Friday, April 25, 2014

Celgene in Surprise $710M Upfront Antisense Deal

Hands up if you had heard of Nogra Pharma and antisense therapeutics before yesterday; or of Giuliani International Limited and antisense, Nogra’s original name?

I can’t imagine that before the $710M upfront licensing deal with Celgene was announced yesterday many would have heard of the company, and for a good reason. 

Substantial scientific doubts…

Nogra Pharma has been developing an antisense oligonucleotide for the treatment of inflammatory bowel diseases with a pivotal phase III study apparently planned this year.  The candidate in question, GED-0301, is a simple first-generation phosphorothioate DNA oligonucleotide targeting Smad7 for gene silencing.  It does not even have a gapmer structure for increased potency, an industry standard for more than a decade now:

‘Phosphorothioate single-stranded oligonucleotides matching regions … and 107–128 (5'-GCTGCGGGGAGAAGGGGCGAC-3', oligo 4) of the humanSmad7 complementary DNA sequence (GenBank accession number AF010193) were synthesized in the sense and antisense orientations and used as described’

Although this was not the case in this original 1999 publication which provided the mechanistic rationale for GED-0301, later publications on a preclinical model of IBD in mice and subsequent phase Iresults state that this oligonucleotide had been then modified to rule out non-specific immune stimulation, although the functional confirmation of this was not presented.

Also interesting is the fact that in the phase I study which was conducted in 15 subjects, the only evidence for systemic exposure of this oligonucleotide came from only one subject in which it was ‘barely detectable… suggesting that the drug is not probably absorbed following oral administration.’

…but maybe it does something after all

On the other hand, I get the fact that this oligonucleotide, provided orally in enteric coated tablet form, is supposed to act on the intestinal epithelium and mucosa, including associated immune cells.  The drug would therefore in theory not have to reach systemic circulation in order to be effective.  Nevertheless, I would still expect it to show up there following uptake by the intestinal lining as a result of normal oligonucleotide drug elimination typically involving the break-up into smaller pieces which then get released into the blood to be renally excreted. 

At the very least, this apparent absence of oligonucleotide in the blood indicates that cellular uptake is inefficient.  Combine this with the inherent inefficiency of first-generation RNaseH, and you will have a hard time imagining that there would be potent on-target gene silencing.  Nevertheless, an interaction of the phosphorothioate oligonucleotide with particularly gut phagocytic cells is likely and this might have a therapeutic immune-modulatory effect on the disease.  

To convince me of an on-target silencing effect, I would have needed to see much more extensive PK/PD studies, additional control oligonucleotides, as well as a detailed characterization of the non-specific immune modulatory effects of GED-0301.  Just switching it from a non-modified, to a methyl-cytosine modified oligonucleotide without supporting characterization seemed a bit quick.

Moreover, in order to firmly establish the delivery strategy, I would have liked to see RNaseH silencing by the same chemistry and route of administration for a gene that is unrelated to immunology. 

The press release indicated that the phase II results from a blinded study for the treatment of Crohn’s Disease were positive and that they will be presented in a major publication and medical meeting.  It is likely that Celgene liked what it saw in the results and that this explains the enormous deal value.  After all, if Celgene has been able to turn cancer drug Abraxane (albumin-conjugated paclitaxel) into a commercially successful drug (closing in on being a blockbuster), their sales force should also do well in selling another drug of uncertain mechanism and debatable risk/benefit.   


Anonymous said...

Seems that they are going to present data at the TIDES conference May 12-15, Plenary Sessions:

Phase II Clinical Study Results of GED-0301, a Smad7 Antisense Oligonucleotide for the Oral Treatment of Crohn's Disease
GED-0301 is an antisense oligonucleotide which targets Smad7. An oral dosage form that affords delivery and topical activity of GED-0301 in the terminal ileum and right colon was designed and tested in Phase I and II clinical trials. This presentation provides the results from the Phase II Proof of Concept clinical trial.
Salvatore Bellinvia, M.D., Chief Medical Officer, Giuliani SpA, Italy


Anonymous said...

AstraZeneca, now interested in nucleotide therapeutics?

Anonymous said...

Is it just me or is the perception of deteriation in quality of this an actual reality?

The lack of reader participation indicates most readers have now seen through Dirk's pasty thin veneer of scientific objectivity to understand him as the marionette of vested money interests looking to make a quick buck.

Worse, the lack of participation from Dirk himself, indicates he too has tired of renting himself out for such purposes. It is a tacit acknowledgement of knowing his game is up.

Anonymous said...

This drug is released in the terminal ileum/right colon area.

But there are also many crohn's sufferers whose crohn's affects other regions.

Do you think this drug could be easily adapted so it can be active throughout the gut/digestive tract??


Anonymous said...

anyone have the ph11 data from TIDES??

Dirk Haussecker said...

It's been said they pulled out of that TIDES presentation. Too much daylight and peer-review for Celgene?

RE Crohn's. Yes, it's also my understanding that Crohn's can basically present throughout GI tract, so that would indeed be a formulation challenge.

Anonymous said...

Did the phase 2 data satisfy you? Only two weeks of dosing and it beats all approved drugs in rates of remission?

JRosenblum said...

Maybe time to revisit this post:
19 Mar 2015 NEJM with pretty great results:

The proportions of patients who reached the primary end point were 55% and 65% for the 40-mg and 160-mg mongersen groups, respectively, as compared with 10% for the placebo group (P<0.001). There was no significant difference in the percentage of participants reaching clinical remission between the 10-mg group (12%) and the placebo group. The rate of clinical response was significantly greater among patients receiving 10 mg (37%), 40 mg (58%), or 160 mg (72%) of mongersen than among those receiving placebo (17%) (P=0.04, P<0.001, and P<0.001, respectively). Most adverse events were related to complications and symptoms of Crohn’s disease.

We found that study participants with Crohn’s disease who received mongersen had significantly higher rates of remission and clinical response than those who received placebo. (Funded by Giuliani; EudraCT number, 2011-002640-27.)

Dirk Haussecker said...

Not sure, GI expert seems partly perplexed by results, partly asking questions about trial design:

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