RNAi is the Future of Cardiovascular Disease

At least, this is what Big Pharma and Biotech is saying right now following deals between pure-play RNAi companies Arrowhead Pharmaceuticals and Dicerna with Amgen and Eli Lilly, respectively, and the sale of The Medicines Company with its lead PCSK9 RNAi asset really being only a matter of timing.  Besides its new relationship with Eli Lilly announced yesterday, Dicerna has an ongoin CVD-related NASH/NAFLD collaboration with Boehringer-Ingelheim.  In addition, Wave Life Sciences and Akcea, the commercial Ionis spin-out, have been pursuing cardiovascular targets along with Pfizer and Novartis, respectively, using the competitive RNaseH antisense gene knockdown technology.

Drugging the undruggable

Part of the attraction of RNAi for CVD for the pharmaceutical industry is because the targets that come from large genetic studies (e.g. ApoCIII, Apo(a), ANGPTL3) based on chance alone are not readily druggable.  To make matters worse, amorphous lipid macromolecular aggregates are particularly difficult to target with either small molecules or antibodies.

Infrequent dosing

What a difference 10 years can make.  When Protiva (now Arbutus) was one of the first to enter a systemically administered RNAi therapeutic against LDLc-related ApoB into the clinic a decade ago, it often found itself ridiculed for using RNAi in such an indication.  Systemic RNAi back then required relatively frequent (1-3 weeks) intravenous administration which would make it an unlikely modality for widespread diseases that ideally require decade-long preventive treatment strategies.

Fast-forward to the present and now we have subcutaneously delivered RNAi with potential dosing frequencies of up to once-a-year as evidenced by the lead candidate of this crop, phase III asset Inclisiran by The Medicines Company.  If the remarkable safety profile holds up following about 2000 patient years of clinical experience, such a drug should be very widely prescribed, not least because it should enjoy great adherence, one of the major impediments of treatment success in cardiovascular disease.   

Undoubtedly, it has been the Inclisiran performance so far that has attracted the attention of players like Eli Lilly and Amgen, the latter of which, of course, should know particularly well about the competitive threat from RNAi having an antibody-based PCSK9 agent on the market (Repatha).  Beyond the upcoming slew of phase III read-outs with Inclisiran, it will equally be interesting to see the types of new targets being pursued and the clinical validation of targets like Apo(a) by the antisense competition.

Marina Biotech Continues to Drive Sector Consolidation, Acquires Novosom’s Liposomal Delivery IP

Marina Biotech, formerly known as mdRNA, continues to snap up assets in the oligonucleotide therapeutics and diagnostics space, this time acquiring the liposomal delivery IP from Novosom, a privately held drug delivery company based in Germany. This comes only a week after shareholders approved mdRNA’s merger with tkRNAi company Cequent Pharmaceuticals to form Marina Biotech. It will be curious to see whether Marina’s strategy of challenging Alnylam's industry-leading position by taking advantage of the depressed market for oligonucleotide therapeutics will succeed in luring Big Pharma and pay off for shareholders. The investment this time: $5M in newly issued stock.

Similar to Silence Therapeutics, Marina acts on the premise that in order to capture those lucrative partnerships, being able to provide a choice of delivery technologies, plus some claims in RNAi triggers, too, is key. This, of course, is in contrast to Tekmira’s so far quite successful strategy of doing one thing very well, meaning clinically maturing and expanding the applicability of its industry-leading SNALP delivery technology and avoid some of the deal frenzy and dilution of effort.

By the looks of it, Novosom has to be considered one of the more bona fide delivery companies. Similar to Tekmira’s SNALP, Novosom’s SMARTICLES can change their surface electrical charge and therefore reconcile (serum and storage) stability with endosomal release functionality. Unlike SNALPs, however, these liposomes also contain anionic lipids, in addition to cationic and neutral lipids, and do not employ PEG stabilizers. This stability can be attributed to the negative charge of SMARTICLES at phyisiologic pH which ought to avoid various interactions with host factors and resulting toxicities often associated with positively charged lipids. However, as the pH acidifies upon endosomal uptake of these particles, they become positively charged and competent for membrane disruption and cytoplasmic release. For similar reasons, ionizable SNALPs as practiced by Tekmira not only employ PEGylation, but are also essentially uncharged at physiologic pH.

In terms of IP, from the looks of it, Novosom has assembled a respectable IP estate with various fairly broad patents granted also in the important US market. This should provide Marina with considerable options to leverage its other liposomal assets, trp-cage targeting technology and amino acid-derived lipids, that I have felt lacked robust patent protection when used in liposomal formulations similar in composition to Tekmira’s SNALPs.

Theory and IP, of course, are only part of the equation. In terms of actual data, the literature bears out the tolerability of these liposomes. In terms of in vivo knockdown efficacy, I haven’t really seen much for liposomal delivery of siRNA in the peer-reviewed literature. There was, however, a paper on the liposomal delivery of a CD40 antisense oligo (under license from ISIS) in a rodent inflammatory disease model and that supported specific CD40 knockdown and disease amelioration while the unformulated antisense oligo appeared to be inactive. In general, based on the literature and also Novosom’s website, their technology seems to be in the late rodent stage and yet to be validated in larger mammals including non-human primates and Man.

There should, however, be an open IND for the delivery of a DNAi compound (no mis-spelling) by PRONAI which makes use of Novosom’s technology. However, it appears that PRONAI’s funding situation may have delayed actual dosing.

Novosom also entered into at least 2 collaborations with RNAi companies. One with (now defunct) DNA-directed RNAi company Nucleonics for treating hepatitis viral infections, and one with Boehringer-Ingelheim for the validation of drug targets in the liver and lung. Again, because Novosom is a private company I can only speculate whether the lipids used by Nucleonics in their soon aborted phase I study stemmed from the Novosom collaboration. Similarly, the status of the Boehringer-Ingelheim collaboration is unclear to me. Who knows, but maybe Boehringer-Ingelheim is actively looking for (liposomal) delivery and triggers for the development of RNAi Therapeutics, which raises another point: although the press release did not specify this, but selling what looks like the entire IP estate would appear to be tantamount to selling the entire company, existing partnerships and programs included.

But back to the fundamental question: Consolidating into a one-stop-shop, almost an ‘anti-Alnylam’, a la Marina and Silence versus technological deep-dive a la Tekmira- which strategy will create more shareholder value? The next 3 months should provide for some of the answers.

Please let your voice be heard and vote on the right.