A drug called MC-1101 (MacuCLEAR®, MacuCLEAR Inc., Richardson, TX, USA) was being trialled in dry AMD. It could be given topically by spray on to the ocular surface and was said to improve choroidal blood flow. No data have been added to the registration for NCT02127463, a Phase II/III trial aiming to recruit 60 patients since 2014. Data collection was expected to be complete by 2016. NCT01601483 has been terminated, and NCT01922128 was completed in 2013.
NCT02684578 is a trial of metformin, an old, very cheap drug used in type 2 diabetes, versus placebo, in California. The drug will be given to people without diabetes for 18 months. The trial will end in 2019. NCT00332657 and NCT00307398 were trials of anecortave in people with wet AMD in one eye and dry in the other, with the aim of preventing the development of wet AMD in the dry eye. It recruited 2500 people but was terminated because of lack of effectiveness.
NCT01342926 was a trial of GSK933776 (GlaxoSmithKline, Middlesex, UK), an antibody targeting amyloid beta, but it had no effect on growth of GA or on VA.
Another antibody against amyloid beta was (or is) RN6G from Pfizer (New York, NY, USA). Three trials were registered as NCT00877032 with 57 patients, NCT01577381 with 10, and NCT01003691 with 24. The second was terminated early after only the 10 recruits. No results are yet published.
Summary
We have reviewed the evidence on 23 drugs or groups of drugs. In 10 cases, there was some evidence showing no or very little benefit, or even harm, so when it comes to reporting back to the NIHR
programmes, mainly HTA, we are minded to exclude these from further consideration. They are alprostadil, eculizumab, dorzolomide, OT 551 eye drops, prednisolone, sirolimus, tandospirone, trimetazidine, visaline and emixustat. In the case of prednisolone, we note that a trial of an implantable steroid is under way. The current evidence on lampalizumab suggests benefit, but very large trials are under way, sponsored by the manufacturer, so no new research is indicated meantime.
There is a little evidence of benefit from glatarimer, but only shrinkage of drusen. This is too sparse to prompt NIHR research and we think future trials can be left to the manufacturer in the meantime. It is used in multiple sclerosis and the manufacturer, Teva Pharmaceutical Industries (headquartered in Petah Tikva, Israel), is one of the fifteenth largest Pharma companies in the world [according to their website (www.tevapharm.com; accessed 19 June 2107)]. So if glatarimer (also known as copaxone) works, there is a major incentive to do further research. However, no new research has been published since 2008, from which we conclude that Teva do not think the drug is worth pursuing (they may have further unpublished data).
There is some evidence of benefit from ranibizumab in pigment epithelial detachment (PED) in apparently dry AMD, but we think that more sensitive assessment of patients with PED may disclose evidence of wet AMD, so we are excluding this.
L-dopa is a drug very widely used in Parkinson’s disease. An impressively large study324from the USA found that people taking L-dopa were less likely to develop AMD and that if they did develop it, they did so about 7 years later than people not taking L-dopa. Epidemiological studies such as this can be difficult to interpret due to confounding variables (i.e. the people taking L-dopa may be different in other ways from people not taking it, so the L-dopa may be a correlate not a cause). There have been past occasions where a large observational study suggests benefit but a subsequent trial has not shown any. Nevertheless, we think L-dopa merits further study, perhaps using the very large UK general practice databases such as Clinical Practice Research Datalink (CPRD) or THIN. This epidemiological research does not fit with NIHR remits. It might appear to fit with the MRC Population Systems and Medicine theme, but that appears to exclude vision and other central nervous system conditions. The MRC Neurosciences and Mental Health Board seems focused on basic science research. So it is not clear who would fund a UK study into whether or not L-dopa protects against AMD.
That leaves two topics that seem to justify NIHR research. The first is high-potency statins, such as atorvastatin 80 mg daily. The evidence from observational studies (mainly comparing the frequency of AMD in people taking statins and those not taking statins) is mixed and contradictory. The evidence from intervention studies comes mainly from a RCT by Guymeret al.,283using simvastatin 40 mg, which showed some benefit. But simvastatin 40 mg is not a potent dose. Vavvaset al.286found more impressive benefits from atorvastatin 80 mg but in a case series not a RCT. Atorvastatin is now out of patent and cheap, so no drug company would fund a trial. We recommend that the HTA programme do so. Any such study should use genetic subtyping, because Guymer and colleagues283found that simvastatin worked much better in
some people than others. There is also an issue about stage of AMD, with statins appearing more effective if used early. So selection of people for a statin trial would be important.
The second is fenretinide, which is a visual cycle inhibitor which may reduce the deposition of abnormal and toxic lipofuscin. There is one trial, run and written up by the manufacturer’s staff, which had mixed results. Progression of GA was little different overall, but there were better results in the subgroup that achieved the most plasma RBP lowering. However, progression to wet AMD was halved by fenretinide. We think, based on the understanding of the physiopathology of AMD and the visual cycle, and on the results from Mataet al.,144that an independent trial in a selected subgroup may be justified.