Page 1 o 5
© Annals o T ansla ional Medicine. All igh s ese ed. Ann T ansl Med 2019;7(Suppl 8):S337 | h p://dx.doi.o g/10.21037/a m.2019.09.105
Edi o ial Commen a y
The isks o con e ing pos -hoc indings in o p ima y ou comes
in subsequen ials
Filipe B. Rod igues1,2,3, Joaquim J. Fe ei a2,3,4
1UCL Hun ing on’s Disease Cen e, UCL Queen Squa e Ins i u e o Neu ology, Uni e si y College London, London, UK; 2Labo a o y o Clinical
Pha macology and The apeu ics, Faculdade de Medicina, Uni e sidade de Lisboa, Lisbon, Po ugal; 3Ins i u o de Medicina Molecula , Lisbon,
Po ugal; 4CNS—Campus Neu ológico Sénio , To es Ved as, Po ugal
Co espondence o: Joaquim J. Fe ei a. Labo a o y o Clinical Pha macology and The apeu ics, Faculdade de Medicina, Uni e sidade de Lisboa,
Lisbon, Po ugal. Email: [email p o ec ed].
P o enance: This is an in i ed a icle commissioned by he Academic Edi o D . Zhenxiang Zhao (Depa men o Neu ology, Henan P o incial
People’s Hospi al, People’s Hospi al o Zhengzhou Uni e si y, People’s Hospi al o Henan Uni e si y, Zhengzhou, China).
Commen on: Reilmann R, McGa y A, G ache ID, e al. Sa e y and e icacy o p idopidine in pa ien s wi h Hun ing on's disease (PRIDE-HD): a
phase 2, andomised, placebo-con olled, mul icen e, dose- anging s udy. Lance Neu ol 2019;18:165-76.
Submi ed Sep 03, 2019. Accep ed o publica ion Sep 18, 2019.
doi: 10.21037/a m.2019.09.105
View his a icle a : h p://dx.doi.o g/10.21037/a m.2019.09.105
Hun ing on’s disease (HD) is a de as a ing neu odegene a i e
condi ion caused by a iple epea expansion o he
hun ing in gene (1). Al hough a e i is amongs he mos
equen au osomal dominan causes o demen ia, equen ly
a ec ing indi iduals in he mos p oduc i e decades o
hei li es. Clinically, i is cha ac e ized by a classic iad
o luc ua ing neu opsychia ic symp oms, and p og essi e
mo emen and cogni i e diso de s, accompanied by o he
symp oms such as weigh loss and sleep impai men . I is
se e ely debili a ing, has a huge impac on quali y o li e and
is a al, wi h a median su i al a e mo o onse o a ound a
qua e o a cen u y (2).
The culp i gene ic de ec was i s assigned o
ch omosome 4 in 1983 (3) and sequenced in 1993 (4).
Whils g ea hope had been placed on his disco e y, nea ly
h ee decades la e he e is s ill no cu e o any in e en ion
ha delays o s ops disease p og ession (5). Ne e heless,
se e al p omising compounds a e cu en ly ac i e in he
d ug de elopmen pipeline (6).
Wi h ega ds o symp om managemen he he apeu ic
a mamen a ium is b oad, al hough ew in e en ions a e
suppo ed by high quali y e idence (7). As an example,
o he hype kine ic mo emen diso de (i.e., cho ea)
cha ac e is ic o HD, he e a e cu en ly wo FDA-app o ed
medica ions— e abenazine and deu e abenazine—
al hough uncla i y s ill exis s abou how dissimila hei
e icacy and sa e y p o iles a e (8,9).
HD is a p omising disease model o s udy
neu odegene a ion, due o se e al cha ac e is ics, including:
a p ecise pa hogenic agen (4), a na u al his o y ha
comp ises a long p esymp oma ic phase (10,11) ollowed
by an ex ended diseased su i al (12), a b oad symp oma ic
spec um including mos o he clinical ea u es p esen
on neu odegene a i e diseases (mo o , beha iou al and
cogni i e) (1), well- alida ed assessmen ools (13-16),
pionee ing imaging and bio luid bioma ke s (10,17), and
well-o ganized esea ch and pa ien ne wo ks (18). These
ac o s ha e encou aged d ug de elope s o in es in HD as
shown by he p opo iona ely high numbe o clinical ials
conduc ed in his a e disease popula ion. Un o una ely,
he success a e o he de elopmen pipeline unde pe o ms
when compa ing wi h o he diso de s (5).
Gene ic in e en ions a e only now coming o
age due o ecen b eak h oughs in DNA and RNA
manipula ion echniques, and op imiza ion o d ug s abili y,
immunogenici y and deli e y. The e is op imism ha
hese new ools may help change he a e o diseases like
Hun ing on’s. The ideal d ug de elopmen p og am needs
o happen wi h minimal human and inancial bu den and
maximal e iciency. This includes in o ma i e p eclinical
da a and ea ly phase ial esul s, bu also ea ly “go/no go”
decision imings and c i e ia.
P idopidine is an in e es ing molecule om he
pha macological pe spec i e (Figu e 1). Ac ing on he
337
Rod igues and Fe ei a. Con e ing pos -hoc indings in o p ima y ou comes
© Annals o T ansla ional Medicine. All igh s ese ed. Ann T ansl Med 2019;7(Suppl 8):S337 | h p://dx.doi.o g/10.21037/a m.2019.09.105
Page 2 o 5
dopamine gic sys em—which is p ima ily in ol ed in
he genesis o he disease pheno ype—i is classi ied
as a modula o as i can ha e bo h an agonis ic and
an agonis ic e ec s h ough a s a e-dependen e ec on
dopamine ecep o s. When he e is o e ac i i y i ac s as an
an agonis , unde unde ac i i y condi ions as an agonis , and
has li le o no in luence unde physiological ci cums ances.
In addi ion, i also seems o in e ac wi h N-Me hyl-D-
aspa a e (NMDA) and sigma-1 ecep o s.
Thus a p idopidine has been es ed in ou successi e
andomized con olled ials (RCTs) in HD, en olling a
g and o al o o e 1,000 pa icipan s (Table 1) (19,20,22,24).
Un o una ely, in all o hem he p ima y ou come was
no me .
A i s , a small RCT es ed 50 mg o p idopidine a day
agains placebo in 58 people wi h mani es HD, ec ui ed
om 6 cen es in Sweden and No way. The ial ollowed
pa icipan s o 4 weeks and was no able o show an e ec
on i s p ima y ou come, a composi e cogni i e sco e.
Ne e heless, seconda y and explo a o y analyses e ealed
a nominal imp o emen in he modi ied mo o sco e
(mMS), especially in a subg oup o mo e se e ely a ec ed
pa icipan s. This subsco e o he Uni ied Hun ing on’s
Disease Ra ing Scale (UHDRS) o al mo o sco e (TMS)
comp ises i ems ela ed wi h olun a y mo o con ol (i.e.,
i ems 4–10 and 13–15) (19).
Building up on hese esul s, wo ollow-up andomized
con olled s udies ensued: he Me maiHD s udy in
32 Eu opean cen es and he HART s udy in 27 No h
Ame ican cen es. Based on he assump ion ha p idopidine
could ha e an e ec on olun a y mo emen con ol, bo h
we e designed and powe ed o show a di e ence in he
mMS and ec ui ed people wi h mani es HD and a mMS
o 10 o mo e.
The Me maiHD s udy ec ui ed 437 pa icipan s o
in es iga e 45 and 90 mg o p idopidine daily compa ed
wi h placebo o e 26 weeks. Alas, his ial did no show an
e ec o i s p ima y and seconda y ou comes. None heless,
he analyses we e s a is ically signi ican o he compa ison
90 mg e sus placebo in he pe -p o ocol sample (i.e., 70%
o g ea e compliance wi h ea men and comple ed he
s udy) o he mMS and in he in en ion- o- ea sample o
he UHDRS TMS (20).
The HART s udy had a simila design and es ed
3 dosages o p idopidine (20, 45 o 90 mg daily) agains
placebo in 227 pa icipan s. The p ima y ou come e alua ed
a 12 weeks depic ed no di e ences be ween he di e en
dosages and he placebo a m, howe e seconda y analyses
showed a signi ican di e ence o UHDRS TMS o he
compa ison 90 mg e sus placebo (22).
Las ly, he PRIDE-HD s udy ec ui ed 408 pa icipan s
wi h mani es HD, a leas 25 poin s on he UHDRS TMS
and 90% o less in he UHDRS independence sco e (IS),
om 53 si es ac oss 12 coun ies in Eu ope, No h Ame ica
and Aus alia. Follow-up was 53 weeks, and ou doses o
p idopidine (45, 67.5, 90 and 112.5 mg daily) we e es ed
agains placebo. The p ima y ou come was changed in
he UHDRS TMS a 26 weeks and ailed o be achie ed.
Explo a o y analyses o all es ed dosages showed simila
esul s a 52 weeks. Explo a o y analyses e ealed an e ec
on he UHDRS o al unc ional capaci y (TFC) in he 45 mg
a m. Subg oup pos -hoc es s ound his e ec o be mo e
e iden in pa icipan s in ea lie disease s ages (24).
To summa ise, he clinical de elopmen pipeline o
p idopidine began wi h a nega i e, ela i ely small and
sho -las ing ial aimed a cogni ion bu wi h in e es ing
indings on a olun a y mo emen s’ seconda y ou come. I
was ollowed by wo well-powe ed bu also nega i e ials
designed o in es iga e he e ec s on olun a y mo emen s.
Bo h showed di e ences in a semi-s uc u ed neu ological
exam scale a he highes es ed dosage (90 mg daily). A
o h well-powe ed ial was deployed o in es iga e he
e ec s on mo o signs ac oss a ange o dosages. The
ial was also nega i e, and none o he dosages shaped
compelling di e ences a e 6 mon hs and 1 yea on mo o
signs, bu explo a o y in es iga ions disclosed an e ec
on unc ional capaci y wi h low-dose p idopidine in ea ly
disease.
The cumula i e e idence om hese ou ials seems
o suppo ha p idopidine is ela i ely sa e and well-
ole a ed. The a p io i hypo hesis ha i has an e ec on
he cogni i e ea u es o HD has been p o en alse. The
indings on mo o e ec s lea n om he ea lies ials
we e no eplica ed in a la ge buil - o -pu pose ial. We e
he i s ones spu ious posi i e esul s s emming om
explo a o y analyses, o we e he esul s o he la e ials
jus un o una e? The in es iga o s blame an unexpec edly
high esponse by he placebo g oup in he p ima y
Figu e 1 P idopidine molecule.
Annals o T ansla ional Medicine, Vol 7, Suppl 8 Decembe 2019 Page 3 o 5
© Annals o T ansla ional Medicine. All igh s ese ed. Ann T ansl Med 2019;7(Suppl 8):S337 | h p://dx.doi.o g/10.21037/a m.2019.09.105
Table 1 Clinical ials’ cha ac e is ics
Name NCT N Design Popula ion Du a ion
(weeks) Ac i e a m(s) Compa a o P ima y
ou come
Seconda y/
explao a o y
ou comes
Sponso Resul s
Lundin
e al. 2010
(19)
N/A 58 RCT Mani es HD 4 P idopidine
50 mg/d (n=28)
Placebo
(n=30)
Weigh ed
cogni i e
sco e a
4 weeks*
Mo o ,
beha iou al, sleep,
cogni ion, sa e y
and ole abili y
Neu oSea ch
Sweden AB
NS ∆ in p ima y
ou come, and ∆ on
mMS (baseline
mMS ≥10)
Me maiHD
(20)
NCT00665223 437 RCT Mani es HD
(mMS ≥10)
26 P idopidine
45 (n=148) and
90 mg/d (n=145)
Placebo
(n=144)
mMS a
26 weeks
Mo o ,
beha iou al,
cogni ion, sa e y
and ole abili y
Neu oSea ch
A/S
NS ∆ in p ima y
ou come, and ∆ on
UHDRS TMS (90 mg/d)
and mMS (90 mg/d,
pe -p o ocol)
Squi ie i
e al. 2013
(21)
N/A 353 OLE Comple ion
o Me maiHD
26 P idopidine
90 mg/d (n=353)
N/A Sa e y and
ole abili y a
52 weeks**
Adhe ence Neu oSea ch
A/S
P idopidine is sa e and
well- ole a ed
HART (22) NCT00724048 227 RCT Mani es HD
(mMS ≥10)
12 P idopidine
20 (n=56), 45
(n=55) and
90 mg/d (n=58)
Placebo
(n=58)
mMS a
12 weeks
Mo o , unc ion,
beha iou al,
cogni ion, sa e y
and ole abili y
Neu oSea ch
A/S, Neu o-
Sea ch
Sweden AB
NS ∆ in p ima y
ou come, and ∆ on
UHDRS TMS (90 mg/d)
Open-HART
(23)
NCT01306929 118 OLE Comple ion
o HART
156 P idopidine
90 mg/d (n=118)
N/A Sa e y and
ole abili y a
156 weeks
Mo o and
unc ion
Te a
Pha maceu ical
Indus ies
P idopidine is sa e and
well- ole a ed
PRIDE-HD
(24)
NCT02006472 408 RCT Mani es HD
(TMS ≥25 &
IS ≤90)
52 P idopidine
45 (n=81), 67.5
(n=82), 90 (n=81),
and 112.5 mg/d
(n=82)
Placebo
(n=82)
TMS a
26 weeks
Mo o , unc ion,
beha iou al,
cogni ion, quali y
o li e, sa e y and
ole abili y
Te a
Pha maceu ical
Indus ies
NS ∆ in p ima y
ou come, ∆ on UHDRS
TMS (45 mg/d)
Open
PRIDE-HD
NCT02494778 248 OLE Comple ion
o PRIDE-HD
364 P idopidine
90 mg/d (ongo-
ing)
N/A Sa e y and
ole abili y a
364 weeks
N/A P ilenia S udy e mina ed bu
ye no epo ed
*, based on Symbol Digi Modali ies Tes , Ve bal Fluency Ca ego ical, S oop Colo Naming, S oop Wo d Reading and S oop In e e ence Tes ; **, double blinded phase
plus OLE; ∆, change. N/A, no applicable o a ailable; RCT, andomized con olled ial; HD, Hun ing on’s disease; NS, non-signi ican ; mMS, modi ied mo o sco e (UHDRS
TMS i ems 4–10 and 13–15); UHDRS TMS, Uni ied Hun ing on’s Disease Ra ing Scale o al mo o sco e; OLE, open-label ex ension.
Rod igues and Fe ei a. Con e ing pos -hoc indings in o p ima y ou comes
© Annals o T ansla ional Medicine. All igh s ese ed. Ann T ansl Med 2019;7(Suppl 8):S337 | h p://dx.doi.o g/10.21037/a m.2019.09.105
Page 4 o 5
ou come. Indeed by he end o he s udy pe iod, his was
he a m wi h he la ges e ec size. The sponso , Te a
Pha maceu ical Indus ies L d., ocused hei a en ion on
explo a o y and pos -hoc subg oup analyses concluding ha
“p idopidine demons a es slowing o p og ession o Hun ing on
disease in PRIDE-HD s udy as measu ed by To al Func ional
Capaci y”. A e spa ked c i icism om he clinical and
scien i ic communi y, awa e o he po en ial damages caused
by such in e p e a ions, he Eu opean Hun ing on’s Disease
Ne wo k oned down he sponso ’s s a emen explaining
ha “ his should no be misunde s ood as a demons a ion o
disease modi ica ion o o neu op o ec ion”.
While he e a e mul iple possible jus i ica ions o hese
esul s, one should always conside he possibili y ha
p idopidine, as any o he compound in de elopmen , may no
induce he hypo hesised clinical e ec . The cen al ne ous
sys em he apeu ic a ea has a low success a e om i s -in-
man o egis a ion o a ound 7–8% compa ing wi h he
g and mean o 11%, and o he he apeu ic a eas such as
ca dio ascula whe e he success a e is a ound 20% (25).
In neu ology, he d ug de elopmen pipeline pe o ms
app eciably poo ly in he phase III and egis a ion phases (25).
In HD only 2 molecules su i ed hese phases, and o e all
he success a e is e en lowe han ha o o he he apeu ic
a eas (5). Many easons ha e been hypo hesized o explain
such phenomenon: incomple e unde s anding o he disease
physiopa hology; weak associa ion be ween he he apeu ic
a ge , and he disease pa hogenesis and na u al his o y;
limi ed animal models; incomple e e alua ion o p eclinical
e ec s; subop imal pha macokine ic and pha macodynamic
cha ac e is ics; limi a ions o cu en s udy designs
(no bioma ke s, sho s udy du a ions); unen husias ic
comme cial in e es s, among o he s.
P idopidine is an example whe e se e al o hese ac o s
came in o play, hal ing he al eady low chances o i s -in-
man o egis a ion success. I is well s ablished ha only
a small p opo ion o science gene a es posi i e esul s,
including igo ous and well- epo clinical ials (26).
While he scien i ic milieu should ewa d p og ess, indus y
and esea che s a e o en mo i a ed by o he ac o s. As
emp ing as i may sound o ega d hese a e - he-e en
announcemen s ele an , his o y has hough us ha
hypo heses and new ials gene a ed by pos -hoc posi i e
esul s a e legi ima e bu may be w ong.
Unde s andably and in he absence o be e app oaches,
his s a egy is equen ly used ac oss medicine. P idopidine
seems unlikely o be clinically help ul o people wi h HD
bu we hope his s o y will each us abou he design o d ug
de elopmen p og ammes and wha o a oid in he u u e
in o de o deli e e icacious medicines and op imise d ug
de elopmen .
Acknowledgmen s
None.
Foo no e
Con lic s o In e es : The au ho s ha e no con lic s o in e es
o decla e.
E hical S a emen : The au ho s a e accoun able o all
aspec s o he wo k in ensu ing ha ques ions ela ed
o he accu acy o in eg i y o any pa o he wo k a e
app op ia ely in es iga ed and esol ed.
Re e ences
1. McColgan P, Tab izi SJ. Hun ing on's disease: a clinical
e iew. Eu J Neu ol 2018;25:24-34.
2. Rod igues FB, Ab eu D, Damásio J, e al. Su i al,
mo ali y, causes and places o dea h in a Eu opean
Hun ing on's disease p ospec i e coho . Mo Diso d Clin
P ac 2017;4:737-42.
3. Gusella JF, Wexle NS, Conneally PM, e al. A
polymo phic DNA ma ke gene ically linked o
Hun ing on's disease. Na u e 1983;306:234-8.
4. A no el gene con aining a inucleo ide epea ha
is expanded and uns able on Hun ing on's disease
ch omosomes. The Hun ing on's Disease Collabo a i e
Resea ch G oup. Cell 1993;72:971-83.
5. T a essa AM, Rod igues FB, Mes e TA, e al. Fi een
yea s o clinical ials in Hun ing on's disease: a e y low
clinical d ug de elopmen success a e. J Hun ing ons Dis
2017;6:157-63.
6. Rod igues FB, Fe ei a JJ, Wild EJ. Hun ing on's disease
clinical ials co ne : June 2019. J Hun ing ons Dis
2019;8:363-71.
7. Bachoud-Lé i AC, Fe ei a J, Massa R, e al.
In e na ional guidelines o he ea men o Hun ing on's
disease. F on Neu ol 2019;10:710.
8. Rod igues FB, Dua e GS, Cos a J, e al. Te abenazine
e sus deu e abenazine o Hun ing on's disease: wins o
dis an cousins? Mo Diso d Clin P ac 2017;4:582-5.
9. Rod igues FB, Dua e GS, Cos a J, e al. Me a- esea ch
me ics ma e : le e ega ding a icle "indi ec ole abili y
Annals o T ansla ional Medicine, Vol 7, Suppl 8 Decembe 2019 Page 5 o 5
© Annals o T ansla ional Medicine. All igh s ese ed. Ann T ansl Med 2019;7(Suppl 8):S337 | h p://dx.doi.o g/10.21037/a m.2019.09.105
compa ison o deu e abenazine and e abenazine o
Hun ing on disease". J Clin Mo Diso d 2017;4:19.
10. Tab izi SJ, Scahill RI, Owen G, e al. P edic o s o
pheno ypic p og ession and disease onse in p emani es
and ea ly-s age Hun ing on's disease in he TRACK-HD
s udy: analysis o 36-mon h obse a ional da a. Lance
Neu ol 2013;12:637-49.
11. Paulsen JS, Hayden M, S ou JC, e al. P epa ing o
p e en i e clinical ials: he P edic -HD s udy. A ch
Neu ol 2006;63:883-90.
12. Rod igues FB, Fe ei a JJ. O e all su i al and causes
o dea h in neu odegene a ion-an o e looked and
unde epo ed heme. JAMA Neu ol 2017;74:1379.
13. Mes e TA, Busse M, Da is AM, e al. Ra ing scales
and pe o mance-based measu es o assessmen o
unc ional abili y in Hun ing on's disease: c i ique and
ecommenda ions. Mo Diso d Clin P ac 2018;5:361-72.
14. Mes e TA, Ca lozzi NE, Ho AK, e al. Quali y o li e in
Hun ing on's disease: c i ique and ecommenda ions o
measu es assessing pa ien heal h- ela ed quali y o li e and
ca egi e quali y o li e. Mo Diso d 2018;33:742-9.
15. Mes e TA, Fo jaz MJ, Mahlknech P, e al. Ra ing scales
o mo o symp oms and signs in Hun ing on's disease:
c i ique and ecommenda ions. Mo Diso d Clin P ac
2018;5:111-7.
16. Mes e TA, an Duijn E, Da is AM, e al. Ra ing scales o
beha io al symp oms in Hun ing on's disease: c i ique and
ecommenda ions. Mo Diso d 2016;31:1466-78.
17. By ne LM, Rod igues FB, Johnson EB, e al. E alua ion o
mu an hun ing in and neu o ilamen p o eins as po en ial
ma ke s in Hun ing on's disease. Sci T ansl Med 2018.
doi: 10.1126/sci anslmed.aa 7108.
18. Landweh meye GB, Fi ze -A as CJ, Giuliano JD, e al.
Da a analy ics om en oll-HD, a global clinical esea ch
pla o m o Hun ing on's disease. Mo Diso d Clin P ac
2016;4:212-24.
19. Lundin A, Die ichs E, Haghighi S, e al. E icacy
and sa e y o he dopamine gic s abilize P idopidine
(ACR16) in pa ien s wi h Hun ing on's disease. Clin
Neu opha macol 2010;33:260-4.
20. de Yebenes JG, Landweh meye B, Squi ie i F, e al.
P idopidine o he ea men o mo o unc ion in
pa ien s wi h Hun ing on's disease (Me maiHD): a phase 3,
andomised, double-blind, placebo-con olled ial. Lance
Neu ol 2011;10:1049-57.
21. Squi ie i F, Landweh meye B, Reilmann R, e al. One-
yea sa e y and ole abili y p o ile o p idopidine in pa ien s
wi h Hun ing on disease. Neu ology 2013;80:1086-94.
22. Hun ing on S udy G oup HART In es iga o s. A
andomized, double-blind, placebo-con olled ial
o p idopidine in Hun ing on's disease. Mo Diso d
2013;28:1407-15.
23. McGa y A, Kiebu z K, Able V, e al. Sa e y and
explo a o y e icacy a 36 mon hs in open-HART, an
open-label ex ension s udy o p idopidine in Hun ing on's
disease. J Hun ing ons Dis 2017;6:189-99.
24. Reilmann R, McGa y A, G ache ID, e al. Sa e y and
e icacy o p idopidine in pa ien s wi h Hun ing on's
disease (PRIDE-HD): a phase 2, andomised, placebo-
con olled, mul icen e, dose- anging s udy. Lance
Neu ol 2019;18:165-76.
25. Kola I, Landis J. Can he pha maceu ical indus y educe
a i ion a es? Na Re D ug Disco 2004;3:711-5.
26. Muna ò MR, Nosek BA, Bishop DVM, e al. A mani es o
o ep oducible science. Na u e Human Beha iou
2017;1:0021.
Ci e his a icle as: Rod igues FB, Fe ei a JJ. The isks
o con e ing pos -hoc indings in o p ima y ou comes in
subsequen ials. Ann T ansl Med 2019;7(Suppl 8):S337. doi:
10.21037/a m.2019.09.105