Symptomatic and structural benefit of cathepsin K inhibition by MIV-711 in a subgroup with unilateral pain: post-hoc analysis of a randomised phase 2a clinical trial.

OBJECTIVES: Osteoarthritis (OA) development programmes face challenges due to discordance between structural changes and symptoms. A novel cathepsin-K inhibitor, MIV-711, recently reported structural benefits, but did not demonstrate a significant difference from placebo in symptoms. Previous work suggests that pain from non-target joints may confound OA pain outcomes. We therefore conducted an exploratory analysis in participants with predominantly unilateral knee pain from the MIV-711-201 trial. METHOSD: Participants scoring below median contralateral knee NRS pain at baseline from the MIV-711-201 phase 2a clinical trial (n=119) were analysed by treatment group for differences in change from baseline in WOMAC pain, quantitative magnetic resonance imaging bone area and cartilage thickness with a repeated-measures mixed model adjusting for relevant co-variates. RESULTS: In the subgroup with unilateral knee pain, treatment with MIV-711 100 mg led to greater reduction in WOMAC pain compared to placebo (-5.0, 95% CI: -8.69 to -1.3, p=0.008), while 200 mg did not (-2.5, 95% CI: -6.5 to 1.6, p=0.23). MIV-711 treatment was associated with a reduced change in bone area compared to placebo (200 mg; -19.6 mm2 , 95% CI: -36.2 to -3.0, p=0.02, and 100 mg; -12.5 mm2 , 95% CI: -27.8 to 2.8, p=0.11,). No observed differences between treatment groups in cartilage thickness were found in this subgroup. CONCLUSIONS: In a subgroup with predominantly unilateral knee pain, significant reduction in OA pain by MIV-711 100 mg treatment was found, with concurrent beneficial structural effects, highlighting the importance of appropriate pain inclusion criteria in OA trials.

Inhibition of merozoite invasion and transient de-sequestration by sevuparin in humans with Plasmodium falciparum malaria.

SEVERE MALARIA: Even with the best available treatment, the mortality from severe Plasmodium falciparum malaria remains high. Typical features at death are high parasite loads and obstructed micro- vasculature. Infected erythrocytes (IE) containing mature parasites bind to the host receptor heparan sulfate, which is also an important receptor for merozoite invasion. To block merozoite invasion has not previously been proposed as an adjunctive therapeutic approach but it may preclude the early expansion of an infection that else leads to exacerbated sequestration and death. SEVUPARIN IN PHASE I STUDY: The drug sevuparin was developed from heparin because heparan sulfate and heparin are nearly identical, so the rationale was that sevuparin would act as a decoy receptor during malaria infection. A phase I study was performed in healthy male volunteers and sevuparin was found safe and well tolerated. SEVUPARIN IN PHASE I/II CLINICAL STUDY: A phase I/II clinical study was performed in which sevuparin was administered via short intravenous infusions to malaria patients with uncomplicated malaria who were also receiving atovaquone/proguanil treatment. This was a Phase I/II, randomized, open label, active control, parallel assignment study. Sevuparin was safe and well tolerated in the malaria patients. The mean relative numbers of ring-stage IEs decreased after a single sevuparin infusion and mature parasite IEs appeared transiently in the circulation. The effects observed on numbers of merozoites and throphozoites in the circulation, were detected already one hour after the first sevuparin injection. Here we report the development of a candidate drug named sevuparin that both blocks merozoite invasion and transiently de-sequesters IE in humans with P. falciparum malaria. TRIAL REGISTRATION: ClinicalTrials.gov NCT01442168.