Biomedical Engineering Reference
In-Depth Information
2.3.3 Nplate
in trial desig n. Fo r Nplate, patients were split into splenecto-
miz ed p atie nts (Stu dy 1 ) and th ose w ho were no t (Stud y 2), and
then eac h group was tre ated for 24 w eeks. Fo r those treated
with Nplate, (1) 6 1% o f non splen ectomized patien ts and 38 %
of splenectomized patients had a d urable platelet res ponse (vs.
5 a nd 0% on placebo, respe ctively); (2) 8 8% of nons plenec -
tomized patients and 79% of s plenec tomized patie nts ha d an
overall p la te le t response (vs. 1 4 and 0% on placebo, respec -
tively ); (3 ) 2 0% of no nsp le nectomized patients an d 26% o f
splen ectomized patien ts req uired rescue thera py during the trial
(vs. 62 an d 57 % on plac ebo, respe ctively ); a nd (4) Np la te
patients achieved platelet counts of at least 50
Amgen's Nplate (romiplostim) was approved by the FDA in
August 2008 and by the EMEA in February 2009 for the
treatment of idiopathic thrombocytopenic purpura (ITP): a
autoimmune disease resulting in impaired blood clotting. This
bleeding condition is caused by the production of antibodies
against platelets, and it has a relatively low incidence of 66
cases per 1 million patients in adults [14]. The treatment of
ITP has been revolutionized by the launch of two ITP products
over the last few years: Nplate (an injectable peptide throm-
bopoietin mimetic FP made up of two identical immuno-
globulin IgG1 Fc domains, covalently linked to a peptide
containing two thrombopoietin receptor-binding domains)
and GlaxoSmithKline's (GSK) Promacta 1 /Revolade 1
(eltrombopag, a nonpeptide, orally available thrombopoietin
mimetic, approved by the FDA in November 2008 and Europe
in March 2010). Both drugs are approved for use only after
patients have been shown to be refractory to other (often
cheaper) therapies (e.g., corticosteroids). Before the approval
of these two drugs, the only ITP therapies were to prescribe
immune suppressors such as corticosteroids and Rituxan 1 ,
administer immunoglobulins, remove the spleen, and/or
administer platelet transfusions. The only Nplate Phase III
trials are for ITP; 13 therefore, we do not factor in indication
expansion as a key sales driver for the drug.
We believe there are tw o factors that different iate Nplate
positively from Prom acta. Firs t, Promact a has a black-bo x
warning (the mos t serious advisory warning that the FDA
provide s on labels, which we think restricts sales uptake).
From a safety perspective, both drugs may increas e the risk
for reticulin deposit ion within the bone marrow, whi le
Promacta may also cause hepatot oxicity: the focus of its
black-bo x war ning. As a result, while both drugs require
frequent hemato logic monit oring, Promact a patients also
need frequent hepatic and ocular monit oring. 14 Both may
increase the risk for hemato logical mali gnancies , particu-
larly in patient s with mye lodyspla stic syndro me, and both
have a simi lar range of adverse reac tions. Second, Nplate
has a shorter therapeutic time lag. 15
T here are othe r factors d ifferen tiating the two dru gs, but we
th ink their impact is minor (e.g., Nplate' s once-weekly SC
administration profile is lik ely to be similar in terms of
complianc e t o Promac ta ' s onc e-daily ta blet ad min is tra tio n).
Bo th drug s a ppe ar to have simila r e fficacy acc ording to effica cy
data on each drug' s U.S. label, although direc t comparisons of
Phase III trial results might be problematic, 16 given differences
10 9 /L on a
mean of 12.3 w eeks in splene ctomized patie nts and 15.2 w eeks
in non splene ctomized patien ts , compare d with 0. 2 and
1.3 w ee ks, respectively, for placebo [15]. M eanwhile, in
Studies 1 and 2 for P romacta, patients rece ived 6 w eeks o f
daily drug thera py, then 6 w eeks off therapy. The p ercentage of
patients experien cing an in crease in p latelet c oun t fro m
30
<
10 9 / L was 59 and 70% for Promacta patients
(vs. 16 and 11% for placebo). In S tudy 3, pa tients either
received 6 months o f P romacta o r p lacebo. In this trial, patients
on Promacta for 6 m on th s had 1 1.3 wee ks on averag e with a
platelet count above 50
10 9 /L to
50
10 9 platelets (vs. 2 .4 wee ks for
placebo), and only 18% required r escue the rapy during the trial
cou rse (vs. 40 % fo r plac ebo). T hu s, we think b oth drug s have a
similar i mpact on (1) th e n umber of patients requ i rin g rescue
therapy, and (2) the average number of weeks with a p latelet
cou nt a bove 50
10 9 .
2.3.4 Dulagl utide and Albigl utide
Both Eli Lilly's dulaglutide (LY2189265) and GSK/Human
Genome Sciences' albiglutide are GLP-1 (glucagon-like
peptide-1) analogs, in development for the treatment of
type 2 diabetes (T2D). GLP-1 analogs function by stimulating
insulin secretion, inhibiting glucagon secretion and lowering
blood glucose. Albiglutide is a FP composed of modified
human GLP-1 fused to human albumin. Meanwhile, dulaglu-
tide is a FP comprised GLP-1 (7-37) that has been linked to the
Fc section of human IgG4. Both albiglutide's albumin fusion
and dulaglutide's IgG4 Fc fragment are designed to extend
half-life of the active component, thereby reducing dosing
frequency (see Chapter 3).
T2D treatme nt is shaped by the 2009 updat e to the 2006
consensus algorithm publishe d by the Amer ican Diabetic
Associat ion and the Europe an Associ ation for the Study of
Diabetes (ADA/ EASD) [16], which split s T2D therapy into
tiers. Metformi n (a gener ic oral bigua nide drug) is general ly
consider ed to be the first-line T2D drug, and this forms part
of Step 1 ther apy in Tier 1 (“wel l validated” ) of the algo -
rithm. However, many patients on metform in monothe rapy
fail to maint ain glyc emic goals: in a U.K. stud y, it
was shown that 19-86 % of patients who had had diabetes
for
13 According to clinicaltrials.gov and Amgen's website, as of April 2011.
14 http://www.oregon.gov/OHA/pharmacy/therapeutics/docs/ps-2009-12-
thrombopoeisis.pdf
15 http://hematology.wustl.edu/conferences/presentations/Sanfilippo
20110318.ppt
16 The trial results for Promacta and Nplate are taken from the U.S. labels of
each drug, unless otherwise stated.
4 months achi eved glyc ated hemoglo bin (HbA1 c)
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