Cancer RNAi Therapeutics Moving On

As RNAi Therapeutics targeting genes expressed in the liver, especially for orphan indications, have captured much of the recent interest in the technology, it is time to once again pay closer attention to RNAi Therapeutics in the oncology space.

Atu027 and TKM-PLK1 Moving into Phase II

Silence Therapeutics have just announced that they got the green light from the German regulators to test Atu027 in combination with small molecule gemcitabine in pancreatic cancer.  Following a short phase Ib to establish the safety of the combination (note: the original phase I was a monotherapy trial), the plan is to rapidly move into phase II which will aim at establishing proof of concept for efficacy.  Depending on the funding situation, it is possible that the company will expand Atu027 into other indications in phase II, possibly in collaboration with private investigators in the UK.

Clearly, the strength of Atu027 is its safety profile so far, one that has surpassed my own expectation for this positively charged lipoplex formulation.  The clinical attraction meanwhile is that Atu027 aims at a quite novel anti-cancer mechanistic approach by inhibiting metastatic spread by fortifying the vascular endothelia. 

The challenge with Atu027, however, is that the gene target, PKN3, remains a relative black box.  This not only demands a certain leap of faith in mechanistic terms, but also complicates the clinical development as biomarkers and other tools are not readily available.

This is quite different from TKM-PLK1, the cancer RNAi Therapeutics by Tekmira.  Polo-like kinase 1 is a hot target, but specificity/safety issues have so far dogged drug development efforts with small molecules, most notably represented by Boehringer-Ingelheim.  By contrast, the SNALP RNAi delivery approach promises to be more cancer tissue targeted and consequently should avoid some of the dose-limiting toxicity observed so far, especially the hematologic ones.

TKM-PLK1 has flown a bit under the radar and the phase I update late last year did not capture much attention.  This is probably because the response rate did not seem too much to get excited about.  However, as Ian MacLachlan, the CSO of Tekmira, pointed out at the AsiaTides meeting last week, it was a small dose-escalating phase I trial (20-30 patients) in advanced solid cancer patients and only four patients actually received TKM-PLK1 for two or more cycles (6 infusions over 2 months) at 0.6 mg/kg or above, dose and durations you would think would be required for advanced cancer patients to get a chance to respond in the first place. Notably, two out of those four showed signs of efficacy: one partial response and one with stable disease after more than 6 months on study drug.

In light of that, the phase I profile of TKM-PLK1 supports my view that it could be the foundation for an exciting PLK1-related cancer franchise for Tekmira and I look forward to seeing the full results presented at the upcoming AACR meeting.  My attention will be particularly focused at any direct measures of target knockdown.  Beyond that, with the company’s healthy financial situation, I look forward to a rich phase II strategy involving a number of solid cancers and innovative study designs such as patient selection based on genetic criteria.  As good as Tekmira's science is, they now also need to be as proactive and innovative on the clinical front.

ALN-VSP02 and CALAA01 Falling Behind

As TKM-PLK1 and Atu027 are moving into phase II, fellow early movers in oncology RNAi ALN-VSP02 and CALAA01 are falling behind. 

The next step for ALN-VSP02 will be a phase I in hepatocellular carcinoma (‘real’ liver cancer) in China under a license by Alnylam to Ascletis.  As noted by Patrick Lu of Sirnaomics at AsiaTides though, it would be a mistake to believe that the Chinese regulatory environment is any less demanding than in the West.  Au contraire, it seems that much more paperwork is required to file an RNAi-realted IND as the authorities there are keen on building their expertise in this new technology.  Expect a delay of at least 6 months from IND application to the green light to go ahead, after all the paperwork has been submitted.  For Tekmira watchers, I expect the $5M milestone thus in 2014, not in 2013.

While ALN-VSP02 still has a pulse, despite of the fact that it lacks the long circulation thought to be necessary for cancer uptake (note: delivery to liver cancer is a very different animal from delivery to normal liver; TKM-PLK1 is a long circulating SNALP), RIP CALAA-01 by Arrowhead Research.  Having said that, the value of CALAA-01 to Arrowhead Research has not been lost entirely as the company has filed for a patent covering a low/high dose strategy of minimizing immune stimulation.  

As the recent high-profile pulling from the market of a pegylated peptide (Omontys by Affymax) due to hypersensitivity, even anaphylactic reactions demonstrate (and also the infusion reactions reported by Alnylam in their SNALP RNAi Therapeutics trials), administration-related hypersensitivity reactions are an issue for the entire drug development arena.  In order to rescue the value of a number of blockbuster franchises, I expect that changing administration schedules could be one area attracting increased attention.  A patent here could have unexpected value.   

A New Crop of Cancer RNAi Therapeutics

Behind TKM-PLK1 and Atu027, a new crop of cancer RNAi Therapeutics is emerging.   Dicerna has signaled that it will finally move into clinical development (Q1 2014) with a liposomal Dicer-substrate formulation with a focus on liver cancer.  Of note, the liposomal formulation process is quite distinct from that of SNALP involving sequential core and envelope formation steps, potentially amenable to ligand-directed targeted delivery.

Another program worth following is another one for liver cancer, the subject of a collaboration of Korean company Bioneer andSanofi-Aventis.  The attraction of that program is that the nanoparticle here, SAMiRNA, comprises a single molecule, even to the extent that the RNAi trigger and delivery components can be manufactured on a single column.  Although I’m opposed to the fundamental notion that the ease of route of administration and the manufacturing process should drive drug development, don’t underestimate the attraction of meeting idealistic product profile when it comes to partnering with Big Pharma.    

The efforts above are a reminder that cancer could be an even bigger commercial opportunity for RNAi Therapeutics than liver-related indications.  The genome-wide targeting opportunity with RNAi Therapeutics has not been lost.  The pharmaceutical industry is watching.

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