SurModics Inc (SRDX)

[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

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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.”