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once-daily or twice-daily 50mg doses com pared with the 100mg once-daily dose. The EMEA ap proved
50mg once daily in com bi na tion with a sulphonylurea, or 50mg twice daily in com bi na tion with metformin
or a thiazolidinedione, in Feb ru ary 2008: the pre vi ously ap proved 100mg once-daily dose of vildagliptin
will not be avail able. In No vem ber 2007, the EMEA cleared Eucreas, a sin gle-tab let com bi na tion of
Galvus and metformin, and its Eu ro pean roll-out com menced in March 2008. US ap proval has also been
af fected by skin tox ic ity wor ries. Galvus was filed with the FDA in March 2006, and had its re view pe riod
ex tended by the FDA by three months from No vem ber 2006 af ter clin i cal data were sub mit ted to sup port
the pro posed dos ing and in di ca tions as well as com ple ment ear lier data on the risk:ben e fit pro file. Then in
Feb ru ary 2007 the FDA is sued an ‘ap prov able’ let ter for the prod uct and re quested ad di tional data, in -
clud ing a clin i cal study in pa tients with re nal im pair ment. This has de layed the de vel op ment of Galvus in
the US for at least two years. Novartis is now con duct ing safety stud ies, but a resubmission for US reg u la -
tory ap proval is not ex pected be fore 2010, and the Swiss gi ant’s CEO hinted in Jan u ary 2008 that it may
not seek to refile Galvus with the FDA at all. Galvus was filed for Japanese approval in April 2008.
Januvia may have an ad van tage over Galvus in terms of half-life and the po ten tial for true once-a-day
dos ing. Galvus looks like it low ers blood sugar better than Januvia and an a lysts are pro ject ing an nual
sales peak sales of more than $2 bil lion for Galvus. The per cep tion is that many di a be tes spe cial ists are
ex cited about the po ten tial of these agents, but are wait ing to see more data on their risk:ben e fit pro file.
Con cerns re main that these agents could be af fect ing sub strates other than DPP-IV, ex ert ing their met a -
bolic ef fects in sub strates with the po ten tial for ad verse ef fects. The com mer cial po ten tial of DPP-IV in hib -
i tors ob vi ously ex ceeds that of the GLP-1 ag o nist due to their oral avail abil ity, un less the lat ter are
suc cess fully de vel oped in a form that re quires in fre quent in jec tion. Ul ti mately, the value of both ap -
proaches will hinge on how the is sue of beta cell func tional im prove ment and pres er va tion plays out. Re -
nal pro file could be one point of dif fer en ti a tion be tween Januvia and Galvus and ac cord ing to Novartis,
Galvus has a dif fer ent re nal pro file than Januvia. Januvia is ex creted about 75% through the kidney.
Galvus on the other hand, is only slightly excreted by the kidney, about 23%.
Be sides Merck and Novartis, a num ber of other com pa nies are de vel op ing DPP-IV in hib i tors. Bris -
tol-Myers Squibb’s Onglyza (saxagliptin) com menced phase III tri als in 2006, and is be ing co-de vel oped
with AstraZeneca; it was filed for both US and EU ap proval in June 2008. A large num ber of other com pa -
nies, in clud ing Roche and Novo Nordisk, have pre clin i cal DPP-IV in hib i tor can di dates. Probiodrug’s (Ger -
many) P93/01 (li censed to Merck and OSI Pharmaceuticals, USA) and Mitsubishi Tanabe Pharma’s
(Ja pan) TA 6666 (li censed to GlaxoSmithKline) are both in phase II. A large num ber of other com pa nies,
in clud ing Roche (Swit zer land) and Novo Nordisk (Den mark), have DPP-IV in hib i tors candidates in early
stages of development.
The more fa vor able side ef fect pro file of the DPP-IV agents rel a tive to sulphonylureas and glitazones
means that there is po ten tial for these drugs to have strong up take as sec ond line, add-on agents in Type
II di a be tes pa tients who are not ad e quately con trolled on metformin alone. The fact that the DPP-IVs
have much less in va sive oral dos ing, to gether with their lack of weight gain and the po ten tial to im prove
beta cell func tion, should po si tion them for broader ap peal (un like Amylin and Lilly’s Byetta (exenatide),
which is gen er ally pre scribed by en do cri nol o gists and spe cial ists). There is po ten tial for these oral
antidiabetics to re place older sulphonylureas at a sig nif i cantly higher price point. How ever the ad van -
tages must be bal anced against the com plex ity of the DPP-IV path way and the long-term na ture of the
head-to-head tri als that will be re quired to dem on strate any favorable effects on beta cell function in
humans.
Byetta is an incretin mi metic (GLP-1 ag o nist) and syn thetic form of exendin 4, a pep tide iso lated from the
sal i vary se cre tions of the Gila mon ster liz ard. It is in di cated as an ad junc tive ther apy to help im prove
blood sugar con trol in Type II di a bet ics not ad e quately con trolled by metformin and/or a sulphonylurea.
Its sales have per haps not achieved the lev els once fore cast ($650 mil lion in 2007), de spite Lilly’s ex per -
tise in the di a be tes field. In April 2008, one an a lyst re ported that Januvia was tak ing sales from Byetta,
partly as it is ap proved as a stand-alone treat ment, and also be cause it is an oral, once-daily drug,
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