Rare dis­ease drug­mak­er Ul­tragenyx builds case for its gene ther­a­py fran­chise with fresh tri­al up­dates

Fo­cused on com­bat­ing a smat­ter­ing of rare dis­eases with an ar­se­nal of bi­o­log­ics, small mol­e­cules, and gene ther­a­pies, Ul­tragenyx Phar­ma­ceu­ti­cal this week is­sued some up­dates on two of its ex­per­i­men­tal gene ther­a­pies as it works on build­ing a fran­chise for one-time cures.

On Fri­day, the com­pa­ny un­veiled ear­ly da­ta on the ef­fect of DTX401, its gene ther­a­py un­der in­ves­ti­ga­tion, in pa­tients with glyco­gen stor­age dis­ease type Ia (GS­DIa), a dis­ease that af­fects rough­ly 6,000 peo­ple glob­al­ly and is char­ac­ter­ized by the in­abil­i­ty to reg­u­late blood sug­ar.

Nine pa­tients are en­rolled in the open-la­bel Phase I/II tri­al, which has three co­horts en­com­pass­ing three pa­tients each. In the first co­hort, pa­tients re­ceived a small­er dose of DTX401, the sec­ond group was giv­en a high­er dose, and the third, con­fir­ma­to­ry co­hort was giv­en the same high­er dose, but oth­er amend­ments were made, in­clud­ing pa­tients re­ceiv­ing a small­er corn­starch dose at the start of the con­trolled fast­ing chal­lenge.

In 1984, un­cooked corn­starch was found to be the most ef­fec­tive ther­a­py for main­tain­ing suit­able blood glu­cose con­cen­tra­tions — al­though corn­starch has dra­mat­i­cal­ly im­proved the qual­i­ty of life for pa­tients with GSD type I, it has a lim­it­ed du­ra­tion of ac­tion, ac­cord­ing to the NIH.

The three pa­tients in Ul­tragenyx’s Phase I/II con­fir­ma­to­ry co­hort showed more rapid re­duc­tions in corn­starch re­quire­ments com­pared to the first two co­horts, and across all groups, pa­tients demon­strat­ed mean­ing­ful and sus­tained corn­starch re­duc­tions over time and sig­nif­i­cant in­creas­es in time to hy­po­glycemia.

At week 12, pa­tients in co­hort 3 had re­duced mean dai­ly corn­starch in­take by 57%, com­pared with 38% in the first co­hort and 14% in the sec­ond co­hort. Four of the six pa­tients in the first two co­horts have now dis­con­tin­ued day­time corn­starch, and one pa­tient has com­plete­ly dis­con­tin­ued corn­starch.

The com­pa­ny will re­port longer-term da­ta in the sec­ond half of this year, and pend­ing dis­cus­sions with the FDA, will kick off a late-stage study by the end of 2020 if Covid-19 does not dis­rupt time­lines.

Ear­li­er in the week, the com­pa­ny al­so pro­vid­ed an up­date on its oth­er ex­per­i­men­tal gene ther­a­py, DTX301, which is be­ing primed for use in OTC de­fi­cien­cy, the most com­mon urea cy­cle dis­or­der caused by a ge­net­ic de­fect in a liv­er en­zyme re­spon­si­ble for am­mo­nia detox­i­fi­ca­tion.

The up­date comes from an­oth­er mul­ti-co­hort Phase I/II tri­al. On Wednes­day, the com­pa­ny said a third pa­tient in co­hort three is a con­firmed re­spon­der, and ad­di­tion­al longer-term da­ta in co­horts 1 and 2 show sus­tained ef­fi­ca­cy of treat­ment, with re­spons­es up to 2 years and 1.5 years, re­spec­tive­ly.

In both the OTC and GSD tri­al, the safe­ty pro­file of the com­pa­ny’s re­spec­tive gene ther­a­pies ap­peared to be tol­er­a­ble. Pa­tients in both tri­als ex­pe­ri­enced ALT el­e­va­tions, but those were re­solved with steroid ther­a­py.

But one an­a­lyst, Baird’s Mad­hu Ku­mar — who drew a com­par­i­son with DTX301 and Arc­turus Ther­a­peu­tics’ OTC mR­NA drug-in-de­vel­op­ment — preached cau­tion, sug­gest­ing the use of steroids in OTC pa­tients was not nec­es­sar­i­ly a risk-free propo­si­tion.

“While this ta­per­ing course of steroids was able to blunt the liv­er en­zyme el­e­va­tions com­mon­ly seen with AAV GT drugs like DTX301, we em­pha­size that in the con­text of OTC de­fi­cien­cy par­tic­u­lar­ly, there are po­ten­tial sig­nif­i­cant safe­ty risks as­so­ci­at­ed with steroid ther­a­py, in par­tic­u­lar, the po­ten­tial for steroids them­selves to trig­ger hy­per­am­mone­mic crises,” he wrote in a note. “These crises are trig­gered by steroids through in­duc­tion of cata­bol­ic me­tab­o­lism by the drugs which, in the con­text of a dys­func­tion­al urea cy­cle as is found in OTC de­fi­cient pa­tients, can trig­ger the ac­cu­mu­la­tion of am­mo­nia.”

So­cial: Emil Kakkis, Ul­tragenyx CEO

BiTE® Plat­form and the Evo­lu­tion To­ward Off-The-Shelf Im­muno-On­col­o­gy Ap­proach­es

Despite rapid advances in the field of immuno-oncology that have transformed the cancer treatment landscape, many cancer patients are still left behind.1,2 Not every person has access to innovative therapies designed specifically to treat his or her disease. Many currently available immuno-oncology-based approaches and chemotherapies have brought long-term benefits to some patients — but many patients still need other therapeutic options.3

Is a pow­er­house Mer­ck team prepar­ing to leap past Roche — and leave Gilead and Bris­tol My­ers be­hind — in the race to TIG­IT dom­i­na­tion?

Roche caused quite a stir at ASCO with its first look at some positive — but not so impressive — data for their combination of Tecentriq with their anti-TIGIT drug tiragolumab. But some analysts believe that Merck is positioned to make a bid — soon — for the lead in the race to a second-wave combo immuno-oncology approach with its own ambitious early-stage program tied to a dominant Keytruda.

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FDA de­lays de­ci­sion on No­var­tis’ po­ten­tial block­buster MS drug, wip­ing away pri­or­i­ty re­view

So much for a speedy review.

In February, Novartis announced that an application for their much-touted multiple sclerosis drug ofatumumab had been accepted and, with the drug company cashing in on one of their priority review vouchers, the agency was due for a decision by June.

But with June less than 48 hours old, Novartis announced the agency has extended their review, pushing back the timeline for approval or rejection to September. The Swiss pharma filed the application in December, meaning their new schedule will be nearly in line with the standard 10-month window period had they not used the priority voucher.

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Leen Kawas, Athira CEO (Athira)

Can a small biotech suc­cess­ful­ly tack­le an Ever­est climb like Alzheimer’s? Athi­ra has $85M and some in­flu­en­tial back­ers ready to give it a shot

There haven’t been a lot of big venture rounds for biotech companies looking to run a Phase II study in Alzheimer’s.

The field has been a disaster over the past decade. Amyloid didn’t pan out as a target — going down in a litany of Phase III failures — and is now making its last stand at Biogen. Tau is a comer, but when you look around and all you see is destruction, the idea of backing a startup trying to find complex cocktails to swing the course of this devilishly complicated memory-wasting disease would daunt the pluckiest investors.

GSK presents case to ex­pand use of its lu­pus drug in pa­tients with kid­ney dis­ease, but the field is evolv­ing. How long will the mo­nop­oly last?

In 2011, GlaxoSmithKline’s Benlysta became the first biologic to win approval for lupus patients. Nine years on, the British drugmaker has unveiled detailed positive results from a study testing the drug in lupus patients with associated kidney disease — a post-marketing requirement from the initial FDA approval.

Lupus is a drug developer’s nightmare. In the last six decades, there has been just one FDA approval (Benlysta), with the field resembling a graveyard in recent years with a string of failures including UCB and Biogen’s late-stage flop, as well as defeats in Xencor and Sanofi’s programs. One of the main reasons the success has eluded researchers is because lupus, akin to cancer, is not just one disease — it really is a disease of many diseases, noted Al Roy, executive director of Lupus Clinical Investigators Network, an initiative of New York-based Lupus Research Alliance that claims it is the world’s leading private funder of lupus research, in an interview.

Gilead bol­sters its case for block­buster hope­ful fil­go­tinib as FDA pon­ders its de­ci­sion

Before remdesivir soaked up the spotlight amid the coronavirus crisis, Gilead’s filgotinib was the star experimental drug tapped to rake in billions competing with other JAK inhibitors made by rivals including AbbVie and Eli Lilly.

Now, long term data on the drug — discovered by Gilead’s partners at Galapagos and posted as part of a virtual medical conference — have solidified the durability and safety of filgotinib in patients with rheumatoid arthritis, spanning data from three late-stage trials. An FDA decision on the drug is expected this year.

Covid-19 roundup: Mod­er­na read­ies to en­ter PhI­II in Ju­ly, As­traZeneca not far be­hind; EU ready to ne­go­ti­ate vac­cine ac­cess with $2.7B fund

Moderna may soon add another first to the Covid-19 vaccine race.

In March, the mRNA biotech was the first company to put a Covid-19 vaccine into humans. Next month, they may become the first company to put their vaccine into the large, late-stage trials that are needed to prove whether the vaccine is effective.

In an interview with JAMA editor Howard Bauchner, NIAID chief Anthony Fauci said that a 30,000-person, Phase III trial for Moderna’s vaccine could start in July. The news comes a week after Moderna began a Phase II study that will enroll several hundred people.

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New safe­ty da­ta ex­pose po­ten­tial weak­ness as Pfiz­er's abroc­i­tinib takes on Dupix­ent in eczema

Last September, when Pfizer celebrated positive data from a second Phase III study of abrocitinib, many watchers applauded the efficacy but were still waiting to see whether the JAK1 inhibitor is “safe enough to be a formidable competitor to Dupixent,” the clear leader in the atopic dermatitis field. The full slate of safety data are now out and, according to one analyst, the answer is: probably not.

José Basel­ga finds promise in new class of RNA-mod­i­fy­ing can­cer tar­gets, lock­ing in 3 pre­clin­i­cal pro­grams with $55M

Having dived early into some of the RNA breakthroughs of the last decades — betting on Moderna’s mRNA tech and teaming up with Silence on the siRNA front — AstraZeneca is jumping into a new arena: going after proteins that modify RNA.

Their partner of choice is Accent Therapeutics, which is receiving $55 million in upfront payment to steer a selected preclinical program through to the end of Phase I. After AstraZeneca takes over, the Lexington, MA-based startup has the option to co-develop and co-commercialize in the US — and collect up to $1.1 billion in milestones in the long run. The deal also covers two other potential drug candidates.

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