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.”

Brian Kaspar. AveXis via Twitter

AveX­is sci­en­tif­ic founder fires back at No­var­tis CEO Vas Narasimhan, 'cat­e­gor­i­cal­ly de­nies any wrong­do­ing'

Brian Kaspar’s head was among the first to roll at Novartis after company execs became aware of the fact that manipulated data had been included in its application for Zolgensma, now the world’s most expensive therapy.

But in his first public response, the scientific founder at AveXis — acquired by Novartis for $8.7 billion — is firing back. And he says that not only was he not involved in any wrongdoing, he’s ready to defend his name as needed.

I reached out to Brian Kaspar after Novartis put out word that he and his brother Allen had been axed in mid-May, two months after the company became aware of the allegations related to manipulated data. His response came back through his attorneys.

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Novartis CEO Vas Narasimhan [via Bloomberg/Getty]

I’m not per­fect: No­var­tis chief Vas Narasimhan al­most apol­o­gizes in the wake of a new cri­sis

Vas Narasimhan has warily stepped up with what might pass as something close to a borderline apology for the latest scandal to engulf Novartis.

But he couldn’t quite get there.

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FDA to Sarep­ta: Your wide­ly an­tic­i­pat­ed fol­lowup to Ex­ondys 51 is not get­ting an ac­cel­er­at­ed OK for Duchenne MD

In one of the least anticipated moves of the year, the FDA has rejected Sarepta’s application for an accelerated approval of its Duchenne MD drug golodirsen after fretting over safety issues.

In a statement that arrived after the bell on Monday, Sarepta explained the CRL, saying:

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Levi Garraway. Broad Institute via Youtube

Roche raids Eli Lil­ly for its next chief med­ical of­fi­cer as San­dra Horn­ing plans to step down

We found out Monday morning where Levi Garraway was headed after he left Eli Lilly as head of oncology R&D a few days ago. Roche named Garraway as their new chief medical officer, replacing Sandra Horning, who they say is retiring from the company.

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Af­ter a posse of Wall Street an­a­lysts pre­dict a like­ly new win for Sarep­ta, we're down to the wire on a crit­i­cal FDA de­ci­sion

As Bloomberg notes, most of the Wall Street analysts that cover Sarepta $SRPT are an upbeat bunch, ready to cheer on the team when it comes to their Duchenne MD drugs, or offer explanations when an odd setback occurs — as happened recently with a safety signal that was ‘erroneously’ reported last week.

Ritu Baral Cowen
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UP­DAT­ED: No­var­tis spin­off Nabri­va fi­nal­ly scores its first an­tibi­ot­ic ap­proval

In May, Nabriva Therapeutics suffered a setback after the FDA rejected its antibiotic for complicated urinary tract infections — the Novartis spinoff has now had some better luck with the US agency, which on Monday approved its other drug for community-acquired bacterial pneumonia.

The drug, lefamulin, has been developed as an intravenous and oral formulation and been tested in two late-stage clinical trials. The semi-synthetic compound, whose dosing can be switched between the two formulations, is engineered to inhibit the synthesis of bacterial protein by binding to a part of the bacterial ribosome.

Saqib Islam. CheckRare via YouTube

Spring­Works seeks $115M to push Pfiz­er drugs across fin­ish line while Sat­suma sells mi­graine play in $86M IPO

SpringWorks and Satsuma — both biotech spinouts that have closed B rounds in April — are loading up with IPO cash to boost their respective late-stage plans.
SpringWorks

Bain-backed SpringWorks is the better-known company of the two, and it’s gunning for a larger windfall of $115 million to add to $228 million from previous financings. In the process, the Stamford, CT-based team is also drawing the curtains on the partnerships it has in mind for the pair of assets it had initially licensed from Pfizer.

Mi­nor­i­ty racial groups con­tin­ue to be dis­mal­ly rep­re­sent­ed in can­cer tri­als — study

Data reveal that different racial and ethnic groups — by nature and/or nurture — can respond differently in terms of pharmacokinetics, efficacy, or safety to therapeutics, but this disparity is not necessarily accounted for in clinical trials. A fresh analysis of the last decade of US cancer drug approvals suggests the trend continues, cementing previous research that suggests oncology trials are woefully under-representative of the racial makeup of the real world.

Van­da shares slide af­ter FDA spurns their big end­point and re­jects a pitch on jet lag re­lief

Back in the spring of last year, Vanda Pharmaceuticals $VNDA served up a hot stew of mixed data for a slate of endpoints related to what they called clear evidence that their melatonin sleep drug Hetlioz (tasimelteon) could help millions of travelers suffering from jet lag.

Never mind that they couldn’t get a planned 90 people in the study, settling for 25 instead; Vanda CEO Mihael H. Polymeropoulos said they were building on a body of data to prove it would help jet-lagged patients looking for added sleep benefits. And that, they added, would be worth a major upgrade from the agency as they sought to tackle a big market.