Alnylam announced last week that it has obtained the necessary approvals to start recruiting patients for their 3rd clinical RNAi Therapeutics candidate: ALN-TTR01. This is a truly exciting program, not only because it is supported by quite impressive pre-clinical data, but especially because it highlights the unique benefits that RNAi Therapeutics can bring to medicine which should also translate into favorable economics. In a related vein, ALN-TTR is now the 3rd clinical candidate based on SNALP delivery* that has entered the clinic within the last 18 months and thus demonstrates another important dynamic in RNAi Therapeutics: once a delivery technology has been established for a given tissue, a wealth of clinical candidates will flow from that.
ALN-TTR01 targets the transthyretin gene, a gene predominantly expressed in the liver and whose normal function is to facilitate the transport of Vitamin A and thyroxin, but when mutated is prone to misfold and deposit itself into a number of tissues as amyloid fibrils. This causes damage to the surrounding tissues, and typically first manifests itself as either predominantly polyneuropathy (FAP) or cardiomyopathy (FAC) depending on the genotype. Once a person becomes symptomatic, typically from around the age of 40 to 60, they usually will progress and succumb to the disease within 10-15 years. It is estimated that around 10,000 people are affected by the polyneuropathy-biased form of the disease largely in the Western world, with another possibly 40,000-100,000 affected by the cardiomyopathy-biased form largely in Africa. In addition, misfolding of normal/wild-type TTR may contribute to ageing more generally as it is quite common to find amyloid fibrils in autopies of men older than 80 years (for a more detailed review of TTR amyloidosis in the clinic, click here).
The only disease-modifying treatment available is liver transplantation. However, because of the limited supply of donor livers and limited efficacy, there is still tremendous need for new treatment options. Recently, fellow Cambridge-based FoldRx has announced late-stage clinical results for FAP with a protein-targeted oral small molecule aimed at stabilizing the correct fold of transthyretin, Tafamidis. While the top-line data indicate Tafamidis to have some potential as the first disease-modifying pharmacological agent for TTR amyloidosis, the unmet need will remain to be very high and based on this mechanism of action may actually synergize with an RNA-targeted drug like ALN-TTR.
Conservatively, peak annual sales for new drugs that can have a significant impact on this disease could therefore be in the $500M-1B range, largely for FAP in Western societies. This is quite attractive for an emerging biotech company like Alnylam, because large salesforces would not be required and the potential for rapid development. As with other ‘orphan’ diseases for which there are no great treatment options available, it is also possible that the eligible patient numbers are an underestimate and breakthroughs in drug development will lead to more patients being diagnosed with the condition. Optimistically, economic development in less wealthy societies could lead to a further expansion of patients that could afford the treatment.
The attraction of targeting the RNA in TTR amyloidosis is that the disease-causing protein will never be made in the first place. By contrast, a protein-targeting agent would have to constantly keep the protein in check. Similarly, ALN-TTR should also be an approach that is superior to liver transplantation in that it also addresses the potential of the wild-type TTR (as would be produced by the donor liver) to add to pre-existing deposits (applies to some, but not all genotypes) by targeting both mutant and wild-type TTR mRNA. In mouse models, this strategy has even been shown to effectively reverse such pre-existing deposits. Of note, down-regulation of TTR per se should be well tolerated and no untowards effects related to this have been reported in the very impressive non-human primate pre-clinical studies.
ALN-TTR is also exemplary because the target has been selected mindful of available delivery technologies (SNALP, developed with Tekmira Pharmaceuticals). To be clear, we are still early in the clinical learning curve for SNALP delivery, but given the unprecedented amount of non-human primate data in the peer-reviewed and patent literatures (by multiple groups) that demonstrate SNALP to be able to reliably, potently, and apparently without much toxicity knock down essentially any gene in the liver of non-human primates, one would think that the clinical experience should be similarly swift and impressive as the translation of SNALP from mouse to non-human primates (30g to 5-10kg) in the last 5 years.
ALN-TTR01 employs 1st generation SNALP technology which, as a rule of thumb, can knock down genes in the liver by half at dosages of around 1mg/kg in pre-clinical animal models. The preliminary efficacy findings with SNALP-ApoB1 in the clinic are consistent with the notion that similar ED50 dosages can be expected in humans. The present clinical trial, however, only aims to escalate ALN-TTR01 to a dose of 0.4mg/kg. Since the siRNA in ALN-TTR01 is a very potent one with an in vitro IC50 value in the low pM range, it is possible that TTR01 may show some knockdown at 0.4mg/kg. Accordingly, the ED50 value of this particular candidate was reported to be 0.3mg/kg in non-human primates. The reason why Alnylam chose not to go higher than 0.4mg/kg may be because Tekmira’s ApoB and Alnylam’s ALN-VSP02 results have indicated that they may run into relevant toxicities dosages of around 1mg/kg.
So while ALN-TTR01 has some promimse to be the TTR candidate that Alnylam will aim to fully develop, an important part of the dose-finding puzzle is that Alnylam has plans to develop a second TTR candidate, ALN-TTR02, in parallel which now employs 2nd generation SNALP formulations which have 10-50 fold lower ED50s in animal models as reported earlier this year (see here and here). As such 0.4mg/kg should already serve as a stringent test for the safety of SNALP delivery in general. Speaking of delivery and safety, the TTR program is also an excellent choice in that the liver is the target organ for the delivery, but not significantly impaired by the disease itself. Such impairment could impact both the efficacy and safety of SNALP delivery. In summary, while it is possible that ALN-TTR01 will eventually be abandoned because the rapid improvement of SNALP efficacy and safety dictate that follow-up candidates should receive priority, there is significant value that Alnylam will gain from this phase I trial.
Since the company is not blinded to the results and the initial efficacy of ALN-TTR can be assessed readily by measuring TTR in the blood, first results may become available early in 2011. ALN-TTR has all the potential to become Alnylam’s most valuable pipeline asset, both for its intrinsic commercial potential as well as an example of the unique characteristics that RNAi Therapeutics can bring to drug development.
* SNALP-RNAi candidates that have already entered clinical phase:
Declared SNALP-RNAi candidates about to enter the clinic:
SNALP-PLK1 (Tekmira; IND expected any time now);
a candidate by Roche for which the IND should be filed by year-end (undisclosed candidate);
ALN-PCS (Alnylam’s next RNAi Therapeutics candidate to enter clinic in H1 2011).