submit to the journals

Interview

Interview with Sarah Sheikh, Senior Medical Director, Biogen, Cambridge, MA, US
Interview with Sarah Sheikh, Senior Medical Director, Biogen, Cambridge, MA, US
Katrina Mountfort, Freelance Medical Writer for Touch Medical Media, UK

Opicinumab, an investigational add-on therapy in multiple sclerosis

The past decade has seen an explosion of new disease-modifying therapies (DMTs) for multiple sclerosis (MS). However, though able to slow disease progression, these therapies are not directly addressing the need for repair in the damaged central nervous system (CNS).1 In an expert interview conducted at MSParis2017, the seventh Joint Meeting of the European Committee for Treatment and Research in MS and Americas Committee for Treatment and Research in MS (ECTRIMS-ACTRIMS; 25–28 October), Sarah Sheikh of Biogen discussed the recent initiation of the phase II clinical trial AFFINITY, which is evaluating opicinumab as an investigational add-on therapy in people with relapsing multiple sclerosis (MS). The trial design is based on data from a post-hoc analysis of a phase II trial, SYNERGY, which identified a specific population that may be more likely to respond to treatment.

The use of opicinumab aims to improve current disability in patients with MS by a reparative approach using remyelination, which repairs the damaged regions of the central nervous system (CNS). What that means for patients, if successful, is that they can feel and function better. This is a unique approach, Dr Sheikh explained; no-one has ever achieved repair of the human CNS. By contrast, the anti-inflammatory DMTs currently on the market aim to slow disability progression associated with CNS inflammation. Opicinumab is a monoclonal antibody that is administered intravenously and acts as an antagonist of leucine rich repeat and immunoglobin-like domain-containing protein 1 (LINGO 1).2 This allows oligodendrocyte precursor cells to migrate to lesions and differentiate to allow the remyelination process to occur.

To date, two phase II trials have been performed using opicinumab. The RENEW trial in patients with optic neuritis provided proof of biological activity.3 Results from the phase II SYNERGY trial in MS were presented last year.4 The study was a randomized, double-blind, placebo-controlled, dose-ranging phase II study that evaluated the efficacy and safety of opicinumab among 418 participants with relapsing forms of MS (both relapsing-remitting and secondary progressive) over 72 weeks. Opicinumab was administered intravenously every four weeks at doses of 3 mg/kg, 10 mg/kg, 30 mg/kg or 100 mg/kg. All study participants received concurrent treatment with 30 mcg interferon beta-1a intramuscular injection once weekly. An inverted U-shaped dose response with opicinumab was observed, with more favourable outcomes in the 10 and 30 mg/kg groups, and the optimum dosage over multiple outcome measures and sensitivity analyses found to be 10 mg/kg. However, despite showing evidence of clinical effect, opicinumab missed the study’s primary endpoint, a multicomponent measure combining improvement of physical function, cognitive function, and disability.5 Having anticipated a linear dose response as the endpoint, investigators sought to identify the patient subgroup that had responded well to opicinumab and created the observed U-shaped dose response.

The results of a post-hoc analysis of SYNERGY data, using a systematic multivariate hypothesis agnostic approach, were presented at MSParis2017. This analysis identified three predictive factors of an increased clinical effect of opicinumab versus placebo: shorter disease duration (of ≤20 years), lower baseline magnetisation transfer ratio (MTR) values in T2 lesions, suggesting a relative lack of myelin content, and lower baseline diffusion tensor imaging-radial diffusivity (DTI-RD) values in T2 lesions, indicating higher structural integrity.6 These features suggested that repair of MS lesions may be possible through remyelination. The subgroup of patients with these characteristics (25–30% of the original population) performed much better in terms of clinical outcomes compared with the original population; for example, the proportions of participants with 12-week confirmed improvement over 72 weeks were 36% for placebo and 81% for the 10 mg/kg opicinumab group versus 49% and 63%, respectively, in the intention-to-treat population.

As a result of these findings, the phase II AFFINITY study has been initiated with a select patient population. The study aims to enrol 240 patients and will investigate opicinumab as an add-on therapy to anti-inflammatory DMTs (interferon, dimethyl fumarate or natalizumab). Participants will be randomised to opicinumab, administered as a fixed dose (750 mg monthly intravenous infusion), or placebo. The overall response score (ORS), an integrated measure of both the improvement and worsening of disability over time, will be used as the primary outcome measure at 72 weeks. The ORS includes well-established components: Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk Test (T25FW), 9-hole peg test (9HPT) and is sensitive to change, allowing integrated assessment of both worsening/improvement of disability over time.7 Clinical and MRI endpoints will also be evaluated.7

Remyelination using opicinumab is a new and exciting potential approach to treating MS. The innovative approach of the AFFINITY trial should identify patients most likely to respond to opicinumab and offers hope of lesion repair. Dr Sheikh concluded by expressing her excitement at being involved in a study that offers a huge opportunity to learn and contribute to the field, and ideally to allow patients with MS to feel and function better.

References

1. Hemmer B, Hartung HP, Toward the development of rational therapies in multiple sclerosis: what is on the horizon?, Ann Neurol, 2007;62:314–26.

2. Ruggieri S, Tortorella C, Gasperini C, Anti lingo 1 (opicinumab) a new monoclonal antibody tested in relapsing remitting multiple sclerosis, Expert Rev Neurother, 2017;17:1081–9.

3. Cadavid D, Balcer L, Galetta S, et al., Safety and efficacy of opicinumab in acute optic neuritis (RENEW): a randomised, placebo-controlled, phase 2 trial, Lancet Neurol, 2017;16:189–9.

4. McCroskery P, Selmaj, K., Fernandez, O. et al., Safety and tolerability of opicinumab in relapsing multiple sclerosis: the phase 2b SYNERGY trial (P5.369), Neurology, 2017;88:Suppl P5.369.

5. Biogen, Biogen reports top-line results from phase 2 study of opicinumab (anti-LINGO-1) in multiple sclerosis, Available at: http://media.biogen.com/press-release/investor-relations/biogen-reports-top-line-results-phase-2-study-opicinumab-anti-lingo (accessed 9 November 2017).

6. Sheikh S, et al., Predictors of an opicinumab treatment effect and identification of an efficacy subpopulation: a post hoc analysis of the SYNERGY study, Presented at: MSParis2017, the 7th Joint Meeting of ECTRIMS-ACTRIMS, Paris, France, 25–28 October 2017. Abstract P718.

7. Chang I, et al., Overall response score: a novel disability endpoint that allows for the integrated assessment of improvement and worsening over time in patients with MS, Presented at: MSParis2017, the 7th Joint Meeting of ECTRIMS-ACTRIMS, Paris, France, 25–28 October 2017. Abstract P718.