FOI 5155 - Document 1
s47G
response to MSAC CA 1530
Purified human alpha1-proteinase inhibitor
1. “Minimum  clinically  important  differences  for  the  primary  outcome  in  the  core  randomised
controlled trials (RCTs), i.e. Computed tomography (CT)-measured lung density, are not established
in the literature…” [MSAC CA 1530, p1]
Lung CT densitometry changes have proven to be the most sensitive marker of disease progression in
patients with A1PI deficiency and COPD as compared to pulmonary function tests or quality of life
assessments  (Dirksen  2009,  Chapman  2015).  However,  in  absence  of  an  established  minimum
clinically important difference (MCID) for lung density decline rates, the results seen in the RAPID and
EXACTLE  trials may  be  difficult  to  interpret.  To  help  address  this  issue,  a  group  of  renowned  A1PI
researchers in Birmingham, UK are currently working to establish the MCID based on the CT density
outcomes  from  the  placebo-controlled  trials  (Dirksen  1999,  Dirksen  2009,  Chapman  2015).  The
researchers recently proposed an MCID of -2.89 g/L (95% CI: -2.59, -3.25) at the American Thoracic
Society conference held in May 2018 (Crossley et al 2018).
Based on the annual preservation of lung tissue (0.74 g/L/year) demonstrated in the RAPID trial in
favor of  A1PI  therapy,  the  proposed  MCID would  be  achieved  within  3.9 years  as compared  to an
untreated patient. As the treatment effect was robust and largely consistent between the RAPID and
RAPID  OLE  trials  in  the  Early  Start  patients  who  received  4-years  of  weekly  infusions,  a  patient
continuously treated with A1PI 60 mg/kg each week can reasonably expect to maintain a reduced rate
of  lung  density  decline  well  beyond  the  point  at  which  the  proposed  MCID  has  been  reached,
demonstrating a worthwhile clinical improvement in this rare and often fatal disease.
2. “No  significant  differences  were  observed  between  A1PI  and  placebo  for  the  remaining
effectiveness outcomes.” [MSAC CA 1530, p1]
Demonstrating  clinical  efficacy  in  A1PI  deficiency  leading  to  COPD  is  challenging.  It  requires
quantitative documentation of lung function changes in a chronic and slowly progressive process that
may  take  decades  to  manifest  clinically  (Wewers  and  Crystal  2013).  Despite  showing  a  significant
effect on lung density, the RAPID study did not show any statistical signal of efficacy in the secondary
endpoints.
There are several possible reasons for this: First, and importantly, the study was powered to detect
the  treatment effect on lung density measures, not changes  in pulmonary  function tests,  diffusion
capacity  of  carbon  monoxide  (DLco),  Incremental  Shuttle  Walking  Test  (ISWT),  or  St.  George’s
Respiratory Questionnaire (SGRQ) scores. The sample size and trial duration reflect those necessary
to  demonstrate  an  effect  to  slow  the  annual  lung  density  rates,  whereas  it  has  been  shown  that
significantly more patients followed for periods longer than 2 years would be required to investigate
benefits of A1PI therapy in the secondary endpoints. Furthermore, those estimates are based on the
use of placebo which would be considered unethical for the treatment of A1PI deficiency. Secondly,
the sensitivity of the clinical endpoints to detect change is much lower compared to CT lung density;
EXACTLE,  the  second  largest  study  in  A1PI  deficiency,  established  CT  scans  and  DLco  as  the  most
sensitive measures.
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FOI 5155 - Document 1
s47G
response to MSAC CA 1530

Purified human alpha1-proteinase inhibitor

3.  “A1PI meets three of the four criteria warranting rule of rescue. It is unclear whether the proposed
service provides worthwhile clinical improvement.” [MSAC CA 1530, p146]
s45

  The recent work by Crossley et al to describe
the MCID for CT density decline provides further clinical context for the results seen in the RAPID trial,
and further demonstrates that A1PI offers worthwhile clinical improvement when evaluated across
the appropriate time horizon, noting that A1PI deficiency is a chronic and slowly progressive disease.
Furthermore, evidence from a post hoc analysis of the RAPID programme suggests a mortality benefit
following A1PI therapy. During the RAPID programme, the time required for progressive emphysema
to develop into respiratory crisis was used to simulate the life-years gained as a result of A1PI therapy.
Respiratory  crisis was  defined  as  death,  lung  transplant  or  a  crippling  respiratory  condition.  Seven
patients withdrew with an average terminal lung density of 20 g/L. Using the average baseline lung
density for all patients (46 g/L) and the rate of decline in lung density in A1PI versus placebo-treated
patients, the projected time to terminal lung density was 16.9 years for those receiving A1PI therapy,
compared with 11.3 years in the placebo group (Figure 1). This indicates a gain in life-years of 5.6 years
with A1PI therapy (McElvaney et al 2017).  Although conducted in a small sample size, these data are
supported by results from the National Heart, Lung, and Blood Institute observational study showing
that patients receiving A1PI therapy had a greater survival than those not receiving treatment (Alpha-
1-Antitrypsin Deficiency Registry Study Group, 1998).

Figure 1
Extrapolation  of  the  effect  of  A1PI  replacement  therapy  on  the  predicted  time  to
reach terminal respiratory function in RAPID-RCT.

Source: Chapman et al 2018 International Journal of COPD 18(13): 419-432
No comments on the economic evaluation or financial implications are provided in this response as
Section  C,  D,  E  were  redacted  from  the  report  provided  to s47G
  due  to  the  commercial  in
confidence nature of the material.

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FOI 5155 - Document 1
s47G
response to MSAC CA 1530

Purified human alpha1-proteinase inhibitor

REFERENCES
Alpha-1-Antitrypsin Deficiency Registry Study Group (1998). Survival and FEV1 decline in individuals
with  severe  deficiency  of  alpha1-antitrypsin.  The  Alpha-1-Antitrypsin  Deficiency  Registry
Study Group, Am J Respir Crit Care Med, 158(1), pp. 49-59.
Chapman, K., Burdon, J., Piitulainen, E., Sandhaus, R., Seersholm, N., Stocks, J., Stoel, B., Huang, L.,
Yao, Z., Edelman, J. & McElvaney, N. (2015). Intravenous augmentation treatment and lung
density in severe Alpha-1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-
controlled trial, Lancet 386(9991), pp. 360-368
Chapman, K. R., Chorostowska-Wynimko, J., Rembert Koczulla, A., Ferrarotti, I., & McElvaney, N. G.
(2018).  Alpha  1  antitrypsin  to  treat  lung  disease  in  alpha  1  antitrypsin  deficiency:  recent
developments and clinical implications. Int J Chron Obstruct Pulmon Dis 13: 419–432.
Crossley, D., Subramanian, D., Stockley, R. A., & Turner, A., M. (2018). Proposal and validation of a
minimal  clinically  important  difference  (MCID)  for  annual  pulmonary  CT  density  decline.
American Journal of Respiratory and Critical Care Medicine 197:A3905
Dirksen, A., Dijkman, J. H., Madsen, F., Stoel, B., Hutchison, D. C., Ulrik, C. S., Skovgaard, L.T., Kok-
Jensen,  A.,Rudolphus,  A.,  Seersholm,  N.,  Vrooman,  H.  A.,  Reiber,  J.  H.,  Hansen,  N.C.,
Heckscher, T., Viskum, K. & Stolk, J. (1999). A randomized clinical trial of alpha(1)-antitrypsin
augmentation therapy, Am J Respir Crit Care Med 160 (5 Pt 1), pp. 1468-1472.
Dirksen,  A.,  Piitulainen,  E.,  Parr,  D.G.,  Deng,  C.,  Wencker,  M.,  Shaker,  S.B.  &  Stockley,  R.A.  (2009).
Exploring the role of CT densitometry: a randomised study of augmentation therapy in alpha1-
antitrypsin deficiency. Eur Respir J 33(6), pp. 1345-1353.
McElvaney, N.G., Burdon, J., Holmes, M., Glanville, A., Wark, P. A., Thompson, P. J., Hernandez, P.,
Chlumsky, J., Teschler, H., Ficker, J. H., Seersholm, N., Altraja, A., Makitaro, R., Chorostowska-
Wynimko, J., Sanak, M., Stoicescu, P. I., Piitulainen, E., Vit, O., Wencker, M., Tortorici, M. A.,
Fries, M., Edelman, J. M & Chapman, K. R. (2017). Long-term efficacy and safety of alpha1
proteinase  inhibitor  treatment  for  emphysema  caused  by  severe  alpha1  antitrypsin
deficiency: an open-label extension trial (RAPID-OLE), Lancet Respir Med, 5(1), pp. 51-60.
Wewers, M. D., & Crystal, R. G. (2013). Alpha-1 Antitrypsin Augmentation Therapy. COPD: Journal of
Chronic Obstructive Pulmonary Disease 10(S1): 64-67

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