FDA slaps par­tial hold on Macro­Gen­ics for bis­pe­cif­ic can­cer tri­als as liv­er tox spurs safe­ty fears

Leery about signs of liv­er tox­i­c­i­ty among pa­tients tak­ing a B7-H3 × CD3 bis­pe­cif­ic un­der de­vel­op­ment at Macro­Gen­ics $MGNX, the FDA has slapped a par­tial hold on the ear­ly-stage pro­gram.

The par­tial hold — which af­fects their monother­a­py tri­al as well a com­bi­na­tion ef­fort with their own PD-1 check­point MGA012, part­nered with In­cyte — will stop re­searchers from re­cruit­ing new pa­tients, but peo­ple who have al­ready signed up can con­tin­ue treat­ment.

Scott Koenig

Macro­Gen­ics was quick to down­play the move, not­ing that signs of el­e­vat­ed transam­i­nas­es in the sin­gle-drug study were quick­ly re­solved. And the biotech got some quick help from an­a­lysts, who haven’t been pay­ing all that much at­ten­tion to this pro­gram’s par­tic­u­lar po­ten­tial. CD3, though, plays a promi­nent role in some lead­ing bis­pe­cif­ic ef­forts, and the an­a­lysts would like to know more if the prob­lem here may ex­tend to oth­er de­vel­op­ers.

Macro­Gen­ics has been test­ing this bis­pe­cif­ic in pa­tients with non-small cell lung, blad­der and head and neck can­cer, mesothe­lioma, melanoma, and oth­er B7-H3 pos­i­tive tu­mors.

Jonathan Chang

Leerink’s Jonathan Chang passed along man­age­ment’s con­fi­dence that it can get past this hitch in short or­der and has al­ready pitched a new plan to boost sup­port­ive care in the tri­als.

Over­all, man­age­ment seemed bull­ish that the par­tial clin­i­cal hold could be lift­ed as ear­ly as Jan­u­ary 2019 based on the reg­u­la­to­ry dis­cus­sions so far and the changes be­ing pro­posed, in our view. Man­age­ment in­di­cat­ed that liv­er func­tion test (LFT) el­e­va­tions were ini­tial­ly ob­served in the Q2 week­ly dos­ing reg­i­men, which re­solved with a re­duc­tion in dose. How­ev­er, LFT el­e­va­tions were then ob­served in a cou­ple more pa­tients at a low­er dose.

Umer Raf­fat at Ever­core ISI is in the group that wants to learn more AS­AP.

We sus­pect the liv­er tox in the B7-H3 x CD3 DART may be ON-tar­get tox of this spe­cif­ic com­bi­na­tion. Al­though the com­pa­ny says B7-H3 ex­pres­sion is high in sol­id tu­mors and min­i­mal in nor­mal tis­sues, oth­er sources (see an im­age from the Hu­man Pro­tein At­las at bot­tom) sug­gest B7-H3 (aka CD276) has medi­um to high ex­pres­sion in var­i­ous tis­sues, in­clud­ing the liv­er… If nor­mal cells al­so ex­press B7-H3, then this DART may in­duce more im­mune ac­ti­va­tion than ex­pect­ed, in non-tu­mor en­vi­ron­ments like the liv­er. This is just a hy­poth­e­sis, and we need to see fur­ther clin­i­cal da­ta on safe­ty – it’s hard to make a de­fin­i­tive call giv­en the lim­it­ed de­tail we’ve seen thus far.

“As we’ve iden­ti­fied to the FDA, we be­lieve that transamini­tis ob­served in pa­tients ad­min­is­tered MGD009 was like­ly a cy­tokine-me­di­at­ed event,” not­ed CEO Scott Koenig in a state­ment. “We are work­ing with the FDA and will pro­vide an up­date when we have ad­di­tion­al in­for­ma­tion. This par­tial clin­i­cal hold does not im­pact on­go­ing clin­i­cal stud­ies for enobli­tuzum­ab and MGC018, our oth­er B7-H3-tar­get­ed mol­e­cules.”

In a stun­ning turn­around, Bio­gen says that ad­u­canum­ab does work for Alzheimer's — and they're prep­ping a pitch to the FDA

Biogen has confounded the biotech world one more time.

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

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 62,600+ biopharma pros reading Endpoints daily — and it's free.

Vas Narasimhan. Getty Images

Failed PhI­II fe­vip­iprant tri­als pour more cold wa­ter on No­var­tis' block­buster R&D en­gine — and 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.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 62,600+ biopharma pros reading Endpoints daily — and it's free.

Take­da tees up $420M deal for celi­ac an­ti­dote, con­tin­u­ing R&D re­fo­cus

Sometime in the 1st century AD, a patient presented to Arataeus looking like a varicose ghost. He was “emaciated and atrophied, pale, feeble and incapable of performing any of his accustomed works,” the Greek physician wrote, with hollow temples and huge veins running all over his body.

A dysfunctional digestive system, Arataeus concluded – an imbalance he attributed to a “heat” deficiency in a system he and other Greeks regarded as functioning similarly to an oven – and coined a term: coeliac disease, after the Greek word for abdomen.

UP­DAT­ED: Clay Sie­gall’s $614M wa­ger on tu­ca­tinib pays off with solid­ly pos­i­tive piv­otal da­ta and a date with the FDA

Back at the beginning of 2018, Clay Siegall snagged a cancer drug called tucatinib with a $614 million cash deal to buy Cascadian. It paid off today with a solid set of mid-stage data for HER2 positive breast cancer that will in turn serve as the pivotal win Siegall needs to seek an accelerated approval in the push for a new triplet therapy.

And if all the cards keep falling in its favor, they’ll move from 1 drug on the market to 3 in 2020, which is shaping up as a landmark year as Seattle Genetics prepares for its 23rd anniversary on July 15.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 62,600+ biopharma pros reading Endpoints daily — and it's free.

Photo credit: Jacquelyn Martin

Where are the in­ter­change­able biosim­i­lars?

In June 2017, Leah Christl, former biosimilar lead at FDA, told a conference in Chicago that interchangeable biosimilars were likely coming to the US market within two years.

And although no interchangeable biosimilar has been approved by FDA yet, and Christl has since moved on to Amgen, progress on interchangeable biosimilars has been slow in the intervening years.

Most recently, Boehringer Ingelheim announced that it has completed, as of last April, a switching study necessary for launching an interchangeable biosimilar for Humira (adalimumab), although the company did not offer any further details on the timing of its submission to FDA or whether there will be an advisory committee to review the data. Boehringer already has an adalimumab biosimilar approved by FDA, which it will launch in the US on 1 July 2023.

UP­DAT­ED: The FDA sets a reg­u­la­to­ry speed record, pro­vid­ing a snap OK for Ver­tex's break­through triplet for cys­tic fi­bro­sis

The FDA has approved Vertex’s new triplet for cystic fibrosis at a record-setting speed.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 62,600+ biopharma pros reading Endpoints daily — and it's free.

FDA re­buffs lit­tle As­ser­tio Ther­a­peu­tic­s' long-act­ing ACTH for­mu­la­tion, shares sink

Tiny Assertio Therapeutics’ shares plunged pre-market on Tuesday, after the FDA has spurned its man-made version of the hormone ACTH, which was being reviewed as a diagnostic for patients presumed to have adrenocortical insufficiency.

The Lake Forest, Illinois-based drugmaker said its development partner West Therapeutic Development had received a complete response letter from the US regulator, which indicated that that certain “pharmacodynamic parameters were not adequately achieved” for the product.

IM­brave150: Roche’s reg­u­la­to­ry crew plans a glob­al roll­out of Tecen­triq com­bo for liv­er can­cer as PhI­II scores a hit

Just weeks after Bristol-Myers Squibb defended its failed pivotal study pitting Opdivo against Nexavar in liver cancer, Roche says it’s beat the frontline challenge with a combination of their PD-L1 Tecentriq with Avastin. And now they’re rolling their regulatory teams in the US, Europe and China in search of a new approval — badly needed to boost a trailing franchise effort.
Given their breakthrough and Big Pharma status as well as the use of two approved drugs, FDA approval may well prove to be something of a formality. And the Chinese have been clear that they want new drugs for liver cancer, where lethal disease rates are particularly high.
Researchers at their big biotech sub, Genentech, say that the combo beat Bayer’s Nexavar on both progression-free survival as well as overall survival — the first advance in this field in more than a decade. We won’t get the breakdown in months of life gained, but it’s a big win for Roche, which has lagged far, far behind Keytruda and Opdivo, the dominant PD-1s that have captured the bulk of the checkpoint market so far.
Researchers recruited hepatocellular carcinoma — the most common form of liver cancer — patients for the IMbrave150 study who weren’t eligible for surgery ahead of any systemic treatment of the disease.
Roche has a fairly low bar to beat, with modest survival benefit for Nexavar, approved for this indication 12 years ago. But they also plan to offer a combo therapy that could have significantly less toxicity, offering patients a much easier treatment regimen.
Cowen’s Steven Scala recently sized up the importance of IMbrave150, noting:

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 62,600+ biopharma pros reading Endpoints daily — and it's free.

That $335M JV Bay­er set up on CRISPR/Cas9? They’re let­ting the biotech part­ner car­ry on

Bayer committed $300 million to set up a joint venture on CRISPR/Cas9 tech with CRISPR Therapeutics $CRSP. But they’re handing off control now to the smaller biotech while retaining a couple of opt-ins for programs nearing an IND.

Bayer $BAY made much of the fact that they were going all-in on gene editing when they did their deal 3 years ago with CRISPR Therapeutics, which pitched $35 million in on their end. This was the cornerstone of their plan to set up new JVs that could make some serious leap forwards in hot new R&D spaces. Now CRISPR will have full management control of Casebia as they pursue programs in hemophilia, ophthalmology and autoimmune diseases.
Samarth Kulkarni, the CEO at CRISPR, made it sound like a natural progression.