Ocular Applications Back in the Focus of Oligonucleotide Therapeutics

Following yesterday's disclosure that yet another one of GSK’s target picks for clinical development under their antisense options agreement with ISIS Pharmaceuticals is an ocular one, I thought it worth highlighting that ocular applications are regaining traction in oligonucleotide therapeutics in general.  This follows a temporary lull in the area due to setbacks with older generations of the technologies and funding issues for the industry.

Aptamers still in the lead

It may surprise you, but the eye is the one area in oligonucleotide therapeutics where aptamers, nucleic acids binding protein targets based on their shape not sequence (similar to antibodies), are most advanced.  Despite of the fact that the first approved aptamer, Macugen, is considered a great disappointment as it lost out to the monoclonal antibody competition in the VEGF market for wet AMD and DME, there are at least two new development candidates that are poised to become blockbusters in the same market: Fovista by Ophthotech targeting PDGF which has shown unprecedented activity in a phase II study in combination with anti-VEGF antibody Lucentis, and an earlier-stage, but potentially superior VEGF/PDGF bispecific aptamer approach by privately held SomaLogic.

It is now thought that the Macugen failure was due to it not targeting the relevant VEGF isoforms.  In other words, it was a failure of target selection/biological insight, not a failure of the technology.  Aptamers should work well for trapping extracellular proteins for ocular applications, because unlike their often rapid elimination following systemic administration, they can be maintained at elevated concentrations in the eye for sustained periods of time.  Their limitation, however, is in the number of targets available to them, similar to monoclonal antibodies.  Nevertheless, it should be kept in mind that with even just 2 or 3 commercial successes in a therapeutic area, a platform technology can be considered tremendously valuable there.

Gene-regulatory oligos catching up

Although ocular drug development has also been popular in both the antisense and especially RNAi fields, previous technology generations were inadequate to effect robust gene modulation, especially target gene knockdown.  This holds true for 1^st (à Vitravene) and 2^nd generation (cRaf inhibitor by iCo Therapeutics) antisense and the ‘naked’ RNAi trigger folly of the early days of RNAi Therapeutics (à Acuity Pharmaceuticals, Sylentis, Quark, and Sirna/Allergan to name just some of the worst offenders of sound science).

The reason why antisense and RNAi are both staging a comeback in ophthalmology is due to the use of higher affinity chemistries (e.g. cET by ISIS) and self-delivering RNAi triggers, both in the form of (partially) double-stranded (e.g. sd-rxRNAs by RXi Pharmaceuticals) and single-stranded RNAi triggers (à ISIS Pharmaceuticals).  The increased stability and lipophilicity combined with small molecular size should allow such an RNAi approach to efficiently penetrate the vitreous of the eye following needle injection and reach deep into the retina and other ocular structures.  Similarly, what used to be a mediocre 40% knockdown for ASOs could now be a genetically much more useful 70-80% knockdown with gen2.5 RNaseH.

It is too early to tell whether RNaseH gen2.5, ssRNAi, or sdrxRNAs will win out in the end.  At least in terms of timing, it will be as much a matter of investing in the technologies as it is about their potential.  In particular, I am disappointed by the failure of RXi Pharmaceuticals to recognize the need to further develop their sd-rxRNA chemistry.

So keep your eyes peeled as clinical results from the new wave of gene-modulating Oligo Therapeutics will start to emerge in 2016 and beyond.  It is possible that QPI-1007 by Quark Pharma for ocular neuroprotection for NAION may be earlier than that, although the chemical nature of this ‘2^nd generation’ non-AtuRNAi trigger remains unclear to me and therefore might be, or might not be a 'self-delivering' RNAi trigger.  If not this one, the upcoming clinical development of CTGF-targeting RXI-109 for retinal scarring by RXi Pharmaceuticals should be an interesting one to follow.

Fate of Quark Wet AMD Program in Limbo

PF-4523655 is arguably RNAi's most advanced clinical candidate. A naked, 19bp blunt-ended intravitreally injected AtuRNAi molecule, it had completed a phase II study in diabetic macular edema (DME) for which the results suggested a benefit over laser treatment; there was another phase II study of the same molecule in wet age-related macular degeneration (wet AMD) for which Quark, along with partner Pfizer had yet to report results.

These studies were also important for Silence Therapeutics, as an advance of any of these programs into phase III would have spelled the long-awaited non-dilutive funding (about $4M). Unfortunately, despite the suggestive DME efficacy data, Pfizer was not satisfied with the commercial competitiveness of the results in light of the newer VEGF pathway inhibitors. Therefore, Pfizer and Quark agreed that Quark would run a phase IIb study on its own dime testing higher doses of ‘655 in a head-to-head trial with VEGF MAb Lucentis. Pfizer would retain opt-in rights.

Still, the results from the wet AMD trial were outstanding. Expectations were relatively low though as in March 2011, as Quark attempted (yet again) to go public, the company disclosed that ‘655 was ‘not superior’ compared to Lucentis at the primary endpoint. Still, full results remained to be reported, probably in H2 2011. These results, however, never came. Since clinicaltrials.gov indicated that the study had been completed, it became obvious that there had been no positive surprises.

In its full-year results presentation, Silence Therapeutics today confirmed that while ‘[t]he trial demonstrated a dose-dependent increase in benefit of PF-04523655. Quark is now awaiting results from the Phase IIb trial in diabetic macular oedema before deciding on plans for the drug in age-related macular degeneration.’ In other words, not good for Quark and not good for Silence Therapeutics either: the fate of the wet AMD program now depends on the results from the phase IIb DME trial. It also seems that, like for DME, Pfizer has handed back the compound to Quark for wet AMD based on changes in the clinicaltrials.gov database in November 2011 that show ‘Pfizer’ being changed to ‘Quark’ in a number of entries relating to the sponsor of the trial. The silence (small letter) by Quark can be explained by the fact that it seems to have given up on going public for the time being.

From a medical point of view, the DME and wet AMD developments are a pity. If it is indeed the commercial profile vis-à-vis the protein-based VEGF pathway inhibitors that is keeping ‘655 from going into phase III, and not lack of efficacy, it may indicate some unjustified bias against RNAi Therapeutics. Both classes are intravitreally injected and there are many patients that are dissatisfied with the efficacy of these proteins. As a result, patients seek help from (expensive) treatments (such as acupuncture) that have not passed, or even undertaken formal clinical studies. What would be attractive with a molecule such as ‘655 is that it is not supposed to work as a VEGF pathway inhibitor and would thus offer a complementary mechanism of action (anti-apoptotic). On the other hand, since Quark has been so coy with the data, I suspect that bias alone may not explain Pfizer’s decision. Maybe with a sounder basis of delivery, next-generation RNAi Therapeutics candidates can address that void.

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.

RNAi Therapeutics and Innate Immunity- Keeping the Field Honest

As part of the RNAi Therapeutics review series in Human Gene Therapy earlier this year, former Protiva scientists Adam Judge and Ian MacLachlan (both now with Tekmira following the Protiva-Tekmira reunion) made some rather bold statements with regards to the interpretations of a number of pre-clinical RNAi Therapeutics validation papers (‘Overcoming the innate immune response to small interfering RNA’). As part of the same reviews series, in the risk section of “The Business of RNAi Therapeutics”, I also cautioned that some of the first RNAi Therapeutics candidates may show clinical efficacy, but not necessarily for all the right reasons.

The reason for this should not come as a surprise to anybody in the oligonucleotide therapeutics field: long known from the experience with antisense and other oligonucleotide therapeutics classes, oligonucleotides such as siRNAs have the potential to induce innate immune responses which can have antiviral and anti-angiogenic activity independent of their gene knockdown capacity. In fact, there are significant efforts to harness this biological property for therapy in its own right, particularly the TLR responses. Furthermore, the potential for inducing innate immune responses by synthetic and DNA-directed RNAi has been well documented since 2003 and many of the pathways involved elucidated. Nevertheless, one should not ignore the fact that while RNAi Therapeutics may actually be able to take advantage of such activity as part of synergistically acting immunostimulatory RNAi Therapeutics, the risk is that the oligo-dependent immune responses are quite complex and therefore often difficult to predict and in the worst case may cause serious adverse events.

Since many of the early RNAi Therapeutics validation papers involved antiviral and anticancer applications, it was therefore reasonable to suspect that some of the studies misinterpreted therapeutic effects as the result of RNAi gene knockdown when, in fact, innate immune responses accounted for the majority of the activity. In support, the Tekmira researchers now report that almost all of the unmodified siRNAs reported in a sample of such papers were immunostimulatory whereas a single siRNA that, somewhat disturbingly so, was used as the control siRNA in many of the studies proved to be the exception having no such detectable activity. I should add, however, that the assay conditions were rather stringent (types of cells used and high siRNA concentrations) and just because an siRNA may induce immune responses under these conditions does not prove that these were actually responsible for the treatment effect seen in each of the cited studies. Also, if TLR therapeutics history is any guide, oligonucleotides that elicit immune responses in small animal models, do not necessarily do so in primates.

Given its potential as a whole new class of therapeutics, the scientific and clinical bar for RNAi Therapeutics is set particularly high and reports like the effect of TLR3 stimulation by siRNAs on preclinical models for wet AMD and the present paper by Tekmira tend to get quite a bit of press. While they remind us of the complexities involved in establishing a functional new drug discovery platform, they should also be regarded as promoting that process. In fact, the handful of bona fide RNAi Therapeutics groups, pure-plays and Big Pharma subsidiaries alike, are already taking oligo-induced innate immune responses very seriously and have taken advantage of the rapid progress in the field by applying best practices for identifying and correcting these responses (modification, siRNA structure) in developing the latest crop of RNAi Therapeutics candidates.

The acquisition of former TLR therapeutics company Coley Pharmaceuticals by Pfizer for example may be interpreted as Pfizer investing in solving siRNA-induced innate immune responses as one of the main challenges for RNAi Therapeutics they had identified. Similarly, Sirna Therapeutics and Protiva in their prominent 2005 Nature Biotech paper on RNAi delivery in a mouse model of hepatitis B recognized the potential of unmodified siRNAs to elicit non-specific viral suppression and solved the issue by appropriately modifying the siRNAs. Around the same time, Alnylam somewhat quietly generated IP related to double-strand RNA immune stimulation that it then exclusively licensed to Tekmira. Clearly, the main players in the field have not chosen to ignore the issue, but have invested considerable efforts with tangible results.

But what about the current RNAi Therapeutics clinical candidates that have already entered the clinic? There are one phase III (Opko Health) and two phase II (Sirna/Merck-Allergan and Quark-Pfizer) siRNA candidates for the treatment of wet AMD that obviously have naturally come under increased scrutiny. As far as I am aware, all three of these are ‘unformulated’, intravitreally injected siRNAs with one of them, Opko’s, being an unmodified siRNA. While it is not clear how well the mouse TLR3 studies translate into humans, they certainly raise the concern that non-specific responses might be responsible for any thus far clinically observed therapeutic effects, particularly since in the recent Nature study gene knockdown by this route was very limited at best (cholesterol-conjugated siRNAs, however, administered by the same route were shown to mediate functional gene silencing in the same study).

As is the case with Alnylam’s lead candidate ALN-RSV01 for the treatment of RSV infection which has raised similar concerns, it will be important to be forthcoming in the interactions with the regulatory agencies such that safe trials can be designed based on our best understanding of the mechanisms of action of the different siRNAs. While I haven’t read the documents, it certainly wouldn’t be the first time if such non-specific effects were noted as potentially contributing to treatment. In the future, it would not surprise me at all to see openly declared immunostimulatory siRNA drug candidates enter the clinic. If, however, these issues are not addressed upfront, and should adverse events occur as a result, this could easily backfire and future trials rendered much more onerous- something that should be in nobody’s interest. As for the prospects of the individual drug candidates in question, even if non-specific effects contributed to the therapeutic efficacy of these candidates, as long as they are safe and well tolerated they may very well be viable drugs.

Finally, it is curious as to what exactly motivated Tekmira to re-test an entire battery of published siRNAs for their potential of inducing non-specific effects. It is possible that Tekmira has evaluated siRNA therapeutics for a number of the same applications like flu and wet AMD and were frustrated to see publications come out that according to their experience should have been artefacts (scientists tend to measure themselves by the number of publications and their impact factors and don’t like to see their own published work de-valued this way). Another part of the answer may also have been to keep the field honest at this early stage of RNAi Therapeutics drug development before long-term damage is caused: “However, surprisingly few of the reported studies have adequately tested, or controlled, for the potential effects of siRNA-mediated immune stimulation, making the many published claims of therapeutic efficacy a collective liability for the RNAi field that remains to be addressed.” By setting a rigorous new standard, Tekmira also signals their expertise not only in RNAi delivery, but also in siRNA chemistry and safety (like Coley, Tekmira has a long-standing interest in the use of immunostimulatory oligonucleotides for therapy). Supporting their claim, Tekmira/Protiva’s publications on abrogating TLR7/8 responses and SNALP RNAi delivery have proven to be extremely reproducible in many different laboratories.

The road to RNAi Therapeutics reality won’t be smooth. As much as it is important to tackle the scientific hurdles head-on, investors and the press should also make an effort to discriminate between ‘good’ and ‘bad’ science.

Journal Club: Study Shows TLR3 Induction by siRNAs with Anti-angiogenic Effects, Questioning Ongoing RNAi Clinical Trials for Wet AMD

RNAi is a relatively young therapeutic platform and we are rapidly learning about the gene-specific and non-specific effects of RNAi triggers in vivo. Ultimately, the value of RNAi Therapeutics lies in the gene-specific knockdown of therapeutic target genes, but it is clear that non-specific class effects may confound the analysis of pre-clinical and clinical results. This is especially true for a number of the early RNAi Therapeutics candidates that entered the clinic at a time when less was known about issues such as off-targeting, cytokine induction via TLR-7, and now also TLR3.

The study by Kleinman et al. from the University of Kentucky that appeared yesterday in the high-profile journal Nature (Nature doi 1038/Nature 06765), investigated siRNA therapy for wet age-related macular degeneration (AMD). Of note, there are at least 3 RNAi clinical trials ongoing for AMD: a phase III candidate by Opko Health, bevasiranib, involving intravitreal injection of an unmodified siRNA against VEGF; a phase II candidate by Allergan/Merck(Sirna Therapeutics) involving a chemically modified siRNA against VEGF-R1, also intravitreally injected; and last but not least a phase I, likely intravitreally injected “AtuRNAi” compound targeting a novel, non-VEGF pathway gene by Pfizer/Quark Biotech. Kleinman and colleagues showed that pretty much all of the siRNAs they injected, 2’O-methyl modified (Allergan drug) or not (Opko), suppressed laser-induced choroidal neovascularisation (CNV) in mice, a commonly used model for wet AMD, independent of whether their sequence was directed against an angiogenesis gene or not. Furthermore, such siRNAs were not taken up by the cells in the back of the eye, consistent with a lack of target gene knockdown. Through a series of elegant experiments, they showed that this non-specific antiangiogenic effect was mediated by binding of the dsRNA to the TLR3 receptor on the cell-surface of endothelial cells and the subsequent induction of IL-12 and interferon gamma, both of which alone could account for the observed CNV suppression.

At the moment, I cannot explain the discrepancy between these data and studies by the Opko (formerly Acuity) and Sirna Therapeutics groups that showed sequence-specific down-regulation of target-genes and cellular uptake of siRNAs using the same methods employed by the Kentucky group. Be that as it may, since TLR3 receptors are known to bind dsRNA and upregulate the IL-12 cytokine and interferon-gamma and it always amazed me how unformulated siRNAs may so efficiently be taken up in the eye, the conclusions of the studies appear credible. This receptor is different from the cytokine induction potential via TLR-7 which can be abrogated by chemical modifications, particularly 2’O-methyl.

Well, that’s the bad news. But there is also reason to be optimistic. Importantly, the authors showed that by conjugating a VEGF siRNA to cholesterol, the siRNAs were taken up into the cells and were able to knockdown its target gene and reduce CNV, even in mice lacking TLR3. All of this was achieved at the remarkably low amount of only 1ug administered siRNA per eye. This shows that RNAi could still be used very efficiently in a gene-specific manner to address AMD. Interestingly, a cholesterol-conjugated siRNA for VEGF-R1, the target for the Allergan/Merck drug, failed to ameliorate CNV, casting a doubt on the viability of this gene target that’s been relatively little characterized in the context of wet AMD. However, one should add that only one siRNA was tested for this and at the low 1ug dosage.

Cholesterol conjugation for siRNA delivery was first pioneered by Alnylam, and from recent presentations it appears that this is becoming an increasingly important technology, particularly with the elucidation of its uptake pathway in a recent Nature Biotech paper.

The authors further found that TLR induction was dependent on the length of the siRNA. DsRNAs of 21bp or longer induced this response, smaller ones did not. Also, it is very likely that this response to 21bp dsRNAs and longer could be abrogated by chemical modifications. Moreover, it would be interesting to speculate that since TLR3 is a dsRNA-specific binding protein on the cell surface, one may even harness this binding property for siRNA delivery if binding could be separated from TLR3 activation and demonstrated in the article for small dsRNAs.

Finally, as we learn more about these potential non-specific class effects of RNAi triggers (in this case synthetic dsRNAs, not DNA-directed RNAi), strategies can be designed to either avoid them by the judicious design of siRNAs (chemical modifications, length and structure of RNAi trigger) or even harnessed for a synergistic therapeutic effect. Although the number of supplemental figures of this paper (!) would indicate that there had been considerable resistance to the publication of this study, studies like this are extremely valuable in informing future RNAi development programs. This information can also be used to better monitor the safety of RNAi drug candidates already in clinical trials that may very well depend on such non-specific effects for therapeutic efficacy. Even for these drugs, not all hope is lost as firstly it remains to be seen whether and how these mouse studies would translate into the human setting. It is also true that many approved drugs work, but not through their anticipated mechanism of action, and some of the future RNAi drugs may be no exception to this.

Opko Health Announces Initiation of First Phase III Trial of an RNAi Therapeutic

Less than a week after the signing of two significant alliances between RNAi Therapeutics companies with Big Pharma, it is today up to Opko Health to announce the initiation of the first phase III clinical trial for an RNAi Therapeutic. Opko Health is an ophthalmic focused company that was recently formed through a string of mergers and acquisitions with one of the companies involved being Acuity Pharmaceuticals. It is from Acuity that Opko inherited two advanced clinical RNAi Therapeutics programs, one of which is the subject of today’s announcement.

In the proposed COBALT study, Cand5 (bevasiranib), an unmodified siRNA against VEGF, will be given once every 8 or 12 weeks in patients with wet age-related degeneration (AMD). The goal is to assess its safety and, more importantly, whether it has equivalent efficacy compared to a the currently leading wet AMD drug Lucentis, which is another VEGF inhibitor that is given once every 4 weeks by needle injection.

Although the sweet spot for RNAi Therapeutics are targets that are otherwise undruggable by small molecules and monoclonal antibodies, Opko is one of a handful of companies targeting the VEGF pathway for AMD and diabetic retinopathy (see “RNAi and the Eye” post on May 1, 2007). This is in spite of the fact that other widely prescribed drugs, namely the monoclonal antibody Lucentis and the RNA aptamer by OSI Pharmaceuticals already serve this market. While this may reduce development risk and function as a proof-of-concept, RNAi Therapeutics for these applications will have to compete directly with such therapies in terms of safety and tolerability, potency, and duration of efficacy.

The reason why Opko wants to challenge Lucentis on duration is because each needle injection carries a risk of damaging the eye and causing discomfort to the mostly elderly patients. This becomes a particularly pressing issue for a repeat-administered therapy such as for wet AMD. Therefore, being able to reduce the frequency of injections by half or even more without a loss in efficacy would make an RNAi Therapeutics a very attractive treatment option. Indeed, pre-clinical studies published last year on the silencing of liver-expressed ApoB100 by systemic administration (Zimmermann et al. (2006) Nature 441: 111-4) support the notion that RNAi Therapeutics may have comparable or even better pharmacokinetics compared to what is usually observed for therapies such as monoclonal antibodies

While a positive outcome would certainly help the field of RNAi Therapeutics, there is cause to be skeptical. In particular, bevasiranib is an unmodified siRNA that is given without a particular performance enhancing formulation. This may result in suboptimal gene silencing due to RNA instability issues and inferior cell delivery and ultimately exhibit poor pharmacokinetics. Indeed, results from the C.A.R.E. phase II studies in 129 wet AMD patients were mixed and did not show statistically significant evidence for improvement of acuity. Opko clearly sees the need for optimizing RNAi delivery and have two years ago formed an alliance with the RNAi nano-delivery company Intradig to develop topical and other formulations for Cand5. Whether this will directly impact the current studies is unclear.

I am therefore more optimistic about the approach taken by Merck (formerly Sirna Therapeutics) and their partner Allergan to develop a slow-release formula of a modified siRNAs against the VEGF-receptor that when combined may significantly reduce the need for frequent needle injections. Phase II studies for that trial have started earlier this year.