Saturday, August 23, 2008

Leerink Swann Report on Alnylam- A Review

Preface:

Honestly, I’m not sure where to begin writing about the Leerink Swann (LS) report by Alsenas and Yoo. One does not need to look hard to find plenty of acceptable areas to take issue within this less-than-glowing assessment of RNAi. Is their report accurate? I will examine their assessment point by point. LS discusses some areas of RNAi technology that are, and will be, areas that will continue to progress, but overall the report is intellectually dishonest at best. Let’s face it, we’ve all seen examples in politics (on many sides in many issues) that are “true” but intellectually dishonest. For example, I could say that “history has taught us that airplanes don’t fly.” That is technically a true statement if one looks prior to December 17th, 1903 when the Wright brothers took the first flight; however, it’s clearly a misleading statement. There are a number of examples that read similarly to the fact that “history has taught us that airplanes don’t fly” in the LS article on Alnylam Pharmaceuticals, and I cannot understand how or why such instances would be presented as honest reporting by a reputable firm.

The meat of the report:

Leerink Swann initiated a sell rating on Alnylam, expecting a valuation of $14-16 in 2009 based on cash (currently over $13 per share) and a valuation of $200 million for their IP and technology. LS claims that Alnylam is “narrowly” focused on RNAi and that RNAi is better suited for research than as a drug platform. Additionally LS investigates the respiratory syncytial virus drug ALN-RSV01 as “underwhelming” and evidence of a lack of systemic delivery capabilities for RNAi. LS states that RNAi delivery is impossible at the moment, and will probably be a hurdle never surmounted. Furthermore, LS believes that the number of collaborators working with Alnylam (and paying for the privilege) is a liability and not an asset. Moreover, LS states that Alnylam “will use its significant cash position of $538 million...to “diversify” or “forward integrate” by acquiring another technology or clinical product.

I will look at a small portion of the statements made by this report simply because documenting a group of clear errors is enough to toss out the report in its entirety.

Valuation:

LS values Alnylam’s IP and technology at $200 million. That’s all well and good, but how did they arrive at that number? They don’t say. However, we can ascribe a more realistic valuation than the professionals at LS by comparing actual dollars rendered for RNAi and similar technologies. First of all, when someone (Roche) is willing to pay $273 million dollars for non-exclusive access to 4 of 20 disease areas using Alnylam’s IP and technology, not counting the future milestones and royalties but an upfront $273 million, it’s difficult to realistically value Alnylam’s entire IP at $200 million. So far, Alnylam has over $500 million in the bank mostly derived from licensing (non-exclusively) their technology to a few Pharmas, namely Novartis, Roche, and Takeda. The authors disingenuously attribute these payments to “The pharmaceutical industry is often swept by new technology fads.” Well, even if that’s all Alnylam has to offer, wouldn’t those dollar amounts suggest that it’s a fad many of the other pharmas are going to try? Science has shown us that this is not the latest fad, but rather a monumental discovery that has the ability to revolutionize medicine.

Let’s look at a few other players that own IP space on platform technologies. First and foremost is Isis Pharmaceuticals that owns the IP on many RNA chemistries and more importantly the use of single-stranded oligonucleotides designed to repress messenger RNA, collectively grouped under the term “antisense.” The early days of antisense were plagued by disappointments and one can see the vestiges of the early adopters (Genta etc.), but Isis has overcome the initial troubles and developed a working and robust platform based on antisense. Reading the LS report, one comes to the conclusion that there are no oligo-based drugs that demonstrate efficacy. Isis’ pipeline is full of effective drugs. Recently one such drug was partnered for hundreds of millions upfront with potentially a more than a billion dollars in milestones and royalties of 30-50% of sales. Does that sound like nothing is working with oligo-based drugs? Perhaps the authors simply read only the investing reports on Isis and not the scientific literature. It is interesting to note that LS also downgraded Isis stock to hold at $14 from $17, it has since moved back up and closed yesterday at $18...

Another company that owns IP around a platform of potential drugs is Sangamo Biosciences. This company produces specific proteins (zinc-finger proteins ZFP) that bind to DNA and perform several possible functions mainly to either inhibit or increase the expression of messenger RNA and consequently increase or decrease the amount of that gene’s expressed protein. The design and production of these molecules requires human hands and many ZFPs are then tested to determine which has the ideal properties for the specific disease state being investigated. Subsequently, the molecules need to be delivered to the interior of the cell and then into the nucleus. (The production of one molecule is much more time consuming than the production of RNAi where a computer chemically assembles the individual bases into the drug.) Is this starting to sound like antisense and RNAi? Yep, there’s a reason for that: all three require delivery in the form of either chemical modifications, a chemical delivery vehicle (e.g., liposome/SNALP), or possibly through an engineered viral genome. Antisense is the smallest and therefore easiest to deliver naked, or without a carrier. RNAi is about twice the size of antisense (similar size, but 2 strands instead of one) while ZFPs are up to 20 times the size of antisense molecules. Does this sound like ZFPs are easier to deliver than antisense or RNAi? For the sake of the valuation of RNAi IP and technology, let’s assume that RNAi is equally valuable as ZFPs.

LS has a price target of $18 for Sangamo (SGMO) stock or about $650 million for the IP and technology. Why such a high valuation for SGMO IP compared to Alnylam? They must have a list of multi $100 million dollar collaborations right? Nope. But they do have about $76 million in the bank at the moment... Remember, LS thinks Alnylam’s IP is worth $200 million. Does that make sense? Not really, but as LS says, “Alnylam is narrowly focused on the development of a Nobel Prize winning technology called RNAi.” I am not saying Sangamo is not worth that much for fundamental IP, but clearly there is a rational disconnect between the valuations of these two companies by LS.

Which brings us to the next point: Alnylam is ‘narrowly’ focused on a technology that could be applicable to every gene in the genome (read this as potentially 10’s of thousands). Huh? Yep, you read that correctly. Alnylam owns the bulk of IP for RNAi, half of the company Regulus that controls the majority of IP for a closely related technology to regulate genetic pathways via microRNAs, and recently acquired the fundamental IP for RNAi’s cousin RNAa that can be used to increase production of gene products. Can anyone honestly say that this is narrow? Too broad would be a more believable tale to weave, but then they might have to back that up with data that would cast shadows on the remainder of their story.

Perhaps I should be generous and alter their statement to read that Alnylam is narrowly focused on respiratory syncytial virus. This is currently the only drug Alnylam has in Phase II clinical trials; however, I’ll be quick to point out that they have a number of other programs that will soon be entering clinical trials including liver cancer, hypercholesterolemia, Huntington’disease, Progressive Multifocal Leukoencephalopathy (PML), hepatitis C virus (HCV), and biodefense projects including Ebola virus. The authors state the results for the RSV trials as “difficult to interpret and undewhelming.” They are especially difficult to interpret when one leaves out a major portion of the positive data. Compared to the control group, approximately 1/3 displayed similar symptoms to non-treated individuals, 1/3 had reduced symptoms (by about 38%), and 1/3 had no symptoms (based on the controls, one would expect 12 subjects to not show symptoms but 24 were symptom free). The authors kindly neglected the group that displayed no symptoms but were shown to have a very low viral infection. Is this a fair approach to science? Additionally, Alnylam conclusively demonstrated that the viral reduction was due to specific RNAi mechanisms and not due to non-specific activation of the immune system. Read the actual data here, it is not difficult to interpret.

Was the study underwhelming? I guess if one has expectations of complete obliteration of all RSV virus, then yes it was underwhelming. But then again, every other drug trial would be underwhelming as well. To be fair, it was a difficult trial. Alnylam had to develop a model system for a virus that had never been done before. Because they were administering the virus to healthy volunteers, they used a mild strain of the virus that would be least likely to harm the test subjects. Would they have had stronger data if they used a strain that was much more likely to be lethal in elderly/infant populations? Maybe, but how are you going to sell that study to volunteers and the ethics board? LS also objected to an additional study in lung transplant patients where RSV is a serious disease that can lead to tissue rejection (to be sure, it is serious if one’s lungs are rejected...). This study provides an additional look at the ALN-RSV01 safety profile and a more optimized administration route of nebulized drug PRIOR to testing in infants. There can be no doubt that Alnylam has chosen to move into the pediatric tests in a cautious manner, but that is to be expected.

One additional point to make about the authors contention with ALN-RSV01: they claim that it will not be worth much money and that they will have competition with Synagis, a monoclonal antibody for the PREVENTION of RSV infections. First of all, the market is large enough that Synagis is a billion dollar drug and secondly ALN-RSV01 is a TREATMENT for RSV infections. Synagis does not enter the cells where the virus replicates - thus it is used as a prophylactic in premature infants where RSV infections are quite dangerous. (I like analogies, so how about “antibiotics are worthless because condoms exist?”) ALN-RSV01 does enter the cells and shut off the viral replication capacity of those cells. It is tempting to speculate on the potential synergism between the two drugs.

ALN-RSV01 is as simple as an RNA-based drug can be. It is a non-modified RNA oligo pair dissolved in saline water. It is literally misted into the lungs and absorbed by the cells it contacts. There is no delivery vehicle and it is not a systemic drug. Why not? It works without either chemical modifications or a delivery vehicle. Simple enough.

Systemic delivery:
This seems to be the Authors’ main objection to the RNAi platform. They claim that systemic delivery is not currently possible with RNAi (but remember, delivery of a much larger molecule with Sangamo should be no problem and thus Sangamo should be valued much more highly than Alnylam...). There is no doubt that delivery is the rate-limiting step for achieving the potential that lies within RNAi. In fact, John Maraganore (the CEO of Alnylam) has stated as much when he said that Alnylam would be working on delivery for many different tissue types for years. Does that mean that they can not effectively deliver RNAi? They can, they have demonstrated so with Tekmira using technology developed by Alnylam, Protiva (now part of Tekmira), Tekmira, and Robert Langer’s lab at MIT. Yes, Alnylam delayed their IND filing for VSP and PCSK9 last year, but in hindsight it appears to have been a wise move. They had liposome (stable nucleic acid lipid particles - SNALPs) formulations that were effective, but near the date of filing the aforementioned technology came together to achieve a 10 fold increase in RNAi activity. I’d wait a few months and file for an IND using those formulations as well. The beauty of the SNALP system is that it is easily tunable to different sized particles and each can have different properties determined by different lipid or lipidoid formulations. This is where the MIT lab has aided in the production of tissue-specific and/or property optimization of Tekmira’s SNALPs. SNALPs can be engineered to be stable in serum for long periods and be slowly delivered or be rapidly absorbed by the liver depending on the desired pharmacokinetics. Each drug may have differing desirable characteristics and with SNALPs it is easier than ever to design such properties into delivery.

The process of producing a delivery vehicle is not easy, but the assessment of such technology is simple. The only two questions that matter are: does enough of the drug get in the cell to be effective? and is the formulation toxic? Tekmira/Protiva developed delivery vehicles that were effective and not toxic, the newer formulations are better. End of story, I won’t even bother with their quotes here. If you want to see data and read about the advances made at Tekmira, please read the Prospectus (type in 'Tekmira' under company name, then select 'management information circular dated 6 May, 2008).

This system is currently being used to actively and specifically target RNAi to the liver. Read that again, EFFECTIVE DELIVERY TO THE LIVER. Oh, fine, you say. That’s only one organ...with dozens of known targets. Many of them would be major blockbusters - cholesterol reduction, hepatitis C, cancer etc. Personally, I don’t think Alnylam needs to be able to deliver to any tissue besides the liver to become a major player in pharmaville; however, Alnylam and its collaborators are actively targeting many other tissue types (CNS, eye, lung, tumors, heart, smooth muscle) with both SNALPs and many other technologies. Delivery will not be a one-size-fits-all endeavor, and it doesn’t matter. Each cell type has specific differences and these will call for different delivery vehicles. Each cell type will probably have multiple targets so delivery optimization will result in many additional drugs for these tissues. To convince yourself of the value of RNAi with delivery to only one area, read the list of major drugs that each big pharma has currently. They are not long lists of major drugs.

Leerink Swann states that “Alnylam has approximately 25 drug delivery collaborations...which we see as signs of desperation rather than strength.” Technically this statement is true, but it’s true in the sense that historically airplanes don’t fly. It is a sign of desperation. Now before you get your shotgun, hear me out. Big pharma and small biotech companies alike are so desperate for innovation they are clamoring for RNAi and have partnered with Alnylam. The authors did not mean it this way, but instead meant it as an act of desperation for Alnylam. Perhaps they didn’t bother to read which direction the money was flowing. Investing is simple. Follow the money. If Alnylam had paid Roche to help, it would be Alnylam that was desperate; it was, in fact, Roche, Takeda, Novartis, etc. who paid Alnylam, implying that they were desperate enough to pay for the privilege of using Alnylam’s IP on a non-exclusive basis. Again, I feel compelled to point out that we are talking over a half a billion dollars in cash, not including milestones and royalties. Additionally, the list of collaborators has been altered recently to include a number of 50/50 splits with Alnylam. Alnylam renegotiated the contract with Medtronic from a small royalty with milestones to a 50/50 split. Alnylam is allowed to pick at least one of the drugs Tekmira is developing for 50/50 splits. Alnylam has the right to a 50/50 split on 4 drugs of their choice with Takeda. Does this sound like Alnylam is desperate? Domineering maybe, but they are not desperate.

From the tone of the article, it has not escaped our attention that there may be desperation from investors on the short side of the trade rather than those who have researched and paid for the right to use RNAi.

LS ends their “investment thesis” section with “When Alnylam uses its significant cash position and high share price to “diversify” or “forward integrate” by acquiring another technology or a clinical product, we will take it as a sign that the management team has acknowledged the difficulties with its current approach as well.” I know you’re wondering if a reputable financial analyst would say this in their research report, or if I made it up. The answer is no, a reputable analyst would not say this, and no, I didn’t make it up. See other articles on this blog for additional information on the pipeline.

13 comments:

big bones said...

What are the thoughts on Calando's work on RNAi and milestone payments to Alnylam? Does this project have merit?

Thanks

ranak said...

Dirk,

The toxicity issue of liposomal delivery is crucial. If, as the author says, it has not been possible to inject higher animals with multiple liposomal formulations, that severely limits the use of SNALP etc. for siRNA delivery. I got the same reaction regarding liposomes from a siRNA expert at the Beyond Genome conference. In that regard, viral formulations may present a better option, and you may have a better insight into that. What do you feel about Tacere Bio's technology?

The problem with SNALP and other formulations is that the toxicity arises from the addition of head groups that can allow it to escape the endosomes more efficiently. If MIT/Alnylam can come up with an effective balance between the siRNA payload that is delivered to the cell and the endosome escaping ability, that should move things in the right direction. But, if via high-throughput screening, they are still unable to come up with lipidoids that can be injected multiple times in higher animals, then we will see a limit in liposomal technology.

-Ranak

Dirk Haussecker said...

Ranak- I agree that getting SNALPs into the therapeutic window is critical and it is correct that repeat administration of SNALP-RNAi has not been published in a peer-reviewed journal. Repeat administration is not only limited by the tox of SNALP, but also potential immunogenicity of the components (e.g. peg). The risk for both is reduced with lower required doses. In that regard it is encouraging that Tekmira has presented 0.1mg/kg EC50 SNALPs at this year's Keystone conference.

One of the potential toxicities by liposomes is premature fusing with the plasma membrane instead of the endosomal membrane. One strategy that can be used for liposomes, and e.g. is also employed by Mirus, is to activate fusogenicity in a pH-dependent manner as the particle enters the endosome.

I hope that filing an IND with a SNALP formulation will be an indication that repeat administration is possible based on the animal tox studies. Alnylam has guided for this to occur this year.

Dirk Haussecker said...

Just to add to this, liposomes aren't created equal. I think this is often forgotten when the toxicity of liposomes is discussed.

The reason why so many companies were and are interested in collaborating with Protiva, and not Tekmira which owned the fundamental liposome patents for oligonucleotide delivery at the time, is the know-how of the group around Ian MacLachlan which I can attest from having done a fair amount of liposomal reading. This is also the reason why the collaboration agreements are explicitly divided into access to IP and access to know-how. If anybody meets the chronic application challenge, I would expect to hear it from Vancouver first.

ranak said...

Dirk,

Mirus and similar technologies may present an alternate approach to liver targeting, and Roche has it in the bag. Liposomes are indeed different for different formulations, and that's why I would be interested in seeing the screening results from MIT/Alnylam. Theoretically, they should cover the entire range of permutations/combinations, and if they still see some toxicity, then Mirus et al. will attract some more attention.

The way I see it, Tekmira/Protiva had a core IP in the manufacturing process. Indeed, Ian Maclachlan et al. have done a lot of work in liposomes, and that's why I am surprised that the MIT/Alnylam collaboration did not include Tekmira. Have they limited themselves in some ways? It does look like Alnylam has built its collaborations very carefully and smartly, with Roche also doing its due diligence.

-Ranak

Dirk Haussecker said...

Ranak- Tekmira indeed has access royalty-bearing access to technologies coming out of the Alnylam-MIT collaboration. This makes sense, since lipidoids could be a building block for SNALP liposomes.

Yes, I trust that Roche can think for itself, but believe that in the case of Mirus it has coordinated with Alnylam. Roche has therefore decided to gain access to both Tekmira and Mirus technologies, IMO the two leading systemic delivery technologies. It has also made a sizeable investment in Tekmira at a 200% premium then.

I do not see your concern here, as building alliances is certainly the least of Alnylam's weaknesses.

GS said...

Fantastic post Dirk!

Perhaps you could think about forwarding it to Leerink Swann? Or better still, also a PR company that published the LS story etc.

Compared to the agenda-driven dribble of LS, your views are very well researched & objective.
I guess LS got what they wanted, which was to knock the ALNY share price!

Anonymous said...

I am extremely skeptical of all naked siRNA drugs such as the AMD (eye) and RSV (lung) ones. The recent Nature paper showing that TLR3 binding of naked siRNA in the eye and a subsequent interferon response is the cause of the antiangiogenic phenotype of putative RNAi AMD drugs is a huge blow and a wakeup call.

It is wholly unanswered how these nakes siRNAs enter the cytosol. In fact, it is unanswered whether they do reach the cytosol at all. We know that in Drosophila cells, famous for taking up naked siRNA for RNAi, there is a specific receptor mediated endocytosis event which occurs. This apparently does not occur in mammalian cells. No one has shown it to occur in eye (or lung or any other mammalian) cells, yet these drugs are in clinical trials. There is a huge disparity here. My opinion is that no functional siRNA enters the cytosol of any mammalian cells in any tissue, period. All attempts to make a drug of naked siRNA despite this are futile, and frankly, dangerous to test in humans even with local delivery. At the very least, it is extremely premature to be trying to deliver naked siRNA locally to tissues in humans when one considers the evidence that in fact no delivery likely occurs to the cytosol.

I'd love to hear someone else's opinion about this, and if they disagree please enlighten me.

With regard to systemic delivery with lipid nanoparticles, the jury is still out on whether they can be used to deliver to anywhere other than the liver, and also whether they will have inherent chronic toxicity which cannot be avoided. In fact, systemic delivery of macromolecules is an unsolved problem, and I have to say that unfortunately I think there is a decent chance that it will never be achieved in any generally applicable fashion. If you look at the "progress" being made in this field, it is really a situation of people continuing to bang their head against a wall and the "new ideas" consists of regurgitating old ones and recombining them into ever more complex and difficult to characterize particles like SNALPS which seem to never be adequately biochemically dissected for their mechanism of interaction with cells. Clearly, new delivery ideas are needed, and to start out one must avoid nonspecific toxicity, obviously.

Dirk Haussecker said...

Anonymous-

I understand your points, and it was also surprising to me to see a number of publications come out that reported that naked, unformulated siRNAs are supposedly taken up by a number of mammalian epithelial mucosa, lung and cervix in particular. Given 5' RACE data etc. that shows RNAi is definitely occurring under these circumstances the question is probably not whether, but how efficient this is (as to your comment: "My opinion is that no functional siRNA enters the cytosol of any mammalian cells in any tissue, period.").

As to your comment that what did not work 10 years ago will never work, I guess we just have to agree to disagree. Without pioneering research, we would live in a world without monoclonal antibody and other therapeutics.

Anonymous said...

Hi Dirk,

I see your point. I remain skeptical of 5' RACE analysis when done in the absense of analyzing changes in expression of other potential off target genes. In particular, if an immune response is illicited, many genes may be turned off (or on), and pleiotropic effects are likely seen and reflected in a vast array of changes in the transciption profile of the affected cells. Microarray analysis would suffice to show specificity, but I think more important is direct verification that the exprected RNAi products are in the affected tissue is needed. By this I mean, direct biochemical detection of the cleaved mRNA and it needs to be cleaved at exactly the expected site based on the introduced siRNA.
I think it is remotely possible that some of these naked siRNAs are entering cells without delivery vehicles, but it is far from proven and 5'RACE is insufficient by itself in my opinion. Imaging would also help, perhaps with siRNA bearing biotin tags for subsequent fluorescent analyis ex vivo to verify cytosolic delivery and correlate this with putative RNAi activity. These are the detailed types of studies so badly needed but which are skipped right over because there is so much money involved and time is of the essence.

As for systemic delivery of oligos into cells, I don't mean to say that it will definitely never be accomplished. Certainly, I really hope it is figured out as that would open the door to RNAi therapy's true potential. But, from my perspective, I think it is clear that there is a long long way to go and no amount of economic pressure on Alnylam and other companies desperate for efficient and safe delivery methods is going to produce this in the near term. SNALPS, in my opinion, are a quick fix. They are adequate to publish a Nature paper here and there, and perhaps maybe they'll be ok for targeting the liver and toxicity won't be so bad for limited duration treatment. But to systemically deliver tumor-suppressing siRNA to solid tumors, brain etc. I think an entirely new and novel approach would be needed for delivery, and this approach would have to satisfy some exceptionally stringent and so far yet to be satisfied requirements.

Dirk Haussecker said...

"By this I mean, direct biochemical detection of the cleaved mRNA and it needs to be cleaved at exactly the expected site based on the introduced siRNA."

That's exactly what the 5' RACE technique does, namely confirm that the target was cleaved at the predicted site.

"SNALPS, in my opinion, are a quick fix. They are adequate to publish a Nature paper here and there, and perhaps maybe they'll be ok for targeting the liver and toxicity won't be so bad for limited duration treatment."

That seems like a good start to me.

Anonymous said...

Oops sorry about that, I misunderstood 5'RACE and thought it was just mRNA quantification...but I now see that it is indeed a way to determine the end site of mRNA cleavage products. Thanks for correcting me :)

I should add that the two papers which contained all the preclinical data for the anti-CNV siRNA (which are referred to as such in the Kleinman et al. Nature 2008 paper showing TLR3 receptor activation is the primary cause for antiangiogenic activity in CNV mouse models):

Reich, S. J. et al. Small interfering RNA (siRNA) targeting VEGF effectively inhibits
ocular neovascularization in a mouse model. Mol. Vis. 9, 210–216 (2003).

and

Shen, J. et al. Suppression of ocular neovascularization with siRNA targeting VEGF
receptor 1. Gene Ther. 13, 225–234 (2006).

both do not use 5'RACE to identify RNAi cleavage products. More recent studies do use 5'RACE, and that is great. But at least in the case of the anti-CNV (and AMD) naked siRNA drugs currently in clinical trials (some past phase II I believe), no confirmation of RNAi cleavage products was made prior to going into humans. In addition, they used the anti-GFP siRNA which has anonomously low immunogenicity (as described in "Misinterpreting the therapeutic effects of siRNA caused by immune stimulation" by Ian MacLachlan et al. Human Gene Therapy 2008). This of course just reinforces the fact that without confirmation of RNAi cleavage products in the target tissue, there is room for erroneous interpretation of the data.

As for SNALPS targeting the liver, yes it is better than nothing, and obviously the liver is a fantastic organ to target for a number of diseases, not the least of which is for lipid disorders (hypercholesterolemia etc.). There is nothing wrong with targeting the liver, and surely a sizeable industry could be supported solely based on that. But of course the hope is that RNAi can be used elsewhere, and that will require, in my opinion, a quantum leap in delivery technology above what is currently used. Certainly, there is lots of room for ingenuity in the delivery field and now there are apparently multiple billions of dollars on the line for siRNA delivery...which is a good thing because it will hopefully stimulate new ideas for delivery systems.

And I'm sorry if I came off as overly pessimistic, I'm not really. I am just trying to guard my optimism and attempt to stay grounded in the reality that the delivery problem is far from solved and that it is not clear how it will be solved...i.e. there aren't any good leads in the literature or industrial pipeline at the moment as far as I can tell.

Anonymous said...

sorry, I severely misspelled "anomalously"...it made me laugh when I saw it so I thought I'd point it out

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