Sarep­ta's Ex­ondys 51 is not cost-ef­fec­tive, nor par­tic­u­lar­ly ben­e­fi­cial for DMD pa­tients — ICER

Par­ents with chil­dren suf­fer­ing from Duchenne mus­cu­lar dy­s­tro­phy (DMD) — a rare, pro­gres­sive mus­cle wast­ing dis­ease that dis­pro­por­tion­ate­ly af­fects young boys — cheered in 2016 when Sarep­ta Ther­a­peu­tics’ Ex­ondys 51 (eteplirsen) was con­tro­ver­sial­ly ap­proved by the FDA, un­der pres­sure from pa­tient ad­vo­cates and de­spite stiff op­po­si­tion from with­in and out­side the agency. Crit­ics lam­bast­ed the agency’s de­ci­sion, cit­ing in­suf­fi­cient da­ta — and now, an in­creas­ing­ly in­flu­en­tial ICER has con­curred: The un­der­ly­ing ev­i­dence sup­port­ing the drug is sparse, and giv­en its cur­rent pric­ing, it is cer­tain­ly not cost-ef­fec­tive.

There are rough­ly 6,000 young boys suf­fer­ing from DMD — caused by the ab­sence of dy­s­trophin, a pro­tein that helps keep mus­cle cells in­tact — in the Unit­ed States. Symp­toms tend to kick in and pro­gres­sive­ly wors­en be­tween the ages of 3 to 5, lead­ing the pa­tient to be typ­i­cal­ly wheel­chair-bound by their ear­ly teens. Even­tu­al­ly, pa­tients suc­cumb to the dis­ease by their 30s. Cor­ti­cos­teroids, which work by di­min­ish­ing in­flam­ma­tion and lim­it­ing the im­mune sys­tem’s ac­tiv­i­ty, are com­mon­ly used to treat DMD.

The gener­ic steroid pred­nisone is al­so fre­quent­ly used to treat DMD. In 2017, the cor­ti­cos­teroid de­flaza­cort, brand­ed Em­flaza, was al­so sanc­tioned FDA ap­proval, with an eye-pop­ping $89,000-per-pa­tient an­nu­al price tag by Marathon Phar­ma­ceu­ti­cals. Marathon did not in­vent the drug, and pre­vi­ous­ly US pa­tients had been able to im­port it for as lit­tle as $1,000. Un­der fire for its pric­ing, Marathon agreed to be ac­quired by PTC Ther­a­peu­tics $PTCT, which pledged to re­duce the price.

ICER eval­u­at­ed the ef­fi­ca­cy, safe­ty and cost-ef­fec­tive­ness of four treat­ments, in its draft re­port on Wednes­day. It looked at the steroids de­flaza­cort and pred­nisone — as well as the ex­on-skip­ping drugs: the ap­proved eteplirsen and the ex­per­i­men­tal golodirsen (both come from Sarep­ta $SRPT, and each treat­ment is de­signed to treat a dif­fer­ent sub­set of DMD pa­tients).

Over­all, the ev­i­dence sup­port­ing each of the four treat­ments is lack­ing, and their im­pact on pa­tients un­clear, ICER found.

De­spite ev­i­dence that cor­ti­cos­teroid treat­ment ben­e­fits all DMD pa­tients, the “op­ti­mal dos­ing…and du­ra­tion of ther­a­py re­main un­clear. Rel­a­tive­ly small clin­i­cal tri­als have pro­vid­ed on­ly short-term ef­fi­ca­cy da­ta, even though long-term use…is the norm,” ICER re­view­ers said. “Al­though ob­ser­va­tion­al stud­ies have pro­vid­ed longer-term da­ta, un­cer­tain­ty about the nat­ur­al his­to­ry of the dis­ease, lack of con­sis­tent dos­ing and out­come mea­sures, and a pauci­ty of com­par­i­son da­ta be­tween cor­ti­cos­teroids leave a sub­stan­tial gap in un­der­stand­ing the ef­fi­ca­cy and ad­verse ef­fects of long term steroid ther­a­py, par­tic­u­lar­ly with re­spect to dif­fer­ences be­tween de­flaza­cort and pred­nisone.”

Ob­ser­va­tion­al — but in­con­sis­tent — da­ta sug­gests there may be some greater ben­e­fit on mo­tor func­tion with de­flaza­cort, and the mag­ni­tude of the ben­e­fits may be small, re­view­ers said, adding that de­flaza­cort has not been shown to im­prove pul­monary func­tion out­comes com­pared with pred­nisone. Giv­en the side-ef­fects of cor­ti­cos­teroids, de­flaza­cort has been in the spot­light for its po­ten­tial of small­er ad­verse-events: Un­de­sired weight gain ap­pears to be greater with pred­nisone than de­flaza­cort, while cataract for­ma­tion and re­duc­tion in growth ap­pear to be greater with de­flaza­cort, the non-prof­it found.

For ex­on-skip­ping ther­a­pies — which are de­signed to work by skip­ping the delet­ed ex­on, al­low­ing the re­main­der to join and form a com­plete gene to boost dy­s­trophin pro­duc­tion — da­ta are “lim­it­ed to sur­ro­gate out­comes from very small tri­als, and the thresh­old for dy­s­trophin ex­pres­sion suf­fi­cient for mean­ing­ful clin­i­cal im­prove­ment has yet to be de­fined,” re­view­ers said, not­ing that over­all, eteplirsen and golodirsen treat­ment re­sults “in very small in­creas­es in dy­s­trophin.”

Ex­treme­ly lim­it­ed ran­dom­ized da­ta for eteplirsen did not show im­prove­ments in the six-minute walk test, ver­sus place­bo — al­though no func­tion­al out­come re­sults have been re­port­ed for golodirsen. The safe­ty pro­file of eteplirsen ap­pears to be be­nign, and no safe­ty da­ta are yet avail­able golodirsen, they added.

ICER con­duct­ed its cost-ef­fec­tive­ness analy­sis us­ing qual­i­ty-ad­just­ed-life-years (QALYs), a mea­sure of the state of health of a per­son or group in which the ben­e­fits — in terms of length of life — are ad­just­ed to re­flect the qual­i­ty of life.

DMD drug dos­ing is weight-based, and ICER used to cal­cu­late cost-ef­fec­tive­ness us­ing an­nu­al cost es­ti­mates for a 40 kg pa­tient.

Source: ICER

Click on the im­age to see the full-sized ver­sion

Based on the avail­able ev­i­dence, when com­pared to pred­nisone, de­flaza­cort is pro­ject­ed to have very high costs rel­a­tive to its ben­e­fits, ICER said.

The ICER re­port does not ac­cu­rate­ly rep­re­sent Em­flaza’s re­al val­ue, a PTC spokesper­son told End­points News in an emailed state­ment. “ICER’s re­liance on the QALY stan­dard is not par­tic­u­lar­ly use­ful for eval­u­at­ing the ac­tu­al needs of in­di­vid­ual pa­tients with rare dis­or­ders and the im­pact Em­flaza has on the lives of pa­tients and fam­i­lies…”.

In ad­di­tion, “(P)reser­va­tion of am­bu­la­tion and up­per ex­trem­i­ty func­tion were not re­flect­ed in the cost analy­sis giv­en the da­ta demon­strat­ed that pa­tients tak­ing de­flaza­cort were able to have near­ly an ad­di­tion­al 3 years of am­bu­la­tion over pa­tients tak­ing pred­nisone,” the spokesper­son added.

For eteplirsen, at its cur­rent price, no plau­si­ble treat­ment ef­fects were found to make this treat­ment reach cost-ef­fec­tive­ness thresh­olds be­low the $150,000 bench­mark, per QALY gained. Sim­i­lar re­sults are ex­pect­ed of golodirsen if it is priced sim­i­lar to eteplirsen, ICER con­clud­ed.

Sarep­ta, un­sur­pris­ing­ly, was not hap­py with ICER’s find­ings. In a state­ment, the com­pa­ny called the in­sti­tute’s ap­proach “fa­tal­ly flawed” as it re­lates to rare and ge­net­ic dis­ease and ill-equipped to “ac­com­mo­date the FDA ac­cel­er­at­ed ap­proval process”.

“If the goal is to sup­port a cost ef­fec­tive­ness ap­proach that pro­motes true in­no­va­tion while act­ing as a watch­dog for waste in the sys­tem, ICER is fail­ing,” Sarep­ta said on Thurs­day.

ICER’s DMD draft re­port is now open to pub­lic com­ment un­til June 18. Akin to NICE in the UK, ICER is an in­de­pen­dent body that an­a­lyzes the cost-ef­fec­tive­ness of drugs and oth­er med­ical ser­vices in the Unit­ed States. Un­like NICE, though, ICER is not gov­ern­ment-af­fil­i­at­ed, but its de­ter­mi­na­tions are be­com­ing in­creas­ing­ly piv­otal with re­spect to pay­ers and law­mak­ers.


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