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

Brian Kaspar. AveXis via Twitter

AveX­is sci­en­tif­ic founder fires back at No­var­tis CEO Vas Narasimhan, 'cat­e­gor­i­cal­ly de­nies any wrong­do­ing'

Brian Kaspar’s head was among the first to roll at Novartis after company execs became aware of the fact that manipulated data had been included in its application for Zolgensma, now the world’s most expensive therapy.

But in his first public response, the scientific founder at AveXis — acquired by Novartis for $8.7 billion — is firing back. And he says that not only was he not involved in any wrongdoing, he’s ready to defend his name as needed.

I reached out to Brian Kaspar after Novartis put out word that he and his brother Allen had been axed in mid-May, two months after the company became aware of the allegations related to manipulated data. His response came back through his attorneys.

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We­bi­nar: Re­al World End­points — the brave new world com­ing in build­ing fran­chise ther­a­pies

Several biopharma companies have been working on expanding drug labels through the use of real world endpoints, combing through the data to find evidence of a drug’s efficacy for particular indications. But we’ve just begun. Real World Evidence is becoming an important part of every clinical development plan, in the soup-through-nuts approach used in building franchises.

I’ve recruited a panel of 3 top experts in the field — the first in a series of premium webinars — to look at the practical realities governing what can be done today, and where this is headed over the next few years, at the prodding of the FDA.


ZHEN SU — Merck Serono’s Senior Vice President and Global Head of Oncology


ELLIOTT LEVY — Amgen’s Senior Vice President of Global Development


CHRIS BOSHOFF — Pfizer Oncology’s Chief Development Officer

A premium subscription to Endpoints News is required to attend this webinar. Please upgrade to either an Insider or Enterprise plan for access. Already have Endpoints Premium? Please sign-in below. You can contact our Subscriptions team at help@endpointsnews.com with any issues.

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Bob Smith, Pfizer

Pfiz­er is mak­ing a $500M state­ment to­day: Here’s how you be­come a lead play­er in the boom­ing gene ther­a­py sec­tor

Three years ago, Pfizer anted up $150 million in cash to buy Bamboo Therapeutics in Chapel Hill, NC as it cautiously stuck a toe in the small gene therapy pool of research and development.

Company execs followed up a year later with a $100 million expansion of the manufacturing operations they picked up in that deal for the UNC spinout, which came with $495 million in milestones.

And now they’re really going for it.

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SEC calls out lit­tle Ther­a­peu­tic­sMD for its in­sid­er con­tacts with an­a­lysts to boost share price, then halt rout

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In two instances in June and July of 2017, TherapeuticsMD allegedly violated the Regulation Fair Disclosure rule by sharing material information with certain sell-side analysts and not the public, resulting in a more favorable stock move than otherwise would be expected.

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Therapists Marcela Ot'alora and Bruce Poulter are trained to conduct MDMA-assisted psychotherapy. In this reenactment, they demonstrate how they help guide and watch over a patient who is revisiting traumatic memories while under the influence of MDMA. (Photo: Multidisciplinary Association for Psychedelic Studies)

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The first time Lori Tipton tried MDMA, she was skeptical it would make a difference.

“I really was, at the beginning, very nervous,” Tipton said.

MDMA is the main ingredient in the club drug known as ecstasy or molly. But Tipton wasn’t taking pills sold on the street to get high. She was trying to treat her post-traumatic stress disorder by participating in a clinical trial.

After taking a dose of pure MDMA, Tipton lay in a quiet room with two specially trained psychotherapists. They sat next to her as she recalled some of her deepest traumas, such as discovering her mother’s body after Tipton’s mother killed two people and then herself in a murder-suicide.

Video: Putting the AI in R&D — with Badhri Srini­vasan, Tony Wood, Rosana Kapeller, Hugo Ceule­mans, Saurabh Sa­ha and Shoibal Dat­ta

During BIO this year, I had a chance to moderate a panel among some of the top tech experts in biopharma on their real-world use of artificial intelligence in R&D. There’s been a lot said about the potential of AI, but I wanted to explore more about what some of the larger players are actually doing with this technology today, and how they see it advancing in the future. It was a fascinating exchange, which you can see here. The transcript has been edited for brevity and clarity. — John Carroll

UP­DAT­ED: As­traZeneca’s Imfinzi/treme com­bo strikes out — again — in lung can­cer. Is it time for last rites?

AstraZeneca bet big on the future of their PD-L1 Imfinzi combined with the experimental CTLA-4 drug tremelimumab. But once again it’s gone down to defeat in a major Phase III study — while adding damage to the theory involving targeting cancer with a high tumor mutational burden.

Early Wednesday the pharma giant announced that their NEPTUNE study had failed, with the combination unable to beat standard chemo at overall survival in high TMB cases of advanced non-small cell lung cancer. We won’t get hard data until later in the year, but the drumbeat of failures will call into question what — if any — future this combination can have left.

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Ted Ashburn. Oncorus

Cowen, Per­cep­tive lead $79.5M Se­ries B for 's­tand­out' biotech shep­herd­ing on­colyt­ic virus to clin­ic

As several Big Pharma players secure biotech partners in the oncolytic virus space for new immuno-oncology combos, Cowen and Perceptive Advisors have come out with their own bet on a startup that promises to shine.

The marquee investors are joining MPM, Deerfield, Celgene, Astellas, Arkin and UBS in backing the drug developer, Oncorus, which will now deploy the $79.5 million in Series B cash toward clinical development of its lead program. Other new investors include Surveyor Capital, Sphera Funds, IMM Investment, QUAD Investment Management, UTC Investment, SV Investment Corp and Shinhan Investment-Private Equity, the last five of which are Korean-based funds.

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