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.


Im­age: Kristof­fer Trip­plaar for Sipa USA. AP Im­ages

Dan Skovronsky, Eli Lilly CSO

UP­DAT­ED: An­a­lysts are quick to pan Eli Lil­ly's puz­zling first cut of pos­i­tive clin­i­cal da­ta for its Covid-19 an­ti­body

Eli Lilly spotlighted a success for one of 3 doses of their closely-watched Covid-19 antibody drug Wednesday morning. But analysts quickly highlighted some obvious anomalies that could come back to haunt the pharma giant as it looks for an emergency use authorization to launch marketing efforts.

The pharma giant reported that LY-CoV555, developed in collaboration with AbCellera, significantly reduced the rate of hospitalization among patients who were treated with the antibody. The drug arm of the study had a 1.7% hospitalization rate, compared to 6% in the control group, marking a 72% drop in risk.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 90,300+ biopharma pros reading Endpoints daily — and it's free.

UP­DAT­ED #ES­MO20: Trodelvy da­ta show that Gilead­'s $21B buy­out may have been worth the big pre­mi­um

Gilead CEO Dan O’Day has been on a shopping spree. And while some analysts gawked at the biotech’s recent $21 billion Immunomedics buyout, new data released at virtual ESMO 2020 suggest the acquisition may have been worth the hefty price.

The deal, announced last weekend, will give California-based Gilead $GILD Trodelvy, which was recently approved for metastatic triple-negative breast cancer (mTNBC).

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 90,300+ biopharma pros reading Endpoints daily — and it's free.

#ES­MO20: As­traZeneca bur­nish­es Tagris­so's ad­ju­vant NSCLC pro­file with 'un­prece­dent­ed' re­duc­tion in brain mets. Can they win over skep­tics?

When AstraZeneca trumpeted “momentous” and “transformative” results for Tagrisso earlier this year at ASCO, some practitioners threw cold water on the ADAURA fervor. Sure, the disease-free survival data look good, but overall survival is the endpoint that matters when it comes to choosing adjuvant therapy for non-small cell lung cancer patients, the experts said.

The OS data still aren’t here, but AstraZeneca is back at ESMO to bolster their case with a look at brain metastasis data.

Exelixis CEO Michael Morrissey (file photo)

#ES­MO20: Look out Mer­ck. Bris­tol My­ers and Ex­elix­is stake out their com­bo’s claim to best-in-class sta­tus for front­line kid­ney can­cer

Now that the PD-(L)1 checkpoints are deeply entrenched in the oncology market, it’s time to welcome a wave of combination therapies — beyond chemo — looking to extend their benefit to larger numbers of patients. Bristol Myers Squibb ($BMY} and Exelixis {EXEL} are close to the front of that line.

Today at ESMO the collaborators pulled the curtain back on some stellar data for their combination of Opdivo (the PD-1) and Cabometyx (the TKI), marking a significant advance for the blockbuster Bristol Myers franchise while offering a big leg up for the team at Exelixis.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 90,300+ biopharma pros reading Endpoints daily — and it's free.

Donald Trump and White House chief of staff Mark Meadows, before boarding Marine One (Getty Images)

Pric­ing deal col­laps­es over Big Phar­ma's re­fusal to is­sue $100 'cash card­s' be­fore the elec­tion — re­port

Late in August, as negotiations on a pricing deal with President Trump reached a boiling point, PhRMA president Stephen Ubl sent an email update to the 34 biopharma chiefs that sit on his board. He wrote that if the industry did not agree to pay for a $100 “cash card” sent to seniors before November, White House chief of staff Mark Meadows was going to tell the news media Big Pharma was refusing to “share the savings” with the elderly — and that all of the blame for failed drug pricing negotiations would lie squarely on the industry.

#ES­MO20: Alk­er­mes of­fers their first snap­shot of a ben­e­fit for their next-gen IL-2 drug. But why did 1 pa­tient starve to death?

Everyone in the cancer R&D arena is looking to build new franchises around better drugs and combos. And one busy pocket of that space is centered entirely on creating an IL-2 drug that can be as effective as the original without the toxicity that damned it to the sidelines.

Alkermes $ALKS formally tossed its hat into the ring of contenders at virtual ESMO today, highlighting the first glimpse of efficacy for their candidate, ALKS 4230, as both a monotherapy as well as in combination with Merck’s Keytruda.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 90,300+ biopharma pros reading Endpoints daily — and it's free.

Albert Bourla (Photo by Steven Ferdman/Getty Images)

Pfiz­er match­es Mod­er­na with their full Covid-19 tri­al blue­print — As­traZeneca says it will un­veil its pro­to­col 'short­ly'

Yesterday, after sustained public pressure as Moderna released its Phase III Covid-19 trial blueprint, Pfizer released its own full trial design for their vaccine trials. The move was designed to boost transparency and shore up public trust in the vaccines, but it also revealed differences in how the two companies are approaching the much-watched studies while failing to satisfy the demands of the fiercest advocates for transparency.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 90,300+ biopharma pros reading Endpoints daily — and it's free.

#ES­MO20: Re­gen­eron, Sanofi eye an­oth­er first for their PD-1 con­tender Lib­tayo with promis­ing da­ta for on­col­o­gy niche

Regeneron and Sanofi took another step forward in the long march towards a greatly expanded market for their late-bloomer PD-1 checkpoint Libtayo.

The two occasional allies posted an objective response rate of 31% for Libtayo among 84 patients suffering from advanced cases of basal cell carcinoma at virtual ESMO. That spotlights progress for 26 patients, 5 of whom had a complete response. The data also reflect a boost in the number of responses seen from the last cut of the numbers.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 90,300+ biopharma pros reading Endpoints daily — and it's free.

Albert Bourla, Pfizer CEO (Steven Ferdman/Getty Images)

Pfiz­er ex­ecs con­fi­dent­ly tap their top 10 block­busters-to-be. But what are the chances of sur­viv­ing PhI­II, let alone hit­ting these big peak sales es­ti­mates?

Pfizer’s top executive team doesn’t lack for confidence.

Where many Big Pharmas would be reluctant to put a peak sales figure on their late-stage drugs, Pfizer CEO Albert Bourla has shrugged off the usual diffidence to outline where the pharma giant expects to get $15 billion-plus.

The list, outlined this week during their investor presentations, is topped by 3 drugs in the $3 billion-plus peak sales category. They are:

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 90,300+ biopharma pros reading Endpoints daily — and it's free.