessments were conducted in the
`clinic. Prior to performing pulmonary function
`tests (FEV1, FVC, FEF25–75) on study-visit days,
`subjects were not to use long-acting bron-
`chodilators within 12 h or short-acting bron-
`
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`

`178
`
`chodilators within 8 h of their clinic visit. Pul-
`monary function tests were performed according
`to ATS standards for spirometry.18 Pulmonary
`function results were converted to the percent
`predicted for age, gender, and height using the
`equations of Knudsen.20 The baseline pulmonary
`function was calculated as the mean of measure-
`ments taken 3 days before and immediately prior
`to the first AERx treatment. Efficacy was assessed
`by comparing the pulmonary function on treat-
`ment days 8, 11, and 15 with the baseline pul-
`monary function values.
`Safety was assessed by measuring bron-
`choconstrictor response, calculated from pul-
`monary functions prior to and 30 min after treat-
`ment on treatment days 1, 2, 8, 11, and 15, and
`testing for antibodies to rhDNase. Serum speci-
`mens were tested with a radioimmunoassay21 for
`total antibodies to rhDNase, including IgE, IgG,
`and IgM antibodies. Monitoring for adverse
`events was performed at each visit.
`Subjects were to be withdrawn from treatment
`if they experienced an acute respiratory exacer-
`bation resulting in a .25% drop in FEV1, required
`intravenous antibiotics, were hospitalized, expe-
`rienced an anaphylactic reaction after treatment
`or if they experienced severe or life threatening
`(grade 3 or 4) toxicity according to the World
`Health Organization Common Toxicity Crite-
`ria.22
`The primary efficacy analysis was based on the
`subset of evaluable subjects. A subject was con-
`sidered as evaluable if he or she completed all
`treatments and assessments according to proto-
`col. Subjects who reported missing two consecu-
`tive or a total of three nonconsecutive doses were
`not considered to be evaluable. The intent-to-treat
`and on-treatment population for safety analyses
`consisted of all subjects who completed one or
`more doses of study drug. Compliance with treat-
`ment was assessed by history and by reviewing
`the AERx device electronic dosing record. The
`primary efficacy outcome variable for the study
`was the overall mean improvement in FEV1
`(mean of treatment days 8, 11, and 15) relative to
`baseline. The mean relative improvement in all
`pulmonary function parameters (FEV1, FVC,
`FEF25–75) was also calculated separately for treat-
`ment day 8, 11, and 15 relative to baseline. A 95%
`confidence interval was calculated for each
`parameter. The Wilcoxon Signed Rank test was
`used to calculate the statistical significance of
`each efficacy endpoint. The mean change in FEV1
`
`GELLER ET AL.
`
`at 30 min post-treatment was calculated on treat-
`ment days 1, 2, 8, 11, and 15. The mean change
`on each of these days was considered as signifi-
`cant if the 95% confidence interval excluded zero.
`The patient population selected for this study
`had the same characteristics as the subset of sub-
`jects with a moderately low baseline FEV1 and the
`most robust response to rhDNase in the pivotal
`phase 3 study.8 In that study, CF subjects aged
`8–19 years with a baseline FEV1 of 25–75% of pre-
`dicted, demonstrated an 11.1% ([613.9% [SD])
`improvement in FEV1 after 14 days of treatment
`with rhDNase. If the true effect of the AERx rhD-
`Nase systems was an 11% change from baseline,
`then with 16 efficacy evaluable subjects, the prob-
`ability was 0.88 that the observed mean im-
`provement should be greater than or equal to 7%.
`A sample size of 16 evaluable subjects was there-
`fore selected for this study.
`
`RESULTS
`
`A total of 20 subjects were enrolled from five
`clinical trial sites in the United States. The mean
`age of study participants was 13.8 6 2.7 years
`(range, 9–18 years). Fifteen males and five females
`were enrolled. Sixteen subjects were using Pul-
`mozyme® prior to entering the study.
`One subject withdrew prior to dosing due to a
`pulmonary exacerbation during the 14-day
`washout period and is not included in the effi-
`cacy or on-treatment safety analysis. Two subjects
`were not considered evaluable for efficacy due to
`mild pulmonary exacerbations that resulted in a
`drop in FEV1 of .25% during the dosing period,
`and one noncompliant subject missed dosing on
`2 consecutive days. These three subjects were in-
`cluded in the safety analyses only. The efficacy
`analysis is based on the results of 16 subjects: 13
`subjects using Pulmozyme® regularly prior to the
`study and three subjects not using Pulmozyme
`prior to the study. All 19 subjects who took one
`or more doses of study medication completed the
`final study visit and provided safety data. Com-
`pliance as recorded by the electronic log was con-
`sistent with the stated history with one notable
`exception. One subject reported compliance with
`therapy but according to the electronics log took
`the majority of his doses on only 3 days.
`The sixteen subjects who were using Pul-
`mozyme prior to the study underwent a 14-day
`washout period prior to study treatment. Five
`
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`

`BOLUS INHALATION OF rhDNase
`
`179
`
`TABLE 1. PULMONARY FUNCTION IMPROVEMENT WITH AERX RHDNASE SYSTEM
`
`Statistic
`
`N
`Mean relative
`change in FEV1
`(% predicted)
`95% CI
`p-valuea
`
`Overall
`(days 8, 11, 15)
`
`Day 8
`
`Day 11
`
`Day 15
`
`16
`7.8
`
`16
`6.6
`
`16
`6.9
`
`16
`9.9
`
`4.0, 11.7
`0.001
`
`2.0, 11.3
`0.008
`
`3.1, 10.7
`0.003
`
`5.0, 15.0
`0.002
`
`ap-values are from Wilcoxon signed rank test.
`
`subjects had a decrease in FEV1 during that time
`and the remaining 11 subjects had an increase in
`FEV1 or remained unchanged by the end of the
`washout period. There was no significant mean
`change in FEV1 observed for the group during the
`14-day washout (1.68 L [96% CI 1.45, 1.90]) vs.
`1.76 L [96% CI 1.50, 2.02] for days 214 and 0, re-
`spectively).
`A significantly mean increase in FEV1 com-
`pared to baseline was seen on treatment days 8,
`11, 15, and overall (mean of treatment days 8,
`11, and 15) for the primary efficacy population
`(Table 1).
`Individual subject changes in FEV1 on treat-
`ment days 8 and 15 (Primary Analysis group) are
`presented in Figure 2. With the exception of two
`subjects, most subjects remained stable or had an
`increase in FEV1 over the 15-day treatment pe-
`riod, with 12 subjects improving in the first week.
`A significant mean relative increase was seen
`on day 15 compared to baseline for FVC (7.48%,
`p , 0.001) and FEF25–75 (16.45%, p , 0.018). There
`were too few subjects who were Pulmozyme
`naive (n 5 3) versus chronic users (n 5 13) to
`
`FIG. 2. Percent change in FEV1 from baseline. Primary
`analysis.
`
`draw any conclusions as to the effect of prior
`treatment on differential response to rhDNase
`treatment. After day 15, the thirteen Pulmozyme
`non-naive subjects were returned to their regular
`rhDNase delivered by nebulizer. Pulmonary
`function measurements did not differ when as-
`sessed 2 weeks after the final AERx bolus dose
`for these subjects.
`Adverse events reported by at least 10% of all
`subjects included cough (26%), upper abdominal
`pain (16%), sore throat (16%), and rhinorrhea
`(11%). These symptoms are seen frequently in CF
`subjects, and are similar to those reported in pre-
`vious rhDNase trials. No hospitalizations or other
`serious adverse events were reported during the
`study.
`The study was conducted between the months
`of December and June, the peak season for res-
`piratory viruses. Two subjects experienced acute
`respiratory exacerbations during treatment, re-
`sulting in a drop in FEV1 of .25% from baseline
`measurements on treatment day 11. Both subjects
`recovered from their chest infections unevent-
`fully with oral antibiotics.
`Nineteen subjects provided both pre-treatment
`and 4-week post-treatment blood specimens. No
`serum antibodies to rhDNase were detected in
`any subject prior to or after treatment in the
`study.
`Overall there were no significant changes in the
`mean difference in FEV1 (% predicted) measured
`prior to and 30 minutes post-treatment on any
`study-visit dosing day (Table 2). Airway reactiv-
`ity to rhDNase administration defined as $10%
`drop in FEV1 30 minutes after treatment was in-
`frequent, occurring on only two individual occa-
`sions in different subjects. Both subjects contin-
`ued on therapy without a recurrence in FEV1
`drop or other significant sequelae. Neither sub-
`ject required rescue medications as a result of the
`transient drop in FEV1. Overall, there was no con-
`
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`

`180
`
`GELLER ET AL.
`
`TABLE 2.
`
`INCIDENCE OF BRONCHOSPASM WITH BOLUS-INHALED RHDNASE: PRE-TREATMENT
`AND 30 MIN POST-TREATMENT DIFFERENCES IN FEV1 (% PREDICTED)
`
`0
`
`1
`
`Day
`
`7
`
`10
`
`14
`
`N
`Mean difference
`95% CI
`MIN, MAX
`N (%) with .10% drop
`
`18
`21.8
`23.7, 0.0
`29.7, 4.4
`0
`
`18
`18
`0.5
`1.7
`21.7, 2.6
`0.0, 3.3
`27.2, 7.0 212.3, 6.3
`0
`1
`
`18
`19
`20.7
`20.3
`22.3, 0.9
`22.6, 2.0
`213.3, 12.2 25.0, 6.8
`1
`0
`
`sistent pattern of acute pulmonary response to
`AERx bolus therapy, with most subjects experi-
`encing both random increases and decreases af-
`ter treatment. No single subject experienced a
`consistent or sustained decrease in FEV1 post-
`treatment.
`
`DISCUSSION
`
`This proof-of-concept study demonstrates that
`short-term bolus inhalation of rhDNase with the
`AERx device is associated with a significant im-
`provement in FEV1 in this small group of CF pa-
`tients. Though this study did not directly com-
`pare the AERx® System with nebulizer delivery
`systems, the pulmonary function changes seen in
`this study are of similar magnitude as those seen
`in previous studies of rhDNase when delivered
`by nebulizer.
`This is the first demonstration of efficacy and
`safety of bolus inhalation of a protein that acts lo-
`cally in the lung. Bolus delivery of other drugs
`by inhalation has been shown to be effective, that
`is, insulin in diabetic subjects,13 and fentanyl for
`cancer pain.15 However, these drugs are absorbed
`from the lung and act systemically, as opposed
`to rhDNase which acts topically in the lung.
`The adverse events reported (cough, sore
`throat, rhinorrhea) are similar to those previously
`reported with rhDNase delivered by nebulizer.8
`Short-term bolus inhalation of rhDNase appears
`to be safe with no evidence of bronchial reactiv-
`ity or antibody formation to the drug.
`This study had certain limitations which de-
`serve mention. First, we used a nominal dose of
`rhDNase that was smaller than the standard neb-
`ulizer dose, but was estimated to give a similar
`lung dose of drug because of the higher efficiency
`of the AERx® System. Lung dose was not mea-
`sured in our subjects, so there is no evidence we
`
`were correct in our assumption. However, the es-
`timate of lung dose was based on deposition data
`for both nebulizers and the AERx® System, so it
`is likely that the estimate was reasonably close. It
`is also likely that the precision of the lung dose
`with the AERx® System is greater than that of a
`nebulizer because it has built-in features to guide
`the patient through the proper breathing tech-
`nique, whereas there is no breathing guide with
`nebulizers.
`Second, we did not perform a direct compari-
`son of rhDNase delivered by the AERx® System
`versus by nebulizer, so the study cannot be con-
`strued as showing equivalence or superiority of
`one delivery system over the other. The purpose
`of this study was simply to test the concept of bo-
`lus delivery of rhDNase in a small group of CF
`patients as an alternative to standard nebulizer
`delivery. Further large-scale dose-ranging stud-
`ies are necessary to answer questions on the ideal
`dose of rhDNase for the AERx® System, and the
`efficacy and safety of bolus rhDNase delivery in
`a larger population.
`Subjects in this study who were already taking
`rhDNase on a regular basis were required to dis-
`continue the use of the medication for a 2-week
`washout period. A washout of 2 weeks was cho-
`sen based on the results of a Phase II rhDNase trial
`reported by Eisenberg.23 In that study, subjects
`with CF received 10 mg of rhDNase by nebulizer
`twice a day for 14 days, followed by a 14-day
`washout period for a total of six treatment cycles.
`Pulmonary function improved during the 14-day
`cycles of rhDNase administration and returned
`completely to baseline when rhDNase was discon-
`tinued for 14 days, producing a see-saw pattern
`over the 6 treatment cycles. Therefore, a 14-day
`washout was considered adequate in the current
`study for subjects using rhDNase to allow their
`lung function to re-equilibrate and enhance mea-
`surement of the effect of bolus rhDNase on FEV1.
`
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`

`BOLUS INHALATION OF rhDNase
`
`The absence of a decline in FEV1 during the 14-
`day washout period in our study was inconsis-
`tent with the observations from the Eisenberg
`study. There are a few possible explanations for
`this finding. It may be an artifact due to the small
`number of subjects. Alternatively, there may have
`been a significant study effect, with some of the
`subjects becoming more adherent with other
`daily therapies like chest physiotherapy. This was
`particularly true of one subject who had greater
`than a 35% improvement in FEV1 during the 14-
`day washout period after having almost no vari-
`ability of pulmonary function in the months prior
`to the study. He admitted that chest physiother-
`apy had been “neglected” as a part of his daily
`regimen until he started the study. His pul-
`monary function continued to improve an addi-
`tional 10% after 1 week of bolus rhDNase.
`The patient populations and doses of rhDNase
`between studies were also different. The dose of
`rhDNase that our subjects were taking chroni-
`cally was much lower than in the Phase II study
`(2.5 mg qd vs. 10 mg bid), which may have a dif-
`ferent impact on pulmonary function when
`abruptly discontinued. The subjects in the Eisen-
`berg study were naïve to rhDNase, whereas most
`of our subjects had been taking rhDNase for
`months to years, which may abolish the see-saw
`pattern of pulmonary function changes that were
`previously observed. Even so, a longer washout
`period was not felt to be ethical due to the risk of
`a pulmonary exacerbation while not taking rhD-
`Nase. Also, despite the lack of decline in FEV1
`during the baseline period, our patients still had
`a significant improvement in FEV1 after 15 days
`of AERx bolus therapy.
`Two previous studies examined more rapid de-
`livery of rhDNase by jet nebulization, using a
`well-baffled nebulizer that produces smaller
`aerosol droplets. Shah et al. compared the Hud-
`son T-Updraft II nebulizer with the Pulmo-Aide
`compressor to the Sidestream/CR50 system in
`173 CF subjects.12 Geller et al. compared the Hud-
`son T-Updraft II/Pulmo-Aide system with the
`Sidestream/Mobilaire system in 749 CF sub-
`jects.11
`The Sidestream/Mobilaire and Sidestream/
`CR50 systems generate aerosols with a smaller
`particle size than the Hudson T-Updraft II/
`Pulmo-Aide system. Mass median aerodynamic
`diameters (MMAD) were 2.1, 3.4, and 4.9 mm, re-
`spectively. The treatment times with the Side-
`stream/Mobilaire (1.8 min) and Sidestream/
`
`181
`
`CR50 (4.8 min) were shorter than the Hudson T-
`Updraft II/Pulmo-Aide system (9.1 min).
`Both studies demonstrated that the Sidestream
`nebulizer systems with its smaller droplet size
`and faster delivery times produced a slightly
`greater improvement in pulmonary function
`compared to the Hudson T-Updraft II/Pulmo-
`Aide System without affecting the safety profiles.
`In both studies, there was a trend toward a
`greater improvement in FEV1 as droplet size de-
`creased. For example, Geller et al.11 demonstrated
`a mean improvement in FEV1 of 4.2% with the
`Sidestream/MobilAire versus 2.5% with the
`Hudson T-Updraft II/PulmoAide in a CF popu-
`lation with mild lung disease who were treated
`for 2 weeks. Shah et al.12 demonstrated a median
`improvement in FEV1 of 16% with Sidestream/
`CR50 versus 11% with the Hudson T-Updraft
`II/PulmoAide in moderately severe subjects, al-
`though the differences did not reach statistical
`significance. The current study goes one step fur-
`ther to show that bolus inhalation of rhDNase in
`only three breaths is feasible in CF patients.
`In conclusion, this study provides encouraging
`preliminary data that bolus delivery of rhDNase
`with the AERx® System is feasible, is reasonably
`well-tolerated, and is associated with an im-
`provement in pulmonary function. The delivery
`of rhDNase with the AERx® is worthy of study
`in a larger controlled trial of CF patients.
`
`ACKNOWLEDGMENT
`
`Results from this paper were presented in part
`at the 14th Annual North American Cystic Fi-
`brosis Conference, Baltimore, Maryland.
`
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`Received on August 6, 2002
`in final form, February 10, 2003
`
`Reviewed by:
`Thomas O’Riordan, M.D.
`
`Address reprint requests to:
`David Geller, M.D.
`The Nemours Children’s Clinic
`83 West Columbia Street
`Orlando, FL 32806
`
`E-mail: dgeller@nemours.org
`
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`This article has been cited by:
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`2:4, 763-767. [CrossRef]
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`AAPS Journal 7:1, E20-E41. [CrossRef]
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