ANALYZING AND FORECASTING THE FUSION PROTEIN MARKET AND PIPELINE - Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges - page 30

needle, accor ding to its U.S. med ication guide. The needle
used in administeri ng Bydureo n is a rel atively large 23-
gauge needle, 20 pote ntially negatively im pacting compli-
ance. Mean while , for dula glutid e, Lilly has indicated that
the drug is highly soluble and can be administ ered using a
small-gauge needl e 21 . Second, Byd ureon is a synt hetic drug
derived from the Gila lizar d, while both albiglutide and
dulagluti de include forms of huma n GLP-1 and GLP- 1
analogs, which should carry a lower risk of immu nogenicity.
A recent (D ecember 2010) publica tion indicat ed that there
have been no repor ts of antibodies against dulaglut ide [25].
Meanwhil e, anti-a lbiglu tide antibodi es have been obser ved,
however, these were transi ent and non-ne utralizi ng, and
were not thoug ht to impact effica cy or safe ty. Furthermor e,
these antibodies affected muc h lower percentages of the
patient popul ation than exenatide (2.5% for albiglutide [24]
vs. 49% [28] for exenatide ). Last, it seems that albiglutide
pivotal Phase III trial s com plete in Septe mber 2011
to Dec ember 2012, 22 while dulagluti de Phase III trials
complete betwee n May 2012 and Novemb er 2012; there-
fore, it seems likel y that both drugs will rece ive a regula tory
decision (if succe ssfully subm itted) at appro ximat ely the
same time .
The side effect and safety profile are also key for T2D
dr ugs. Longer-acting GLP-1 agonists have been linked to
lowe r n ausea a nd likely b et ter p at ient compl iance [29]. As
di scussed, T2D treatment fail ur e with monotherapy inevi-
t a b l y l e a d s t o c o m b i n a t i o n t h e r a p y ; h owever, t h e s i d e
effe ct profile is less favo rable for patients on more t han
one drug. This is a potential issue, give n r elatively poor
pa tient compliance in this population: it has been esti-
mated t hat between 36% and 93% of patients take

provide a stronger picture of the safety and side effe ct
profile of these drugs.
In sum mary, we think both albiglutide and dulaglut ide are
well placed to carve themselves out part of the GLP- 1
market, as they have advantages associa ted with being
composed of human protei ns, they have a sma ller needle
gauge, and although they have generated les s data than
Bydureo n, it seems that they have favorable safety and
efficacy profil es. Based on the Phase II effica cy d escribed
earlier and becau se dula glutide is set to be marketed by Lilly
(who have substant ial experience with the exenta tide fra n-
chise), this drug may initially capture a slight ly g reater share
of the market if bo th drugs are launched at a simi lar time.
However, we caut ion that othe r factor s emerging between
now and a pote ntial market laun ch could likely play a rol e in
shaping uptake. We note that the perf ormance of Lilly's
other long- acting GLP- 1 agoni st Bydureo n will also likely
impact dulagluti de's positioni ng.

2.3.5 VEG Ftrap-E ye

Afliber cept is an FP made up from the Ig doma in 2 of VEGF
recepto r-1, fuse d to the Ig domain 3 of VEG F recepto r-2,
which is then fuse d to the IgG1 Fc. In Octobe r 2006, a
codevelo pment/copr omotion collabo ration betwee n Regen-
eron and Bayer for the treat ment of eye disease s with
afliberce pt was sign ed in Octobe r 200 6. As part of this
deal, Bayer has comme rcializ ation rights outs ide the United
States and will split profit s equally with Regeneron, while
Regeneron has exclusive rig hts to the U.S. mark et [32].
Afliber cept, termed VEGF trap Eye for ophth almolog ical
indicati ons, was subm itted to the FDA as an ophth almologi -
cal formulat ion for the treat ment of wet age- related macula r
degeneration (wet AMD) in Februa ry 2011. 23 The drug is
also in earli er-stage development for the treat ment of central
retinal vein occl usion (CRVO) and diabetic macular edema
(DME). Afliber cept is als o in development in a different
formulat ion as VEG F trap for a range of cance rs, as part of a
codevelo pment/copr omotion collabo ration with Sanofi-
Aventis. However, as afliberce pt failed to meet the prima ry
endpoint in Phase III trials for both pancreat ic cance r (in
2009) and nonsm all-cel l lung cance r (in 201 1), 24 and devel-
opment was stop ped on ovarian cance r (in 2009) [33], our
risk-adjus tments to sales of thi s drug mean that fore casts fall
below the top-6 drug sales forecas ts for 2016. 25 Th erefore,

80%
of t he p re sc ri be d m edic a tions [30]. Thus, safety and s ide
e ffe c t p r o fi l e a r e k ey, w h e n l ooking at new T2D drugs. The
main side effe cts with Byetta are nausea, vomiting, and
di arrhea. In t he 2-year pooled ana lysi s, ther e was 39%
nausea i ncidence during weeks 0-10 in the intention to
treat population [ 31]. Si milar ga strointestinal si de effe cts
were noted in Phase II tri als for albiglutide a nd dulaglu-
tide. In a Phase II trial, patie nts taking a lbigluti de most
frequently experienced na usea (11.8-54.3%), vomiting
(0-41.2%), and headache ( 5.9-23.5%) [24]. M eanwhile,
Ph ase II data from t he EGO t rial indicated that, the most
c o m m o n a d ve r s e even t s w e r e n a u s e a ( 1 3 . 8 % ) , d i a r r h e a
(13.8%), and a bdominal distension (13.8%), at the
hi ghest dose of dul aglutide [26]. Phase III data should

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23 The drug received a unanimous recommendation from the FDA advisory
committee meeting in June 2011. While the FDA does not always follow
committee meeting recommendations, we nevertheless view this positively.
24 According to Regeneron press releases.
25 We note that after writing this chapter, Regeneron reported that VEGF
trap significantly improved survival in previously treated metastatic colo-
rectal cancer patients; see Regeneron press release on June 6, 2011,
“ZALTRAP TM (aflibercept) Significantly Improved Survival in Previously
Treated Metastatic Colorectal Cancer Patients.”

20 See “What's new in diabetes medications”, Ackerman, UP Diabetes
Outreach, July 2011 (www.diabetesinmichigan.org/PDF/pdfUPDON/
Whats%20New%20in%20DM%20Meds.pdf).
21 http://files.shareholder.com/downloads/LLY/0x0x258459/5acdc123-
b0e7-498c-ab5c-92c599f205f2/Eli_Lilly_12-11-08.pdf
22 Based on Phase III clinical trial completion dates in www.clinicaltrials.
gov, as of August 14, 2011.