Tekmira’s ambition to grow a substantial clinical pipeline suffered a setback when it announced today that the IND for its candidate for the treatment of hypercholesterolemia, TKM-ApoB, has been delayed following a review of pre-clinical data. These data indicated that the ‘performance characteristics of the specific lipid nanoparticle formulation [...] have not met the Company’s expectations for the intended application'. This is the second substantial delay of Tekmira's pioneering ApoB program, and comes after the abandonment of a first ApoB candidate earlier this year.
The press release makes it very difficult to understand what the reason for the delay could have been. Given that LNP-siRNA delivery has been successfully demonstrated in hundreds of non-human primates, I have a hard time believing that they suddenly could not find a formulation that was able to potently knock down ApoB in the IND-enabling large animal studies. Even if they had some problems, it should not have led to an open-ended delay. I also don’t think that they could not get rid of the innate immunostimulatory potential of the siRNA they have been working with, because Tekmira had said that new modification patterns for this siRNA were able to abrogate immune stimulation also in the more sensitive ‘whole blood assay’ that they had developed. On the other hand, a clinically desirable profile for a given indication does consist of many more aspects besides potency and immune issues. Given that 2nd gen formulations are relatively recent, whereas DLinDMA-based 1st gen formulations have been quite thoroughly studied, some 2nd gen-related growing pains might be expected.
There have been questions raised about ApoB as a safe target for the treatment of hypercholesterolemia. Data in the RNAi literature itself and from the clinical program of ApoB-antisense molecule mipomersen (ISIS/Genzyme) show that inhibiting ApoB causes some, and sometimes indeed very significant accumulation of fat in the liver. While the medical importance is not clear yet, fatty liver and associated elevations in liver enzymes have raised some concerns. If Tekmira indeed sees the same toxicities that Mirus/Roche and Alnylam have seen (Marina Biotech and RXi also seem to have given up on ApoB), then it may be in the Company’s best interest to abandon the program. Accordingly, the press release was quick to highlight that the development of the company’s other 2 development candidates, one for solid cancers (TKM-PLK1) and one for Ebola infection (TKM-EBOLA) would be accelerated.
TKM-ApoB is also a particularly challenging indication as hypercholesterolemia is a chronic condition where you would have to safely administer a drug for sustained periods of time. Moreover, the regulatory bar for cardiovascular drug candidates has been raised quite a bit in recent years, especially in the US (outcome studies for most populations and increased safety scrutiny). The acute cancer and infectious disease indications may therefore be clinically more straightforward candidates to develop and, with Ebola, also offer earlier financial returns.
What speaks against the abandonment of ApoB as a target were references in the press release that the company would continue to study other formulations with ApoB. This, however, could also be interpreted as boilerplate or even a political move given that ApoB represents one of the five target picks from Alnylam and for that reason alone Tekmira may want to keep it alive at least on paper.
Overall, I am disappointed that the opportunity for TKM-ApoB to provide unequivocal clinical proof-of-concept data of potent gene knockdown with LNP-siRNA in the near-term will be missed. This now falls on the shoulder of Alnylam’s TTR program.
While clearly a bearish development, today’s news also provide some reason for optimism. One is that the strategic re-organization should be slightly positive for Tekmira’s finances as the new lead programs will be partly (PLK1- probably Alnylam and possible NCI support newly mentioned) and fully (Ebola) funded by others. Moreover, the company understands the importance of credible public relations by admitting to difficulties and calling disappointments what they are. It is also not pushing programs into the clinic because it is attractive to do so in the short-term: bonuses for the achievement of milestones; a relatively strong share price especially good if management does not intend to be there in the long run and a sale of the company was intended, etc- we’ve seen it all.
Just as RNAi Therapeutics was heating up, today is a humble reminder that in drug development setbacks can crop up when they are least expected. It will be important for the company to provide more clarity on today's development in the coming weeks, at least to the extent that it does not compromise their strategic position in RNAi triggers.