Ryan Watts, Denali CEO

De­nali un­veil proof-of-con­cept da­ta for brain de­liv­ery tech in rare dis­ease, with eyes on much big­ger in­di­ca­tions

Near­ly a year af­ter un­veil­ing their brain de­liv­ery tech­nol­o­gy in Sci­ence Trans­la­tion­al Med­i­cine, De­nali has de­liv­ered promis­ing new re­sults from a tri­al that used it on pa­tients with a rare ge­net­ic dis­ease and could point down the road to stud­ies and treat­ments in larg­er in­di­ca­tions.

De­nali stud­ied five pa­tients with Hunter syn­drome, a con­di­tion where pa­tients are miss­ing a key en­zyme in­volved in the body’s stor­age and dis­pos­al sys­tem. Con­se­quent­ly, they ac­cu­mu­late mas­sive lev­els of sev­er­al dam­ag­ing mol­e­cules, with se­vere con­se­quences for mus­cu­lar and cog­ni­tive de­vel­op­ment.

The cur­rent stan­dard treat­ment is an in­fu­sion of an ar­ti­fi­cial ver­sion of the miss­ing en­zyme, but it isn’t com­plete­ly ef­fec­tive and can’t reach the brain or im­prove cog­ni­tion. De­nali’s drug is de­signed to do both, at­tach­ing the en­zyme to an an­ti­body that can get across the blood-brain bar­ri­er.

In the first tri­al,  all five pa­tients saw dra­mat­ic re­duc­tions in the two dam­ag­ing mol­e­cules in urine sam­ples, with he­paran sul­fate drop­ping 76% and der­matan sul­fate drop­ping 82%. The new da­ta add to an ini­tial slice un­veiled in No­vem­ber.

Ca­r­ole Ho

Cru­cial­ly, there were al­so dra­mat­ic re­duc­tions of he­paran sul­fate in the cere­brospinal flu­id, a test of whether or not the drug is hav­ing an im­pact on the brain. Four of five pa­tients fell to nor­mal lev­els, an av­er­age drop of 85%, and a fifth fell to near nor­mal lev­els af­ter drop­ping 73%.

The weak­er re­sponse in the fifth pa­tient can be traced to his high lev­els of an­ti-drug an­ti­bod­ies, said De­nali CMO Ca­r­ole Ho, but they were able to over­come those an­ti­bod­ies by in­creas­ing the dose.

“We have not ex­pe­ri­enced any lim­i­ta­tions at this point,” Ho told End­points News. “We were ac­tu­al­ly quite pleas­ant­ly sur­prised to see the speed of re­sponse and mag­ni­tude of re­sponse. We have not seen this lev­el of nor­mal­iza­tion so quick­ly.”

De­nali is now plan­ning a Phase II/III tri­al for the study, where they will try to prove that the bio­mark­er im­prove­ments they’ve shown trans­late in­to im­prove­ments in cog­ni­tion or be­hav­ior. The biotech will be go­ing against a hand­ful of oth­er ap­proach­es to the lyso­so­mal dis­or­der, as JCR Phar­ma­ceu­ti­cals ad­vances their own an­ti­body ap­proach and com­pa­nies such as Sang­amo and Avro­bio look to push a gene ther­a­py for­ward.

De­nali thinks they have bet­ter da­ta and de­liv­ery than JCR and have ad­van­tages over the gene ther­a­py ap­proach­es, ar­gu­ing that the AAV vec­tor of­ten used to de­liv­er a gene for the miss­ing en­zyme isn’t very con­sis­tent in how it spreads through the brain.

“We see a lot of vari­a­tion with AAV,” CEO Ryan Watts told End­points, adding that their an­ti­body could al­so be giv­en on top of gene ther­a­py. Avro­bio us­es lentivirus in­stead of AAV, but that faces its own lo­gis­ti­cal hur­dles, as the cells have to be edit­ed out­side the body and reim­plant­ed.

Watts said the Hunter re­sults should pro­vide proof-of-prin­ci­ple for a much larg­er pipeline De­nali is look­ing to bring for­ward. The com­pa­ny now has a long list of pro­grams for oth­er en­zyme dis­or­ders to at­tack with their an­ti­body tech­nol­o­gy, in­clud­ing San­fil­ip­po syn­drome, Gauch­er dis­ease, and Pompe dis­ease.

There are al­so part­ner­ships with Bio­gen on a new de­liv­ery ve­hi­cle for the Alzheimer’s drug ad­u­canum­ab and with Take­da for tack­ling fron­totem­po­ral de­men­tia. And, on top of their Parkin­son’s and ALS work, they have plans to ex­pand in­to new ar­eas, such as in­fec­tious dis­ease and on­col­o­gy.

They will look, Watts said, to bring most of their pro­grams for­ward in-house. That’s a lot of can­di­dates for vir­tu­al­ly any biotech not named Re­gen­eron, Am­gen or Gilead, but Watts not­ed they have some­thing most young biotechs don’t: $1.5 bil­lion in cash in the bank.

Tar­get­ing a Po­ten­tial Vul­ner­a­bil­i­ty of Cer­tain Can­cers with DNA Dam­age Re­sponse

Every individual’s DNA is unique, and because of this, every patient responds differently to disease and treatment. It is astonishing how four tiny building blocks of our DNA – A, T, C, G – dictate our health, disease, and how we age.

The tricky thing about DNA is that it is constantly exposed to damage by sources such as ultraviolet light, certain chemicals, toxins, and even natural biochemical processes inside our cells.¹ If ignored, DNA damage will accumulate in replicating cells, giving rise to mutations that can lead to premature aging, cancer, and other diseases.

Fol­low biotechs go­ing pub­lic with the End­points News IPO Track­er

The Endpoints News team is continuing to track IPO filings for 2021, and we’ve designed a new tracker page for the effort.

Check it out here: Biopharma IPOs 2021 from Endpoints News

You’ll be able to find all the biotechs that have filed and priced so far this year, sortable by quarter and listed by newest first. As of the time of publishing on Feb. 25, there have already been 16 biotechs debuting on Nasdaq so far this year, with an additional four having filed their S-1 paperwork.

Steve Cutler, Icon CEO (Icon)

In the biggest CRO takeover in years, Icon doles out $12B for PRA Health Sci­ences to fo­cus on de­cen­tral­ized clin­i­cal work

Contract research M&A had a healthy run in recent years before recently petering out. But with the market ripe for a big buyout and the Covid-19 pandemic emphasizing the importance of decentralized trials, Wednesday saw a tectonic shift in the CRO world.

Icon, the Dublin-based CRO, will acquire PRA Health Sciences for $12 billion in a move that will shake up the highest rungs of a fragmented market. The merger would combine the 5th- and 6th-largest CROs by 2020 revenue, according to Icon, and the merger will set the newco up to be the second-largest global CRO behind only IQVIA.

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Tom Barnes (Orna)

The mR­NA era is here. MPM be­lieves the fu­ture be­longs to oR­NA — and Big Phar­ma wants a seat at the ta­ble

If the ultra-fast clinical development of Covid-19 vaccines opened the world’s eyes to the promises of messenger RNA, the subsequent delays in supply offered a crash course on the ultra-complex process of producing them. Even before the formulation and fill-finish steps, mRNA is the precious end product from an arduous journey involving enzyme-aided transcription, modification and purification.

For Bristol Myers Squibb, Novartis Institutes for Biomedical Research, Gilead’s Kite and Astellas, it’s time to rethink the way therapeutic RNA is engineered.

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Tal Zaks, Moderna CMO (AP Photo/Rodrique Ngowi, via still image from video)

CMO Tal Zaks bids Mod­er­na a sur­prise adieu as biotech projects $18.4B in rev­enue, plots post-Covid ex­pan­sion

How do you exit a company after six years in style? Developing one of the most lucrative and life-saving products in pharma history is probably not the worst way to go.

Tal Zaks, Moderna’s CMO since 2015, will leave the mRNA biotech in September, the biotech disclosed in their annual report this morning. The company has already retained the recruitment firm Russell Reynolds to find a replacement.

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Glax­o­SmithK­line re­thinks strat­e­gy for Covid-19 an­ti­body — not the Vir ones — af­ter tri­al flop. Is there hope in high-risk pa­tients?

In the search for a better Covid-19 therapeutic, GlaxoSmithKline and Vir have partnered up on two antibodies they hope have a chance. GSK is also testing its own in-house antibody, and early results may have shut the door on its widespread use.

A combination of GSK’s monoclonal antibody otilimab plus standard of care couldn’t best standard of care alone in preventing death and respiratory failure in hospitalized Covid-19 patients after 28 days, according to data from the Phase IIa OSCAR study unveiled Thursday.

Mod­er­na's Stéphane Ban­cel plans to dou­ble down on vac­cine pro­duc­tion, new vari­ants as mR­NA rules in pan­dem­ic fight

Stéphane Bancel thought he’d be sleeping more by now.

The 48-year-old Moderna CEO figured that by 2021 he’d have his vaccine through the clinic, authorized, and in mass production — that the hard part would be over. Instead, he’s still working Saturdays and Sundays, talking with his lab and manufacturing teams and fielding calls with two to three world leaders a day to answer their concerns about supply and emerging new variants.

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S&P ex­pects steady ero­sion in Big Phar­ma's cred­it pro­file in 2021 as new M&A deals roll in — but don't un­der­es­ti­mate their un­der­ly­ing strength

S&P Global has taken a look at the dominant forces shaping the pharma market and come to the conclusion that there will be more downgrades than upgrades in 2021 — the 8th straight year of steady decline.

But it’s not all bad news. Some things are looking up, and there’s still plenty of money to be made in an industry that enjoys a 30% to 40% profit margin, once you factor in steep R&D expenses.

Ken Frazier, Merck CEO (Bess Adler/Bloomberg via Getty Images)

UP­DAT­ED: Mer­ck takes a swing at the IL-2 puz­zle­box with a $1.85B play for buzzy Pan­dion and its au­toim­mune hope­fuls

When Roger Perlmutter bid farewell to Merck late last year, the drugmaker perhaps best known now for sales giant Keytruda signaled its intent to take a swing at early-stage novelty with the appointment of discovery head Dean Li. Now, Merck is signing a decent-sized check to bring an IL-2 moonshot into the fold.

Merck will shell out roughly $1.85 billion for Pandion Pharmaceuticals, a biotech hoping to gin up regulatory T cells (Tregs) to treat a range of autoimmune disorders, the drugmaker said Thursday.

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