How does TDP-43 bog up the brains of ALS, FTLD pa­tients? AC Im­mune en­lists Penn sci­en­tists to find out

AC Im­mune, the Swiss biotech known for its tau ap­proach to Alzheimer’s, is shin­ing light on an­oth­er mis­fold­ing pro­tein be­lieved to be re­spon­si­ble for oth­er neu­rode­gen­er­a­tive dis­eases in a new re­search pact with the Uni­ver­si­ty of Penn­syl­va­nia.

Vir­ginia Lee

The trans­ac­tive re­sponse (TAR) DNA bind­ing pro­tein, or TDP-43 in short, is found in most hu­man tis­sues but its mis­fold­ed form was iden­ti­fied in 2006 as a com­mon patho­log­ic sub­stance link­ing fron­totem­po­ral lo­bar de­gen­er­a­tion (FTLD) and amy­otroph­ic lat­er­al scle­ro­sis (ALS). Re­searchers have since sug­gest­ed that when in the wrong shape, the pro­tein ac­ti­vates the “cell au­tophagy gene” ATG7, which prompts neu­rons to de­com­pose.

John Tro­janows­ki

Of­fer­ing a grant to John Tro­janows­ki and Vir­ginia Lee — co-di­rec­tors of Penn’s Cen­ter for Neu­rode­gen­er­a­tive Dis­ease Re­search and a mar­ried cou­ple — AC Im­mune now wants to de­ci­pher “the gov­ern­ing prin­ci­ples of how patho­log­i­cal forms of TDP-43 spread from neu­ron to neu­ron.” The ul­ti­mate goal is to sup­port de­vel­op­ment of both ther­a­peu­tic and di­ag­nos­tic ap­proach­es in FTLP and oth­er ail­ments.

Both renowned in the field of neu­rode­gen­er­a­tion, Tro­janows­ki and Lee are cred­it­ed for elu­ci­dat­ing the role of pro­tein cul­prits such as tau, al­pha-synu­cle­in, the Abe­ta pre­cur­sor pro­tein, and TDP-43 in neu­rode­gen­er­a­tive dis­eases.

AC Im­mune has sev­er­al an­ti­bod­ies in its ar­se­nal de­signed to bind to TDP-43 and lined up pre­clin­i­cal proof-of-con­cept stud­ies set to an­nounce re­sults lat­er this quar­ter. It’s hint­ing that TDP-43 might even be a tar­get for Alzheimer’s — an im­por­tant new av­enue to in­ves­ti­gate at a time the dom­i­nant amy­loid be­ta hy­poth­e­sis has all but crum­bled.

Sci­en­tists from the Uni­ver­sité Laval in France have gen­er­at­ed an an­ti­body can­di­date. When in­ject­ed to mice en­gi­neered to ex­hib­it symp­toms of ALS, the drug ap­peared to re­duce the num­ber of TDP-43 ag­gre­gates and de­crease in­flam­ma­tion in the brain, while im­prov­ing the mice’s cog­ni­tive and mo­tor per­for­mance.

An­drea Pfeifer

AC Im­mune al­so finds at least one oth­er spe­cial­ist play­er in the TDP-43 are­na. Aquin­nah, a biotech based out of Cam­bridge, MA, has re­ceived small but no­table in­vest­ments from Pfiz­er, Ab­b­Vie and Take­da to work on break­ing down the pro­tein buildups. It’s al­so in­ter­est­ed in ap­ply­ing these small mol­e­cule drugs to tau for Alzheimer’s.

“The field is still in­ves­ti­gat­ing the pre­cise caus­es of neu­rode­gen­er­a­tive dis­eases and how to pre­vent, treat and even cure them, in­clud­ing neu­ro-or­phan in­di­ca­tions such as FTLD,” AC Im­mune CEO An­drea Pfeifer said in a state­ment. “In­creas­ing our knowl­edge of the role of TDP-43 in dis­ease pathol­o­gy will mark valu­able progress in this ef­fort.”

RWE chal­lenges for to­day's bio­phar­ma

The rapid development of technology — and the resulting avalanche of data — are catalysts for significant change in the biopharmaceutical industry. This translates into urgent pressures for today’s biopharma, including a need to quickly and affordably develop products with proven therapeutic efficacy and value. This urgency is expedited by the growth of value-based contracting, where access to reimbursement and profit depends on these abilities.

UP­DAT­ED: In a stun­ning turn­around, Bio­gen says that ad­u­canum­ab does work for Alzheimer's — but da­ta min­ing in­cites con­tro­ver­sy and ques­tions

Biogen has confounded the biotech world one more time.

In a stunning about-face, the company and its partners at Eisai say that a new analysis of a larger dataset on aducanumab has restored its faith in the drug as a game-changer for Alzheimer’s and, after talking it over with the FDA, they’ll now be filing for an approval of a drug that had been given up for dead.

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As shares suf­fer from a lin­ger­ing slump, a bruised Alk­er­mes slash­es 160 jobs in R&D re­struc­tur­ing

With its share price in a deep slump after suffering through a regulatory debacle over their depression drug ALKS 5461, Alkermes CEO Richard Pops is taking the ax to its R&D organization in a restructuring aimed at cutting costs ahead of its next attempt at a rollout in a tough field.

Richard Pops, Endpoints via Youtube

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Acor­da's Ron Co­hen brings the ax back out as new drug sales on­ly trick­le in while cash cow is led to the slaugh­ter

With its new drug earning meager sums and its one-time cash cow reduced to a bony shadow of its former self, Acorda Therapeutics today is rolling out a new restructuring aimed at slashing the staff and cutting costs to get through the hard times ahead.

The biotech is chopping a quarter of its staff today, carving back R&D as well as SG&A expenses. And CEO Ron Cohen is cutting deep.

Under the new austerity budget, Acorda’s R&D expenses for the full year 2019 are expected to be $55 – $60 million, reduced from $70 – $80 million. SG&A expenses for the full year 2019 are expected to be $185 – $190 million, reduced from $200 – $210 million. R&D expenses for the full year 2020 are expected to be $20 – $25 million and SG&A
expenses for the full year 2020 are expected to be $160 – $165 million.

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RAPT Ther­a­peu­tics re­turns to Wall Street to re­vive IPO bid

On May 24, FLX Bio, a small cancer and inflammation biotech with backing from GV, changed its name to RAPT Therapeutics and filed confidentially for an IPO. On July 5th, they filed to raise up to $86 million. On July 22, they announced the IPO with a $75 million goal.  And on August 1, they abruptly and without explanation called it all off.

Now, without explanation, they’re reviving the bid, filing again for a $75 million IPO, this time with a new bookrunner and a new drug candidate in the clinic. The terms will be the same: 5 million shares at $14-$16 per share. It would give them a diluted market value of $351 million.

EY vet set to re­place re­tir­ing Am­gen CFO Meline

Ahead of its third-quarter results next week, Amgen on Tuesday disclosed the planned retirement of David Meline, who has served as the company’s chief financial officer since 2014.

Meline will be replaced by Ernst & Young vet, Peter Griffith, as CFO come January 1, 2020 — but until then Griffith will serve as executive vice president, finance.

“Over the last 5 years at Amgen, Meline instituted many major changes that led to operational efficiencies and margin expansion while successfully returning cash to shareholders. Now that Amgen is on solid footing, it was a good time to step away,” Cowen’s Yaron Werber wrote in a note. “We do not anticipate any major changes to strategy or operations immediately due to this transition as Amgen is on solid footing.”

Eli Lil­ly’s USA, di­a­betes chief En­rique Con­ter­no is head­ing out af­ter 27 years, and he’s be­ing re­placed by a com­pa­ny in­sid­er

Close to 3 years after Eli Lilly CEO Dave Ricks added the title of president of the US operations to Enrique Conterno’s resume, which included his helmsmanship of the diabetes franchise, the Peruvian born exec is set to retire after a 27-year run at the pharma giant.

Lilly put out the news just as it was posting Q3 results, with a mix of upbeat and downbeat results in the latest set of numbers from Lilly.
Conterno — a grizzled, deeply experienced and sometimes gruff veteran of the pharma world — was a high-profile figure at Lilly, stepping up to expanded duties as the company was forced to deal with intense pricing pressure on the diabetes side of the business. He had replaced outgoing US president Alex Azar, who later popped up as head of Health and Human Services in the Trump administration.
As head of the diabetes unit, Conterno had to deal with an extraordinarily competitive field as payers demanded bigger discounts. Trulicity’s success helped generate new revenue for the company, but Q3’s miss on revenue had a lot to do with the need for discounting the drug ahead of Novo Nordisk’s rival therapy, Rybelsus, which was priced on the wholesale level at an almost identical rate.

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No­var­tis hands off $80M in cash to part­ner up with a top biotech play­er in the fi­bro­sis sec­tor

Never underestimate the power of a good showing at a scientific conference.
In a presentation late last year, the researchers at Pliant Therapeutics launched a series of discussions about the preclinical data they were pulling together around their work on their small-molecule integrin inhibitor aimed at transforming growth factor beta, or TGF-β, a key pathway involved in fibrosis.
And they got some serious attention for the work.
“We got interest from pharma partners and at the end Novartis basically made it,” says Pliant CEO Bernard Coulie.

Vas Narasimhan. Getty Images

UP­DAT­ED: Failed PhI­II fe­vip­iprant tri­als pour more cold wa­ter on No­var­tis' block­buster R&D en­gine — and briefly spread the chill to a high-pro­file biotech

Back in July, during an investor call where Novartis execs ran through an upbeat assessment of their Q2 performance, CEO Vas Narasimhan and development chief John Tsai were pressed to predict which of the two looming Phase III readouts — involving cardio drug Entresto and asthma therapy fevipiprant, respectively — had a higher likelihood of success. Tsai gave the PARAGON-HF study with Entresto minimally better odds, but Narasimhan emphasized that their strategy of giving fevipiprant to more severe patients gave them confidence.

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