Thursday, May 31, 2012

ALN-RSV01 Data Put Regulators in a Bind

ALN-RSV01 has been a controversial drug candidate in the field of RNAi Therapeutics not because of doubts that it has antiviral activity, but strong suspicion that it may reduce RSV levels by a non-RNAi mechanism of action, likely related to the activation of innate immunity.  The latest topline data from a phase IIb study in adult lung transplant patients are consistent with Alnylam's most advanced clinical candidate having such antiviral efficacy*.  The data show that inhalation of ALN-RSV01 in RSV-infected lung transplant patients results in improvement in a key important outcomes measure in this underserved orphan patient population: the incidence of new or progressive bronchiolitis obliterans syndrome (BOS) for which RSV infection is a major risk factor and which is associated with transplant rejection and death.

* antiviral efficacy, a secondary outcomes goal is yet to be reported

Despite of what appear to be clinically significant data- ALN-RSV01 treatment was associated with more than 50% relative risk reductions in new or progressive BOS in all reported patient groups (intent-to-treat or not)- critics will point out that, strictly speaking, ALN-RSV01 has barely missed its pre-specified primary endpoint in terms of statistical significance: p-values of slightly below 0.06 in the intent-to-treat populations (note: p-values in the arguably more relevant last-observation-carried-forward population was below the magic 0.05 mark).  This result in probably the largest clinical study of its kind (87 patients enrolled) is consistent with an earlier phase IIa study which was also strongly in favor of ALN-RSV01, but which had suffered particularly from imbalances in patient baseline characteristics which might have skewed results in favor of ALN-RSV01.

Despite the encouraging data, Alnylam made it abundantly clear that it is far from certain that it will further develop ALN-RSV01 for this patient population: having poured what must have been tens of millions into this clinical candidate which has been abandoned for development in the commercially much more attractive infant population due to the aforementioned mechanistic and resulting safety concerns, investing more in an orphan indication with maybe 500 to 1000 annual cases after running the probably largest study of its kind in this patient population would be difficult to justify in economic terms.

As a result, the company more or less said that the ball is now in the court of regulators in the US and Europe to make a tough public health decision: approve ALN-RSV01 with the present data and/or provide us with a path forward towards expanding the patient population without too much added effort (e.g. bone marrow transplant patients), or we will abandon this program and have lung transplant patients continue to be treated for RSV infection with highly questionable agents for which there is no clinical evidence of benefit (inhaled ribavirin is particularly notorious in that regard). Judging from the body language, another pivotal large or even larger phase III study certainly is not in the cards and religious adherence to p= 0.05 won't be taken lightly. 

In my opinion, the secondary outcomes from this trial, including lung function, transplant rejection, and overall survival, all of which were not disclosed yesterday, will tip the scales.  Full results are to be presented at the European Respiratory Society meeting in September of this year.  Mark your calendars.

Wednesday, May 23, 2012

PBL Grants Alnylam Non-Exclusive License to RNAi Trigger IP, Increasing Alnylam Partnering Prospects

The fact that Alnylam has started to advertise itself as a product- and not platform-based company can be partly attributed to the the loss of its once strong position in RNAi Trigger intellectual property.  After it became clear that the company not only forfeited its gate-keeping potential (see Kreutzer-Limmer and Tuschl patent prosecutions), it got even worse when other IP, most notably the Baulcombe US patent issued earlier this year interfered with that company’s freedom-to-operate in RNAi triggers, once its core value proposition.  This also meant that prospects for product partnering deals that have been promised by the company to happen this year were quite low. 

Today’s announcement that the IP commercialization arm of various British plant research organization, Plant Bioscience Ltd (PBL), is granting Alnylam a worldwide, non-exclusive license to the Baulcombe IP thus removes some of the overhang.  This IP, and the US patent in particular, covers much of the size range for which Alnylam’s exclusively held core Tuschl II overhang IP is useful for, including all of the RNAi triggers in Alnylam’s development pipeline (for a more detailed background on the IP, see here).  Of course, it does not remove the overhang that Tekmira owns the delivery technology on which Alnylam’s most valuable pipeline assets rely on…

It is notable that PBL granted Alnylam solely a non-exclusive license.  This is because the licensing organizations of academic institutions generally prefer to provide exclusive licenses to drug developers with gate-keeping IP positions as this arguably increases the value of the IP versus a scenario in which critical IP is divided between competing companies.  This could thus be consistent with PBL considering Alnylam’s IP estate as non-gatekeeping- as I do.  

Today’s development is positive in two ways.  For one, it acknowledges the scientific contributions of the plant community in the discovery of RNAi.  It also indicates that Alnylam is becoming more realistic about its own IP position and will take additional licenses to IP even if it does not control them outright.  Having said that, I do not consider it likely that it will likewise seek RNAi trigger IP licenses from competing companies such as Silence Therapeutics (e.g. Zamore) unless it can do so after a bankruptcy, or even that Alnylam’s management and BoD will abandon personal pride and brinkmanship in light of Tekmira.

Brief comment on Facebook IPO 'outrage'

Just as I find it incredulous that a newspaper like the New York Times poses the (really rhetorical) question of whether insider trading is part of the fabric of Wall Street (if they don't even know what  has been going on in their backyard for decades, why does the NY Times get so much acclaim?), I find it unbelievable (well not really as it is about gaining business advantage and popular votes) that the story about the potentially illegal sharing of insights between the research and investment banking arms of financial institutions such as Morgan Stanley is getting so much attention.  It's been happening in biotech all along.  What is ironic, without violating the Chinese Wall, it seems almost impossible for biotech companies these days to raise capital.  

Thursday, May 17, 2012

ASCO 2012: Silence and Alnylam Provide Update on RNAi Therapeutics Candidates for Solid Cancer

It is this time of the year again when abstracts for the upcoming ASCO mega-cancer meeting are released (ASCO 2012 in Chicago, June 1-5).  Among the poster abstracts were phase I updates for Atu027 by Silence Therapeutics and ALN-VSP02 by Alnylam for advanced solid cancers and cancers with liver involvement, respectively.  Although the full details are yet to be presented at the meeting and the abstract date was in early February (this particularly means that critical data from the high-dose cohorts for Atu027 are missing), I will post here the abstracts as appetizers, each one followed by some brief comments. Highlights are mine.


Abstract No. e13597 by Silence Therapeutics

Antimetastatic activity of Atu027, a liposomal small interfering RNA formulation, targeting protein kinase N3 (PKN3): Final results of a phase I study in patients with advanced solid tumors.

Developmental Therapeutics - Experimental Therapeutics

Author(s): Dirk Strumberg, Beate Schultheis, W Meyer-Sabellek, C. Vank, F Gebhardt, A. Santel, O. Keil, K. Giese, J. Kaufmann, Joachim Drevs; University of Bochum, Marienhospital Herne, Department of Internal Medicine III, Herne, Germany; Silence Therapeutics AG, Berlin, Germany; Tumorzentrum UniFontis am Eduarduskrankenhaus, Köln, Germany

Background: Atu027 contains siRNA-lipoplexes, which elicits RNAi mediated suppression on PKN3 in vascular endothelial cells. In various xenograft mouse models, silencing of PKN3 expression and significant inhibition of invasive growth, lymph node and pulmonary metastasis formation was shown. Methods: Atu027 was applied to patients (pts) as a single 4h-infusion with subsequent follow-up for 3 wks. Thereafter pts were treated twice weekly for 4 weeks. In case of SD, pts were treated until PD. Dose escalation was associated with assessment of toxicity, pharmacokinetics (PK), and multiplex biomarker analyses in plasma from treated pts. Results: A total of 33 pts have received Atu027 of 11 dose levels (DL) up to 0.336 mg/kg. No pre-medication was required. No cytokine activation (TNF-α, IL-1β, IFN-γ, IL-6) was observed. In some subjects transient activation of the complement system (C3a, Bb, sC5b-9) was found, but without any clinical relevance. PK-data showed dose-dependent increase in plasma siRNA as well as lipid levels. Among various biomarkers tested, sVEGFR-1 plasma levels decreased significantly upon treatment. Across all dose levels, Atu027 was well-tolerated. Adverse events possibly related to Atu027 were fatigue grade G1 (6pts), hair loss G1 (2pts), sweating G1 (1pt), and abdominal pain G2 (1pt). G3 AEs not considered as DLTs were elevated lipase (2 pts, DL2+DL10) and diarrhea (1 pt, DL5). So far, no DLTs were seen in the last DL. Stable disease after 3 and 6 months was observed in 10 and 3 pts, respectively. Two pts with neuroendocrine cancer had disease stabilization for 9 and 12 months, respectively, including partial regression of pulmonary metastases in 1 pt. Another patient with breast cancer had regression of liver metastases.Conclusions: Atu027 is well-tolerated and anti-metastatic activity has been observed. Soluble VEGFR-1 might serve as a biomarker. So far, 0,336 mg/kg is the recommended dose for further phase II trials.

Comments: Importantly, dose escalation in this dose-finding study could proceed to the second highest planned dose level (0.336mg/kg), which at least based on the previously presented PK data should be well above the dose necessary (~0.25mg/kg) for obtaining solid target gene knockdown in endothelial cells.  As 0.336mg/kg was dose cohort 10 (up to 11 planned) and 33 patients have been dosed, this means that one cohort probably included 6 instead of 3 the subjects. I am curious to learn the reason for this in June and particularly will be looking for more insight on the complement activations which have been described to be ‘without any clinical relevance’.  Also of interest is that the soluble version of the VEGF-receptor 1 was found to decrease significantly upon treatment (maybe as an adaptation to an anti-angiogenic mechanism of Atu027?) leading the company to speculate that this could serve as a biomarker in future trials.  On the efficacy front, still nothing really conclusive can be said and there were no additional ‘hints’ of efficacy in the higher dose cohorts as one might have hoped.   Overall, however, I look forward to the updated and fleshed-out data in 2 weeks.

For a discussion of the Atu027 results at last year’s ASCO meeting, click here.

Abstract No. 3062 by Alnylam Pharmaceuticals

Developmental Therapeutics - Experimental Therapeutics

Author(s): Maria Alsina, Josep Tabernero, Geoffrey Shapiro, Howard Burris, Jeffrey R. Infante, Glen J. Weiss, Andres Cervantes-Ruiperez, Mrinal M. Gounder, Luis Paz-Ares, Rick Falzone, Jamie Hill, Jeffrey Cehelsky, Akshay Vaishnaw, Jared Gollob, Patricia LoRusso; Molecular Therapeutics Research Unit, Vall d'Hebron University Hospital, Barcelona, Spain; Dana-Farber Cancer Institute, Boston, MA; Sarah Cannon Research Institute, Nashville, TN; Virginia G. Piper Cancer Center at Scottsdale Healthcare, Scottsdale, AZ; Department of Hematology and Medical Oncology, INCLIVA, University of Valencia, Valencia, Spain; Memorial Sloan-Kettering Cancer Center, New York, NY; University Hospital - Virgen del Rocio, Seville, Spain; Alnylam Pharmaceuticals, Cambridge, MA; Karmanos Cancer Institute, Detroit, MI

Background: ALN-VSP02 is an RNA interference (RNAi) therapeutic comprised of lipid nanoparticle-formulated small interfering RNAs targeting vascular endothelial growth factor (VEGF)-A and kinesin spindle protein (KSP). In a phase 1 trial, ALN-VSP02 administered as an iv infusion q2 wks was well-tolerated and showed evidence of anti-VEGF pharmacology and antitumor activity. Methods: Patients treated on the phase I trial with stable disease (SD) or better after 4 months (8 doses) were eligible to continue on an extension study until disease progression. Main objectives included continued evaluation of safety/tolerability and assessment of disease response. Results: Seven of 37 patients (18.9%) evaluable for response went onto the extension study, including 1 of 7 (14.2%) at 0.4 mg/kg, 2 of 5 (40%) at 0.7 mg/kg, and 4 of 11 (36.3%) at 1.0 mg/kg. All had progressed after one or more prior therapies. Tumor types included head and neck squamous cell carcinoma, angiosarcoma, endometrial cancer, renal cell carcinoma (RCC, N=2), and pancreatic neuroendocrine tumor (PNET, N=2). At the time of enrollment, 6 had SD and one (endometrial cancer with multiple liver metastases) had an unconfirmed partial response (PR). The average length of time on treatment (including phase I and extension studies) was 9.5 months (range 5-19). As of January 2012, 3 patients remain on study, including the endometrial cancer patient with an ongoing PR who has had >80% tumor regression after 19 months of treatment at 0.7 mg/kg and two patients with RCC and PNET with continued SD after nearly 1 year of treatment at 1.0 mg/kg. The other patients with RCC and PNET at 1.0 mg/kg with SD came off after 8.5 and 5.5 months, respectively, for adverse events that included fatigue or elevated alkaline phosphatase. A decrease in spleen volume, likely an on-target effect and not associated with any adverse events, occurred to a greater degree on the extension study than on the phase I trial and was most pronounced in patients receiving ≥ 12 doses. Conclusions: ALN-VSP02 has preliminary activity against endometrial cancer, RCC and PNET and a favorable safety profile that permits chronic dosing. Phase II trials are warranted in these and other VEGF-overexpressing tumors.

Comments: Final results for this study were presented at last year’s ASCO meeting (for a discussion click here). The new data relate to the open-label extension phase which is of particular interest as it relates to the longer-term safety and tolerability of ALN-VSP02, and possibly first-generation SNALP delivery technology in general.  It is too early to tell to what extent siRNA sequence and modification-dependent effects played a role, but the apparent spleen toxicity is consistent with what one might expect from such formulations. Although the spleen is not an essential organ and most of us will do just fine without one, this could become a dicey issue for a chronically dosed drug like ALN-PCS02 in a ‘lesser’ disease such as many types of hypercholesterolemia.  Overall, however, this is an encouraging start for the longer-term safety of SNALP delivery technology.  Based on the indications of efficacy, another more focused study may be warranted before a final determination as to the viability of ALN-VSP02 for the treatment of cancers with liver involvement.

Wednesday, May 16, 2012

Rosetta Genomics Obtains First Medicare Coverage of a MicroRNA Dx

It all looked like it would be the first commercial success story of small silencing RNAs when Rosetta Genomics launched a series of microRNA tests in late 2008, among them mirView Mets for the identification of the tissue origin of Cancers of Unknown Primary (CUP).  This PCR-based test took advantage of two critical properties of microRNAs for cancer diagnostics: 1) stability (unlike messenger RNAs used e.g. in the comparable PCR-based Oncotype Dx test by Genomic Health, microRNAs are relatively stable); 2) surprisingly informative on cancer biology.

[Correction May 17, 2012: While the first-generation miRview Mets test was qRT-PCR-based, the Medicare-covered second-generation miRview Mets2 involves the parallel detection of 64 microRNAs on a micro-array.]

Less than four years after the launch, however, the test (actually that of the improved version miRview Mets 2) was hardly selling (less than $100k/quarter) and Rosetta Genomics, which only yesterday had a market cap of ~2M with important chunks of debt maturing next week and in early 2013, was fast approaching bankruptcy, this time for real it seemed. Matters were made worse after falling out with former US distribution partner Prometheus Labs.

However,  the CUP Dx market should have been an attractive half-a-billion-dollar opportunity with approximately 150-200,000 cancer patients in the US alone that may benefit from such tests according to Rosetta Genomics and its closest competitor, Pathway Diagnostics.  By determining the tissue origin of metastatic cancers and of primary tumors that are highly dedifferentiated and where this is not possible by other means (such as classical histological examination), the tests would aid in the diagnosis of the cancers, thus informing treatment decisions.  According to a recent cost-effectiveness study by Pathway Diagnostics, that company’s Affmetrix gene expression array-based CUP test has real positive impacts, including improved quality-adjusted life expectancies enabled by better treatment decisions based on the improved diagnoses (caveat: this study used historical controls).   

Just like Rosetta Genomics today, Pathway’s Tissue of Origin (TOO) received Medicarecoverage last summer.  The reason why Rosetta Genomics shares (ticker: ROSG) popped today by a cool 200% (!) is that coverage by major healthcare providers is critical for the adoption of today’s molecular diagnostics as these often come at price tags on the order of $3500 a test (e.g. the price of TOO according to a presentation by Affymetrix).   

The importance of Medicare coverage (other major insurance companies usually follow Medicare’s lead) is also illustrated by the OncotypeDx test which can probably be considered the most successful of that type of expression-based molecular diagnostics in the space: launched in early 2004, it sold a mere $400,000 a quarter the year thereafter.  When it, however, received Medicare coverage in early 2006, sales exploded 10-fold.  Today, Genomic Health is selling around $200M worth of that test annually and sports a market capitalization of a billion US dollars- >100x that of Rosetta Genomics despite today's pop.  Numbers for Pathway Dx are more difficult to come by as it is privately held (it completed a $30M financing in 2010 though).

Today’s news is a huge step towards similar commercial success, at least in the sense that it makes an immediate bankruptcy of Rosetta Genomics quite unlikely. The remaining employees, however, have their work cut out for them: get a foot in the door with oncologists, possibly by winning over KOLs and other activities such as cost-effectiveness studies, gently growing the sales organization from the currently only four oncology specialists to compete with Pathway and take a decent piece of the market.  

For the sake of long-suffering shareholders, the company may also consider avoiding excessive dilution partly by effectively shutting down the commercialization of their other microRNA diagnostics which by comparison look much less attractive commercially.  At the same time, they should strive to monetize their relatively strong IP position in microRNA Rx and Dx, foremost the recently issued European patent for the promising miR34a replacement cancer therapy to which microRNA Therapeutics company Mirna Therapeutics would probably require access.

For more numbers on the miRviewMets2 test performance, clinical use along with immunohistochemistry, and competitive profile with regard to the mRNA-based Pathwork and bioTheranostic CUP tests, the Meiri et al. paper just published in The Oncologist is a must-read.

Update (May 17, 2012): Shortly after the close of the markets, Rosetta announced the issuance of $2.2M worth of stock (no options, it seems) at a 30% discount, increasing the share count by about 50% (about 2 million shares will be outstanding after the secondary).  The pain from the dilution will be mitigated by the fact that this should take care of the $750k+interest payment due to their friends at Prometheus by May 22nd, thus allowing the company to stay in business.  Also worth noting are the overhang stemming from ~200k shares that will likely be converted from existing debt at a share price of ~$1.4, representing another approx. 10% dilution at significant discount.  

And finally, here's a youtube video giving you an introduction to Rosetta's scientists:

Wednesday, May 9, 2012

Skin RNAi Delivery Advance by TransDerm

Santa Cruz skin RNAi Therapeutics company TransDerm, along with collaborators from Stanford University and Thermo Fisher, recently published a paper establishing proof-of-concept for a local delivery technology that may be the first clinically relevant skin RNAi delivery approach (Lara et al., 2012).  Until now, the field of skin RNAi has been hampered either by overly painful and locally restricted delivery methods such as single-point needle injections, in vivo model systems that represent rather glorified in vitro models (e.g. co-transfections of target gene with RNAi trigger), or magic topical creams that almost work too well for me to believe.  The new data on TransDerm's dissolvable microneedles in a clinically relevant model system look promising by comparison and warrant a first clinical evaluation.  Nevertheless, for more aggressive development efforts in a number of diseases, further improvements in their knockdown potency are needed to sufficiently reduce the risk of clinical failure due to lack of efficacy.

The study by Lara and colleagues combined two prior lines of research by TransDerm: self-delivering RNAi (sdRNAi) triggers that allow for cellular delivery without nanoparticle formulation, and dissolvable microneedles.  The sdRNAi triggers had been validated in keratinocyte cell lines and skin equivalents in vitro before (Hickerson et al. 2011), although at quite high, micromolar concentrations of the oligonucleotides. Despite of the fact that born-again RXi Pharmaceuticals only in 2010 announced a collaboration with TransDerm on their particular brand of sdRNAi triggers, sd-rxRNAs, the published TransDerm research involved the Accell sdRNAi trigger design by Dharmacon (part of Thermo Fisher), most likely cholesterol or related lipophilic siRNA conjugates with additional modifications to enhance stability.  The dissolvable microneedles meanwhile had first been tested in conjunction with siRNA and plasmid delivery in transgenic mice expressing reporter genes (Gonzalez-Gonzalez et al. 2010).  Proof-of-concept for knocking down an endogenously expressed (human) gene by dissolvable microneedle-mediated sdRNAi triggers remained to be established and was only now accomplished by the Lara et al. study.

Specifically, the study targeted the CD44 gene, a gene that is more or less uniformly expressed throughout the human epidermis.  This feature allowed for the evaluation of knockdown efficiency of an endogenously expressed gene throughout the epidermal layers, not just by RNA and protein-level analyses from lysates, but also detailed immunohistochemistry.  In what I consider the best in vivo model yet, the latest research involved full-thickness human skin that was xenografted onto the backs of (immunocompromised) mice.  For skin disorders such as single-gene dominant-negative pachyonychia congenita (PC) which is the lead program at TransDerm, this may be as good an in vivo model system you can get bar clinical trials or xenograft models with skin from patients (which in this case may not be feasible technically).  In this system, repeat daily microneedle administrations achieved ~50% knockdown of the CD44 target gene.

Dissolvable microneedle delivery technology

The three major obstacles in achieving efficient skin RNAi delivery are 1) the penetration of the tough outer layer of the skin consisting of dead skin cells (stratum corneum), 2) achieving sufficient tissue distribution, and 3) achieving functional uptake into the target cells.  Moreover, the delivery ideally would avoid stimulating pain receptors in the dermal layer of the skin as normal needles would do.  The microneedle approach could potentially overcome all these obstacles.  

The technology involves an array of micron-sized needles (see illustration with penny for scale) based on a solution of ~20% polyvinyl alcohol.  Polyvinyl alcohol is an FDA-approved ingredient for medical uses, including those involving systemic exposure.  For RNAi trigger delivery, it has the added advantage that hydrophilic molecules such as nucleic acids readily diffuse into it (loading stage) and that it readily dissolves upon exposure to biological milieus, thus releasing the active ingredient.

The needles obviously function to penetrate the stratum corneum thereby addressing obstacle 1.  Because of their limited depth of penetration, however, they do not cause the pain that normal intradermal needle injection does, something which turned out to be a major drawback of the phase I study in PC that TransDerm reported on 2 years ago (Leachman et al. 2010).  By appropriately spacing the microneedles, it should also be possible to achieve a homogeneous tissue distribution (challenge No. 2).  Finally, the sdRNAi trigger design would address functional cellular uptake (challenge No. 3).

Despite the promising data, the 50% knockdown efficiency indicates that there is a need for further improvement.  This could come from a denser spacing of the needles which would appear to be a relatively simple engineering problem and more efficient sdRNAi trigger designs.

Meanwhile, TransDerm is in the process of manufacturing GMP-grade microneedle in order to go back into the clinic next year for the PC indication.  According to Roger Kaspar, scientific founder and CEO of TransDerm, the company and their various collaborators seem to believe that the current ~50% knockdown efficiency is adequate for PC based on genetic evidence from a related disease (epidermolysis bullosa simplex, aka EBS).   

Wednesday, May 2, 2012

Pfizer Gives Quark another Chance to Prove Worth of Ophthalmic RNAi Drug Candidate

Quark announced on Tuesday that it reached an agreement with Pfizer to test PF-04523655 (‘655), a drug that has already undergone phase II studies in diabetic macular edema (DME) and wet AMD, in yet a third indication: open-angle glaucoma

‘655 is an Atu-siRNA that Quark had licensed from Silence Therapeutics and in turn sublicensed to Pfizer.  Based on mixed phase II results which included a dose-dependent improvement in visual acuity, Quark and Pfizer had decided that Quark will run a phase IIb study in DME (testing higher dosages of the drug in a head-to-head with Lucentis) on its own dime with Pfizer retaining an opt-in.  The wet AMD indication meanwhile seems to be off the table now entirely, finding no mention in the latest press release. 

Testing the intravitreally injected ‘655 for open-angle glaucoma (OAG) is based on the relatively novel mechanism of action of targeting the apoptosis stress-response gene RTP801/REDD1 which should be neuroprotective and, according to preclinical studies, apparently also neuroregenerative.  OAG is a neuropathy characterized by retinal ganglion cell death and consequent optic nerve damage and is often caused by elevated intraocular pressure.  Because of this, most drugs, such as topical beta blockers, aim at reducing intraocular pressure.  In addition to unmet efficacy needs and partly because of side effects, demand for new agents remains strong.  Quark’s very own QPI-1007 RNAi Therapeutics candidate for example is being developed for related conditions (also based on neuroprotection), as is one from Spanish RNAi Therapeutics company Sylentis (SYL040012 which aims at reducing intraocular pressure, but with hopefully less side effects than competing agents).

Added motivation for testing ‘655 in OAG comes from the phase IIa results in DME which showed the dose-dependent improvement in visual acuity without the concomitant decrease in retinal thickness as is the case for the angiogenesis inhibitors such as Lucentis and is in line with the hypothesized neuroprotective mechanism of ’655.


The revision of the agreement does not seem to be associated with an immediate financial benefit to Quark Pharmaceuticals, a company which has long been struggling to become a publicly traded company (in my opinion, a reverse takeover with Silence Therapeutics may be their best hope- although it would ‘only’ land them on the AIM public market in the UK).  Similar to the case with DME, it seems that the phase IIa trial of ‘655 in OAG will be run (and paid for) by Quark, and should the results please Pfizer, the Big Pharma company may opt into further development through the payment of an exercise fee.

Similarly, it does not seem to be the case that Silence Therapeutics will have any immediate windfall from the deal amendement.  As the co-inventor of ‘655 and licensor of key patents covering ‘655, Silence Therapeutics stands to collect a mid-teens percentage of the milestone payments that Quark receives from Pfizer.  The potential earn-out from those, however, have increased from $95M to $120M according to the press release that was just issued by Silence Therapeutics.  
By Dirk Haussecker. All rights reserved.

Disclaimer: This blog is not intended for distribution to or use by any person or entity who is a citizen or resident of, or located in any locality, state, country or other jurisdiction where such distribution, publication, availability or use would be contrary to law or regulation or which would subject the author or any of his collaborators and contributors to any registration or licensing requirement within such jurisdiction. This blog expresses only my opinions, they may be flawed and are for entertainment purposes only. Opinions expressed are a direct result of information which may or may not be accurate, and I do not assume any responsibility for material errors or to provide updates should circumstances change. Opinions expressed in this blog may have been disseminated before to others. This blog should not be taken as investment, legal or tax advice. The investments referred to herein may not be suitable for you. Investments particularly in the field of RNAi Therapeutics and biotechnology carry a high risk of total loss. You, the reader must make your own investment decisions in consultation with your professional advisors in light of your specific circumstances. I reserve the right to buy, sell, or short any security including those that may or may not be discussed on my blog.