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.”

De­vel­op­ment of the Next Gen­er­a­tion NKG2D CAR T-cell Man­u­fac­tur­ing Process

Celyad’s view on developing and delivering a CAR T-cell therapy with multi-tumor specificity combined with cell manufacturing success
Transitioning potential therapeutic assets from academia into the commercial environment is an exercise that is largely underappreciated by stakeholders, except for drug developers themselves. The promise of preclinical or early clinical results drives enthusiasm, but the pragmatic delivery of a therapy outside of small, local testing is most often a major challenge for drug developers especially, including among other things, the manufacturing challenges that surround the production of just-in-time and personalized autologous cell therapy products.

Paul Hudson, Getty Images

UP­DAT­ED: Sanofi CEO Hud­son lays out new R&D fo­cus — chop­ping di­a­betes, car­dio and slash­ing $2B-plus costs in sur­gi­cal dis­sec­tion

Earlier on Monday, new Sanofi CEO Paul Hudson baited the hook on his upcoming strategy presentation Tuesday with a tell-tale deal to buy Synthorx for $2.5 billion. That fits squarely with hints that he’s pointing the company to a bigger future in oncology, which also squares with a major industry tilt.

In a big reveal later in the day, though, Hudson offered a slate of stunners on his plans to surgically dissect and reassemble the portfoloio, saying that the company is dropping cardio and diabetes research — which covers two of its biggest franchise arenas. Sanofi missed the boat on developing new diabetes drugs, and now it’s pulling out entirely. As part of the pullback, it’s dropping efpeglenatide, their once-weekly GLP-1 injection for diabetes.

“To be out of cardiovascular and diabetes is not easy for a company like ours with an incredibly proud history,” Hudson said on a call with reporters, according to the Wall Street Journal. “As tough a choice as that is, we’re making that choice.”

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 67,500+ biopharma pros reading Endpoints daily — and it's free.

What does $6.9B buy these days in on­col­o­gy R&D? As­traZeneca has a land­mark an­swer

Given the way the FDA has been whisking through new drug approvals months ahead of their PDUFA date, AstraZeneca and their partners Daiichi Sankyo may not have to wait until Q2 of next year to get a green light on trastuzumab deruxtecan (DS-8201).

The pharma giant this morning played their ace in the hole, showing off why they were willing to commit to a $6.9 billion deal — with $1.35 billion in a cash upfront — to partner on the drug.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 67,500+ biopharma pros reading Endpoints daily — and it's free.

Large advertisements for the drug Vivitrol decorate the walls of Grand Central Station on June 15, 2017 in New York City. (Photo: Andrew Lichtenstein via Getty)

FDA slaps down Alk­er­mes for mis­lead­ing Viv­it­rol ads — don't for­get vul­ner­a­bil­i­ty to opi­oid over­dose

The ads piqued interest as soon as they started appearing in 2016: at Grand Central Station, on the Red Line in Cambridge, and on a billboard off the New Jersey Turnpike. All showed a young person, generally with his or her arms crossed, and the question, “what is Vivitrol?”

Vivitrol’s maker, Alkermes, was in the midst of a marketing and lobbying campaign to promote the anti-opioid addiction drug — a campaign that would face significant backlash for tarnishing competitors despite little evidence for Vivitrol’s superiority.

FDA in-house re­view spot­lights an is­sue with one of Hori­zon's end­points but notes ef­fi­ca­cy for lead drug

The FDA in-house review highlights a disagreement of investigators’ use of a key endpoint by Horizon Pharma in the late-stage trial for the top drug in its pipeline, but largely agreed that the antibody was effective.

Horizon submitted a BLA for thyroid eye disease (TED) drug teprotumumab in March, less than two years after they bought the drug (and the rest of a division) from Narrow River for $145 million upfront. With breakthrough status, priority review, orphan designation and in-house sales projections of up to $750 million, the one-time Roche reject became the marquee pipeline asset for a company that’s developed some of the world’s most expensive drugs.

Seat­tle Ge­net­ics de­tails pos­i­tive OS and PFS da­ta for tu­ca­tinib in breast can­cer

Seattle Genetics $SGEN is showing off more positive data around tucatinib, its pivotal-stage drug for HER2 positive breast cancer.

A month after hearing about solidly upbeat hazard ratios, we learned today that the estimated progression-free survival rate at one year was 33% in the tucatinib arm compared to 12% for patients taking trastuzumab and capecitabine alone.

Median PFS was 7.8 months (95% CI: 7.5, 9.6) in the tucatinib arm, compared to 5.6 months (95% CI: 4.2, 7.1) in the control arm.

Bat­tered, cash hun­gry In­tec feels the burn of No­var­tis re­jec­tion

It’s a case of some bad timing for Intec.

Just when a key trial testing the company’s Accordion drug delivery tech imploded in Parkinson’s disease, they handed Novartis data from a successful PK study of a custom Accordion pill engineered to deliver a Novartis compound to entice the Swiss drugmaker into signing a licensing agreement.

Novartis said thanks, but no thanks.

For the cash-strapped Israeli drug developer, the failure to clinch the deal marks a big blow. As of the third quarter, the company has $15.7 million in cash and equivalents, which HC Wainwright analysts estimate will keep the lights on into mid-2020.

Bris­tol-My­ers shows off a low-pro­file AML con­tender it gained from Cel­gene buy­out — and they’re tak­ing it straight to the FDA

Bristol-Myers Squibb reaped an enormous pipeline with its much-criticized $64 billion megadeal to buy Celgene. And it got a few hidden gems in the deal.

One of those gems was brought out for display on Tuesday, with a late-breaker at ASH on CC-486, which is now being prepped for regulatory filings at the FDA and elsewhere.

Celgene top-lined the positive results in a maintenance setting for acute myeloid leukemia a few months ago, but at ASH investigators pulled back the curtains on the all-important data they believe will give them an advantage in the commercial wars to come.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 67,500+ biopharma pros reading Endpoints daily — and it's free.

De­sert­ed by Astel­las and Mer­ck, lit­tle Cor­re­vio still can't win over FDA pan­el con­cerned with its AFib drug's safe­ty

When the FDA spurned Astellas’ pitch for atrial fibrillation drug vernakalant in 2008, regulators made it abundantly clear that it wasn’t the efficacy they had a problem with — two Phase III trials had shown the drug successfully restored 52% of patients’ heartbeat from irregular to normal — but the cardio safety issues for a drug that was to compete with well established, low-risk options. One licensing deal, one clinical hold and several studies later, the chances of approval aren’t looking any better.