Tekmira Grabs Leadership Position in Messenger RNA Therapeutics

Messenger RNA Therapeutics is the latest addition to the RNA Therapeutics tool box.  A simple concept, it has only been recently revived outside the therapeutic vaccine realm when it was shown (e.g. Kariko et al. 2012 and Kormann et al. 2011) that certain nucleic acid modifications can minimize, if not abolish innate immune responses triggered by these long RNAs.

Of course, in addition to representing an increased innate immune challenge compared to RNAi Therapeutics, like RNAi Therapeutics, the key technical challenge for mRNA Therapeutics is the effective delivery into the cytoplasm of target cells.  When AstraZeneca paid Moderna Therapeutics $240M in upfront alone earlier this year for a limited technology license, I half rolled my eyes telling myself ‘not again’.  

The ‘not again’ refers to Big Pharma getting distracted by supposedly gate-keeping IP claims regarding the RNA inducer all the while ignoring the critical importance of delivery.  As we know, this mis-attribution of value has caused much trouble in the history of RNAi Therapeutics.

Enter Tekmira

I further believed that the SNALP LNP technology by Tekmira is most readily adapted for mRNA delivery among the RNAi delivery technologies.  So it was pleasing when Tekmira disclosed last week at the 1^st International mRNA Health Conference in Tuebingen, Germany, that they indeed have been pursuing mRNA delivery and presented first data indicating that they are most advanced in this effort.

As it is difficult to compare the amounts of proteins expressed with the different technologies due to the unique half-life of each mRNA and protein, the leadership hypothesis is partly based on an assumption, namely that there is a close relationship between SNALP LNP delivery of siRNA and mRNA.  More importantly, however, due to their ample experience of commercially translating SNALP LNP delivery for RNAi Therapeutics with over half a dozen SNALP-enabled candidates that have entered clinical development and with the demonstration of scale-up, they should have a first-mover advantage.

Liver and solid cancers

In particular, Tekmira presented data on mRNA delivery in mice for the liver and solid cancers.  The liver is of interest both as a target organ itself and also as a factory for the production of proteins secreted into the circulation.  The data showed that robust levels of the luciferase marker protein could be made in the liver.  However, the data also reminded me of one (certainly not insurmountable) challenge with mRNA Therapeutics: the relatively short period of time (<24 a="" as="" been="" boundary="" data="" designed="" expression.="" expression="" gene="" half="" has="" have="" hours="" however="" indicate="" life="" lower="" luciferase="" nbsp="" of="" ote="" p="" platform.="" protein="" reporter="" robust="" short="" so="" specifically="" that="" the="" to="">

In that light, the tumor expression data were particularly intriguing.  Not only were the tumor peak expression levels comparable to the liver, but they also were maintained over a longer period of time (~2 days) and generally declined more gradually.  Since the same mRNA was delivered, this observation would be consistent with delivery to the tumor over time, as one would expect if the EPR effect plays an important role here.  The data also support a depot effect following extravasation meaning that intratumoral SNALP-mRNAs can be stable so that they can be taken up in a delayed fashion and yet be functional.  Such observations incidentally should also prove quite useful for the development of RNAi delivery for solid tumors and I look forward to more such cross-fertilizations between siRNA and mRNA delivery.   

Tekmira the logical partner for AstraZeneca

The new disclosures would seem to warrant AstraZeneca partner with Tekmira on mRNA delivery.  After all, having spent $240M for IP puts them under pressure to do something with their rights.  As I do not think much of Moderna’s own LNP delivery efforts (order my latest OTS 2013 Report to see why), AstraZeneca would be well advised to look outside of that partnership for delivery solutions.

It also so happens that AstraZeneca’s IP rights relate to protein expression for metabolic disorders (--> liver as a critical metabolic organ) and cancers, precisely the two areas where Tekmira’s technology should be most useful initially.    

And who knows, maybe Big Pharma is not always that dense as it sometimes seems and all this had been in the making months ago and the CEO of Tekmira is about to make good on his partnership ‘promise’ (in that case, sincere apologies to AstraZeneca).

OTS 2013 Meeting Report- Now Available

Want to learn how Oligonucleotide Therapeutics are emerging as the 3rd major drug discovery engine after small molecules and recombinant proteins?  If so, then read my report on the 9th annual meeting of the Oligonucleotide Therapeutics Society held this year from October 6-8 in Naples, Italy.  My hope is that by reading the report, corporate decision makers, investors, and scientists will learn about the key dynamics in the field to help them strategically allocate their time and capital.

Please refer to the Meeting Agenda for the presentations at the meeting.

Table of Contents                                                                                          Page

I.                    Introduction                                                                                  2

II.                  Themes and Trends                                                                     3

A.      Multiple high-impact therapeutic opportunities               3

B.      Thinking small: focus on oligonucleotide chemistry        4

C.      New antisense applications mushrooming                       5

D.     Few new oligo inducer structures and delivery                7

E.      The Duchenne muscular dystrophy phenomenon               9

III.                Highlights from the various oligonucleotide modalities              10

A.      Aptamers                                                                          10

B.      Immunomodulatory oligonucleotides                                11

C.      mRNA Therapeutics                                                         12

D.     RNAi Therapeutics                                                           13

E.      LncRNA Therapeutics                                                      17

F.       Therapeutics splice modulation                                       19

G.     MicroRNA Therapeutics                                                  22

H.     RNaseH Antisense                                                            23

Pricing 

(15% discount for those that have ordered the 2013 RNAi Therapeutics Investment Guide)

Drug development companies up to 10 employees: 250 Euros/300 US dollars

Drug development companies over 10 employees: 500 Euros/600 US dollars

Other companies (e.g. financial institutions and investment funds): 500 Euros/600 US dollars

University libraries: 125 Euros/160 dollars

Individuals (private use only): 100 Euros/130 US dollars

Prices exclude 19% VAT for German customers (corporate and non-corporate) and non-corporate customers in the European Union.

Payments either by bank transfer or paypal.

When ordering, the following information is required:

Full name and address

Billing address if different  

Use (corporate, individual etc)

Order by contacting me at myfirstname.mylastnameATgmail.com
My first name: dirk; my last name: haussecker

Regulus Borrows from RNAi Delivery Technologies…5 Years Late

With the gift of birth of having access to all the technology toys from parent companies Alnylam and ISIS, Regulus Therapeutics in 2007 was poised to speed into the clinic a new class of RNA Therapeutics: microRNA Therapeutics.  Today, Regulus has yet to put a single compound into clinical development.  This not only reflects the increased biological complexity of microRNAs as opposed to for example single gene knockdown approaches such as RNAi Therapeutics, it also reflects a fear of breaking with the dogma that for microRNA inhibition ‘naked’ antisense technologies should be used.

It turns out that only now, Regulus finds that in order to optimize the product profile for their lead program, anti-miR122 for the pan-genotypic treatment of HCV infection, they really ought to borrow from RNAi delivery, in this case GalNAc-conjugates from Alnylam.  With this, they will achieve more potent miR-122 inhibition as well as increase the therapeutic window through the targeted delivery.  This is opposed to saturating the target organ along with the rest of the body with ‘naked’ phosphorothioate molecules, a concept I'm struggling to get comfortable with. 

The case for such a facilitated delivery strategy is even stronger for an antiviral anti-miR candidate such as this one because hitting the virus instantly instead of only slowly reaching effective drug concentrations in the target organ reduces the risk of drug resistance.

As a result, Regulus will enter the clinic with RG-101 at a time when the first all-oral HCV therapeutics with high cure rates will have hit the market.  This is a commercial catastrophe for an otherwise scientifically sound target.

One already has to be thankful that a small organization such as Regulus is able to show such flexibility at all (I don't even want to know in which antiquated terms Big Pharma is thinking about microRNA Therapeutics).  This achievement almost makes me afraid to ask why they have not thought it through to the logical end and adopted more structured, and much more potent anti-miR structures along with these delivery technologies?  This armchair CEO would have had a SNALP/structured anti-miR strategy tested in 2008.

However, Regulus Therapeutics has a chance to redeem itself- at least partly.  As it evaluates GalNAcs and LNPs (SNALP?) for an anti-miR program in liver cancer (HCC), it could for example help the RNAi Therapeutics industry understand whether the GalNac-receptor (ASGPR) is suitable for RNAi Therapeutics candidates for the attractive liver cancer indication.  So as Tekmira has followed Arrowhead Research into HBV, maybe Arrowhead Research may want to follow Tekmira (TKM-PLK1) into HCC.

Disclosure: The idea for this blog entry came after I started to look into RGLS ahead of the AASLD meeting (Nov1-5).  I concluded that there would be a good chance that with presenting a promising profile for RG-101 at AASLD and maybe some new data for the Alport Syndrome at the Kidney Week also in early November (Nov5-10), we could see RGLS bounce back into the $9-10 range by mid-November.

From Platform to Products to Platform

Following a number of clinical proof-of-concepts with various RNAi Therapeutics candidates, investors have started to once again not just value RNAi Therapeutics companies for their lead candidates alone, but also their platform technologies.  Recent analyst notes, the $60M fund raisings each by Arrowhead Research and Dicerna, and the pipeline development conference call by Tekmira all support this conclusion.

This is a major change in the perception of the industry from just 2 years ago when it was left for dead by most.  The timely clinical validation of RNAi Therapeutics activity was the last straw left.  To their credit, Alnylam, with the crucial help of Tekmira’s SNALP delivery technology, managed the last-minute turnaround.  At the same time and in the absence of prospects for Roche-type platform deals, RNAi bellwether Alnylam emphasized its transition from platform to product company.

In addition to reminding us of the larger potential of RNAi Therapeutics, positioning yourself as a strong platform company also tells the market that you are ready to take advantage of the most attractive RNAi-amenable markets by developing best-in-class solutions.  I cannot imagine e.g. that a blockbuster RNAi Therapeutic for TTR amyloidosis will not prompt companies which believe to have the better delivery technologies to compete for the revenues.

In order to make a credible case of being a strong platform company, vibrant R&D operations are necessary.  In addition to being indispensable for technical improvements, trying to instead obtain your animal data and formulations from CROs can be dangerous.   One of the reasons why Arrowhead Research and Tekmira should do well in this environment is that they never suffered the drastic layoffs that particularly targeted the basic research organizations while the product-specific teams were mostly left intact.

Selling the platform dream to investors and achieve an acceptable cost of capital will be an important task for RNAi Therapeutics companies to bridge the time until real sales revenues come in.  Instead of hurting investors, a healthy cost of capital and cash cushion also lessens the risk of companies succumbing to a dilutive death spiral and allows their companies, cash-, but not technology-constrained, to capitalize on their technologies in a timely manner.   

ISIS/GSK and Tekmira Come Out with HBV Knockdown Plans

If you did not appreciate the value the pharmaceutical industry has come to place on the HBsAg knockdown concept for achieving a functional cure for chronic Hepatitis B (HBV) infection, the last two days will have woken you up. 

Yesterday, ISIS Pharmaceuticals reported that it had received a $7M milestone payment related to the development of an antiviral RNaseH development candidate (ISIS-GSK3Rx, aka ISIS-HBVRx) which, although undisclosed for competitive reasons, hasgot to be for HBV.  And today, Tekmira publicly announced that they will file an IND for an HBV-RNAi candidate in 2014 while hinting at the partnering potential of such a treatment candidate.

Arrowhead Research is thus not alone in their efforts any more.  Coincidentally, Arrowhead reported today the completion of their enrollment of the phase I single-dose, healthy volunteer study with ARC520, their DPC-delivered candidate for chronic HBV.  Accordingly, the dose escalation was able to run through all the pre-planned 6 dose cohorts up to the top dose of 2.0mg/kg. 

Apparently, there were no signs of significant dose-related toxicities.  The only finding of concern among the 36 volunteers, 24 of which received drug, was 2 cases of lightheadedness of uncertain clinical relevance.  As these occurred at the highest dose, it seems that the company suspects that it could have been drug-related although the study remains blinded for follow-up.

A dose of 2mg/kg without any serious adverse events or dose-limiting toxicities is a great start for DPC delivery technology.  This is especially the case when one considers that the single-molecule subQ version of DPC that I hope will form the basis for the upcoming pipeline candidates, except for the next one perhaps, will be much more potent than the two-molecule version of intravenously delivered ARC520 based on the non-human primate data presented at last year's OTS meeting.

With 2mg/kg of ARC520, I further believe that HBsAg knockdowns of over 90% are likely.  The biggest challenge going forward with this program will be setting a knockdown goal and getting the dose and dose frequency right.

For more about increasingly lively HBsAg knockdown for the treatment of chronic HBV, please follow my HBV Knockdown Blog.

Also today: Tekmira and Arrowhead Research Rapidly Filling Pipeline

In addition to chronic HBV, Tekmira further disclosed development plans for candidates addressing Marburg infection, alcoholism, hypertriglyceridemia and severe orphan glycogen disorders.  The presentation made clear that the company has not sat on its hands since the settlement with Alnylam and is close to having at least 4 drug candidates in active clinical development by early 2015 (TKM-PLK1, TKM-EBOLA, TKM-ALDH2, TKM-HBV).

Meanwhile, previously $200M market cap Arrowhead Research has succeeded with a $60M private placement without having had to offer a discount.  In my opinion, this reflects the broadened investor interest in the space and makes Arrowhead an even better investment as it can now, freed from financial constraints, immediately pursue some of the attractive liver targets with best-in-class solutions and beyond.

Wondering whether we are in an RNA Therapeutics bubble?  Then I suggest you get my OTS 2013 meeting report.  Dare I say that oligonucleotide therapeutics is a more capable and exciting technology than monoclonal antibodies already?  At least if you believe orphan diseases are the way to go in today's pharmaceutical drug development, there is no doubt about it coming out of the meeting. 

Steve Dowdy Responds

Following the tragic events that took place surrounding highly regarded oligonucleotide scientist Steve Dowdy from UCSD there has been much speculation and confusion about the ownership of technology related to RNAi Therapeutics companies Traversa Therapeutics and Solstice Biologics.  This Open Letter by Professor Dowdy is published to present his views on the scientific pedigree of the technology behind Solstice Biologics which received significant VC funding earlier this year.  It would be a shame if the incidence were to cause further damage, also to the field of RNAi Therapeutics, by casting doubts on this promising company and delivery approach.  It is not meant as a criticism of Doug Macron at Gene Silencing News.


October 2, 2013

Shame on You Doug Macron!

I'm lying here in pain with a bullet hole that goes in one side of me and out the other having 
been hit by one of 7 bullets fired from a 45 caliber gun by Hans Petersen from a distance of ~8 
feet during his murder attempt on me and my wife, while we and our children were sleeping two
weeks ago. As you know, within hours Petersen committed another brutal attack, shooting the 
brother of his estranged wife, a crime police said was related to Petersen’s marital problems. I 
remain at an undisclosed location with my family, fearful that Hans Petersen will be released on 
bail and come after me and my family again. So with all of this as a backdrop, you have the 
audacity to write an article based entirely on false and unsupportable statements made by this 
thoroughly discredited person that accuses Curt Bradshaw and I of stealing technology from 
Traversa to start Solstice Biologics, and then you attempt to bolster those accusations by 
quoting emails written by Hans Petersen and purportedly given to you by his brother.

If Hans Petersen and Scott Petersen think we stole anything from Traversa, which we 
emphatically did not, then they should have brought this to the court system long ago, and they 
should stop using Facebook and Linkedin postings to make unsubstantiated claims. And Hans 
Peterson should certainly not be using violence against me, my family or anyone else. If they 
think the work at Solstice is derivative of their work, then the Patent Office and the courts are 
where a civilized society takes their disputes, not by trying to kill the other party.

As for your September 26, 2013 article in Gene Silencing News, where you refer to certain 
email exchanges between me and Hans Petersen and paraphrase a portion of one stating that 
“Dowdy also wrote that a significant amount of the research being conducted on the technology 
in his UCSD lab did not belong to Traversa, and indicated that it could be licensed to a company 
other than Traversa should it continue to be publicized by Petersen,” I am not certain what you 
are trying to imply here. The statement you quote fails to include contextual information with 
respect to what Traversa did and did not hold license rights to and what my role as an academic 
researcher involves. Here is the missing contextual information that should have been included 
in your piece and should have been the subject of diligence with respect to follow up questions 
posed to the Petersen’s:


1) Traversa took a license on particular patent applications developed in my UCSD lab during 2006 (SD2006-150 and SD2009-296 concerning certain PTD-DRBD technology and SD2006-
270 concerning certain RNN technology). The UCSD-Traversa License Agreement by its terms 
did not grant Traversa any rights on other work in my lab (or any other lab) at UCSD beyond the 
referenced applications and continuations, divisions, certain CIPs and foreign counterparts. 

2) Traversa did not sponsor any research in my lab at UCSD and therefore Traversa had no 
first-rights of refusal on any of my future work.

3) I am an academic researcher and no License Agreement by UCSD to any commercial 
licensee includes any obligations on my part or the part of any other personnel at UCSD to stop 
doing academic research. Any implication in your article, based upon the email provided you by 
Scott Petersen, that my academic work at UCSD should automatically flow to Traversa is 
ridiculous and in conflict with the Intellectual Property Policies and Conflict of Interest Policies 
that academic researchers function under in all academic institutions I am familiar with.

4) I was party to a Consulting Agreement with Traversa, that agreement contained obligations to
assign intellectual property rights conceived or discovered in the course of me rendering 
consulting services to Traversa; it did not cover work performed at my UCSD lab.

5) Because I was in the hospital recovering from gunshot wounds, I was unavailable to confirm 
that I sent the email (scrap of email) you included in your Sept 26 article. I cannot confirm that I 
sent the email without seeing it in its entirety. However, the reference to Petersen “continuing to 
publicize the technology” was a reference to my concern that he not disclose technology with 
respect to which Traversa held no rights and that was being developed in my UCSD lab and 
was at a very early stage of development, thus letting the field know what I was working on.

Mr. Macron, you would be well advised to do some basic diligence on the manner in 
which academic laboratories make inventions available to private companies, because 
the line of arguments that the Petersen brothers are feeding you is just false.

Your September 26, 2013 article in Gene Silencing News, also references a Hans Petersen 
email dated May 2013 that he sent to the legal counsel for the Traversa trustee overseeing the 
company's bankruptcy proceedings. You state that in this email “Petersen alleged, among other 
things, that Dowdy and Traversa CSO Curt Bradshaw declined additional investment in the 
company from Dr. Corey Goodman, a pharmaceutical industry veteran and managing partner of 
venture capital firm VenBio, in order to intentionally drive the firm into bankruptcy.” As Corey 
Goodman of venBio has previously informed you, venBio was never approached by 
anyone seeking an investment in Traversa and we did not meet with Dr. Goodman until 
April 2012, by which time Traversa had already entered bankruptcy. As a point of fact, I 
had never met nor spoken with Dr. Goodman prior to April 2012.


Your September 26, 2013 article in Gene Silencing News, also includes the statement that “As 
part of Traversa's bankruptcy proceedings, intellectual property related to the RNN technology, 
which had been licensed from UCSD, returned to the institution and relicensed to Dowdy and 
Bradshaw for use by the new RNAi drug company they founded, Solstice Biologics.” The 
Traversa Board of Directors elected to return the UCSD SD2006-270 patent application to 
UCSD in November 2011 to avoid having to pay UCSD a $100,000 fee that Traversa was in 
arrears on, as well as a separate fee that would come due to UCSD in February 2012; Traversa 
was at this time focused on its PTD-DRBD program and maintained those patents. The return 
of the UCSD SD2006-270 patent application to UCSD was not part of the Traversa bankruptcy 
proceedings it occurred five months prior to the Traversa bankruptcy filing. When Solstice 
Biologics entered into its license with UCSD in December 2012, the SD2006-270 application 
and 2 additional UCSD patent applications were licensed to Solstice Biologics. To be concise, 
the UCSD SD2006-270 application is not Traversa technology; its UCSD technology that was 
licensed to Traversa and then returned to UCSD.

The technology that UCSD licensed to Solstice Biologics was not licensed until December 2012. 
It was not even shown to venBio until April 2012 because it had taken me and my UCSD lab of 
12+ scientists more than 6 years to resolve the challenges with RNN technology and build a 
self-delivering siRNN prototype; only then did we show it to potential investors. 

The Solstice Biologics investors spent a significant amount of time and money to diligence the 
in-licensed UCSD intellectual property and also in reviewing the patent Scott Petersen patent 
application purchased from the Traversa estate before entering into the license and funding of 
Solstice Biologics. Based on those analyses, the investors funded Solstice Biologics.

Lastly, have you even considered that your two primary sources are (1) someone who is 3
currently in jail for 3 counts of attempted murder and (2) a sibling who provided emails written by 
his brother and who, according to your reports, has made inconsistent claims of ownership to 
certain siRNN technology that he later bought from a third party in bankruptcy?

So will you please stop writing these unsubstantiated pieces where Hans Petersen and 
Scott Petersen show you selective emails and make ridiculous claims about the pedigree 
of the technology that Solstice Biologics licensed from UCSD and call into question my 
character and actions and those of Curt Bradshaw?

I give you permission to publish this as is, unedited, under the title of "Steve Dowdy Responds"

Sincerely,

Steve

Steven F. Dowdy, Ph.D.
Professor
Dept. of Cellular & Molecular Medicine
George Palade Laboratories, Room 231B
UCSD School of Medicine
9500 Gilman Drive, MC-0686
La Jolla, CA 92093-0686

Email: sdowdy@ucsd.edu

Merck’s RNA(i) Therapeutics Unit on the Chopping Block

After more than 6 years of playing it safe and producing nothing tangible in terms of clinical development candidates, I fully expect that the time has come for Merck’s RNA(i) Therapeutics unit to be slashed.  This morning, Merck announced a company-wide cost-cutting re-org, as part of which it aims ‘to reduce its focus on platform technologies’.  Remember Roche 3 years ago? 

Similar to Roche, the immediate financial benefits of scrapping the unit not only come in the form of savings in R&D expenses, but also likely tax write-offs due to for example the $1.1B purchase of Sirna Therapeutics in 2006.  Expect the company to exceed analysts’ expectations for coming financial results.

However, the most important factor why I believe the unit's fate had been sealed was the departure of Peter Kim as the Head of Merck Research Laboratories.  It has been said that he had been a key backer of the unit, and with the biologics guy from Amgen, Roger Perlmutter, probably intent to erase Dr. Kim’s legacy…

It is hard for me to feel sorry about such an event.  Their RNAi science was probably the best among the Big Pharmas, but hiding behind the VIOXX experience forever while taking home monthly salaries was asking for trouble.  Meanwhile, the likelihood that Merck will partner with the real innovators in the space on specific product candidates has increased today.