I "shorted" my first stock yesterday and it was Isis. Here's why...The first antisense drug approved by the FDA was Fomivirsen. A drug which treats a rare eye disease associated with AIDS. Besides having no sales from this drug, ever, This AO triggers an immune response which slightly ameliorated the symptoms of this disease. This drug's mechanism of action was a big fat ZERO. Nada. isis has had many big time failures since then. The lilly/Isis partnership brought us Affinitak. Big time loser. isis's much hyped Kynamro was rejected by the EU but was approved by the FDA in a close vote. This drug is toxic and demonstrated inconsistent knockdown of it's target. This drug will prove to be slightly better than Fomivirsen in terms of sales. They will not come close to their sales projections because there was a more efficacious and safer alternative from AEGR. The other day isis released "data" from their "proof-of-concept", small trial for SMA. I was shocked at how well this data was received by the wallStreet types. Adam feurestein called it "eterplirsen-esque". This trial was a small, single-dose design trial with NO placebo cohort. There have been numerous trials with various drugs that demonstrated putative efficacy in a small trial for this disease. ALL failed subsequently when tested in larger numbers and a control group. many of these hacks do not know the differences between a phosphorothioate AO and a radically different synthetic AO like morpholinos. 2'MOE's are highly anionic [they stick to[+] charged proteins which isis calls good biodistribution], more stable then their predecessors, moa is via enzymatic degradation, triggers immune reactions, sulfa linkage is very toxic and so on...PMO's on the other hand are neutrally charged at physiological pH, synthetic [does not break down] can withstand long exposure to stomach pH of 2, survives enzymatic degradation from endosomal entrapment in tac, it's moa is via steric blockade, less off-target effects because
Sentiment: Strong Buy
You seem to have a strong understanding of the technologies, but there are a few things you didn't mention that I am curious of your opinion. I actually like both SRPT and ISIS. I think ISIS's drug has a good chance to work, although I base that more on the pre-clinical data than the very preliminary phase I data we've seen so far. I agree it is too early to draw conclusions from that study, however there are differences between DMD and SMA that make developing drugs for each slightly different. For instance, in DMD you have a great biomarker of dystrophin that you have easily available disease-relevant tissue to sample for biopsy. In SMA, the tissue you want to sample is in the central nervous system, so doing analysis on the relevant tissue is obviously more difficult in human trials, as compared to what they've been able to do in pre-clinical models. So while Isis said they are trying to develop biomarkers, we probably are not going to have a comparable biomarker like dystrophin. However, in terms of chemistry, I agree I would probably be more confident if PMO were used, but I believe I read here, on this message board, that the original generation of PMO are off-patent now, so why not use that if they felt it would be better? Isis's drug has been developed by Adrian Krainer, who is obviously well versed in antisense splice-switching technologies. He co-authored a definitive review of the possibilities of antisense with Ryszard Kole, one of the key driver's of Sarepta's technologies. So I believe that that there was a reason they are going with this approach.
Additionally, this drug is given intrathecally, so it primarily stays localized to the CFS, so toxicities may be different/better than for previous antisense drugs. Also, they think that they will only have to dose it every 6 months. At least from their preclinical models, they were able to very efficiently cause inclusion of exon 7 in SMN2 to produce full length SMN protein. Curious on your thoughts.
You may not know it but Dr. Wilton first used the isis product in his efforts of pre-clinical research into DMD; however because it performed poorly he then used the AVII product which worked so well that AVII worked with him.
Cont'd..Isis's move into splice-switching/exon-skipping with their SMN-RX AO will need to be watched closely. This AO will have to survive long enough to escape endomal entrapment and then enter the nucleus. Protein membranes galore in the cells outplasma membrane, endosome membrane and then the nucleus. How does this anionic AO survive long enough after attaching itself to all these protein structures? Both AO's enter cells through endocytosis. How can the PMO outperform the 2'OME [the 2'MOE's cousin] in exon-skipping[eterplirsen] and achieve 6LOG10 viral RNA reductions while these other AO's are trying to survive marginal effects???? The answers are right in front of us.
Sentiment: Strong Buy
ISIS must be admired for their ability to suck in partnerships to pay for their failures rather than the continued dilution Of AVII/SRPT. In hindsight even the Prosensa partnership with GSK looks nice.