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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