Merck ‘Not Pulling Back in RNAi’ as Company Closes RNAi Trigger Research Unit

[Update: important clarification by Merck on the site closure, here]

As reported by the San Francisco Business Times and Xconomy, Merck will be closing its RNAi Trigger research unit in San Francisco as part of global restructuring efforts that include cutting ~12,000 employees by 2015 as Merck seeks to drive short-term bottom-line growth. While not exactly a move that will instill confidence in RNAi Therapeutics, a Merck spokesperson nevertheless was quoted as stating that ‘[Merck] is not pulling back in RNAi’ and that they have ‘still couple hundred employees working in RNAi’.

Global Pressures

Merck’s announcement is certain to be touted by some as representing a devastating verdict on the feasibility of RNAi Therapeutics. The news, however, comes at a time when confidence in innovative R&D in the pharmaceutical industry in general is at an all-time low to the degree that Big Pharma extols the licensing of phase III candidates (and beyond) as investments in innovation.

You’ve all heard it, too: Economic uncertainty and strained healthcare systems in the US and Europe, the patent cliff and declining R&D productivity worsened by a challenging, extremely risk-averse regulatory environment, all mean that the easiest way for Big Pharma executives to keep their jobs is to slash early-stage R&D and have their successors deal with the mother-of-all R&D productivity declines that undoubtedly will hit the industry 10 years down the line.

Merck actually has been one of the more vocal Big Pharma supporters of R&D. In February it withdrew its long-term financial guidance to preserve R&D flexibility, and Merck's CEO Ken Frazier as recently as in a July 13 opinion piece in the Wall Street Journal warned US politicians that their policies are killing pharmaceutical innovation and threaten US leadership: click here for the must-read.

Merck’s agony of having to decide between Wall Street and Washington-mandated short-term bottom-line growth (mind you, London, Berlin, and Paris are no better when it comes to appreciating the benefits of biomedical innovation), has also been apparent in recent comments on RNAi Therapeutics. In a June 28 interview with FierceBiotech from the BIO International Convention, David Nicholson, Senior VP and Head of Worldwide Licensing and Knowledge Management, stated that Merck has ‘chosen to stick with RNAi’ drawing parallels to the monoclonal antibody space that had undergone similar moodswings before becoming a widely accepted new drug modality.

This interview by the way was also picked up and tweeted by Alnylam which must have been concerned how the SF site closure, a development certainly in the making and rumored then, would be interpreted.

Importantly, the revelation today that a ‘couple hundred’ employees will continue to work on RNAi is consistent with Merck being far from giving up on RNAi Therapeutics, just as Novartis’ decision last fall not to expand their relationship with Alnylam was more a verdict on that specific relationship rather than Novartis' general view of RNAi Therapeutics.

Closure of SF Unit as Focus Shifts Towards Products and Delivery

If you accept these statements and RNAi Therapeutics remains viable at Merck, then the move to close the RNAi Trigger research unit at San Francisco Mission Bay and eliminate ~50 jobs can be interpreted as a shift in Merck's strategic focus from RNAi triggers to products and delivery.

RNAi triggers and related IP, of course, remain important for RNAi Therapeutics development and it is inconceivable that Merck would write off the $1B investment in Sirna Therapeutics' RNAi trigger IP as it continues to consider RNAi Therapeutics. It therefore seems that as Merck puts less effort into RNAi triggers, it must have felt satisfied with its IP position and acquired expertise there so that it was prepared to sacrifice this part of RNAi Therapeutics at a time that every unit, but emerging markets and biosimilars it seems had to contribute their cost savings.

Going forward, much of the success of Merck's RNAi Therapeutics will probably rest on its West Point, Pennsylvania, formulation/delivery unit. Among the research conducted there have been detailed liposomal siRNA delivery studies with the goal of using RNAi as a therapeutic and not merely target validation tool. Still, as Jeremy Caldwell, a person with a target discovery/validation background takes over responsibility for RNAi at Merck, we will have to see how fast Merck will transition RNAi into clinical development.

In addition to progress in delivery, it is the adoption of RNAi Therapeutics by the global R&D organization that will determine the clinical success of the technology at Merck. It may be one of the ironies of Roche’s RNAi efforts that they tried to preserve RNAi innovation by isolating the Kulmbach unit as a Center of Excellence, but then failing to rally broad support for the technology from the disease area groups. Because of liposomal delivery and Merck’s product focus, acceptance of RNAi Therapeutics by its lipid management, metabolic disease, and, of course, oncology groups will be particularly important.

PS (8/2/2011): In a statement to Gene Silencing News, Merck confirmed that the closing of the San Francisco site does not represent a departure from its RNAi Therapeutics strategy and that it still considers the technology to be transformative for human disease treatment.

Preview: Phase II Study of AtuRNAi PF-04523655 for Wet AMD

PF-04523655, formerly known as RTP-801i, is the clinically most advanced RNAi Therapeutic candidate and has been in two phase II studies for diabetic macular edema (DME) and the exudative form of age-related macular degeneration (wet AMD). ‘655 is a 19bp blunt-end AtuRNAi trigger targeting the RTP801/REDD1 apoptotic stress response gene in the choroid. ‘655 was originally discovered by Silence Therapeutics and Quark Pharmaceuticals, licensed to Quark and eventually partnered by Pfizer which is largely in control of clinical development.

Data from the DME study were reported earlier this year (see related blog entry here). These showed that while ‘655 was well tolerated and efficacy was strongly suggestive of superiority versus laser photocoagulation, the old standard-of-care, Pfizer and Quark agreed to run a phase IIb study using higher dosages to take into account the emerging standard-of-care for DME, Lucentis, a monoclonal antibody against VEGF. Data from the phase II wet AMD study should be imminent.

Unlike the DME study, the ~150 patient wet AMD trial design for the wet AMD study, MONET, already took into account Lucentis as the new standard-of-care in that indication. As you can see from the treatment groups below, the goal is to either show superiority to Lucentis, or at least show a synergistic effect when used in combination with Lucentis (a positive outcome would be to show superiority of Arms 4 or 5 over Arm 1). Unlike many other wet AMD/DME-targeting agents in development, ‘655 should not act via the VEGF pathway and therefore has potential as an add-on to Lucentis.

Treatment arms in phase II wet AMD study:

Arm 1: 0.5 mg intravitreal injection of Lucentis given every 4 weeks from baseline to Week 12 (note: 0.5mg once a month is the recommended standard for Lucentis);

Arm 2: 0.5 mg of Lucentis given by intravitreal injection at baseline followed by 3 mg of PF-04523655 given every 2 weeks from Week 4 to Week 12;

Arm 3: 0.5 mg of Lucentis given by intravitreal injection at baseline followed by 1 mg of PF-04523655 given (weekly) from Week 4 to Week 12;

Arm 4: 0.5 mg of Lucentis given at baseline by intravitreal injection followed by 3 mg of PF-04523655 given every 4 weeks from Week 4 to Week 12;

Arm 5: 0.5 mg of Lucentis given by intravitreal injection at baseline followed by 1 mg of PF-04523655 (30 minutes later) given in combination every 4 weeks from baseline to Week 12.

Dosing had been completed and preliminary data from the study were known already in November 2010. Unfortunately, while ‘655 as single agent or in combination with Lucentis did show improvements in mean visual acuity over the 3 month dosing period, 6 and 9 letters respectively, it failed to show superiority to Lucentis at any of the doses at the important 4 month primary endpoint. No remarkable safety events were seen in MONET (all this can be gleaned from reading Quark Pharmaceutical’s latest prospectus). By comparison, large studies with Lucentis (0.5mg, monthly) have shown 6.6-9.8 letter average improvements from baseline at two years.

Outlook for ‘655 in Wet AMD

Most likely due to missing the primary 4-month endpoint, Quark Pharmaceuticals already indicated that following full data review Pfizer is unlikely to directly enter phase III trials, but would either decide to run a phase IIb study or abandon the program altogether. It is disappointing that ‘655 has apparently not shown synergism when used together with Lucentis as one might have expected from the presumed mechanism of action of ‘655, but possibly not from an immunostimulatory antiangiogenic VEGF-related artefact. A synergistic effect, however, may be masked by the initial Lucentis activity and only emerge over time. What is also often forgotten when it comes to the competitive space for the novel therapeutics in ocular diseases is long-term safety, not just absolute efficacy and dosing frequency, so studies with longer dosing than just the 3 months in MONET may be worth the risk. Maybe such safety and efficacy signals will emerge from the upcoming full data presentation.

Finally, instead of combining '655 with an antibody like Lucentis, combining it with the approved anti-VEGF aptamer Macugen (an oligonucleotide) might have practical advantages. Macugen has been struggling in the marketplace following the introduction of Lucentis due to perceived potency disadvantages. Curiously though, it is Pfizer that holds the commercial rights to Macugen, and combining it with '655 to reinvigorate the competitiveness of Macugen must have crossed their mind.

On the Importance of Semple-Wheeler

The Semple-Wheeler (S-W) patents can be considered essential intellectual property (IP) for those liposomal siRNA formulations currently in development that have shown clinical promise. Because Alnylam obtained significant control over Semple-Wheeler (S-W) through a license from Tekmira, this patent estate has been important to Alnylam in controlling access to Tekmira’s SNALP delivery technology and, equally important, keeping Tekmira close to its chest.

Today, I will provide a brief re-cap of S-W and explain why its strategic importance is rapidly waning as patent expiration dates draw close.

What Semple-Wheeler Covers

Most critically, S-W cover LNPs comprising

a) ionizable lipids (e.g. DLinDMA, MC3), a modified lipid that prevents particle aggregation (e.g. PEG-lipid) in addition to the nucleic acid cargo (e.g. siRNA; Semple US6858225); and/or

b) a cationic lipid, a non-cationic lipid, a PEG-lipid conjugate in addition to the nucleic acid (i.e. the chemistry of a SNALP liposome; Wheeler US6815432).

While, until S-W has been tested in court, there will always been some uncertainty as to the real scope of the claims, e.g. in light of such newfangled terms like ‘lipidoids’ or other classes of lipids that may not have been covered by the examples in the specification, such strategies would seem to stand on weak scientific grounds.

Ownership and Control over Semple-Wheeler

Originally, Old Tekmira had an exclusive license to S-W from the University of British Columbia (UBC). Realizing the importance of liposomal delivery for the first wave of value creation in systemic RNAi Therapeutics, Alnylam obtained exclusive rights to Tekmira’s exclusive rights to S-W in January 2007. By this, Old Tekmira’s ability to further monetize this patent estate became greatly limited, and, in the absence of other significant RNAi assets at that time (i.e. lack of Protiva IP, know-how, and trade secrets), was widely regarded as a de facto satellite company of Alnylam.

Fair enough- not only did Alnylam pay $8M in upfront for these rights and is on the hook for milestones and royalties, Old Tekmira was in turn granted RNAi trigger IP and the use of S-W for the selected targets. Interestingly, the latter has been brought into question by Alnylam by stating in their recent Response to Tekmira’s Amended Complaint that Tekmira actually does not have rights to S-W and that Alnylam had given Tekmira such notice:

‘23. Consistent with this pattern, Tekmira has failed to adequately disclose the limitations of its licenses to investors. Despite the clear terms of the license agreements and notice from Alnylam that it lacked licenses to the Semple & Wheeler patent series and Isis patents, Tekmira made representation to the contrary in its public filings with the SEC and in other documents provided to investors.’

It is unclear on what grounds Alnylam makes these claims. Does it claim that Tekmira apparently was never granted such rights, or does it simply mean that Alnylam considers the lawsuit brought by Tekmira as grounds for terminating these rights? In any case, the irony is not lost as it is Tekmira through which Alnylam gained access to S-W and it is for Tekmira to terminate Alnylam's rights if at all.

Strategic Importance of Semple-Wheeler in Light of Upcoming Patent Expirations

In biotechnology, patent infringement typically only becomes ground for lawsuits either when drugs/devices allegedly covered by such claims are about to be commercialized or as generics want to muscle their way onto the markets before the expiration of patents covering an innovator drug. Because of the so called Research Exemption, it is very difficult to enforce patent rights before any commercialization of related drugs, i.e. during the period that patented technologies are being used for drug development pre-commercialization.

Certain licensing and collaboration agreements may be considered to fall between the Research Exemption and the commercialization of drugs, as they may involve technologies covered by 3^rd party patents, even if these patents can be assumed to have expired by the time drugs are ready to be commercialized. In other words, the LCAs may be interpreted as a way of commercializing patents. Although such actions are less common, emotions are running high, so Alnylam may use S-W as pre-text for throwing a wrench into any significant LCA that Tekmira may strike. Old Tekmira e.g. once sued Protiva for allegedly licensing S-W to Merck, and one can only speculate to what extent Alnylam instructed Old Tekmira to do so.

The reason though why such actions are unusual is that chances of enforcing such patent rights are slim if the parties involved in an LCA word their agreement appropriately (e.g. by simply excluding the appearance, implicitly or explicitly, that the partner gains rights to S-W; performing work in countries where S-W is not in force etc etc). As such, Tekmira has substantial freedom to strike deals as long as SNALP-based drugs are not being commercialized before the expiration of the fundamental S-W patents…which should be around 2015-7:

Semple US6858225 (ionizable LNPs):

Date of patent: Feb 22, 20005

Filing date: June 29, 2001

Priority date: May 14, 1997 (claims priority to No. 08/856474)

Approximate term of patent: Feb 22, 2005- May 14, 2017

Wheeler US6815432 (SNALP chemistry):

Date of patent: Nov 9, 2004

Filing date: Feb 24, 2003

Priority date: June 7, 1995 (claims priority to No. 08/5981501; note that although this is just before the famous June 1995 cut-off date, because the patent application of ‘432 was filed after that date, patent terms are according to the new regime)

Approximate term of patent: Nov 9, 2004- June 7, 2015

Tekmira business development prospects

Two factors largely controlled by Alnylam have long held back Tekmira’s full business development potential. In addition to granting Alnylam exclusive rights to S-W, it was particularly Alnylam’s RNAi trigger gate-keeper claim that tied SNALP technology to Alnylam.

Until the expiration of S-W, only those companies with access to S-W (Tekmira, Alnylam, Roche, Takeda, and supposedly Novartis) could commercialize SNALP-based drugs until 2017. Because Tekmira has 8 target picks for which it can use S-W, Tekmira is able to offer an acquirer or product-specific co-development partner more than enough access to S-W until then. 6 years is not a long time in drug development, about the time it would take from initiation of phase I to approval if all goes smoothly. The ~2017 expiration of S-W therefore means that its strategic importance for the development of SNALP-based RNAi Therapeutics is waning rapidly. 2007-8 was a different story.

In this light, a gate-keeping position of Alnylam in RNAi triggers, based on the Tuschl and Kreutzer-Limmer patents would be the real rate-limiting factor, as the terms for these patents may last into 2021-2. However, the RNAi trigger landscape has changed significantly over the last 2-3 years as the importance of Kreutzer-Limmer is rapidly diminishing in Europe and is nowhere to be seen in the US, Tuschl I turns out to be of no relevance for therapeutic applications, and even the validity of Tuschl II is now being questioned. Even if T-II can survive the Utah challenge, as it covers only certain RNAi triggers with certain 3’ overhangs, it is not the type of gate-keeping IP that KL or T-I may have become with a bit of luck.

Consequently, with the strategic importance of S-W waning and access to RNAi triggers ceasing to be a limiting factor, Tekmira’s business development is almost entirely out of Alnylam’s control. If, as a result of the litigation, Alnylam lost all rights to Tekmira’s technology (certainly a plausible outcome if it comes to a trial*), the attraction of partnering with or acquiring Tekmira would increase even more.

* As I am writing this, Alnylam has just filed a $150M shelf registration with the SEC. This typically happens in anticipation of selling stock to the public. The timing of this shelf registration is unusual though, because Alnylam has over $300M in cash/cash equivalents, meaning that with the current and anticipated burn, it should not have a need for raising funds any time soon- under normal circumstances. Given my assessment of the strength of Tekmira’s case and the existential risk to Alnylam’s business, it would not surprise me if Alnylam’s lawyers are advising the company to settle the case. A $150M capital raise may be in the right range to allow for Alnylam to survive and remain an independent company.

A hostile takeover attempt as an alternative explanation? On paper, this would probably make most sense for Alnylam, but I don’t think so.

Solid Calimmune DNA-directed RNAi Therapeutics Candidate for HIV Nearing Clinical Development

With the backing of a $20M grant from the California Institute of Regenerative Medicines (CIRM), Calimmune has made progress in advancing a DNA-directed RNAi (ddRNAi) Therapeutics candidate for the treatment of HIV/AIDS towards clinical development in early 2012 (here a recent blurb in the Financial Times). Similar to an HIV candidate developed by City of Hope (CoH) and Benitec before it, the new treatment involves the modification of a patient’s own blood stem cells (hematopoietic stem cells, HSC) with a gene therapy comprising of an expressed small hairpin RNAi trigger. Although Calimmune is not prepared yet to share the details of this program, based on my review of the research conducted by groups associated with Calimmune, the likely candidate has the potential to become one of the most exciting ddRNAi Therapeutics product candidates to enter the clinic yet.

HIV therapy today and motivation for gene-based stem cell therapies

The treatment of HIV has made tremendous progress. Once a certain death sentence, for those with access it has instead largely become a chronic infection that can be kept in check with cocktails of small molecules targeting a variety of stages in the viral life-cycle (highly active antiretroviral therapies or hAART). Nevertheless, the need for taking daily pills for life comes at the cost of side effects, generally reduced quality of life, and the emergence of viral resistances. There is no cure yet for HIVAIDS.

Actually, there might be one example of a cure for HIV. In 2006, an AIDS leukemia patient, aka the Berlin patient, underwent a bone marrow transplant as a treatment for his leukemia. The doctors selected a bone marrow donor whose cells carried defects in the CCR5 gene on both chromosomes. After the transplantation, the patient was not immediately put back on antiretroviral therapy to allow for recovery of his new hematopoietic system. Surprisingly, despite the absence of drug treatment, the virus has not recurred to this day leading more and more experts to talk of the first functional cure of HIV/AIDS.

In hindsight, this result did not come totally as a surprise. CCR5 had been known to be an important entry receptor for the common CCR5-tropic HIV isolates. Epidemiologic evidence gathered in the mid 90s indicated that people with certain CCR5 deletions on both chromosomes were protected from HIV infection, and those with a CCR5 defect on only one chromosome had, on average, delayed disease progression and improved life expectancies. In fact, this research led to the development and recent approval of a class of drugs blocking the CCR5 protein (e.g. Maraviroc by Pfizer).

There remains, however, great interest in developing gene-based stem cell medicines against CCR5 (and other HIV viral and host targets) in the hope of generating HIV medicines with less side effects, reduced chance of viral resistance (one way of HIV resistance to drugs targeting the CCR5 protein is to bind to CCR5 in the presence of drug), and maybe even a cure. The Berlin patient indicates that CCR5 may be an ideal target for such gene-based stem cell therapies.

Two possible mechanisms by which such a strategy may succeed are based on eradication of HIV-permissive cells as they are killed off by the virus while the CCR5-impaired cells persist, or by improving the immune function of CCR5-impaired cells thereby allowing them to fight HIV infection in other places.

City of Hope/Benitec and the first DNA-directed RNAi Therapeutic for HIV

Calimmune’s ddRNAi candidate is not the first one for HIV. The City of Hope, with the financial backing of Benitec, already entered one into clinical development (rHIV-shl-TAR-CCR5RZ), results from which were reported last year in Science Translational Medicine. Recognizing the advantages, if not need, for targeting multiple stages of the HIV life-cycle at once, this candidate was not a pure ddRNAi therapeutics, but a triple RNA therapeutic that in addition to the shRNA RNAi trigger which targeted the viral tat/rev mRNA involved an expressed TAR RNA decoy and an expressed (RNA) ribozyme targeting CCR5. Notably, all three expression cassettes were driven by U6 promoters.

The expression cassettes were placed in a shared lentiviral vector and thus introduced ex vivo, i.e. outside the body, into hematopoietic stem cells isolated from the enrolled AIDS lymphoma patients. Because hematopoietic stem cell transplantation with full bone marrow ablation is associated with risks, but is standard second-line therapy for AIDS-related lymphoma, this patient population was chosen so that the trial participants would simultaneously receive a treatment benefit for their lymphoma while participating in this experimental trial. As an added measure of precaution, the majority of hematopoietic stem cells were left untreated and given together with the modified stem cells to ensure that the immune system would be reconstituted even if something went wrong with the gene therapy.

Four patients were treated per protocol in the phase I trial. Unfortunately, while there was no obvious significant adverse event as a result of the gene therapy, the molecular analyses indicated that rHIV-shl-TAR-CCR5RZ may not be the most promising RNA therapeutics candidate for HIV. Specifically, while the initial transduction efficiency was in line with what would have been expected for lentiviral delivery (~20%, see X-linked adrenoleukodystrophy trial here), the transduced cell population declined rapidly and the ones that persisted were just about detectable- too few to be therapeutically promising.

If this candidate were to be further developed, an important goal would be to increase the fraction of stem cells that are modified. This could either be by improving the transduction efficiency, by only providing stem cells that were treated with lentivirus instead of providing the untreated stem cells as a backup, or by using a protocol that chemically selects for the modified stem cells after their re-infusion. Still, I am skeptical that this would solve the problem as in light of other lentiviral and retroviral clinical experiences the observed decline in transduced cells seemed to be specific to rHIV-shl-TAR-CCR5RZ. It is therefore possible that some inherent toxicity of the expression cassette itself, possibly due to the use of U6 promoters, accounted for the poor long-term persistence of modified stem cells.

The Calimmune approach: A non-toxic, H1-driven shRNA targeting CCR5

The reason why I feel that Calimmune’s approach may have better prospects is that it has fully accounted for the U6-related shRNA toxicities and selected an H1 promoter-based RNAi expression cassette that was shown to be both safe/stable and, equally important, highly efficient in CCR5 knockdown in human and rhesus HSC-derived cells. Also, I like the fact that it is an RNAi trigger, and not a ribozyme, that is targeting CCR5, as I believe this to be the more efficient knockdown modality.

While Calimmune has yet to fully disclose their eventual clinical candidate, the one reservation that I have about the putative candidate at this time is that they may have failed to take advantage of the combinatorial potential of RNAi Therapeutics. With combinatorial potential I do not necessarily mean here combining ddRNAi with other RNA (like CoH/Benitec) or protein expression modalities- in fact, it may be scientifically 'cleaner' to use just RNAi for now- but targeting at least two HIV-related genes instead of one to minimize the emergence of viral resistance.

The panels on the left depict what in my mind have been the most impressive dataset from the development program. It shows the results from a rhesus monkey model in which the ddRNAi trigger was introduced into blood stem cells from two monkeys (RQ3570 and RQ5427 for those with good eyes) which (panel A) led to solid, long-term (!) 6-20% cell marking in the various cell lineages of the blood. Moreover, when the cells were sorted into those that were transduced (black bars, panel B) versus those that were not (grey bars, panel B) and the CCR5 levels measured in the respective cell populations, the CCR5 was found to be down-regulated by 80-90% in the transduced cells. And since your experiment is only as good as your negative controls, data from a control animal that received a lentivirus without the RNAi trigger (2RC003) show no differences in CCR5 levels between the two cell populations.

While I have yet to see the obligatory HIV in vivo challenge studies with this putative candidate, based on CCR5 genetics, a candidate with such transduction levels and knockdown potencies should stand a good chance at improving CD4+ T-cell counts for enhanced immune system vigor and delaying or maybe even eradicating HIV over time.

It is debatable to what degree a full CCR5 knockout compared to a highly potent CCR5 knockdown would bring additional benefits. Sangamo Biosciences for example has made tremendous progress in increasing the efficiency of gene disruption using their Zinc Finger Nuclease technology. Not surprisingly, this company also has a CCR5 hematopoietic stem cell candidate in the early pipeline. In a 2010 Nature Biotechnology paper, Sangamo reported an estimated frequency of 5-7% homozygous CCR5 gene disruption in human hematopoietic stem cells, and another 10% heterozygous gene disruptions.

Simplistically, taking upper estimates, ddRNAi may provide for 90% CCR5 knockdown in 20% of cells whereas ZFN technology may delete CCR5 altogether in 7% of cells and knockdown CCR5 by half in another 10%. Because these numbers are close and a clean knockout in some cells may make up for the slightly decreased overall knockdown levels, I would be even more excited to see Calimmune's current lead candidate paired with at least another shRNAi trigger, thereby exploiting said combinatorial potential of ddRNAi Therapeutics which ZFNs cannot provide as easily.

Benitec license?

Benitec, of course, will follow Calimmune’s developments with great interest as the company has rights to critical ddRNAi trigger patents. Curiously, both companies are based in Australia, but have significant roots also in the US South-West, so it should be possible to come to an amicable agreement.

License or not, it will be good for the entire field of RNAi Therapeutics, and ddRNAi Therapeutics in particular, for this trial to get underway in 2012 as it should attract significant general interest to a what looks like a solid RNAi Therapeutics candidate.

Acknowledgement: The idea for this blog came from a reader that alerted me to this interesting RNAi Therapeutics candidate that had flown below my radar, and maybe also to placate another reader that complained that the Tekmira-Alnylam feud was taking up too much space and there were other interesting things happening, especially in ddRNAi Therapeutics. So if you know of exciting RNAi Therapeutics developments that you believe I may be missing, please let me know by email (first name dot last name at gmail dot com). In most cases, I won’t be able to write about it immediately, but it won’t be forgotten either.

Update: On March 5, 2012, Calimmune acquired a global, non-exclusive license from Benitec to use ddRNAi in HIV/AIDS.

Tekmira Partner to Initiate Phase I Study for the Treatment of Severe Hypercholesterolemia

Tekmira’s partner and licensee Alnylam Pharmaceuticals announced today the submission of files to a European regulatory agency in anticipation of a phase I study with a candidate targeting PCSK9 for the treatment of Severe Hypercholesterolemia. The primary aim of this early-stage study is naturally the safety and tolerability of ALN-PCS. An important secondary aim, not just for Alnylam but also for the entire field of RNAi Therapeutics, will be assessing drug activity as measured by target protein levels in serum. Initial data are expected by year end.

ALN-PCS represents Alnylam’s 4^th clinical candidate, three of which are based on Tekmira’s SNALP technology (VSP, TTR, PCS). It also represents the 2^nd candidate under its 5x15(TM)program which aims to advance five RNAi Therapeutics candidates into late-stage clinical development by 2015. All disclosed candidates under that program (TTR, PCS, HPN) are based on SNALP technology.

Despite the success of statin in lowering cholesterol, many patients are still considered to be in need of additional treatment options. PCSK9 has emerged as a very attractive target for such uses based on human genetics which suggest PCSK9 knockdown to reduce ‘bad’ LDL cholesterol in addition to being well tolerated. While ALN-PCS is the first RNAi Therapeutics candidate to target PCSK9, other companies have already started clinical development of PCSK9-targeting hypercholesterolemia candidates.

These competitive efforts are based on monoclonal antibodies and antisense approaches and include a recently initiated program by Santaris (LNA antisense) and monoclonal antibody programs by Amgen, Pfizer, and Regeneron amongst others (mostly phase I and II). ISIS with partner BMS together are also developing a PCSK9 antisense candidate. This candidate, however, still appears to be in late preclinical studies following some delays.

The pre-clinical data show that RNAi, antisense, and monoclonal antibodies can all potently down-regulate or bind and inhibit PCSK9. It seems, however, that one advantage of ALN-PCS could turn out to be that it does not simultaneously down-regulate ‘good’ HDL cholesterol as was observed e.g. in a rodent study by ISIS (antisense; significant 50% reductions; Graham et al 2007) or in a non-human primate monoclonal antibody study by Amgen (moderate 20% reductions; Chan et al 2009).

Obviously, it is still early days to speculate on the eventual competitive profile of the various candidates. With regard to safety and tolerability it is notable, however, that the anticipated highest dose with ALN-PCS in the study is 0.25mg/kg. This means that an average Caucasian may receive only about 10-20mg siRNA per week (assuming bi-weekly or monthly administration). While there is still some more uncertainty about the safety profile of non-DLinDMA SNALPs such as ALN-PCS (this candidate uses MC3 while all other SNALP candidates so far made use of DLinDMA), such low doses make me optimistic that the safety profile should be quite competitive.

Adding Tekmira’s efforts, this program is the 5^th SNALP candidate in 3 years to enter clinical development. At least two more are anticipated this year. ALN-PCS therefore further illustrates one of the advantages of RNAi Therapeutics development, namely that once there is a suitable delivery technology for a given target organ, in this case SNALP for liver delivery, the indications can be rapidly expanded to multiple drug targets. This also means that the inventor behind and manufacturer of ALN-PCS, Tekmira, should receive a milestone from its partner and licensee upon initiation of dosing, adding to an increasing royalty stream.

Alnylam Responds to Amended Complaint by Tekmira

Last week, Alnylam responded to the Amended Complaint by Tekmira in which Tekmira disclosed the full scope of Alnylam’s alleged misappropriation and misuse of Tekmira technology and added Alnylam Canada, aka AlCana, as Co-Defendant (related blog entry here). The alleged transgressions included abusing insights into Tekmira trade secrets that Alnylam gained as a result of their collaborator status and by hiring ex-Tekmira employees to file for a battery of patents covering Tekmira technology, also to contest royalty obligations for ‘second-generation’ LNP formulations, disclosing them to Alnylam’s Big Pharma partners to circumvent Tekmira, and breaching the manufacturing agreement by providing Tekmira formulations to Alnylam partners.

Alnylam vague in Response

In its Response, Alnylam brushed aside Tekmira’s allegations that it took unfair advantage of insights into Tekmira trade secrets by simply stating that the written agreements would speak for themselves and gave them freedom to do so and that much of Tekmira’s technology had been in the public domain anyway. In doing so, Alnylam apparently attempts to hoodwink the court by failing to mention and address the significant limitations in the various agreements between the companies regarding the use of Tekmira trade secrets. These limitations stated that any use by Alnylam of Tekmira LNP delivery trade secrets for purposes other than advancing the agreements would have to be first blessed by Tekmira.

Perhaps realizing their failure to do so, Alnylam’s main defense with regard to the MC series of lipids that it now advertises to be its own and independent of Tekmira was based on a waiver to sue that was included in the Supplemental Agreement dated July 2009 between Tekmira, Alnylam, the University of British Columbia, and Alnylam Canada. For example (Fourth Affirmative Defense):

‘Tekmira has granted Alnylam a covenant not to sue on any contention that MC3 and other alleged “MC Trade Secrets” was misappropriated in an agreement to which it is a party.’ [emphasis mine].

See also:

‘15. The Supplemental Agreement and its attachments contemplated the research that ultimately led to the discovery of MC3 and other novel lipids.” [emphasis mine]

This defense, however, fails to address Tekmira’s allegations that the broader MC trade secrets were disclosed by Tekmira to Alnylam pursuant to the Research Plan of the Tekmira Agreement which pre-dates the Supplemental Agreement (and also Consultancy Agreement between the ex-Tekmira employees and Alnylam for that matter) whereas the waiver would only apply to actions carried out pursuant to the Research Program of the Supplemental Agreement and the Consulting Agreement. This distinction may become important as ownership over the broad MC series of lipids would affect the freedom-to-operate for MC3.

Alnylam's defense that Tekmira never realized that ‘MC’ constituted a series of lipids cannot be taken seriously as a) apparently some of the inventors of MC2 did realize this to be a series by filing for the MC3 patent application soon after their firing from Tekmira, b) the nomenclature implies a series (just as KC did before that), and c) Tekmira should easily be able to prove their disclosure of MC trade secrets via emails etc.

Tekmira statement of when MC trade secrets were disclosed to Alnylam (from the Amended Complaint):

‘34. Prior to its filing of the provisional patent application disclosing and staking its claim of ownership of the MC2 compound, Tekmira confidentially disclosed the MC Trade Secrets to Alnylam pursuant to the Research Plan of the Tekmira Agreement.’ [emphasis mine]

Waiver (from the Supplemental Agreement):

’12. Waiver; Non-suit Covenant. In consideration of the foregoing, Tekmira and Protiva hereby (a) waive all prohibitions and restrictions upon [**] (and any other UBC employee involved in the Research Program who was a former Tekmira employee) and each former Tekmira employee who is subject to the provisions of an Employment Agreement arising out of, under or in connection with their former employment by Tekmira, to the extent that any activities of such former Tekmira employee are carried out pursuant to the Research Program, the Consulting Agreements or in connection with the performance of obligations or the exercise of rights under this Supplemental Agreement; and (b) covenant not to sue Alnylam, UBC, AlCana or any of the former Tekmira employees employed by AlCana or UBC, for any cause of action relating to such activities that arises out of, under or in connection with the former employment by Tekmira of such former Tekmira employees. For clarity, a failure by any party to perform its respective obligations under this Supplemental Agreement shall not entitle any other party to sue any non-breaching party. Such former Tekmira employees are intended Third Party beneficiaries of this provision.’ [emphasis mine]

Therefore, even in the unlikely event that the waiver would be judged to allow for the broad misappropriation and use of Tekmira trade secrets and applied retroactive to the effective date of the Agreement (note that even the MC3 provisional was filed before July 2009), it has no bearing on what Alnylam did with the insights into other MC-related trade secrets. Note that the broad MC patent applications were filed by Alnylam alone- consistent with the timeline provided by Tekmira. To make this point clear, the Supplemental Agreement expressly states that it does not release the parties from liabilities arising from the other agreements:

‘19. Entire Agreement. This Supplemental Agreement is the only agreement between or among Tekmira and/or Protiva, on one hand, and any of Alnylam, UBC, and/or AlCana, on the other hand, bearing directly upon the Research Program and the Consultant IP. Except as expressly stated herein, neither this Supplemental Agreement nor any discussions, proposals or negotiations with respect hereto or otherwise with respect to the Research Program will alter the terms of, or constitute a waiver or release of any party’s rights or obligations under, any of the existing agreements between or among Tekmira and/or Protiva, on one hand, and Alnylam and/or UBC, on the other hand, including without limitation the provisions of such agreements regarding the termination of such agreements and the consequences thereof.’

Alnylam Admits to Providing Delivery Formulations and Tekmira Manufacturing Know-How to Novartis and Takeda

Much of the immediate financial damage to Tekmira and their investors arises from Alnylam allegedly stealing Tekmira’s manufacturing trade secrets and violating the manufacturing agreement by providing SNALP/LNP delivery formulations to Big Pharma companies with interest in RNAi Therapeutics. In its Response, Alnylam admits that it provided delivery solutions to Novartis and Takeda. Alnylam denies, however, that Tekmira took adequate care to protect its manufacturing trade secrets which was formalized, amongst other, in the September 2008 MBR agreement which limited Alnylam’s access to Tekmira trade secrets solely for the purpose of their regulatory obligations. Overall, with the Agreement and the Konys emails it should be relatively straightforward to prove this allegation which should be a key element in assessing the financial damage suffered by Tekmira.

The Big Picture Remains Unchanged: Alnylam Intent on Marginalizing Tekmira

If anything, Alnylam’s Response further emphasizes that it has been and still is intent on marginalizing Tekmira by having the audacity to claim ownership and control over Tekmira technology and to advertise itself to be leading in SNALP technology. It's the same company that 4 years ago along with Roche had to admit defeat and seek chemistry and manufacturing help from Protiva, and just 2 years ago still seemed to be learning the ropes of LNP delivery technology (see 2009 Molecular Therapy paper). To top it off, this company now claims that Tekmira’s work, including the newly disclosed lipids, is based on the misappropriation of Alnylam LNP trade secrets.

If that were not enough, Alnylam pretends to be an advocate of Tekmira shareholder interests by casually dropping in the Response that Tekmira failed to issue a financial regulatory filing due to Alnylam’s apparent notice to Tekmira that Tekmira lacked a license to its very own rights to the Semple-Wheeler patents, as well as the ISIS patent estate under its InterfeRx license from Alnylam!

From the Response:

‘23. Consistent with this pattern, Tekmira has failed to adequately disclose the limitations of its licenses to investors. Despite the clear terms of the license agreements and notice from Alnylam that it lacked licenses to the Semple & Wheeler patent series and Isis patents, Tekmira made representation to the contrary in its public filings with the SEC and in other documents provided to investors.’

Remember that Old Tekmira originally provided Alnylam the exclusive license to its rights to Semple-Wheeler for therapeutic RNAi and microRNA applications, in return for Alnylam RNAi target picks under InterfeRx, which includes ISIS, and the use of Old Tekmira SNALP-related IP for these target picks. Obviously, events have escalated and with the apparently unilateral revocation of the licenses Alnylam management apparently wants to cause additional pressure on Tekmira's share price hoping to outlast Tekmira financially, not based on arguments. I wonder which Alnylam top executive or lawyer came up with this admittedly innovative interpretation of the companies' agreements and would not be surprised if this move was also coordinated with Alnylam's connections to the financial world.

On the other hand, Tekmira has told Alnylam that it would not release certain data with regard to the hypercholesterolemia candidate ALN-PCS, for which guidance to submit an IND in H1 2011 has likely been missed, unless Alnylam gave added assurance that it would not use such information for purposes other than the clinical trial.

Why would Alnylam have problems agreeing to this measure and is willing to miss important guidances it gave to investors and resort to desperate acts like the Semple-Wheeler and ISIS stunt? Why does Alnylam not just pay off Tekmira and tell them to go away, as this would seem to be the least costly option to them at the moment? Is it really just greed that has been driving Alnylam’s actions? I cannot believe it and instead suspect that at the root of Alnylam’s conundrum are its deals with Big Pharma in which it took in over half a billion in non-dilutive funding, much of it quite obviously based on the strength of and access to Tekmira’s SNALP technology.

Tekmira continues to advance science

Despite the legal battle with top-heavy Alnylam (ironically it is Alnylam that tells Tekmira to focus on the science), Tekmira continues to make critical advancements in refining and expanding the uses of its LNP delivery technology. Following the recent conference report that it succeeded in generating defined LNPs for respiratory and directed delivery applications and the scale up of manufacturing to 1kg batches, a patent application (WO/2011/066651) by Tekmira published last month disclosed important advances in ensuring the long-term stability and therefore quality of its formulations. In order to avoid any confusion, some of the experimental examples involved MC3 (and MC4) to make it clear that the claims cover SNALPs independent of the specific lipid used. With this, Tekmira demonstrates that it continues to stay a step ahead and provides further reasons of why pharmaceutical companies would want to partner with Tekmira in order to practice SNALP delivery.

Related blog posts:

1) Tekmira Tells Alnylam 'Enough is Enough';

2) Alnylam Responds to Tekmira's Complaint;

3) Tekmira's Amended Complaint Suggests that Alnylam's Transgressions More Severe than Suspected