Replies to post #2027 on SurModics Inc (SRDX)

[mjb_latte]

Report on study behind Merck's suspension of trial:

8/1/08 Diabetes Rep. (Pg. Unavail. Online)
2008 WLNR 14362676

Diabetes ReportCopyright 2008 Espicom Business Intelligence
August 1, 2008


Corticosteroid less effective than laser therapy for treating DMO

A study conducted by the National Eye Institute's (NEI) Diabetic Retinopathy Clinical Research Network has found that triamcinolone, a potential new corticosteroid therapy for the treatment of diabetic macular oedema (DMO), proved less effective than traditional laser treatment, and that the latter method has fewer side effects in the long-term treatment of DMO.

This was the first study to compare the long-term benefits of both treatments and evaluate their potential side effects. While triamcinolone was used in this trial, there is no scientific rationale at this time suggesting that one corticosteroid preparation should be substantially different from another. According to Dr Paul A Sieving, Director of the NEI, the results of this study, which were published in the 26th July online issue of Ophthalmology (10.1016/j.ophtha.2008.06.015), should confirm the use of laser treatment for DMO.

The investigation, which was conducted at 88 sites across the US, included 840 study eyes of 693 subjects with DMO involving the fovea and with visual acuity (VA) of 20/40 to 20/320. Patients were randomly assigned to triamcinolone 1 (n=256) or 4mg (n=254), or traditional focal/grid photocoagulation (n=330). Following treatment, investigators tested each patient to determine whether the procedure had prevented substantial vision loss (defined as reading at least two less lines on a standard eye chart two years after entering the study). Retreatment was given for persistent or new oedema at four-month intervals and the primary outcome was evaluated at two years.

At four months, mean VA was better in the triamcinolone 4mg group than in either the laser (p<0.001) or triamcinolone 1mg groups (p=0.001). By one year, there were no significant differences among groups in mean VA. By the 16-month visit and extending through the primary outcome visit at two years, mean VA was better in the laser group than in either triamcinolone group (at two years, p=0.02 for laser vs triamcinolone 1mg; p=0.002 for laser vs triamcinolone 4mg; and p=0.49 for triamcinolone 1 vs 4mg). Treatment group differences in the VA outcome could not be attributed solely to cataract formation.

Optical coherence tomography results generally paralleled the VA results. Intraocular pressure increased from baseline by 10mmHg or more at any visit in 4, 16 and 33 per cent of eyes in the laser, triamcinolone 1 and 4mg groups, respectively, and cataract surgery was performed in 13, 23, and 51 per cent of eyes in the three groups, respectively.

The researchers found that, while not as effective as the laser treatment, triamcinolone treatment did provide some benefit. Notably, laser treatment had previously been perceived to prevent further vision loss, but not to improve vision. Improvements in vision were not found in the only prior study evaluating laser treatment for DMO because most subjects enrolled in that trial already had good-to-excellent visual acuity and therefore, no room to improve. The current findings raise the possibility that combining laser treatment with corticosteroids might produce greater benefit. The Diabetic Retinopathy Clinical Research Network is currently conducting a study that is comparing a combination of corticosteroids and laser to laser alone.

Editor's note: under a joint development and commercialisation agreement, Merck & Co and SurModics are currently developing the latter's I-vation intravitreal implant system to deliver triamcinolone acetonide in a sustained-release fashion for the treatment of DMO. The product is currently in a Phase IIb trial in patients with the disorder.

[Democritus_of_Abdera]

Re: MRK’s review of TA Study Design...

As a SRDX investor, the best outcome of MRK’s decision to reevaluate their I-vation TA study protocol would be for MRK to accelerate their time table and seek a PhIII trial comparing a combination of photocoagulation with I-vation TA to photocoagulation alone over a 2-3 year period (albeit, being unsophisticated in FDA matters, I don’t know if MRK has this option). The worst outcome would be for MRK to abandon the I-vation TA program.

The major new finding in the DRCR.net July 26 report in Ophthalmology was that photocoagulation had a longer lasting beneficial effect on DME than steroid treatment. The study showed that in the short term (4 months), triamcinolone is the better treatment, but that in the long term (2 yrs) photocoagulation was better. In any event, neither treatment was completely effective and the authors suggested that a combination of steroid and photocoagulation may be more effective than either treament alone. In fact, a DRCR.net study currently is evaluating a combination of intravitreal triamcinolone and focal/grid photocoagulation, a combination of ranibizumab and photocoagulation, and ranibizumab alone as a treatment for DME ( http://public.drcr.net/DRCRnetstudies/studies/ProtocolI_lrtdme/ProtIInfo.html ).”

I suspect that, as a result of the July 26 DRCR.net study, MRK might make the following design changes:

1. A photocoagulation cohort might be added as the baseline control group, dropping the non-treated control.

2. A cohort treated with both TA and photocoagulation might be added

3. The study duration might be extended to two years

4. The primary outcome might be changed to visual acuity

----
For those interested, my notes from the July 26 Ophthalmology paper are:

A. Treatment Paradigm: TA was suspended in an hydrogel vehicle with additional injections at 4 month intervals encouraged (they averaged 3 treatments during the 2 yr period). The occurrence of elevated intraocular pressure may have limited the number of reinjections in some subjects treated with triamcinolone. Photocoagulation was selected for the control group rather than a sham injection so as to compare triamcinolone treatment directly with the only ocular treatment with current clinical trial evidence of a long-term benefit for DME. Visual acuity was the primary outcome measure (OCT results generally paralleled the visual acuity results). The protocol initially included 2 time points for assessing the outcome, 1 year and 3 years, with the latter being required for regulatory purposes. The protocol was amended to have the primary analysis at 2 years and a secondary analysis at 3 years after the Food and Drug Administration indicated that 2-year follow-up may be considered sufficient for DME treatments. The DRCR.net authors argue “that focal/grid photocoagulation currently should be the benchmark against which other treatments are compared in clinical trials of DME.”

<This paradigm differs from that proposed by MRK in the following ways (#msg-30279246): 1) MRK’s primary outcome is change in OCT retinal thickness (visual acuity is a seconary measure), 2) MRK’s study duration is 1 yr and as a PhIIb study is focused on safety, 3) MRK’s control group is a sham control (i.e. no implant, no medication), 4) MRK is examing lower total dosages of triamcinolone (0.1, 0.5, and 0.95 mg/yr vs the 1-4 mg/4 month treatment of DRCR.net), and 5) MRK’s patients are not as seriously affected by DME at the start (i.e. the study eyes have 20/40-160 vision vs DRCR.net’s population having 20/40-320 vision)>

B. Adverse Events: Consistent with other reports, the 4-mg triamcinolone injections were associated with an increased incidence of both elevation of intraocular pressure and development of cataract requiring surgery. Most cases of elevated intraocular pressure were controlled adequately with ocular hypotensive medications .... During the course of the study, some ophthalmologists fell compelled to supplement the study treatment (i.e. of the 843 study eyes, 43 (13%) eyes in the laser group, 46 (18%) eyes in the 1-mg triamcinolone group, and 34 eyes (13%) in the 4-mg triamcinolone group received supplemental treatment for DME. In particular, an intravitreal injection of an anti-VEGF drug was given to 6 (2%), 5 (2%), and 5 (2%) eyes in the 3 groups, respectively).

<I presume the referenced anti-VEGF drugs are either avastin or Lucentis. Their use implies to me that this class of compounds will be an off-label competitor even if the I-vation TA is ultimately approved by the FDA for DME.>

C. Conclusions: Over a 2-year period, focal/grid photocoagulation is more effective and has fewer side effects than 1-mg or 4-mg doses of preservative-free intravitreal triamcinolone for most patients with DME who have characteristics similar to the cohort in this clinical trial. The results of this study also support that focal/grid photocoagulation currently should be the benchmark against which other treatments are compared in clinical trials of DME.

Based on data from the ETDRS (Early Treatment Diabetic Retinopathy Study, 1985), it seems likely that the visual acuity outcome with each of the 3 treatment regimens is superior to the expected untreated course.... “Although the results of the current study confirm the ETDRS finding that focal/grid photocoagulation has a substantial beneficial effect on DME, there is certainly a role for better treatments in the future, because approximately half of the study eyes in the photocoagulation group still had central retinal thickening at 2 years, with approximately 1 in 5 having worsened 10 letters or more from baseline and only approximately 1 in 3 having improved by 10 letters or more. The fact that the 4-mg intravitreal triamcinolone group had a greater positive treatment response on visual acuity and retinal thickening at 4 months, whereas the photocoagulation group had a greater positive response later, raises the possibility that combining focal/grid photocoagulation with intravitreal triamcinolone may produce greater benefit for DME than either focal/grid photocoagulation or intravitreal triamcinolone alone.”

[DewDiligence]

MRK Dumps I-vation Program

[The writing was on the wall.]

http://biz.yahoo.com/bw/080917/20080917006270.html

›Merck & Co., Inc. Discontinues License and Research Collaboration Agreement with SurModics

Wednesday September 17, 4:00 pm ET

No Safety Concerns About I-vation(TM) Platform or I-vation TA; Reflects Merck's Strategic Review of Its Business and Product Development Portfolio

EDEN PRAIRIE, Minn.--(BUSINESS WIRE)--SurModics, Inc. (Nasdaq: SRDX ), a leading provider of surface modification and drug delivery technologies to the healthcare industry, announced today that Merck & Co., Inc. has notified the company that it will discontinue the License and Research Collaboration Agreement the companies signed in June 2007. Merck’s decision triggers an additional $9 million payment to SurModics from Merck.

Merck’s decision to discontinue the collaboration was made following a strategic review of its business and product development portfolio. This decision was not based on any concerns about the safety or efficacy of I-vation™ TA, the I-vation platform or any of SurModics’ other sustained drug delivery systems. Clinical data on I-vation TA generated to date has provided strong support for the tolerability profile of I-vation TA, and more generally, that of the I-vation sustained delivery platform.

“We understand and respect that our partners must undertake strategic reviews which on occasion result in a change of focus or even the discontinuation of projects,” said Bruce Barclay, president and CEO of SurModics. “Merck has been an exceptional partner, and we have a great deal of respect for their development capabilities and highly skilled personnel. While we are disappointed by this decision, our diversification strategy has yielded a broad base of customers and development programs within ophthalmology, as well as across our other areas of business.”

“We remain committed to and confident in the promising future of our ophthalmology business. This commitment includes our development partners, clinicians and the patients that will ultimately benefit from our innovative technologies,” continued Barclay. “Today, we have multiple ongoing customer development programs in ophthalmology evaluating several different drug delivery platforms, including I-vation, microparticles and biodegradable implants. We are in advanced licensing discussions on multiple platforms. In addition, our ability to structure agreements with existing and prospective customers in connection with the I-vation platform is now enhanced. We will continue to work in tandem with our partners to meet their required timelines in developing products for the treatment of diseases of the eye, including diabetic macular edema (DME), age-related macular degeneration (AMD), and other indications.”

Live Webcast

SurModics will host a webcast at 5:00 p.m. ET (4:00 p.m. CT) today to discuss this matter in further detail. To access the webcast, go to the investor relations portion of the company’s website at www.surmodics.com, and click on the webcast icon. If you wish to participate in the conference call, dial 800-257-7087. A replay of the conference call will be available by dialing 800-405-2236 and entering conference call ID 11119987. The audio replay will be available beginning at 7:00 p.m. CT on Wednesday, September 17, until 7:00 p.m. CT on Wednesday, September 24.‹