Clinical Trials

Date: 2018-03-26

Type of information: Results

phase: 2b

Announcement: results

Company: GeNeuro (Switzerland)

Product: GNbAC1

Action mechanism:

• monoclonal antibody. The monoclonal antibody GNbAC1 targets the envelope protein MSRV-Env of an endogenous retrovirus which could play a critical role in the pathogenesis of multiple sclerosis. Discovered in the early 90’s, the Human endogenous retrovirus of type W is closely associated with multiple sclerosis and, due to its neurotoxic properties, could be a causal factor of the disease. This retrovirus is normally latent in the genome of individuals, but it can be re-activated by certain co-factors to expresses a pathogenic protein, MSRV-Env. Recent evidence has demonstrated that this ENV-protein is expressed in multiple sclerosis lesions from an early stage, is pro-inflammatory and inhibits remyelination. By neutralizing MSRV-ENV, GNbAC1 could block a key factor promoting the inflammation on the plaques, as well as allowing the remyelination repair process to restart.
• The development of GNbAC1 is the result of 25 years of research into human endogenous retroviruses (HERVs), including 15 years with the Mérieux Institute and INSERM, before GeNeuro was founded in 2006.

Disease: relapsing-remitting multiple sclerosis (RRMS)

Therapeutic area: Autoimmune diseases - Neurodegenerative diseases

Country: Croatia, Estonia, Hungary, Poland, Serbia, Spain, Ukraine

Trial details:

• This study has been launched in the Hospitals of Geneva and Basel in Switzerland. This is a single ascending dose study. During the study, 10 patients suffering from multiple sclerosis will receive the monoclonal antibody GNbAC1 at two different doses. The main objectives of the study are the safety and pharmacokinetics of the monoclonal antibody in patients. A repeated-dose extension of 6 months is planned. (NCT01639300)
• The CHANGE-MS study is evaluating the effect on MRI lesions parameters, the safety and pharmacokinetics of GNbAC1 in patients with relapsing remitting multiple sclerosis. The double-blind, placebo-controlled study, CHANGE-MS (Clinical trial assessing the HERV-W Env Antagonist GNbAC1 for Efficacy in Multiple Sclerosis) enrolled 270 RRMSpatients in 50 clinical centers in 12 European countries. The primary endpoint measures efficacy based on the number of new T1 enhancing lesions on monthly brain MRI, assessed from weeks 12 to 24 of the placebo-controlled period. Secondary endpoints include: increase in T2 lesion volume through week 24, change in magnetization transfer ration (MTR), change in brain volumes, annualized relapse rate, percentage of patients with EDSS1 progression confirmed at 3 months and change in MS functional composite scores from baseline to week 48, including sub-scale scores. The study is fully funded through GeNeuro’s €362.5 million partnership with Servier signed in 2014, in which Servier is involved in the development and potential commercialization of GNbAC1 in MS in territories outside the USA and Japan, with GeNeuro retaining full rights for these two territories.Subsequent to exercising the option agreement, Servier will also cover the costs of the MS Phase 3 globaldevelopment program. (NCT02782858)

Latest news:

•  • On March 26, 2018, GeNeuro and Servier announced positive results at 12 months from the CHANGE-MS Phase 2b study of GNbAC1 for the treatment of multiple sclerosis (MS). The data showed that GNbAC1 administration had a significant, consistent positive impact on key neuroprotection markers known to be linked to disease progression. In this 270-patient study, conducted in 12 European countries, MRI showed a coherent neuroprotective benefit on brain atrophy. Benefits were seen in cortical and thalamic atrophy, with relative volume loss reductions of 31% and 72% respectively between the highest dose of 18 mg/kg and control group, with a statistically significant dose-relationship for both (p=0.045 and P=0.014 respectively). Whole brain atrophy revealed a 29% relative reduction in brain volume loss over 12 months for the highest dose versus the control group, with a trend in dose-relationship (p=0.079). In addition, the number of T1 hypointense lesion (black holes, a marker of permanent tissue destruction in the brain) of at least 14mm3 volume was reduced by 63% (p=0.014) at the end of the study in the 18mg/kg versus control group.
• The benefit in Magnetization Transfer Ratio (MTR) signal of 18mg/kg relative to the placebo at 6 months remained stable versus the control group over the second period of the trial, in both normal appearing white matter and cerebral cortical bands, consistent with a potential benefit on remyelination.
• For most MRI measures of neuroinflammation, all groups improved from Month 6 to Month 12, however there was no significant separation between treatment groups. The trend seen in post-hoc analyses at 6 months on neuroinflammatory markers, after the primary endpoint of reducing the total number of cerebral Gadolinium-enhancing lesions as measured by MRI was not met, did not translate into a relevant result at 12 months.
• No organ-class related toxicity and no dose dependent adverse events were observed. GNbAC1 continued to show an excellent tolerability profile throughout the study.
• • On August  28, 2017,  GeNeuro  and Servier announced 6-month results from the 12-month CHANGE-MS Phase 2b study of three doses of GNbAC1 for the treatment of patients with relapsing remitting multiple sclerosis. The data showed that GNbAC1 is well tolerated and that there is no statistical difference at 6-months between GNbAC1 and placebo in the study’s primary endpoint of reducing the number of cerebral Gad-enhancing lesions as measured by MRI, nor on the other MRI measures of neuroinflammation.
• Relapses in the overall population decreased by over 50% relative to the year prior to study but there was no significant difference at 6 months between treated and placebo groups.
• Based on the unique mechanism of action and pharmacokinetics of GNbAC1, the study will continue, as planned, exploring potential benefits of the drug on MRI and clinical measures, including remyelination properties, with final results from the full 12-month expected in the first quarter of 2018.
• • On September 14, 2016, GeNeuro announced that enrollment has reached the halfway mark, ahead of schedule, in the CHANGE-MS Phase 2b study of GNbAC1 in patients with relapsing-remitting multiple sclerosis (RRMS). GeNeuro provided the update at the 32nd ECTRIMS Congress, being held in London, UK (14-17 September). The company remains on schedule to report initial results during Q4 2017.
• • On May 31, 2016, GeNeuro announced that the first patients have been treated with its lead product, GNbAC1, in a Phase IIb study in relapsing-remitting multiple sclerosis. The CHANGE-MS plans to enroll 260 patients in 69 clinical centers in 13 European countries. The primary endpoint will examine the cumulative number of active brain lesions determined by MRI after 6 months, followed by additional MRI and clinical measures at 12 months. Preliminary results are expected by fourth quarter 2017.
• • On December 18, 2015, GeNeuro announced that it has initiated its planned Phase IIb study “CHANGE-MS” (Clinical trial assessing the HERV-W Env ANtagonist GNbAC1 for Efficacy in Multiple Sclerosis) with its lead antibody GNbAC1 in Relapsing-Remitting Multiple Sclerosis (RRMS). The study plans to enroll 260 patients in 68 clinical centers in the European Union and Eastern Europe. Preliminary results are expected by the end of 2017.  The aim of the Phase IIb study is to demonstrate on RRMS patients the clinical benefit of GNbAC1 in neutralizing the MSRV-Env protein, which has been identified as a potential key factor fueling the inflammatory and neurodegenerative components of MS. Efficacy will be based on multiple brain magnetic resonance imaging scans, with an initial endpoint analysis after 6 months followed by a 6-month extension. By targeting MSRV-Env, GeNeuro aims to bring to patients a safe and effective treatment for both relapsing-remitting and progressive forms of the disease without hampering the patient’s immune system. Simultaneous with the start of Phase IIb, development partner Servier has exercised its equity investment option, as part of an agreement signed in November 2014, to become a minority shareholder in GeNeuro.
• • On September 3, 2014, GeNeuro announced positive results from a one-year, open-label extension of a Phase IIa study. GeNeuro tested its monoclonal antibody GNbAC1 in 10 multiple sclerosis  patients, nine of which had primary or secondary progressive disease. GNbAC1 targets the MSRV-Env protein expressed by genes of endogenous retroviral origin, which GeNeuro believe plays a critical role in the pathogenesis of multiple sclerosis. The long-term safety profile of GNbAC1 was confirmed, with excellent tolerability among patients following repeat administration, verifying results of the earlier Phase I study. With respect to clinical endpoints, the average Expanded Disability Status Score (EDSS), which measures disease progression, remained stable over one year. MRI analysis revealed that the brain images also remained stable and biomarkers associated with the target showed a consistent decline. These results confirm the safety and tolerability of GNbAC1 and support a positive pharmacodynamic response to the treatment. The positive results of this clinical study represent the successful first step in GeNeuro’s Phase II program. A proof-of-concept clinical study to test the efficacy of GNbAC1 in multiple sclerosis will follow in 2015. • On November 4, 2013, GeNeuro has announced that its GNbAC1 humanized monoclonal antibody was found to have a very good safety profile when administered to patients with relapsing and progressive forms of multiple sclerosis as part of a Phase 2a study. In the completed Phase 2a clinical study including a six-month extension, conducted to establish safety and pharmacokinetics, GNbAC1 demonstrated very good safety following repeated administration at 2 mg/kg and 6 mg/kg. The repeated administrations did not affect the immune system, the TLR4 function was preserved and no signs of induction of immunogenicity were observed.  Enrollment of patients into a multinational Phase 2b study is expected to begin during the first half 2014.
• • On September 18, 2012, GeNeuro has announced the launch of a phase IIa clinical study with  GNbAC1. The randomized placebo-controlled phase IIa study will test single ascending doses of  GNbAC1 in patients with multiple sclerosis for the first time. This clinical study is the first step in the GeNeuro’s Phase II program which will be pursued by a proof-of-concept study planned in 2013.

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