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 30 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.


Im­age: Kristof­fer Trip­plaar for Sipa USA. AP Im­ages

UP­DAT­ED: In sur­prise switch, Bris­tol-My­ers is sell­ing off block­buster Ote­zla, promis­ing to com­plete Cel­gene ac­qui­si­tion — just lat­er

Apart from revealing its checkpoint inhibitor Opdivo blew a big liver cancer study on Monday, Bristol-Myers Squibb said its plans to swallow Celgene will require the sale of blockbuster psoriasis treatment Otezla to keep the Federal Trade Commission (FTC) at bay.

The announcement — which has potentially delayed the completion of the takeover to early 2020 — irked investors, triggering the New York-based drugmaker’s shares to tumble Monday morning in premarket trading.

Celgene’s Otezla, approved in 2014 for psoriasis and psoriatic arthritis, is a rising star. It generated global sales of $1.6 billion last year, up from the nearly $1.3 billion in 2017. Apart from the partial overlap of Bristol-Myers injectable Orencia, the company’s rival oral TYK2 psoriasis drug is in late-stage development, after the firm posted encouraging mid-stage data on the drug, BMS-986165, last fall. With Monday’s decision, it appears Bristol-Myers is favoring its experimental drug, and discounting Otezla’s future.

The move blindsided some analysts. Credit Suisse’s Vamil Divan noted just days ago:

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Novotech CEO Dr. John Moller

Novotech CRO Award­ed Frost & Sul­li­van Best Biotech CRO Asia-Pa­cif­ic 2019

Known in the in­dus­try as the Asia-Pa­cif­ic CRO, Novotech is now lead CRO ser­vices provider for the grow­ing num­ber of in­ter­na­tion­al biotechs se­lect­ing the re­gion for their stud­ies.

Re­flect­ing this Asia-Pa­cif­ic growth, Novotech staff num­bers are up 20% since De­cem­ber 2018 to 600 in-house clin­i­cal re­search peo­ple across a full range of ser­vices, across the re­gion.

Novotech’s ca­pa­bil­i­ties have been rec­og­nized by an­a­lysts like Frost & Sul­li­van, most re­cent­ly with the pres­ti­gious Asia-Pa­cif­ic CRO Biotech of the year award for best prac­tices in clin­i­cal re­search for biotechs for the fifth year. See oth­er awards here.

Suf­fer­ing No­var­tis part­ner Cona­tus is pack­ing it in on NASH af­ter a se­ries of un­for­tu­nate tri­al events

The NASH par­ty is over at No­var­tis-backed Cona­tus. And this time they’re turn­ing off the lights.

More than 2 years af­ter No­var­tis sur­prised the biotech in­vest­ment com­mu­ni­ty with its $50 mil­lion up­front and promise of R&D sup­port to part­ner with the lit­tle biotech on NASH — ig­nit­ing a light­ning strike for the share price — Cona­tus $CNAT is back with the lat­est bit­ter tale to tell about em­ri­c­as­an, which once in­spired con­fi­dence at the phar­ma gi­ant.

Fol­low­ing news of job cuts in Eu­ro­pean R&D ops, Sanofi con­firms it’s of­fer­ing US work­ers an 'ear­ly ex­it'

Ear­li­er in the week we learned that Sanofi was bring­ing out the bud­get ax to trim 466 R&D jobs in Eu­rope, re­tool­ing its ap­proach to car­dio as re­search chief John Reed beefed up their work in can­cer and gene ther­a­pies. And we’re end­ing the week with news that the phar­ma gi­ant has al­so been qui­et­ly re­duc­ing staff in the US, tar­get­ing hun­dreds of jobs as the com­pa­ny push­es vol­un­tary buy­outs with a fo­cus on R&D sup­port ser­vices.

Bris­tol-My­ers star Op­di­vo fails sur­vival test in a matchup with Nex­avar aimed at shak­ing up the big HCC mar­ket

Bris­tol-My­ers Squibb has suf­fered an­oth­er painful set­back in its years-long quest to ex­pand the reach of Op­di­vo. The phar­ma gi­ant this morn­ing not­ed that their Check­mate-459 study com­par­ing Op­di­vo with Bay­er’s Nex­avar in front­line cas­es of he­pa­to­cel­lu­lar car­ci­no­ma — the most com­mon form of liv­er can­cer — failed to hit the pri­ma­ry end­point on over­all sur­vival.

This was a sig­nif­i­cant mile­stone in Bris­tol-My­ers’ tal­ly of PD-1 cat­a­lysts this year. Nex­avar (so­rafenib) has been the stan­dard of care in front­line HCC for the past decade, though Op­di­vo has been mak­ing head­way in sec­ond-line HCC cas­es, where it’s go­ing toe-to-toe with Bay­er’s Sti­var­ga (re­go­rafenib) af­ter re­cent ap­provals shook up the mar­ket.

Bet­ter than Am­bi­en? Min­er­va soars on PhI­Ib up­date on sel­torex­ant for in­som­nia

A month af­ter roil­ing in­vestors with what skep­tics dis­missed as cher­ry pick­ing of its de­pres­sion da­ta, Min­er­va is back with a clean slate of da­ta from its Phase IIb in­som­nia tri­al.

In a de­tailed up­date, the Waltham, MA-based biotech said sel­torex­ant (MIN-202) hit both the pri­ma­ry and sev­er­al sec­ondary end­points, ef­fec­tive­ly im­prov­ing sleep in­duc­tion and pro­long­ing sleep du­ra­tion. In­ves­ti­ga­tors made a point to note that the ef­fects were con­sis­tent across the adult and el­der­ly pop­u­la­tions, with the lat­ter more prone to the sleep dis­or­der.

Gene ther­a­py biotech sees its stock rock­et high­er on promis­ing re­sults for rare cas­es of but­ter­fly dis­ease

Shares of Krys­tal Biotech took off this morn­ing $KRYS af­ter the lit­tle biotech re­port­ed promis­ing re­sults from its gene ther­a­py to treat a rare skin dis­ease called epi­der­mol­y­sis bul­losa.

Fo­cus­ing on an up­date with 4 new pa­tients, re­searchers spot­light­ed the suc­cess of KB103 in clos­ing some stub­born wounds. Krys­tal says that of 4 re­cur­ring and 2 chron­ic skin wounds treat­ed with the gene ther­a­py, the KB103 group saw the clo­sure of 5. The 6th — a chron­ic wound, de­fined as a wound that had re­mained open for more than 12 weeks — was par­tial­ly closed. That brings the to­tal so far to 8 treat­ed wounds, with 7 clo­sures.

Ab­b­Vie gets a green light to re­sume re­cruit­ing pa­tients for one myelo­ma study — but Ven­clex­ta re­mains un­der a cloud

Three months af­ter reg­u­la­tors at the FDA forced Ab­b­Vie to halt en­rolling pa­tients in its tri­als of a com­bi­na­tion us­ing Ven­clex­ta (vene­to­clax) to treat drug-re­sis­tant cas­es of mul­ti­ple myelo­ma, the agency has green-light­ed the re­sump­tion of one of those stud­ies, while keep­ing the rest on the side­lines.

The CANO­VA (M13-494) study can now get back in busi­ness re­cruit­ing pa­tients to test the drug for a pop­u­la­tion that shares a par­tic­u­lar ge­net­ic bio­mark­er. To get that per­mis­sion, Ab­b­Vie — which is part­nered with Roche on this pro­gram — was forced to re­vise the pro­to­col, mak­ing un­spec­i­fied changes in­volv­ing risk mit­i­ga­tion mea­sures, pro­to­col-spec­i­fied guide­lines and an up­dat­ed fu­til­i­ty cri­te­ria.

Dean Hum. Nasdaq via YouTube

Gen­fit goes to Chi­na with a deal worth up to $228M for NASH drug

Fresh off the high of its Nas­daq IPO de­but, and the low of com­par­isons to Cymabay — whose NASH drug re­cent­ly stum­bled — Gen­fit on Mon­day un­veiled an up to $228 mil­lion deal with transpa­cif­ic biotech Terns Phar­ma­ceu­ti­cals to de­vel­op its flag­ship ex­per­i­men­tal liv­er drug — elafi­bra­nor — in Greater Chi­na.

The deal comes more than a week af­ter Gen­fit $GN­FT is­sued a fiery de­fense of its dual PPAR ag­o­nist elafi­bra­nor, when com­peti­tor Cymabay’s PPARδ ag­o­nist, se­ladel­par, fiz­zled in a snap­shot of da­ta from an on­go­ing mid-stage tri­al. The main goal at the end of 12 weeks was for se­ladel­par to in­duce a sta­tis­ti­cal­ly sig­nif­i­cant im­prove­ment in liv­er fat con­tent, but da­ta showed that pa­tients on the place­bo ac­tu­al­ly per­formed bet­ter.