Monday, April 30, 2012

A New Order: Tekmira Senior, Alnylam Junior

There have been a few developments supporting that Tekmira’s campaign to re-gain control over its technology from Alnylam and be recognized for its scientific accomplishments is as strong as ever (see 'Tekmira Tells Alnylam 'Enough is Enough''). 

Notably, based on LinkedIn entries, it appears as if key personnel in Alnylam’s RNAi delivery group got the axe during the latest round of lay-offs at the company.  Among those is Mark Tracy, former President of the Controlled Release Society and who according to LinkedIn 

'Built and led a multi-national RNAi delivery research and development alliance of industry and academic partners that enabled human clinical proof of concept for RNAi and a growing pipeline of clinical products. Matrixed-managed an international multi-department, mutli-organizational team of over 50 FTE. Directed technology assessment and due diligence activities. Headed delivery project and alliance management and business and financial planning.'

which would arguably make him one of the central players in Alnylam's relationship with Tekmira (note the emphasis on 'multi-national/international'). This should further fuel takeover speculations as in a merger there certainly wouldn’t be room left for liposomal delivery research organizations at both Tekmira and Alnylam.  It would further be consistent with the recent $85M dollar fund-raising by Alnylam that followed the take-over script.

Perhaps symbolizing the shifting legal fortunes of the companies, a Court Order has just gone out declaring Tekmira (Protiva) the Senior Party, and Alnylam the Junior Party in the ALN-VSP02 Interference.  As you will remember, the Interference, an intriguing side-show to the Alnylam-Tekmira conflict, was declared by the USPTO when it found that Alnylam’s issued ALN-VSP patent (US 7718629) and a patent application by Tekmira were too close in nature for them to co-exist. The goal of the Interference now is to determine who first invented the subject matter that both patent (applications) are claiming.  

Based on important decisions on Motions by the companies in March, decisions which will set the tone for the rest of the proceedings, it already looked like Alnylam’s case stood on very weak grounds. Still, with Alnylam, as the patent holder, being considered the 'Senior Party', and Tekmira as the competing patent applicant being considered the ‘Junior Party’, Tekmira faced certain procedural disadvantages, including burden of proof with regard to claiming temporal priority in the upcoming phase of the Interference. 

However, in what must be a very satisfying turn of events for Tekmira, the judge now has agreed with the small Vancouver-based company's request that it actually should be the Senior Party, and widely recognized RNAi behemoth Alnylam only the Junior Party:

This not only makes it more likely that Alnylam will lose control over the liver cancer drug candidate at stake, but it is highly symbolic for what could unfold over the next 6 months or so leading up to their $1B day in court.  If it comes to that, the very existence of Alnylam will be in question.   Another question is whether the music will still be playing then.

Tuesday, April 24, 2012

ISIS Claims Scalp of Santaris CEO

After noticing that the former President of the US operations of Danish LNA antisense company Santaris, Art Levin, had just joined muscle microRNA Therapeutics company miRagen, I was alerted that this has been in the wake of a major shake-up at Santaris. Most notably, it appears that the CEO of Santaris, Soren Tulstrup, either handed in his resignation, or, more likely, was let go.

Privately-held Santaris, of course, has been a fierce rival of ISIS for supremacy in the antisense space.  Having former ISIS insider Art Levin join Santaris 2 1/2 years ago was in fact a bit of a coup for that company.  Its LNA technology is probably the most potent/high-affinity in the space for many applications.  ISIS, however, has had the benefit of increased financial might and having built a large patent estate that it is (ab-)using to sue, preferably smaller competitors with the obvious intention of making it difficult, if not impossible for those to raise capital and pursue business development opportunities.  It is rumored that ‘partner’/satellite company Alnylam has probably paid the price in the tens of millions for the privilege of going public.   

Not long ago, ISIS sued Santaris for unduly hiding under the Research Exemption in its various relationships including Pfizer, Enzon, GSK, and Shire.  In parallel, ISIS and microRNA spin-off Regulus have been haunting Santaris by questioning Santaris’ ability to develop its exciting lead candidate, miravirsen, a miR-122 antagonist for the treatment of HCV.  As a result, Santaris was dumped by GSK in favor of Regulus’ miR-122 program despite having the superior data package, which is also born out by the clinical data so far (here for the latest update at EASL).

Regulus announced this week that it was awarded another HCV miR-122 patent, in Japan, concluding with the remark that it was continuing to pay 'attention to hepatitis C'- somewhat ironical given that its clinical entry seems to be delayed forever.  Seeing that announcement, I had thought that this was one of the unnecessary PRs that I often take as a sign of weakness. In hindsight, it was probably just a case of adding insult to injury.

I myself have had reservations about the wisdom of building the company’s financial future on a program for which it may be lacking access to some of the key patents in the space.  Although one may assume that in the wake of its scientifically leading efforts in miR-122/HCV, Santaris will have in turn built IP to which Regulus would need access if it were to develop its own miR-122 antagonist,  such a strategy has been a high-stakes gamble for sure.  Along with the ISIS lawsuit questioning Santaris’ fundamental business development strategy, I would therefore not be surprised if the CEO had faced some tough questions by Santaris' investors about his decisions and consequently was ousted. 

Clearly, an exit in the form of an IPO or takeover had long been overdue for that company.  The company’s technology, pipeline, and relationships, also in light of what’s out there already (i.e. ISIS and AVI Biopharma), should have easily supported this, if not for the lawsuit and threats thereof.

Sunday, April 22, 2012

New Clinical Results Put ALN-PCS Firmly in Business in PCSK9 Race

Alnylam reported on Friday updated results from the phase I single-dose, dose-escalation trial of its hypercholesterolemia candidate ALN-PCS02.  Importantly, the data demonstrate that ALN-PCS can produce clinically meaningful 30-40% reductions in LDLc (the ‘bad’ cholesterol) for much of the 28 study days of the study after only a single infusion of the drug.  This bodes well that ALN-PCS may be useful for the millions of patients that cannot achieve their LDL cholesterol goals despite the availability of statins.

After presenting solid PCSK9 knockdown results in January from subjects receiving up to 0.25mg/kg of the PCSK9 siRNAs which are critically enabled by Tekmira's SNALP delivery technology, the latest data include the results from subjects receiving 0.4mg/kg PCSK9 siRNAs after the decision had been made to increase the top dose based on the favorable safety-efficacy profile thus far.  This was important because despite the solid plasma PCSK9 reductions seen up to 0.25mg/kg (roughly 50% mean reductions throughout the 28 days), both the peak and average mean LDLc reductions until then had been less than 30% and 20%, respectively.  Probably not enough to effectively compete in the hot PCSK9 field.  

Based on the latest data, which included impressive >80% target plasma PCSK9 reductions, it is reasonable that ALN-PCS will be able to achieve average (=sustained) ~45-50% LDLc reductions in a once-every-4-week dosing regime.  This would put it just slightly behind Regeneron’s PCSK9-targeting monoclonal antibody REGN727 in terms of LDLc lowering.  It may be more difficult for ALN-PCS to achieve the LDLc lowering efficacy of Amgen’s PCSK9-targeting antibody AMG145 which has been hailed at the recent ACCconference to produce LDLc lowering of ‘up to’ ~60-80% at apparently pristine safety and tolerability.  I should add, however, that the warts-and-all data on AMG 145 have yet to be made publicly available.

In light of the intense competition in the PCSK9 space and a possible potency disadvantage for this surrogate marker, it will be interesting whether, firstly, the pharmaceutical industry (note, a larger partner will have to be found to financially shoulder the unavoidable outcomes trial), and eventually the market-place will adopt this new class primarily for their absolute LDLc reducing ability or in order for patients to achieve their lipid goals.  Some LDLc proponents, of course, stress that the lower the LDLc, the better.  On the other hand, whether a drug can lower LDLc by 50% or 70% won’t matter for many patients when it comes to simply achieving standard LDLc goals of 100mg/dL or even 70mg/dL.  In that environment, the focus in making the choice between competing drugs would shift to factors beyond mere LDLc lowering potential, particularly safety.

While ALN-PCS is mainly suffering from the fact that it is given following pre-treatment with corticosteroids, something that also had important impacts on the PCSK9 and LDLc efficacy data, the once much-touted safety profile of the PCSK9 antibodies have taken a significant hit with the publication of phase II data from REGN727 (McKenney et al. 2012).  In addition to one serious adverse event, a case of potentially life-threatening inflammation of blood vessels (leukocytoclastic vasculitis) that, however, readily resolved after giving corticosteroids, there was an apparently dose-dependent, adverse event-related increase in the rate of discontinuations, with ~15-20% discontinuing treatment in the biweekly dose cohorts in study 11565.  Next to the case of vessel inflammation, the AE-related discontinuations involved cases of neutropenia, fatigue, injection site rashes, chest pain, and headache/nausea. 

Amgen has yet to publicize more detailed data for AMG145.

Next to multi-dosing and the safety and efficacy impacts of omitting corticosteroids in future studies, another important question for ALN-PCS that remains to be answered in the upcoming trials will be testing the candidate in patients on statins.  REGN727 encountered problems here as patients concomitantly taking statins experienced an LDLc rebound effect after around 2 weeks.  Whether this is a class effect of agents merely blocking extracellular PCSK9 (such as antibodies), instead of inhibiting the synthesis of both intra- and extracellular PCSK9 such as ALN-PCS is an interesting question.  

This mechanistic difference could also be the big wildcard when it comes to the ultimate arbiter of clinical utility, the outcome trials: despite the clear evidence that LDLc levels are inversely related with cardiovascular events, with all the complicated feedback loops of lipid biology and related diseases, mechanistic differences could easily erase 20% differences in LDLc lowering.  An indication that these theoretical considerations are translating into the clinic may be deduced from the observation that (in Alnylam's words) ‘importantly, ALN-PCS demonstrated consistent clinical activity toward both PCSK9 and LDL-C independent of baseline levels of PCSK9, highlighting the unique mechanism of action for a PCSK9 synthesis inhibitor.’

For Alnylam, the near-term challenge will be thus to find a large partner, probably without a stake in PCSK9 yet, willing to take the risk with RNAi Therapeutics mainly for the differentiation it offers over the other PCSK9 approaches.  A stumble of the monoclonal antibody class could easily mean that ALN-PCS becomes the lead candidate in the PCSK9 market, estimated by many to be a multi-billion dollar one. 

Monday, April 9, 2012

Rational Design and Animal Studies Remain Gold Standard in Liposomal Delivery Development

In a recent paper (Chen et al 2012), the ‘Lipidoid Group’ from MIT admitted that their library screening method to find useful lipids for therapeutically relevant in vivo applications was flawed.  Essentially, the lipids in the much-heralded 2008 paper with over 200 citations (Akinc et al: 'A combinatorial library of lipid-like materials for delivery of RNAi therapeutics') were tested as crude lipoplexes in tissue culture, whereas successful in vivo delivery has very different and additional demands (stable circulation, extravasation, tissue penetration, biodegradability etc etc)- as is known from decades of liposomal delivery research.  To improve upon the predictive value of the lipid library screening approach, the group now reports, in a solid academic paper, a microfluidics-based approach for formulating lipids into more SNALP-like particles.

I’ve been following with a mix of amusement and annoyance that the Alnylam-funded MIT LNP effort has been getting so much attention to the point that many, if not most, observers believe that the next-generation LNPs are based on that research.  Needless to say, if one bothered to study the respective research coming from Vancouver versus those from MIT, it should be clear which effort alone is the therapeutically relevant one (the Vancouver one to remove any doubt).  The clinical SNALP pipeline says it all.

Who is to blame for this confusion and mis-attribution of credit?  Much of it comes down to scientific journalism looking for eye-grabbing headlines, best if high-profile institutions like the MIT are involved.  Of course, Alnylam does not always bother to point out the relative therapeutic relevance of company-funded research when it issues a press release to go along with a scientific publication.  At least in that regard does their inordinate investment in 10 MIT post-docs pay off.  A bit of a luxury in these times of lay-offs, if you ask me, and I don't expect it to be renewed as the original contract is running out any day now.  I respect Nature Biotechnology as a journal, but having such high visibility, it also has a responsibility to make sure that its prime criteria for selecting papers for publication is originality and research quality, and not renown as it sometimes seems to be the case.

This brings me to Prof. Rob Langer from the MIT and a talk by him at an OTS meeting a few years ago on his exciting ‘lipidoid’ research.  As most readers will be aware, Prof. Langer is famous, amongst other achievements, for fathering what must be dozens of biotech companies (and probably making a buck or two in the process) in various areas of nanotechnology.  Indeed, the apparent frequency of the spin-outs and the different technologies involved makes me wonder at times how a single person, no matter how genius, can be expert in all of them.  In any case, if VCs are keen to throw money after him that's up to them and their investors.  What bothered me about that talk though was that Prof. Langer played along the theme of ‘lipidoids’ having all these unique and interesting properties, including structural differentiation, without really showing proof for them and which, according to the latest paper, do not seem to exist: a SNALP formulation takes on the shape of a SNALP (in this case one with constitutive positive charge at physiological pH).

Looking at the positive side of things, the latest research shows that microfluidics promises to be a technology that allows you to test various SNALP formulations without it costing you an arm-and-a-leg as is current practice.  However, the research also shows that there is no substitute for testing them in vivo as a first indication of therapeutic utility (a lot of mice were used in that study to arrive at that conclusion).  The research parenthetically also strongly supported my impression that microfluidics is unlikely to yield the 20nm-sized SNALP LNPs as Alnylam said their microfluidics-based collaboration with Vancouver start-up Precision Nanosystem would yield (interesting to see Alnylam-supported LNP microfluidics in both Vancouver and Cambridge).  A recent publication involving Precision Nanosystem by the way suggests the same (Zhigaltsev et al 2012) .  In my opinion, 40nm is going to be a magic number for SNALP LNPs.

With the exception of perhaps 1st-generation LNP delivery to phagocytes, and as had been known in the liposomal research community (including Tekmira, of course) for a long time, rational design approaches and animal experimentation are most likely to rule the delivery space for the foreseeable future.  

Friday, April 6, 2012

Putting Korea on the Map of RNAi Therapeutics

As RNAi Therapeutics is taking a little breather after a hectic and overall quite positive start to the year, I will reflect today on RNAi Therapeutics development in a country that is probably not on your radar when it comes to innovative drug development: Korea (population: ~50 million).

About the size of Kentucky (the 36th largest US state) and located on an peninsula between economic powerhouses China and Japan, the economic development of South Korea has been nothing short of spectacular. 60 years ago one of the poorest country on earth, it is now a developed economy and a leader in various industries including electronics and automobiles. It would be arrogant and a big mistake to view the Apple vs Samsung Tablet Wars as another example of a technologically inferior Asian company 'slavishly' copying Western products and willfully ignoring intellectual property. Instead, it may be a better example that once an attractive market has been spotted and the commitment to excellence been made, the resources to turn it into a reality exist in Korea.

Admittedly, innovative drug development in this country is still nascent and requires improvements on many levels. Furthermore, while its population and yours truly enjoy a quality universal healthcare system, paying $100.000 for a year’s worth of drug therapy is virtually unheard of in this country and it is still unclear where the drug reimbursement chips will have fallen once the first RNAi Therapeutics get approved.

These uncertainties, however, are not holding back RNAi Therapeutics development. It might surprise you that there is probably more therapeutic RNAi development activity in Korea than for example in Germany, a country which made its mark in the early days of the technology (see Tuschl, Kreutzer-Limmer/Ribopharma), but where lack of risk-taking entrepreneurial spirit caused RNAi Therapeutics to join the ranks of many other failed biotechnology efforts there. Even the last Man standing in Germany, Silence Therapeutics, is propped up by largely foreign money and I wonder for how much longer.

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By contrast, the RNAi Therapeutics industry in Korea is quite healthy, although the recent global RNAi Depression has certainly also left its mark there. There are easily over a dozen companies engaged in RNAi therapeutic development: from the small pure-play to the research/reagent vendor looking to expand into therapeutics to the large integrated Chaebol.

With the exception of the pure-play company, it is interesting to note that most efforts are motivated by established business interests rather than by considering the absolute medical and commercial potential of RNAi Therapeutics per se. This can include the selling of oligonucleotides (note: some of the largest oligonucleotide vendors come from Korea), or chemistry and biology expertise which might for example be useful for RNAi delivery purposes (note: Korea is a center of biosimilar development).

The latter tendency of tying RNAi Therapeutics to existing, often non- or only indirect pharmaceutical business interests has the advantage of providing certain funding security. It, however, also carries the risk that should the science not neatly fit into the specific motivations, RNAi Therapeutics could get the axe despite of what I consider the rapidly expanding set of diseases that can be addressed with today’s RNAi Therapeutics technologies.

Of course, this is written by somebody with an interest in seeing resources allocated to RNAi Therapeutics development. You could also take the view that the conservative stance of Germany finds vindication in the good employment numbers and less ugly economic picture amid the EURO crisis, and has made the right decision to virtually exorcise innovative drug development (and have the US do it for them). In fact, in many regards Korean business attitudes are not all that different and closely tied to utility and feasibility. A good illustration of that are the changing names of the College at Dongguk University (Seoul) where I currently hold a position as Assistant Professor:

1) until 1994 College of Agriculture and Forestry
2) 1994-2008 College of Life Resources and Science
3) 2008-2009: College of Life and Science
4) 2009-now: College of Life Sciences and Biotechnology (largely non-drug)

It is a fair question whether it is sustainable to regard RNAi Therapeutics as an extension of ‘safe’ and (still) profitable business activities. Also as a result of scientific inefficiencies that arise from putting RNAi Therapeutics into the strategic straight-jacket of corporations, it would be liberating to see especially the larger Korean companies start viewing RNAi Therapeutics more as an independent value creation opportunity. Once that happens, the country’s pharmaceutical industry stands a good chance at emerging as a leader in one of the major drug development platforms of the future.
By Dirk Haussecker. All rights reserved.

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