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.

Register for the GTC RNAi Research and Therapeutics meeting in San Francisco today (June 20-21).  Get a free RNAi Therapeutics blog T-shirt and 20% discount on registration by entering discount code 'RNABLG13'.

Alnylam Launches Pair of Pre-emptive PR Strikes to Cover Patent Losses

When the therapeutic relevance of a patent (Tuschl-I) that once had the potential to be broadly applicable to RNAi Therapeutics has been lost forever in Europe, and when in another US patent proceeding an important claim covering a cancer drug candidate that has just completed a phase I study has been declared invalid due to lack of written description support and may actually belong to your worst nightmare, it seems hardly a time to declare victories. Nevertheless, the PR department at Alnylam has risen to the challenge and done just that: two press releases (here and here) by the company shortly following these patent outcomes announced with great fanfare that Alnylam’s IP position had been bolstered. The reward for the skilled use of small qualifiers such as ‘requested’ and ‘key’ and obedience? Not just keeping your job, but actually being promoted to Vice President of Investor Relations.

Alnylam vs Silence Therapeutics et al.: Tuschl I in Europe

As Silence Therapeutics can attest, the Tuschl I patent estate, licensed by Alnylam and Merck, was once an effective deterrent against competing RNAi triggers of 21-23 nucleotides and/or base-pairs. While certainly an important contribution to the eventual discovery of RNAi triggers for use in human cells, its main vulnerability in IP terms derived from the fact that its research was mainly conducted in Drosophila fly lysates and tissue culture cells.

Consequently, in both the US and Europe its importance for RNAi Therapeutics has been waning to the point of being essentially relegated to the use of RNAi triggers isolated from Dicer processing reactions in the test tube (my bet is that we will never see such a product candidate). Nevertheless, some passages in the written description and claim language in the European T-I patent EP 1309726 was sufficiently ambiguous that it must have worried companies like Silence Therapeutics, BASF, and Sanofi-Aventis that it might be exploited by a legally aggressive company such as Alnylam as a convenient casus belli, causing them to oppose the patent. Specifically (former) independent claim 10 may have raised such concerns:

‘10. A method of producing knockdown cells, comprising introducing into cells in which a gene is to be knocked down isolated double-stranded RNA of from 21 to 23 nucleotides in length and corresponding to a sequence of the gene, that targets the mRNA corresponding to the gene and maintaining the resulting cells under conditions under which RNAi occurs, resulting in degradation of the mRNA of the gene, thereby producing knockdown cells.’

On February 29 and March 1 there was an unusually lengthy, and therefore probably highly contested Oral Hearing on the case, the outcome of which was quickly claimed by Alnylam (and patent co-owner UMass) as a victory. Particularly, it claimed that the ‘requested claims of the ‘726 patent were upheld without modification’ [emphasis mine]. Turns out that a comment poster on this blog last week got it right in that he/she pointed to the qualifier ‘requested’. To back up, essentially what happens in such an Oral Proceeding is that the Defending Party (here: Alnylam/Umass) submits alternative claim sets in case that the original claim language is rejected by the EPO based on the principle that a weaker patent is better than no patent at all (e.g. for the purposes of appearance).

After reading the now published documents from the Oral Hearing (if you have problems accessing them, you can request them by email from me), what happened is that Alnylam has indeed had the boldness to represent that after having been forced to modify the claims, the new claims were upheld in unmodified form. If you are an Alnylam investor/supporter, you may want to ask the new VP whether you are justified in feeling cheated by such an insincere conclusion and may want to re-think the general credibility of that company.

The upshot in terms of the patent: by clarifying the written description with expressions such as ‘isolating from combination’ and ‘in vitro’ and completely re-writing the claims, T-I is confirmed to be without relevance for RNAi Therapeutics. It remains important, however, for the commercialization of in vitro RNAi-based target discovery/validation services such as offered by companies like Cenix, although only for dsRNAs of 21-23nucleotides in length.

Alnylam vs Tekmira: Alnylam about to lose ‘key’ ALN-VSP patent

Similar to the T-I patent confrontation, Alnylam was quick to claim victory in yet another of its patent fights: ‘Alnylam retains key claims for Kinesin Spindle Protein (KSP) RNAi Patent in Interference Proceedings’. Briefly, last year the USPTO had called an Interference between an issued patent by Alnylam (US 7718629) covering an siRNA sequence in ALN-VSP02 (phase I studies completed) and a patent application by Tekmira which may in fact cover the same sequence.

As the UTPTO cannot grant identical claims in two different patents, the Interference proceeding will decide on the validity and priority of these claims. As Tekmira pointed out, this Interference has no relevance to that company’s pipeline. It could, however, mean that a patent covering a ‘key’ feature of ALN-VSP02 (an siRNA sequence) may not only turn out to be invalid, but actually belong to Alnylam’s worst nightmare: Tekmira.

By now, we all know the drill: look for the little qualifiers. ‘Key claims’ would be the obvious candidate here to home in on. But in this case, not even twisted logic can explain Alnylam’s conclusion, as in fact no claim (at least those contested and related to synthetic RNAi triggers) was ‘upheld’. Quite the opposite, the Appeals Board (BPAI) granted Protiva’s/Tekmira’s Motion 2 which requested that Alnylam’s KSP sequence claim be ruled unpatentable. The explanation was that while the claim covered dsRNAs between 15 and 30 nucleotides, only 19bp siRNAs with 2 nucleotide overhangs were presented in the application (--> lack of written description support). Since all the other claims relating to synthetic RNAi triggers are dependent on claim 1, I’m puzzled as to how Alnylam could ever claim that ‘key claims’ had been upheld, when in fact it looks like all the relevant claims will be revoked.

Claim 1 of US patent 7718629:

‘1. A double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of a human kinesin family member 11 (Eg5) gene in a cell, wherein said dsRNA comprises a sense strand comprising a first sequence and an antisense strand comprising a second sequence complementary to SEQ ID NO:1311, wherein said first sequence is complementary to said second sequence and wherein said dsRNA is between 15 and 30 base pairs in length.’

Protiva’s Motion 1 that Alnylam’s provisional applications be declared invalid as priority documents was denied. The importance of this ruling is that it may affect the outcome of the second stage of the Intererence proceeding which will be about determining priority. Because the provisional applications by Tekmira and Alnylam were filed only two months apart, with Alnylam having the earlier date, chances are that Alnylam would enjoy priority IF Alnylam’s ‘key’ claims were held valid. However, with the above ruling and a recent rejection of claim 32 in a pending patent application by Alnylam (serial number 13/165568), this seems highly unlikely (note: I am unable to see the pending patent application, but claim 32 should be directed at the KSP sequence). By contrast, the Appeals Board decided that, unlike Alnylam’s patent, the KSP sequence claims are supported in the written description in Tekmira's competing patent.

The upshot: Tekmira prevailed on all Motions (filed by Alnylam and Protiva), except for on the validity of Alnylam’s provisional applications for priority purposes and the Appeals Board deferring decision on including claim 32 from the pending patent application which, based on the March 6 rejection does not seem to help Alnylam much anyway. This means that not only are the ‘key’ sequence claims about to be rejected, but Alnylam’s worst nightmare may actually end up owning it.

Don’t take my word for it, you can read the relevant documents yourself here (T-I) and here (Interference). If you are somewhat familiar with reading such documents, it will only take you 30-45min to read (and understand) them each. It seems that Alnylam is relying on the fact that most news organizations and analysts cannot be bothered to read the primary documents and conveniently adopt Alnylam’s version of events. If you do a Google search for news related to Alnylam, you will see that this happens more often than not. After all, Alnylam has more money to feed into the biotech machine: why antagonize a lucrative source of income?

ALN-PCS02 Results Provide Glimpse of First RNAi Therapeutics Blockbuster

If the experts at Roche and other Big Pharma companies got you convinced that RNAi Therapeutics was about to disappear from the scene by pulling the plug on the technology…think again. Alnylam this morning reported tantalizing insights into the safety and efficacy of ALN-PCS02, a SNALP-formulated RNAi Therapeutic targeting PCSK9 for the treatment of hypercholesterolemia. Given that PCSK9 is viewed as potentially the next biggest thing in cardiovascular drug development after statins have come off patent, and considering the results so far from the monoclonal antibody and antisense competition, this RNAi Therapeutic has the potential to become the field’s first blockbuster. As we know, a field does not need too many blockbusters to become more widely accepted, and it is acceptance, not so much lack of scientific progress, which has been lacking over the last 2-3 years. Together with the ALN-TTR01 results reported in November, I expect these results to dramatically change perceptions about RNAi Therapeutics in the pharmaceutical industry. And if I had to write the script, Alnylam will announce a share offering tomorrow or Friday afternoon in order to go hostile on Tekmira to remove the uncertainties arising from their use of Tekmira’s SNALP technology which critically enabled these results and on which most of Alnylam's $400M market cap depends on.

ALN-PCS02 Phase I Data

This trial was a simple single-dose escalation trial in subjects with slightly elevated levels of bad LDL cholesterol. Dosing in the 5 dose cohorts commenced at 0.015mg/kg and went up to 0.250mg/kg with each cohort consisting of 3 subjects receiving an intravenous infusion of ALN-PCS02 and 1 receiving placebo. As could have been expected with this particular rationally designed '2nd gen' SNALP formulation, robust target protein knockdown was observed at the highest dose tested with a mean 60% reduction in plasma PCSK9 levels presumably 3-5 days after administration. In line with PCSK9 genetics, this type of knockdown entailed a mean 39% reduction in bad LDL cholesterol. Importantly, and again consistent with the wealth of non-human primate data, this knockdown was sustained for days and weeks. Given that ALN-PCS02 apparently was well tolerated, with the only noted adverse event being a rash that was likely to be related to the mode of administration and not the drug itself, Alnylam now plans further dose escalation to a) increase knockdown potency, but b) also extend the duration of PCSK9/LDLc suppression. This is particularly desirable in light of the competitive situation.

The PCSK9 Competition

Needless to say, having now two examples in short order where RNAi Therapeutics unambiguously hit their targets, proof-of-concept of technical success can be claimed and one can now focus on the medical and commercial potential of these therapies. In this regard, the competition in the PCSK9 space is fierce. Big Pharma and Big Biotech have fielded their A-teams to develop monoclonal antibodies against PCSK9. Since much of the LDL-related effect is due to PCSK9 in the serum, this target is a particularly amenable to MAb technology.

Sanofi-Aventis/Regeneron are most advanced with REGN727 which is in the middle of a number of phase II studies. Amgen also reported recently phase I results with their PCSK9 MAb. Studies with both compounds have shown more potent LDLc reductions of around 65% compared to the 39% with ALN-PCS02 so far. This, of course, is a good reason for Alnylam to go ahead with its plans and continue dose escalation. However, once you achieve the type of 60-70% reductions in LDLc, the next major focus becomes safety, and so far the RNAi Therapeutic looks quite competitive in that regard.

As discussed in October, the PCSK9 antisense compounds by Santaris and ISIS have fallen a bit behind due to probably both safety (Santaris) and efficacy (ISIS) issues, although I expect ISIS to reciprocate tomorrow by presenting TTR knockdowns at their Investor Day tomorrow that are more pronounced than Alnylam’s first attempt with ALN-TTR01.

[Update 5Jan12: ISIS reported 44% mean TTR reductions at 200mg per week, very similar to ALN-TTR01 at 1mg/kg; and 81% reductions at 400mg per week, a dose that I consider too high for tolerability and commercialization; ISIS also disclosed that the BMS-partnered PCSK9 candidate was dropped citing a slow partner and regulatory concerns about PCSK9 as a drug target].

Overall, we can now conclude that the ALN-TTR01 results were no fluke (I never expected that to be the case anyway) and that in theory all targets in the liver are fair game now for RNAi Therapeutics. Moreover, the data show that the preclinical data with SNALPs translate very well into humans, removing a considerable uncertainty and opening up the prospect of further improvements in SNALP delivery based on what Tekmira and Alnylam have presented over the last few months.

A biotech company does not need many these PCSK9-type products to rise into the ranks of Big Biotech. While there is still a long clinical way to go, I believe that sometimes you are allowed to cheat and look at hard preclinical data, and in doing so I believe that today we may have seen the first glimpse of an RNAi Therapeutics blockbuster. I’m wondering how the Roches and Pfizers will be feeling over the coming months and years as the field of RNAi Therapeutics matures at this rate. It is also an opportunity for new entrants to build strong positions in the space with relatively small investments (still). Am I a bit vindictive today? Yes, definitely.

Brewing Genzyme Takeover Battle Highlights Value of High-Impact Drug Innovation

Orphan disease drug developer Genzyme had emerged as the drug development of the future by developing innovative drugs which have a high impact for diseases of major unmet medical need and then being rewarded for it with exceptional pricing power. Recent manufacturing problems, however, has led to the business model being forgotten over regulatory angst and activist shareholder actions. Sanofi-Aventis probably simply could not resist the depressed share price and was the first to blink, with others, like GSK, quickly moving in from the sidelines.

That high-impact innovation is a critical part of Pharma’s strategy in the face of its small molecule patent cliff freefall should be obvious. GSK, after announcing an orphan disease initiative last year, for example has entered into microRNA and antisense collaborations with Regulus, Santaris, and ISIS, and Sanofi-Aventis has just entered into relationships for microRNA therapeutics with Regulus and a quite significant one with Oxford Biomedica last year for the development of gene therapies for ocular indications (note: Genzyme is one of the more prominent gene therapy companies). Meanwhile, Pfizer and probably almost every other major pharmaceutical corporation are also building orphan disease capabilities.

I think the action around Genzyme illustrates how quickly investor sentiment towards a company or an entire industry like RNAi Therapeutics can change. It is not that Big Pharma can delay their future planning forever, and should an opportune situation arise they are likely to act quickly.

What I find curious about Genzyme though is that they are really platform agnostic, and I believe that caused some pipeline problems and contributed to Genzyme’s weak stock market performance in recent years after some of the low-hanging fruits had been picked.

Of course, this, as illustrated by ‘Genzyme-like’ opportunities like Alnylam’s ALN-TTR, is where the big opportunity is for RNAi Therapeutics. As treatments become individualized down to the gene level, the druggable genome size and and platform efficiency become major issues. In fact, going after Genzyme may actually be a mistake stemming from Big Pharma’s age-old temptation to pay top dollars for growing top-line revenues. Big Pharma does not need (orphan) drug development expertise, which is where it can well compete with biotech companies anyway, but innovative platforms to complement such expertise.

In any case, this should lift the entire biotech sector, and a similar spark, possibly with a Swiss flavor, may soon ignite RNAi Therapeutics.

Regulus and Sanofi-Aventis to Develop MicroRNA Therapeutics for Major Unmet Medical Needs

Regulus Therapeutics and French pharma giant Sanofi-Aventis announced today that they would co-develop MicroRNA Therapeutics with an initial focus on fibrosis (PR by S-A, PR by Regulus, PR by Alnylam and ISIS). The deal demonstrates the need for innovative approaches for the treatment of diseases for which the pharmaceutical industry has long failed to develop meaningful therapies. The deal, valued at potentially over $750M, includes a $25M upfront, relatively realistic $50-60M in mid-term option fees and equity investments and major R&D support by Sanofi-Aventis, and provides Regulus with a nice cash cushion going forward. The ~$50M in realized partnership funding to date from GSK and Sanofi-Aventis should also make shareholders of both RNAi Therapeutics company Alnylam and antisense company ISIS Pharmaceuticals happy which are still the majority owners of Regulus.

Today’s announcement comes less than a month after Regulus Therapeutics secured exclusive access from the University of Wuerzburg to intellectual property related to fundamental work on the role of microRNA-21 in cardiac fibrosis. This should also be the lead program in the collaboration and justify Sanofi-Aventis transferring $25M of hard cash. Beyond the heart, fibrosis, a form of tissue scarring, is also widely observed in other organs such as the lung, kidney, and liver, and new treatment options are desperately sought after. Witness the fate of a drug for idiopathic pulmonary fibrosis (IPF) developed by Intermune of which the data appeared to be somewhat borderline, but which an FDA advisory panel recommended for approval earlier this year essentially because of the very significant unmet medical need (it was subsequently rejected by the FDA).

In addition to miR-21, other microRNAs have also been found to play a role in fibrosis, and both microRNA antisense and microRNA replacement approaches are conceivable. Given that these microRNAs often occur in various tissues, targeted delivery approaches may be preferable. On the other hand, should less specific delivery prove to be well tolerated, it is possible that the same drugs may be of use in other indications such as cancer for which some of these microRNAs, especially miR-21, have also been found to play a role.

The previous deals with GSK involved up to 4 microRNA targets in inflammation and targeting miR-122 for the treatment of Hepatitis C viral infection. Danish competitor Santaris also has an agreement with GSK covering up to 4 antiviral MicroRNA Therapeutics programs. Given that there are significantly less microRNAs than there are genes and microRNA biology is still relatively young, these deals seem to balance the concern of unwittingly giving away too much to Big Pharma with allowing enough flexibility for data-driven drug development.

In addition to proving to be a very good investment for Alnylam and ISIS, being part of Regulus also allows these companies to establish new relationships with major pharmaceutical companies. It is probably not a coincidence that the initial GSK-Regulus partnership was followed by the ISIS-GSK rare and infectious disease deal earlier this year. Of note, Sanofi-Aventis, under the new leadership of CEO Chris Viehbacher, recently entered into a relationship with California company Traversa for the development of protein-based RNAi delivery.

Overall, it is very encouraging to see that a number of companies in Big Pharma do understand the need to invest in potentially transformative new technologies to address major unmet medical needs. I hope that this summer will provide more such proof points.