ANALYZING AND FORECASTING THE FUSION PROTEIN MARKET AND PIPELINE - Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges - page 29

levels of 7% in the first year of metfo rmin treatme nt,

wherea s 55 and 70% of thes e patient s reac hing these targets
had HbA1c measurem ents above these targets at 2 and 3
years [17] . The primary goal of T2 D ther apy is to control
glucose levels. Measuri ng hemoglo bin A1c (HbA1 c) has
been used for mor e than 25 year s as a way of determin ing a
patients average blood g lucose level over 60-90 days [18].
Step 2 (“ad dition al therapy” ) in Tier 1 include s sulphony-
lurea (another generic o ral drug oft en used in secon d-line
therapy), however, this is linked to hypogl ycemia and
modest weight gain . Tier 2 (“less well validated” ) therapi es
then include newer treat ments such as thiazolidine diones
(TZDs), DPP-IV (dipept idyl pept idase IV ) inhibi tors, and
GLP-1 (glucago n-like peptide -1) agonist s. TDZs and DPP-
IV inhibi tors tend to be used in secon d/third line. TDZs are
associa ted with card iovascular and fracture risks [19], while
DPP-IV inhibitor s have a favorable safety profil e but rela-
tively low efficacy. GLP- 1 agonist s, because they need to be
injected, tend to be used mor e in third line than in second
line [20] .
We think the sales performance of GLP-1 a nalogs such
as dulaglutide a nd albiglutide i s dependent on: (1) gene r-
at ing strong efficacy data, in term s of bot h lowering HbA1c
but e qually importantly, i n weight r eduction; (2) demon-
st ra ting a favo ra ble safety profile ( specifica lly on cancer
a n d c a r d i ovas c u l a r ) a n d a f avo r a b l e s i d e e ff e c t p r o fi l e
(s pec ific al ly, on e me si s) ; ( 3) h avi ng a f or mu la tio n th a t
d o e s n o t n eg a t ivel y i m p a c t d o s i n g a n d a d m i n i s t r a t i o n
fr equency, give n t ha t GLP- 1 ana logs wil l l ikel y c onti nue
to be admini stered subcutaneously, w e think the most
import ant f ac tor he re is low frequency dos ing a nd the
scope t o use a s mall needle gauge f or delive ry; and (4)
p o s i t i o n i n g

States. We think either albiglutid e or dula glutide will be the
secon d long- acting once weekly GLP- 1 agonist to hit major
weste rn markets after Byd ureon.
As discusse d, we think HbA 1c and weight loss are the
two import ant effica cy metrics for GLP- 1 drugs . ADA' s
HbA1c target is

<

7%, while the Interna tional Diabet es
Feder ation's target is

<

6.5% [22] . Of the Tier 1 T2D drugs,
both metform in and sulp honylurea reduce HbA1c by 1.0-
2.0%, whereas in Tier 2, TZDs reduce HbA1c by 0.5-1.4% ,
DPP- IV inhibi tors reduce HbA1c by 0.5-0.8% and GLP-1
agonist s reduce HbA1c by 0.5-1.0% [16] . In addi tion to
glucose level cont rol, weight reductio n is increasing ly
important as part of T2D patient treat ment. Metformin
and DPP-IV inhibi tors are both weight neutral, sulph ony-
lurea and TZDs are both associa ted with weight gain,
wherea s GLP-1 agoni sts are assoc iated with weight loss
[16]. A rece nt meta- analysis looki ng at rando mized con-
trolled trials examining four GLP-1 agonist s (Byet ta, albi-
glutid e, liraglut ide, and tas poglutide) showed (1) all four
drugs significa ntly lowered HbA1c by between 0.6 2 and
1.16% and (2) mean weight loss es with these drugs ranged
from 0.7 to 1. 3 kg [23]. We believe that provided future
GLP- 1 agonist s can dem onstrate late-sta ge clinical trial
HbA1c data that falls within this range, the weight loss
efficacy data will be more important in ter ms of differenti-
ating new GLP- 1s from competitors .
Bydureon (likely dulaglutide/lira glutide's key compet-
itor, in our view) has demonstrated r elatively strong effi-
cacy

<

in terms of H bA1c reduction in the Phase III

DU RATION -1 ( 1.9% at 30 weeks f or Bydureon, vs.

1 . 5 % f o r B y e t t a ) [ 2 1 ] . H owever, i n a r e c e n t h e a d - t o -
head trial w ith Victoza (DURATION-6), Bydureon showe d
slightly t o m a r k e t ( p l u s l evel a n d e ffe c t ive n e s s o f less H bA 1c r eduction ( 1 . 3% ) t ha n Vic to z a

1.5%). 18 Meanwhile, Phase II dat a released so far
suggests that dulaglutide m ay have slightly higher efficacy
than al bi gl ut ide, alt hough we not e that it i s di fficul t to
compare dat a between clinical tri als. In Phase II trials,
HbA1c w as 0.9% lowe r wi th w eekly a lbiglutide, ve rsus

ma rke ting s upport ).
We think adm inistratio n fre quency is an important dif -
ferentiator, and one way of looking at the evolution o f the
GLP-1 market is to look at im provements in this char acter-
istic. The first GLP- 1 analogs on the U.S. market was
Lilly/A mylin's Byetta 1 (exenatide , launched in the United
States in 2005), which it has a twice-da ily administ ration
profile. Novo Nordis k's Victoza 1 (liraglu tide, approved in
the United States in Janua ry 2010) is once daily and in the
LEAD-6 Phase III trial, patients on liraglutide dem onstrated
better glyc emic control and tolera ted the drug better than
those on Byetta [21] . However, we think the major growth
drivers for the GLP-1 market (provided they are approved)
are the longe r-acti ng once- weekly drugs . Of thes e, Lilly's
Bydureo n 1 (exenatide LAR) coul d be the first once-we ekly
GLP-1 in the major western mar kets, after it received a
positive CHMP opinion in April 2011 . 17 However, it has also
received two comple te response letters from the FDA,
increasing the risk o f delays or nonappr oval in the United

(

0.5% for exenatide [24]. This
com pares to 1.5% lowe r H bA1c w ith dulagl ut ide ove r
placebo [25]. In terms of w ei ght loss, a lbiglut ide reduced
weight by

0. 2 % f o r p la ce b o a n d

1.1 t o 1.7 kg in t hi s s tudy: numerically better

than placebo of 2.4 kg w eight

loss w ith exenatide. Meanwhil e, dulagl ut ide also reduced
weight by 1.3-2.6 kg (although only ove rweight/obese
patients were included in the trial) [26].
In terms of advanta ges over Byd ureon, GSK has indi-
cated that albigluti de can be administ ered usin g a sma ll-
gauge needle 19 (other sourc es have indicat ed that a 29-ga uge
needle would be used [27] ), likely helping complianc e given
that Byetta is administered with a 29-, 30-, or 31-gauge

0.7 kg, but l ess t ha n the

18 https://investor.lilly.com/releasedetail2.cfm?ReleaseID ¼ 554248
19 http://www.gsk.com/investors/reports/q42008/q42008.pdf 17 Bydureon received European marketing authorization in June 2011.