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.