Mer­ck can’t prove its Alzheimer’s drug works, yet, but it did just ex­plain why it’s spend­ing a for­tune on PhI­II

In­ves­ti­ga­tors for Mer­ck $MRK have very care­ful­ly out­lined all the ear­ly-stage hu­man and an­i­mal da­ta they can muster for their Alzheimer’s drug verube­ce­s­tat. Now in an am­bi­tious Phase III due to read out in mid-2017, tests proved that the BACE drug can suc­cess­ful­ly tar­get one of the key bio­mark­ers for the dis­ease.

They just don’t have any con­vinc­ing da­ta to show whether it will ac­tu­al­ly make a dif­fer­ence in pa­tients’ cog­ni­tive abil­i­ties, or im­prove their abil­i­ty to func­tion in their dai­ly lives.

In many ways, Mer­ck’s case echoes all the up­beat da­ta we’ve heard about Alzheimer’s drugs in re­cent years, and al­so helps ex­plain why this field has been so frus­trat­ing.

First, the da­ta. The key take­away from the ar­ti­cle in Sci­ence Trans­la­tion­al Med­i­cine is that Mer­ck’s drug sig­nif­i­cant­ly re­duced lev­els of amy­loid be­ta in the flu­id sur­round­ing the brain among the ac­tu­al pa­tients tak­ing the drug. Dos­ing was short, with on­ly 32 pa­tients get­ting the drug dai­ly for a week.

That’s not near­ly enough time to de­tect any re­duc­tion in these tox­ic clus­ters by way of a brain scan. And it’s far short of any kind of ev­i­dence that the ther­a­py can ac­tu­al­ly have an im­pact on a dis­ease that dam­ages the brain, per­haps ir­rev­o­ca­bly.

But it does ex­plain why Mer­ck and oth­ers are spend­ing a for­tune on late-stage stud­ies on these BACE drugs.

The mech­a­nism of ac­tion for this drug lies up­stream of amy­loid be­ta. It’s de­signed to in­ter­fere with the pro­duc­tion of amy­loid be­ta, cut­ting the sup­ply of a pro­tein that has be­come one of the chief cul­prits in the dis­ease. Ratch­et down the flow of amy­loid be­ta, the the­o­ry goes, and you can pre­vent the cog­ni­tive and phys­i­cal erup­tions that even­tu­al­ly wipe out a per­son’s mem­o­ry and re­quires care­ful su­per­vi­sion.

The prob­lem with these stud­ies is that com­pa­nies like Mer­ck — and this in­cludes com­pa­nies like Eli Lil­ly, Bio­gen, J&J and many oth­ers — of­ten jump from a Phase I bio­mark­er study in­to broad Phase III stud­ies, look­ing for ev­i­dence that they can bend a re­morse­less dis­ease curve.

Mer­ck al­so in­clud­ed da­ta from its stud­ies in­volv­ing an­i­mals and healthy sub­jects. But aside from pro­vid­ing im­por­tant in­sights on safe­ty, such re­sults rarely mean much of any­thing when it comes to pre­dict­ing ef­fi­ca­cy. But big com­pa­nies are will­ing to over­look big is­sues as they hus­tle in­to late-stage Alzheimer’s tri­als.

Lil­ly was so com­mit­ted to solanezum­ab — which al­so tar­gets amy­loid be­ta — that it mount­ed a new Phase III pro­gram af­ter the last one failed. It al­so re­cent­ly rel­e­gat­ed one key mea­sure on func­tion to a sec­ondary end­point, flag­ging its lack of con­fi­dence on that score.

And most in­ves­ti­ga­tors in the field are mov­ing up­stream in the dis­ease pathol­o­gy, hop­ing to check the dis­ease be­fore it caus­es se­ri­ous dam­age.

De­spite bil­lions spent on new tri­als over the past decade, though, the field has been af­flict­ed by one set­back af­ter the next. Now Mer­ck will take the most ad­vanced study on BACE and help set the stage for a new field in which ri­vals are hus­tling along com­pet­ing ther­a­pies, hop­ing to cash in on one of the biggest un­met med­ical needs in the busi­ness.

Lil­ly will be first up with new Phase III da­ta on solanezum­ab in a mat­ter of weeks. Mer­ck will fol­low in Ju­ly. Some­time over the next year, we’ll be able to un­der­stand much bet­ter just what role amy­loid be­ta plays in Alzheimer’s. And if any­one scores pay dirt da­ta, the pay­off will po­ten­tial­ly be worth bil­lions a year from a new drug fran­chise. Losers will be rel­e­gat­ed to a grow­ing ceme­tery of failed pro­grams.

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.

Biohaven CEO Vlad Coric (Photo Credit: Andrew Venditti)

Pssst: That big Bio­haven Alzheimer's study? It was a bust. Even the sub­group analy­sis ex­ecs tout­ed was a flop

You know it’s bad when a biopharma player plucks out a subgroup analysis for a positive take — even though it was way off the statistical mark for success, like everything else.

So it was for Biohaven $BHVN on MLK Monday, as the biotech reported on the holiday that their Phase II/III Alzheimer’s study for troriluzole flunked both co-primary endpoints as well as a key biomarker analysis.

The drug — a revised version of the ALS drug riluzole designed to regulate glutamate — did not “statistically differentiate” from placebo on the Alzheimer’s Disease Assessment Scale-Cognitive Subscale 11 (ADAS-cog) and the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB).  The “hippocampal volume” assessment by MRI also failed to distinguish itself from placebo for all patients fitting the mild-to-moderate disease profile they had established for the study.

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Janet Woodcock and Joshua Sharfstein (AP, Images)

Poll: Should Joshua Sharf­stein or Janet Wood­cock lead the FDA from here?

It’s time for a new FDA commissioner to come on board, a rite of passage for Joe Biden’s administration that should help seal the new president’s rep on seeking out the experts to lead the government over the next 4 years.

As of now, the competition for the top job appears to have narrowed down to 2 people: The longtime CDER chief Janet Woodcock and Joshua Sharfstein, the former principal deputy at the FDA under Peggy Hamburg. Both were appointed by Barack Obama.

Dan Skovronsky, Eli Lilly CSO (Lilly via Facebook)

Eli Lil­ly tees up dis­cov­ery pact worth more than $1.6B with Merus for T cell-fo­cused bis­pe­cif­ic an­ti­bod­ies

Under science chief Dan Skovronsky, Eli Lilly has taken some big swings at next-gen therapies, including trying to find the next big thing in oncology. Now, after one early failure in the field, Lilly is going back to the bispecific antibody well with a new deal with a Dutch biotech.

Lilly will pay $40 million upfront with an additional $20 million equity stake in Merus NV to identify and develop three bispecific antibodies looking to engage the CD3 antigen on T cells and redirect immune cells, the Indianapolis pharma giant said Tuesday.

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Andrew Allen (Gritstone)

As coro­n­avirus vari­ants trig­ger new alarms, the NIH is putting an un­der-the-radar ‘next-gen’ vac­cine in­to PhI

Over the past year, the world has been transfixed by the development of new vaccines to fight SARS-CoV-2. In a frenzy of activity, the new mRNA approach has delivered pioneering emergency approvals in record time. And with some setbacks, the more traditional big players are coming along with added jabs as the most affluent nations in the world begin to vaccinate large portions of their populations.

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The IPO queue adds 5 more biotechs hop­ing to ring in 2021 by blitz­ing Nas­daq

Following a record year for IPOs — in terms of both proceeds and count — there’s already a long lineup of biotechs ready to jump onto Nasdaq in the new year. The companies are likely looking for much higher raises than they initially projected on their S-1s. Now it’s time to see if investors are still hungry for another round of biotech stocks.

Sana helped set the pace early on, as its founders look to divvy up a fortune from their IPO. And late last week 5 more biotechs crowded in, looking to pick up the pace where 2020 left off. Here they are:

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News brief­ing: Beam bags a $260M pri­vate place­ment; mi­Ra­gen re­brands to Virid­i­an Ther­a­peu­tics

Agios vet John Evans has demonstrated how to raise big money for a little biotech.

The Beam Therapeutics CEO — and ARCH partner — has pieced together a $260 million private placement from a group of backers that includes Perceptive Advisors, Farallon Capital, Casdin Capital, Redmile Group and Cormorant Asset Management. And there are 3 main goals they’ll pursue with it: clinical development, strategic partnerships and general corporate purposes.

As­traZeneca keeps the ball rolling on Dai­ichi-part­nered En­her­tu, pick­ing up 2nd in­di­ca­tion in gas­tric can­cer

AstraZeneca’s big gamble on Daiichi Sankyo’s antibody-drug conjugate Enhertu has already paid off with a big approval in breast cancer more than a year ago. But the partners have big plans for their blockbuster in the making, and a new nod in gastric cancer will raise their spirits even higher.

The FDA on Friday approved Enhertu to treat locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma in patients who have previously undergone at least one round of treatment with a Herceptin-based regimen, AstraZeneca said in a release.

Ox­ford gets £100M to seize a 'break­through mo­men­t' in fight­ing su­per­bugs

Close to 70 years after Oxford scientists purified penicillin and confirmed its effect as an antibacterial drug, the university is establishing a new research institute at the forefront of combating antimicrobial resistance.

The Ineos Oxford Institute for AMR Research will initially be powered by a $136 million (£100 million) donation from Ineos, the UK-based chemicals giant founded by billionaire Jim Ratcliffe, that also plays a hand in manufacturing medical and pharma products.