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Show Journal of Neuro- Ophthalmology 21( 4): 237- 239, 2001. • 2001 Lippincott Williams & Wilkins, Inc., Philadelphia Editorial Treat Early, but Treat Hard: Interferon- p Dose Makes a Difference Daniel D. Mikol, MD, PhD The manuscripts by Rudick ( pp 279- 291) and Galetta ( pp 292- 295) in this issue of the journal reinforce the benefits of early treatment of MS and highlight new therapeutic approaches on the horizon. In an era when treatment options for multiple sclerosis are likely to continue increasing, we must try to make sense of already available therapies. Four disease- modifying drugs have been approved for use in the United States: glatiramer acetate ( Copaxone ® , Teva Neuroscience), mitoxantrone ( Novantrone ® , Im-munex), and two interferon ( IFN)( 3 products IFN( 3- la, ( Avonex ® , Biogen) and IFN( 3- lb ( Betaseron ® , Betaferon ® , Berlex- Schering AG). Another IFN( 3- la ( Rebif ® , Serono) already available outside the United States, is likely to be released here in 2002. IFN( 3- lb was the first drug approved for the treatment of MS in 1993, and IFNps remain the stronghold of disease- modifying therapy. All IFNps have a positive impact on clinical and MRI parameters of disease activity. While the three IFNps are nearly identical structurally ( Avonex ® and Rebif ® are identical), they differ in composition, route of injection, and, most importantly, dose and frequency of injection. In terms of weekly biologic activity, Avonex ® ( 30 ( xg) is 4- 5- fold lower than either Betaseron ® ( 875 ( xg weekly) or high- dose Rebif ® ( 132 ( xg), which are comparable. EXPERIMENTAL EVIDENCE For years, experimental studies have suggested that IFN( 3 efficacy is dose- dependent. A number of biologic response markers induced by 1FN( 3, such as serum neop-terin and the human Mx protein, respond in a dose-dependent fashion, irrespective of whether the agents are Multiple Sclerosis Clinic, University of Michigan, Department of Neurology, 1500 E. Medical Center Drive, Ann Arbor, Michigan. Address correspondence to Daniel D. Mikol, MD, PhD, Multiple Sclerosis Clinic, University of Michigan, Department of Neurology, 1500 E. Medical Center Drive, Ann Arbor, MI 48109; E- mail: dmiko@ umich. edu administered intramuscularly ( IM) or subcutaneously ( SQ) ( 1). IFN( 3- induced changes last less than week, suggesting that injections should given more than once a week. In vitro data indicate that IFN( 3 dose- dependently inhibits T- cell activation ( 2) and transendothelial migration ( 3, 4), and dose- dependently modulates the expression of several immune cell mediators such as interleu-kin- 10 ( 5- 8). Further, IFN- 7- induced expression of major histocompatibility class II molecules is suppressed in a dose- dependent manner by IFN( 3- la ( 9). These different dose- dependent actions are all likely to have beneficial effects on the immunologic processes at play in MS patients. In EAE, an animal model of MS, IFN( 3 has dose- dependent effects on relapse rate, mortality rate, neurologic function and lesion size ( 10, 11). DOSE, SIZE, AND FREQUENCY Pharmacokinetic studies have shown that standard Betaseron ® dosing results in a more consistently elevated and sustained biologic response than standard Avonex ® dosing. Betaseron ® provides sustained increases in IFN( 3- induced biologic markers over the course of a week, whereas Avonex ® shows a decline in parameters on the fifth day ( 12). Rothuizen et al. ( 13) compared the levels of inflammatory response mediators to IFN( 3- la given once- weekly ( 22 ( xg or 66 ( xg) or thrice- weekly ( 22 ( xg). Production of the pro- inflammatory cytokines IFN- 7 and TNF- a was 2 to 3- fold stronger in patients receiving thrice- weekly dosing. While there was no apparent difference between the once- weekly doses of 22 ( xg and 66 ( xg, there was a significant difference between 66 ( xg given once- weekly and 22 ( xg given thrice-weekly, favoring the more frequent dosing schedule. These results are paralleled by the fact that no difference in clinical efficacy or on MRI measures was found between 30 ( xg and 60 ( xg doses of Avonex ® given once weekly ( 14). Taken together, these data suggest a ceiling effect for a single dose; moreover, they indicate that once- weekly dosing is likely to be less effective than more frequent dosing. 237 238 EDITORIAL CLINICAL TRIALS Clinical trials support the greater efficacy of higher doses and more frequent dosing of IFN( 3. The pivotal Betaseron ® trial ( 15,16) was the first to show a dose-dependent effect of IFN( 3- lb on a number of clinical and MRI measures, with 8 mlU ( 250 ( xg) every other day being significantly more effective than 1.6 mlU ( 50 ( xg) every other day. Relapse measures ( exacerbation rate, time to first and second relapse) and MRI measures were dose- sensitive. In general, differences between placebo and 8 mlU were statistically significant, whereas differences between 8 mlU and 1.6 mlU or 1.6 mlU and placebo were not always significant. Dose- response effects have also been demonstrated in the PRISMS and OWIMS trials. In the PRISMS ( Prevention of Relapses and disability by Interferon beta- la Subcutaneously in Multiple Sclerosis) trial ( 17), patients received 22 ( xg ( low- dose) or 44 ( xg ( high- dose) Rebif ® or placebo thrice- weekly for 2 years. Both treatment groups showed a significant reduction in relapse rate ( by 33% and 37% respectively), but for virtually all clinical variables examined, the high- dose group showed greater efficacy, although not to a statistically significant degree. The higher dose did produce a significantly greater reduction in active MRI lesions than did the lower dose. In the OWIMS ( Once Weekly Interferon for MS) trial, patients were given placebo or SQ IFN( 3- la at doses of 22 fxg or 44 ( xg once- weekly for 1 year ( 18). Here, clinical results were less dramatic than in PRISMS, but still emphasize that efficacy is dose- dependent. Double- blind extension data ( 19) from PRISMS provide clear evidence of dose- dependence for numerous clinical and MRI measures. At the end of the initial 2- year period, placebo patients were randomized to receive low or high- dose Rebif ® thrice- weekly for an additional 2 years. The proportion of patients who had confirmed progression of disability was lowest for patients in the high- dose group for the entire 4 years and highest in patients who received placebo for the first 2 years and low- dose Rebif ® for years 3 and 4. The effect was intermediate for patients in the low- dose group for the entire 4 years and patients randomized to the high- dose group after being on placebo for the first 2 years. This same pattern of efficacy was similar for clinical relapse and MRI ( burden of disease and number of active lesions) measures. These results underscore the benefits of starting IFN( 3 treatment at the highest dose early in the disease. In the MSCRG ( Multiple Sclerosis Collaborative Research Group) trial, patients were randomized to either placebo or 30 ( xg IFN( 3- la ( Avonex ® ) IM once- weekly ( 20). Reduction in relapse rate relative to placebo over one year of treatment was 9.6% ( not statistically significant). A 32% reduction in relapse rate was claimed among patients followed at least 2 years, but this figure was derived from post hoc analysis of a subgroup. The overall reduction in relapse rate among all patients receiving Avonex ® was 18% ( P = 0.04) at 2 years. Other clinical outcome measures, such as proportion of relapse- free patients and time to first relapse, favored the Avonex ® - treated group, but not in a statistically significant way. The importance of dose frequency has not been properly addressed in Avonex ® studies. Clanet et al. ( 14) have evaluated 30 ( xg versus 60 ( xg once- weekly and found no differences in progression over 3 years. A larger multicenter trial using Avonex ® is in progress ( 21), but again, treatment groups are receiving 30 ( xg or 60 ( xg of Avonex ® once- weekly. Based upon the numerous studies that emphasize the importance of dose frequency, a more telling study would have been one comparing 30 ( xg Avonex ® at different dose frequencies. When data from the MSCRG, PRISMS and OWIMS studies are compared, an unequivocal dose- response is apparent regarding both clinical and MRI measures. Dose- response relationships are even stronger for MRI indicators than for clinical variables. It is well accepted that IFNps are more effective when used earlier in the disease process, and two studies have shown that IFN( 3- la treatment after an initial demyelin-ating event such as optic neuritis can delay progression to multiple sclerosis. The CHAMPS trial ( 22) showed a more substantial reduction in conversion to MS than did ETOMS ( 23); however, there are a number of differences between the two trials. Most importantly, ETOMS used a weekly dose of just 22 ( xg ( which had no effect on relapse rate in established MS patients ( 18)), compared with 30 ( xg Avonex ® in CHAMPS. Betaferon ® is currently being investigated in patients presenting with a clinically isolated demyelinating syndrome ( BENEFIT trial). This will represent the first early treatment trial using high- dose IFN( 3. HEAD- TO- HEAD TRIALS In determining the effect of dose size and frequency, direct comparison of agents is most informative. Two head- to- head trials between IFN( 3 formulations have been carried out thus far, with results of the INCOMIN ( Betaseron ® versus Avonex ® ) ( 24) and EVIDENCE ( Rebif ® versus Avonex ® ) ( 25) trials recently revealed. In both trials, standard dosing, frequency and route of administration were implemented. The INCOMIN ( Independent Comparison of Interferon) trial was an unsolicited multicenter randomized open- label study by Durelli and colleagues from Italy. At the end of a 1- year treatment period, IFN( 3- lb ( Betaferon ® ) proved significantly more effective than IFN( 3- la ( Avonex ® ) in clinical and blinded MRI outcome measures ( P < 0.05). Two- year results, initially presented at the September, 2001 ECTRIMS meeting in Dublin, Ireland, with full results presented at the Italian Neurological Society meeting in October, 2001, indicate that differences favoring Betaferon ® become more notable during the second year. The primary clinical outcome measure, number of relapse- free patients, was greater in Betaferon ® - treated patients: 51% versus 36% at 2 years ( Betaferon ® versus Avonex ® ; P < 0.036). In addition, fewer patients in the Betaferon ® group had an EDSS increase of at least 1.0 / Neuro- Ophthalmol, Vol. 21, No. 4, 2001 EDITORIAL 239 point at 6 months that was sustained at 2 years: 14% versus 30% ( Betaferon ® versus Avonex ® ; P < 0.005). MRI measures also favor Betaferon ® . Of the patients receiving Betaferon ® for 24 months, 55% were free of new T2 lesions compared with only 26% of those on Avonex ® ( P = 0.0003). The EVIDENCE study ( 25), a randomized, open-label, assessor- blinded study designed to compare IFN( 3- la ( Rebif ® ) 44 fig SQ thrice- weekly to IFN( 3- la ( Avonex ® ) 30 ( xg IM once- weekly, has shown a statistically significant reduction in relapses and MRI burden of disease at 24 weeks, favoring Rebif ® . Rebif ® proved significantly more effective than Avonex ® for all clinical and MRI outcome measures. The primary outcome measure, the proportion of patients remaining relapse-free at 24 weeks, was 74.9% in the Rebif ® group and 63.3% in the Avonex ® group ( P = 0.005). The principal secondary outcome measure was combined unique active- lesion number based on monthly scans; the number of new MRI lesions per patient per scan was 0.8 in the Rebif ® group and 1.2 in the Avonex ® group ( P < 0.0001). Although mild adverse events such as injection-site reactions were more common in the Rebif ® group, there was no difference in terms of serious adverse events, which were infrequent in both groups. Systemic side effects due to IFN( 3 were slightly higher for Avonex ® . The data for 48- week outcomes in the EVIDENCE trial are being analyzed. Thus, there is substantial evidence indicating dose-dependency for both IFN( 3- lb and IFN( 3- la treatment effects on biologic response, immunologic mechanisms, clinical parameters that relate to relapses and overall disability, and MRI measures of disease activity. While there may be a ceiling effect with once- weekly dosing, this frequency of injection appears to be inadequate. Certainly, the convenience of once- weekly dosing needs to be weighed against the overwhelming evidence that supports greater efficacy at higher, alternate day dosing. In light of data from CHAMPS and ETOMS, and with increasing evidence that irreversible axonal injury occurs early in the course of MS, early treatment with disease-modifying therapy is recommended. Results of the PRISMS 4- year data indicate that early introduction of high- dose IFN( 3 provides benefit over low- dose therapy. For IFNps, more is better. REFERENCES 1. Sturzebecher S, Maibauer R, Heuner A, et al. Pharmacodynamic comparison of single doses of IFN- betala and IFN- betalb in healthy volunteers. J Interferon Cytokine Res 1999; 19: 1257- 64. 2. Noronha A, Toscas A, Jensen MA. Interferon beta decreases T cell activation and interferon gamma production in multiple sclerosis. J Neuroimmunol 1993; 46: 145- 53. 3. Leppert D, Waubant E, Burk MR, et al. Interferon beta- lb inhibits gelatinase secretion and in vitro migration of human T cells: a possible mechanism for treatment efficacy in multiple sclerosis. Ann Neurol 1996; 40: 846- 52. 4. Lou J, Gasche Y, Zheng L, et al. 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