Once spurned, Am­gen wins the FDA over with its bone-build­ing os­teo­poro­sis drug Eveni­ty

El­liott Levy (Am­gen)

As ex­pect­ed, Am­gen’s once-re­ject­ed os­teo­poro­sis drug has scored FDA ap­proval, paving the way for a new bone-build­ing op­tion for the one in two post­menopausal women in the Unit­ed States whose weak­ened bones make them high­ly sus­cep­ti­ble to frac­tur­ing.

Ro­mosozum­ab is to be sold un­der the brand name Eveni­ty. It func­tions pre­dom­i­nant­ly as a bone an­a­bol­ic agent that stim­u­lates bone growth by in­hibit­ing a pro­tein called scle­rostin, which ceas­es the pro­duc­tion of bone and en­hances its break­down. The cur­rent stan­dard of care for the 10 mil­lion Amer­i­cans with os­teo­poro­sis is a fam­i­ly of drugs called bis­pho­s­pho­nates — such as al­en­dronate (orig­i­nal­ly sold un­der the brand name Fos­amax by Mer­ck) — that thwart cells called os­teo­clasts that break down bone tis­sue but do not re­build it.

In the US, one in two women over the age of 50 will ex­pe­ri­ence an os­teo­porot­ic frac­ture — an in­ci­dence that sur­pass­es that of heart at­tack, stroke and breast can­cer com­bined, ac­cord­ing to the Na­tion­al Os­teo­poro­sis Foun­da­tion, which es­ti­mates os­teo­poro­sis will be re­spon­si­ble for three mil­lion frac­tures re­sult­ing in $25.3 bil­lion in costs by 2025.

Eveni­ty was test­ed in three late-stage stud­ies: the 7,180-pa­tient place­bo-con­trolled FRAME study in post­menopausal women with os­teo­poro­sis; the 4,093-pa­tient ARCH study in post­menopausal women in os­teo­poro­sis, which test­ed the drug against al­en­dronate; and the 245-pa­tient place­bo-con­trolled BRIDGE study in men with os­teo­poro­sis. All three piv­otal stud­ies showed the mon­o­clon­al an­ti­body was ef­fec­tive, but se­ri­ous CV ad­verse events were ob­served in the ARCH tri­al, which prompt­ed the FDA to orig­i­nal­ly is­sue a com­plete re­sponse let­ter to de­ny ap­proval in post­menopausal women with os­teo­poro­sis.

Tak­ing in­to ac­count the CV sig­nal and feed­back from the FDA about the pauci­ty of an­a­bol­ic agents, Am­gen and Bel­gian part­ner UCB re-sub­mit­ted an ap­pli­ca­tion to mar­ket drug last year, but for a nar­row­er pa­tient pop­u­la­tion: post­menopausal women with os­teo­poro­sis who car­ry a high risk of frac­ture, or pa­tients who have failed or are in­tol­er­ant to ex­ist­ing os­teo­poro­sis ther­a­pies.

In an out­side meet­ing of ex­perts to the FDA in Jan­u­ary, pan­elists large­ly backed the drug, de­spite the CV con­cerns. The FDA ac­knowl­edged the CV is­sue in Eveni­ty’s la­bel by high­light­ing that the use of the drug may in­crease the risk of heart at­tack, stroke and car­dio­vas­cu­lar death in a black box warn­ing, and asked the man­u­fac­tur­ers to con­duct a post-mar­ket­ing five-year ob­ser­va­tion­al fea­si­bil­i­ty study.

“There is no doubt that Eveni­ty is the most po­tent an­a­bol­ic agent for bone, but is al­so like­ly to see rel­a­tive­ly lim­it­ed use giv­en a tar­get pop­u­la­tion with sig­nif­i­cant un­der­ly­ing risk for such CV events al­ready,” SVB Leerink’s Ge­of­frey Porges said.

Even with the lim­it­ed use of the drug in con­text of the CV risk, Eveni­ty rep­re­sents a more than $500 mil­lion world­wide op­por­tu­ni­ty, Jef­feries an­a­lyst Michael Yee said, not­ing that Lil­ly’s os­teo­poro­sis drug For­teo car­ries a black box warn­ing high­light­ing the risk of can­cer and has been rak­ing in $1.5+ bil­lion in the last two years.

“Al­though Eveni­ty showed greater bone min­er­al den­si­ty im­prove­ments than For­teo, we be­lieve the black box warn­ing for CV risk will lim­it up­take to the high­est-risk pa­tients with mul­ti­ple pri­or frac­tures,” BMO Cap­i­tal Mar­kets an­a­lyst Do Kim wrote in a note, ex­plain­ing that al­though For­teo and Tym­los (an­oth­er bone an­a­bol­ic agent, sold by Ra­dius Health) car­ry black box warn­ings for os­teosar­co­ma, the find­ings were in an­i­mal stud­ies and not ver­i­fied in hu­mans.

“Both For­teo and Tym­los re­quire dai­ly dos­ing, com­pared to Eveni­ty’s once-month­ly. We could see pref­er­ence for Eveni­ty in pa­tients with­out pri­or CV events, giv­en less fre­quent dos­ing and as­sum­ing a low­er price,” Kim said.

Al­though Eveni­ty’s la­bel re­flects its su­pe­ri­or bone-build­ing ef­fect, clin­i­cal da­ta showed the treat­ment did not trans­late in­to re­duced frac­ture risk for non-ver­te­bral frac­tures (e.g., hip and wrist frac­tures) which are the most con­se­quen­tial com­pli­ca­tions of os­teo­poro­sis, Porges point­ed out. “Tym­los and For­teo had a sig­nif­i­cant rel­a­tive risk re­duc­tion for non-ver­te­bral frac­tures of 43-53%, while Eveni­ty had a non-sig­nif­i­cant re­duc­tion of 25%.”

Pro­lia, Am­gen’s $AMGN 2018-ap­proved os­teo­poro­sis treat­ment is in­tend­ed for chron­ic treat­ment, as it works by in­creas­ing bone mass for as long as the pa­tient re­ceives it. Eveni­ty is in­tend­ed for short term use —  12 months — to rapid­ly in­crease bone min­er­al den­si­ty and re­duce frac­ture risk in pa­tients with im­mi­nent risk of frac­ture, it is then fol­lowed by an an­tire­sorp­tive agent such as Pro­lia, said El­liott Levy, Am­gen’s se­nior VP of glob­al de­vel­op­ment, in an in­ter­view with End­points News ahead of the FDA de­ci­sion.

In post­menopausal os­teo­poro­sis, bone re­sorp­tion ex­ceeds bone for­ma­tion, and an­tire­sorp­tive agents can help re­store skele­tal bal­ance by re­duc­ing bone turnover, pri­mar­i­ly at the tis­sue lev­el.

There are oth­er ef­fec­tive os­teo­poro­sis ther­a­pies avail­able, Levy said. “But they all take time to work and Eveni­ty, when giv­en for a year, works much more quick­ly, re­duces frac­ture risk much more quick­ly, and then it ap­pears to es­sen­tial­ly re­set frac­ture risk at a low­er lev­el, so when its fol­lowed by an an­tire­sorp­tive agent the risk of frac­ture is low­er than if the pa­tient had not re­ceived Eveni­ty.”

Eveni­ty will launch a week from now, at which point its price will be dis­closed, Am­gen said in a sep­a­rate re­lease on Tues­day.

“Eveni­ty will be priced at a dis­count to an­a­bol­ics, for bet­ter pay­er cov­er­age and to com­pete against pend­ing For­teo gener­ics,” BMO’s Kim sug­gest­ed, mod­el­ing an an­nu­al U.S. gross price of $7,200, well be­low For­teo’s $41,100 and Tym­los’s $21,900.

But the com­bi­na­tion of in­fe­ri­or non-ver­te­bral frac­ture risk re­duc­tion, and safe­ty and la­bel­ing li­a­bil­i­ties, sug­gest Eveni­ty’s adop­tion is like­ly to be mod­est, that Am­gen will un­like­ly pur­sue a price-based strat­e­gy, giv­en Tym­los’ al­ready ag­gres­sive pric­ing and the loom­ing in­tro­duc­tion of biosim­i­lar For­teo, Porges said.


Im­age: El­liott Levy (Am­gen)

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Overview
Transitioning potential therapeutic assets from academia into the commercial environment is an exercise that is largely underappreciated by stakeholders, except for drug developers themselves. The promise of preclinical or early clinical results drives enthusiasm, but the pragmatic delivery of a therapy outside of small, local testing is most often a major challenge for drug developers especially, including among other things, the manufacturing challenges that surround the production of just-in-time and personalized autologous cell therapy products.

Roger Perlmutter, Merck

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Left top to right: Mark Timney, Alex Denner, Vas Narasimhan. (The Medicines Company, Getty, AP/Endpoints News)

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