Abstract
Background: Given the high cost of plasma derived intravenous alpha 1-antitrypsin (AAT), a more efficient method of delivery to the lungs is desirable. Inhaled AAT has been shown feasible for the treatment of alpha 1-antitrypsin deficiency (AATD) and is currently in clinical trials. To better understand patient preferences about possible inhaled AAT therapy, a survey was conducted to explore patient attitudes. Methods: We conducted an email based survey of patients in the Alpha-1 Foundation Research Registry with AATD on intravenous AAT replacement. Respondents were asked to rate their interest in hypothetical nebulized or dry powder inhaled AAT. Results: Respondents reported high levels of interest in both dried powder inhaler and nebulizer delivered inhaled AAT. The interest in dried powder inhaled was higher than interest in nebulized AAT (71% vs 64%, p = 0.0001). The interest in dried powder inhaled AAT was particularly high in respondents currently on bronchodilator therapy (p = 0.0053). Patients were just as likely to use or not use the product if it required 20% more out of pocket cost. Conclusions: There is a high level of patient interest in the development of a commercially available inhaled AAT replacement product.
| Abbreviations | ||
| AAT | = | alpha 1-antitrypsin |
| AATD | = | alpha 1-antitrypsin deficiency |
| BD | = | bronchodilators |
| COPD | = | chronic obstructive pulmonary disease |
| DP | = | Dried powder |
| FEV1 | = | forced expiratory volume in 1 second |
| ICS | = | Inhaled corticosteroids |
| IV | = | intravenous |
Introduction
Alpha 1-antitrypsin deficiency (AATD) is a genetic disease that predisposes patients to chronic obstructive pulmonary disease (COPD) (Citation1). Specific treatment options directed at this population are currently limited, yet include a variety of commercial products of human plasma derived alpha-1-antitrypsin (AAT) delivered by intravenous infusion. Interest in inhalation as a method of drug delivery is now two decades old. The potential value of inhalation would include the ability to target therapy to the lung, to achieve high airway concentrations of AAT, which might abrogate airways inflammation, to achieve targeted therapy with less drug and less cost (and therefore make this human serum-derived limited resource available to more patients), and to have a more convenient delivery system.
Inhaled AAT replacement may prove to be more efficient than intravenous replacement. Studies of distal lung deposition of AAT or surrogate particles of similar size through various inhalation methods show a drug delivery of 12.4% to 70% (Citation2,3,Citation4), compared to 2–3% with intravenous therapy (Citation5). Increased delivery to the target tissues may result in dose reduction that could reduce cost.
The burdens of inhaled AAT include dosing schedules that would be more frequent than once weekly, and the requirement that new formulations of AAT designed for inhalation have research trials that demonstrate clinically meaningful efficacy and safety.
Such trials are ongoing for the treatment of neutrophil elastase excess in cystic fibrosis patients (Citation6) and for AATD (Citation7). Studies have shown that AAT delivered by inhalation reaches the distal lung (Citation2,Citation8–13) and the serum (Citation9,Citation14), demonstrating absorption from the respiratory tract to the systemic circulation. Several studies have also shown that inhaled AAT increases the neutrophil elastase inhibitory activity of epithelial lining fluid, suggesting it may restore normal anti-elastase function (Citation11,Citation15,Citation16). Studies done to show the feasibility of inhaled AAT, while underpowered to prove safety, have not demonstrated substantial side effects in either humans (Citation11,Citation14,Citation17) or animals (Citation5,Citation14,Citation18). A plethora of delivery devices have been shown capable of delivering inhaled AAT particles (Citation3,4,Citation19,20).
However, no publications have systematically studied the potential acceptance of inhaled AAT among individuals likely to receive this therapy. To better understand patient preferences about possible inhaled AAT therapy, a survey was conducted to explore patient attitudes. This paper presents a summary of the survey results.
Methods
A survey using REDCap electronic data capture tools was constructed and emailed to participants (N = 591) who had given their permission for email contact by the Alpha-1 Foundation Research Registry (Citation21). The 29-question self-administered questionnaire was emailed to individuals who reported a PiZZ genotype and did not have a lung or liver transplantation. Invitations were delivered on 11/22/2011 and responses were collected until 1/17/2012.
We investigated interactions between demographics, current therapies, and interest in inhaled AAT augmentation. For data analysis, Likert scales of interest were converted into positive and negative responses, with positive responses being Extremely Interested and Highly Interested and negative responses being Moderately Interested, Somewhat Interested and Not Interested. To further explore the attitudes of AATD individuals, we also explored free text responses for themes. Analyses were performed in JMP 5.1.2 (SAS Institute Inc., Cary, NC) and NVivo 9 (QSR International Pty Ltd, Doncaster, Victoria, Australia). The p-values < 0.05 were considered statistically significant.
Results
Of the 521 delivered surveys, 170 responses were received. One was blank and 11 were duplicates; 158 were from unique patients, representing 30.3% response rate from the study population. Then, 48 respondents reported they were not on intravenous AAT, 2 reported they did not have the ZZ genotype and 1 did not know his genotype but completed the survey. These respondents were excluded, leaving a total study population of 107. Not all respondents answered every question.
Respondents’ ages ranged from 31 to 92 with a mean age of 59.0 ± 10.0 years; 57 respondents (54%) were male. Lung transplant was being considered for 6% of respondents. Another 34% reported they were treated with life style modification, 64% reported use of bronchodilators (BD) and 58% reported use of inhaled corticosteroids (ICS).
We questioned respondents about the importance of new AATD therapies. The most important new therapeutic attribute was “better ability to reduce my symptoms” with 78% indicating this would be of high importance. Half of respondents stated that it was highly important to them that a new therapy not be intravenous (50%) and half stated that lower cost was highly important (51%). Possible advantages and disadvantages of inhaled therapies, drawn from the free text responses, are provided in .
Table 1. Exemplary free-text responses about patient preferences regarding inhalation and intravenous augmentation therapy for AATD
We presented the respondents with a hypothetical AAT replacement therapy which would be similar in efficacy and safety to their current therapy, but was inhaled through a nebulizer for 10 minutes twice daily. A picture of a nebulizer device was provided. Extremely interested individuals (43%) outnumbered those highly interested (21%), moderately interested (21%), and not interested (7%) in this therapy.
We presented the respondents with a hypothetical AAT augmentation therapy which would be similar in efficacy and safety to their current therapy, but was an inhaled dry powder (DP) formulation utilizing a breath-actuated device requiring 1 to 4 puffs to administer the dose twice daily. A picture of a DP inhalation device was provided. Extremely interested individuals (48%) outnumbered those highly interested (23%), moderately interested (14%) and not interested (7%) in this therapy.
Respondents were more likely to be interested in a DP inhalation device than in the nebulizer device (71% vs. 64%, p < 0.0001). Current use of a BD was correlated with interest in inhaled therapy of either kind (p = 0.03). BD use was correlated with interest in DP inhalation device (p = 0.005) but not in the nebulizer device (p = 0.46). Use of ICS was not correlated with interest in either of the inhaled therapies.
Duration of time on AAT replacement therapy was <1 year in 11%, 1–5 years in 45%, 6–10 years in 27% and >10 years in 17%. There was a trend toward less interest in inhaled augmentation therapy the longer respondents had been on IV augmentation. When asked about frequency of IV infusion, no one indicated they received infusion more frequently than weekly. 84% of respondents reported weekly infusion, 1% reported infusion every 10 days, 13% reported infusion every 2 weeks, and 2% reported monthly infusion. Although inhaled therapy would require more frequent dosing, a third of respondents (36%) rated less frequent dosing as highly important.
Over half of respondents (58%) indicated that the out of pocket payments for their AAT augmentation therapy were not burdensome. Half of respondents (49%) paid less than $50 monthly out of pocket for their medication, while 13% paid over $500 monthly. Differences in current out of pocket payments made no difference in interest in inhaled AAT augmentation (data not shown). However, respondents who paid > $100 monthly out of pocket for IV augmentation were more likely to report lower cost as an important attribute in a new therapy (p = 0.0005). When asked how likely they would be to use a product that increased their out of pocket burden by 20%, similar proportions of respondents were in each Likert category between not likely and very likely (20%, 19%, 23%, 18% and 20%).
Discussion
Few FDA approved therapies in pulmonary medicine remain more controversial than augmentation therapy for AATD. Although drug dosing and delivery modalities, biochemical efficacy and clinical outcomes will be important for any new AATD therapies, the cost to develop therapy for a rare disease must be balanced with a high likelihood of acceptance by the affected population.
This survey was an attempt to explore patient preferences for AATD therapies. When presented with potential inhaled augmentation strategies, AATD patients from the US showed a high level of interest, even if the new drug was more costly than current therapies. Respondents were modestly more interested in the DP inhaler than in the nebulizer. This increased interested was primarily in the group currently on a BD, probably because they have more familiarity with and confidence in inhaled dry powdered formulations.
Inhaled augmentation therapy has the potential to address many of the problems patients report with intravenous therapy (such as frequent sticks for IV access) without giving up much of what they like. Still unanswered by the current literature is whether inhaled AAT reaches the connective tissue in sufficient concentrations to protect it and cause clinically significant improvement. Therapeutic targets of fewer exacerbations (Citation22) and more stable lung function (Citation23) on IV AAT augmentation will require study in objective randomized trials as inhaled therapies advance (Citation24).
The proposed inhaled AAT augmentation strategies may also be more efficacious. The half-life in the lungs of inhaled AAT was 69.2 hours in one study (Citation17). The half-life of intravenous AAT is about 5 days (Citation25). With variability in individual patient clearance of serum AAT and the bi-weekly or monthly infusions preferred by some patients, this means that some patients receiving intravenous AAT replacement have a low AAT level at times between infusions. Twice daily inhaled therapy could eliminate those times when the patients may be at risk for lung damage. However, twice daily inhaled therapy can be a burdensome time commitment as pointed out by several respondents (), especially in the case of a nebulizer, which would require about 10 minutes of administration twice daily in addition to the time of preparing the nebulized solution and cleaning the equipment.
There are weaknesses to our study. Our response rate (30.3%) was fair considering we did not send out follow up or reminder emails. Participation in the Alpha-1 Foundation Research Registry is voluntary and, in our experience, tends to include patients who are more active in their care than the general population of AATD individuals. Registry participants may be more empowered than others who could have different responses. The inhaled methods presented to respondents may not accurately represent the future commercially available products. For example, the half-life of inhaled AAT has been shown to be about 70 hours (Citation17). Inhaled AAT may be administered less frequently than twice daily, a prospect that would only make this method of augmentation more appealing to AATD individuals.
We conclude that there is a high level of patient interest in the development of a commercially available inhaled AAT replacement product. Details of administration time, formulation, efficacy, safety, and cost will impact patient acceptance.
Declaration of Interest Statement
Disclosures
In the past year Dr. Strange has research grants with and consulted for Grifols, Inc. He has consulted for CSL Behring, and has research grants with the Alpha-1 Foundation, Alpha-1 Association, PCORI, and the NIH on the topic of AATD.
Authorship contributions
Dr. Monk takes responsibility for the integrity of the work. Dr. Monk contributed to data analysis and drafting the manuscript. Mr. Graves contributed to conducting the survey, retrieving results and linking results to registry data. Dr. Williams contributed to analysis of free text responses. Dr. Strange contributed to study design, data analysis, drafting of manuscript, and manuscript revisions.
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