New Zol­gens­ma da­ta sug­gest com­pa­ra­ble ef­fi­ca­cy to Spin­raza — an­a­lysts

As No­var­tis awaits the FDA de­ci­sion on its spinal mus­cu­lar at­ro­phy (SMA) gene-ther­a­py, Zol­gens­ma, the com­pa­ny that de­vel­oped the treat­ment for the rare, dead­ly in­her­it­ed dis­or­der, AveX­is, pre­sent­ed da­ta snap­shots from on­go­ing tri­als on Sun­day, prompt­ing an­a­lysts to sug­gest that the one-shot ther­a­py was look­ing com­pa­ra­ble to Bio­gen’s ap­proved Spin­raza.

In the on­go­ing late-stage STR1VE study, de­signed to eval­u­ate the ef­fi­ca­cy and safe­ty of a one-time IV in­fu­sion of Zol­gens­ma in pa­tients with SMA Type 1 who are <6 months of age, da­ta showed pa­tients con­tin­ued to show event-free sur­vival well above nor­mal his­tor­i­cal con­trols, AveX­is sug­gest­ed at the Amer­i­can Acad­e­my of Neu­rol­o­gy an­nu­al meet­ing.

SMA caus­es mus­cle weak­ness and pro­gres­sive loss of move­ment, trig­gered by a ge­net­ic de­te­ri­o­ra­tion in the nerve cells con­nect­ing the brain and spinal cord to the body’s mus­cles. Ba­bies with type 1 rarely sur­vive be­yond the first few years of life, while most chil­dren with type 2 sur­vive in­to adult­hood. Types 3 and 4 don’t usu­al­ly af­fect life ex­pectan­cy. The Swiss drug­mak­er has sug­gest­ed a price of $4 -$5 mil­lion for Zol­gens­ma, which it ac­quired via its $8.7 bil­lion takeover of AveX­is.

An­oth­er sig­nif­i­cant up­date was the snap­shot from the STRONG study, which is eval­u­at­ing the in­trathe­cal de­liv­ery of Zol­gens­ma in pa­tients with SMA Type 2. Pa­tients were strat­i­fied in­to two groups based on age at time of dos­ing: pa­tients who are ≥6 months but <24 months, and pa­tients who are ≥24 months but <60 months. The pri­ma­ry ef­fi­ca­cy out­come for pa­tients in the first group is the abil­i­ty to stand with­out sup­port ≥3 sec­onds; the main goal for the sec­ond group is a change in Ham­mer­smith Func­tion­al Mo­tor Scale-Ex­pand­ed (HFMSE) score from base­line. Since dos­ing, 22 mo­tor mile­stones in 10 pa­tients have been achieved across Dose A and Dose B, in­clud­ing two pa­tients who gained the abil­i­ty to stand in­de­pen­dent­ly, one of whom went on to walk alone, and one pa­tient who gained the abil­i­ty to walk with as­sis­tance. The me­di­an du­ra­tion of fol­low-up was 6.5 months and all 30 pa­tients are alive.

“The av­er­age age at en­roll­ment in STRONG was 17 months…these re­sults are chal­leng­ing to in­ter­pret or com­pare with the Spin­raza da­ta since the Bio­gen/Io­n­is study en­rolled pa­tients who were slight­ly old­er (3 years at base­line). Thus, we be­lieve the most com­pa­ra­ble dat­a­point is ef­fi­ca­cy on the HFMSE, which was the pri­ma­ry end­point in Bio­gen/Io­n­is’ Spin­raza tri­al. On this mea­sure, AVXS-101 pro­duced a mean 4.2 point im­prove­ment at a me­di­an fol­low up time of 7.5 months; by com­par­i­son, Spin­raza gen­er­at­ed a ~3 point im­prove­ment at 9 months in the Phase III CHER­ISH study. The mag­ni­tude of these im­prove­ments are ob­vi­ous­ly very close to one an­oth­er, and when we think about STRONG/CHER­ISH de­signs and the re­cruit­ed tri­al pop­u­la­tions, the bal­ance of con­found­ing vari­ables prob­a­bly fa­vors the STRONG study a lit­tle, un­der­ly­ing our con­clu­sion that the ef­fi­ca­cy of gene ther­a­py and Spin­raza are prob­a­bly pret­ty sim­i­lar,” Stifel an­a­lysts wrote in a note.

Ever­core ISI’s Umer Raf­fat sug­gest­ed that in the sec­ond group, al­though Zol­gens­ma ap­pears to kick in faster, both the gene-ther­a­py and Bio­gen’s $BI­IB Spin­raza plateau at the same. But, there is one cru­cial caveat — the pa­tients in AveX­is tri­al seemed to have low­er HFMSE scores to be­gin with, he wrote.

Over­all, no treat­ment-emer­gent deaths have been pre­sent­ed in the new da­ta, he not­ed. Rough­ly two weeks ago, AveX­is dis­closed that one of the in­fants in the STR1VE-EU study died from an in­fec­tion, and au­thor­i­ties are in­ves­ti­gat­ing whether Zol­gens­ma played a role in the death. Al­though reg­u­la­to­ry bod­ies are ex­pect­ed to be ac­com­mo­dat­ing for safe­ty is­sues when it comes to a po­ten­tial once-and-done treat­ment for the lethal dis­ease, com­pe­ti­tion ab­sent these safe­ty con­cerns could cer­tain­ly tem­per adop­tion.

The AveX­is da­ta “looks com­pet­i­tive and like a vi­able op­tion for pa­tients, in­clud­ing new in­trathe­cal dos­ing for Type 2, etc, and be­yond just in­fants (where gene ther­a­py is most com­pet­i­tive to start). We think FDA ap­proval and a fair­ly ‘broad la­bel’ could be com­ing for No­var­tis as soon as this week. Our doc sur­vey sug­gests more than 1/3 of pa­tients could opt for this; hence, Bio­gen es­ti­mates may be too high for Spin­raza,” Jef­feries an­a­lysts wrote in a note.

PTC Ther­a­peu­tics $PTCT and Roche’s oral SMA ther­a­py, ris­diplam, will like­ly be tak­en to the FDA for re­view  lat­er this year for a broad pop­u­la­tion, and could be on the mar­ket by the end of 2020, they added.

“Bot­tom line — we could see a 1/3, 1/3, 1/3 split of mar­ket over time,” Jef­feries an­a­lysts said. Doc­tors sug­gest gene ther­a­pies “could be 30-33% share of new SMA Type I-III pa­tients over time. An es­ti­mat­ed 20-25% could look to switch from Spin­raza to gene ther­a­py (de­pends on weight of pa­tient). 2) Sim­i­lar­ly, docs sug­gest 1/3 share for oral ris­diplam, too, af­ter 3-5 years; 3) Com­men­tary by docs sug­gests an even split of opin­ions on the mar­ket as well — from oral pills ‘very ap­peal­ing’ and ‘game chang­er’ and ‘es­pe­cial­ly at­trac­tive for teens/adults’ to oth­er ther­a­pies need more da­ta and like­ly com­bo,” cit­ing their sur­vey.

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