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

5AM Ven­tures: Fu­el­ing the Next Gen­er­a­tion of In­no­va­tors

By RBC Capital Markets
With Andy Schwab, Co-Founder and Managing Partner at 5AM Ventures

Key Points

Prescription Digital Therapeutics, cell therapy technologies, and in silico medicines will be a vital part of future treatment modalities.
Unlocking the potential of the microbiome could be the missing link to better disease diagnosis.
Growing links between academia, industry, and venture capital are spinning out more innovative biotech companies.
Biotech is now seen by investors as a growth space as well as a safe haven, fuelling the recent IPO boom.

Hal Barron, GSK via YouTube

What does $29B buy you in Big Phar­ma? In Glax­o­SmithK­line’s case, a whole lot of un­com­fort­able ques­tions about the pipeline

Talk about your bad timing.

A little over a week ago, GSK R&D chief Hal Barron marked his third anniversary at the research helm by taking a turn at the virtual podium during JP Morgan to make the case that he and his team had built a valuable late-stage pipeline capable of churning out more than 10 blockbusters in the next 5 years.

And then, just days later, one of the cancer drugs he bet big on as a top prospect — bintrafusp, partnered with Merck KGaA — failed its first pivotal test in non-small cell lung cancer.

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Fast on Glax­o­SmithK­line's heels, Au­rinia wins OK to steer a sec­ond lu­pus nephri­tis drug straight to the mar­ket

GlaxoSmithKline’s Benlysta isn’t alone in the small circle of approved lupus nephritis drugs anymore.

Little Aurinia Pharmaceuticals has gotten the green light from the FDA to start marketing its first and only program, voclosporin, under the brand name Lupkynis — something CEO Peter Greenleaf says it’s been ready to do since December.

Regulators went right down to the wire on the decision, keeping the company and the entire salesforce it’s already assembled on its toes.

Eli Lil­ly's an­ti­body cuts risk of Covid-19 by up to 80% among the most vul­ner­a­ble — but will it have a place next to vac­cines?

Eli Lilly says bamlanivimab lowered the risk of contracting symptomatic Covid-19 in a first-of-its-kind trial involving nursing home residents and staff, paving the way for a new option to protect against the virus.

But how big of an impact it might have, and what role it will play, at a time vaccines are being rolled out to the exact population it is targeting still remains unclear.

Among 965 participants in the study — all of whom tested negative for the coronavirus at baseline — the number of symptomatic cases reported in the bamlanivimab arm was 57% lower than that in the placebo arm (odds ratio 0.43, p=0.00021). In addition to that primary endpoint, all secondary endpoints reached statistical significance.

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Janet Woodcock (AP Images)

End­points poll: Janet Wood­cock takes the (in­ter­im) helm at the FDA. And a large ma­jor­i­ty of our read­ers want her to stay there

It’s official: Janet Woodcock is now the acting chief of the FDA.

And — according to an Endpoints poll — most industry readers would like her to stay there, although a significant minority is strongly opposed.

To recap: Joe Biden is reportedly choosing between Woodcock and former deputy FDA commissioner Joshua Sharfstein as his nominee for the permanent position. Given their respective track records, the decision is set to determine the agency’s lodestar for years to come.

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What’s next for End­points — and how to sup­port our in­de­pen­dent bio­phar­ma news mis­sion

The firehose of biopharma news is gushing these days.

That’s why broader and deeper is the theme for 2021 at Endpoints. You can expect new coverage outside our core R&D focus, with deeper reporting in some key areas. When John Carroll and I launched Endpoints nearly five years ago, we were wading in waist-high waters. Now we’re a team of 25 full-time staffers (and growing) with plans to cover the flood of biopharma news, Endpoints-style.

Charlie Fuchs, Roche and Genentech global head of product development for oncology and hematology (Yale Cancer Center)

Yale can­cer spe­cial­ist Char­lie Fuchs tapped as new glob­al de­vel­op­ment chief for Roche/Genen­tech

Roche and their big sub Genentech have just recruited a top cancer specialist at Yale to head up global product development in oncology and hematology.

I just got word that the pharma giant, which leads one of the most active cancer research operations in the world, recruited Charlie Fuchs, director of the Yale Cancer Center and physician-in-chief of Smilow Cancer Hospital. He’ll join the global operation March 1 and will be based in South San Francisco, where Genentech is based.

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Jonathan Weissman (MIT)

Can a new CRISPR tech­nique un­lock the se­crets of how can­cer spreads?

Jonathan Weissman’s team watched the cancer cells spread across the doomed mouse. Engineered with a bioluminescent enzyme, they appeared in scans first as a small navy blue diamond lodged near the heart; a week later, as a triangle splayed across the mouse’s upper body, with streaks of green and two distinct bright red hubs of activity. By day 54, the mouse resembled a lava lamp.

The images would have been familiar to any cancer biologist, but they didn’t actually tell you much about what was going on: why the cancer was metastasizing or which cells were responsible. For that, Weissman’s team had designed a new tool. Inside the original navy blue diamond, they had engineered the microbiological equivalent of an airplane’s black box — a “molecular recorder” that, after the mouse’s death, could allow them to extract the cells and wind back intimate footage of a single cancer’s ascent.

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Glax­o­SmithK­line scraps a LAG3 study, mark­ing an­oth­er fail­ure for the pipeline af­ter a crit­i­cal set­back

Another gap has appeared in GlaxoSmithKline’s pipeline.

Friday morning the Australian biotech Immutep put out word that Hal Barron’s R&D group at GSK had decided to scrap a Phase II proof-of-concept study in ulcerative colitis for their anti-LAG3 therapy GSK2831781. According to the biotech, the program didn’t survive an interim review.

The trial was stopped by GSK based on the assessment of clinical data as part of a planned interim analysis conducted in consultation with the trial’s Data Review Committee. GSK is conducting further reporting, assessment and analyses of the efficacy and safety data and evaluating the biology to determine next steps for the GSK2831781 development program.

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