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.
