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ABSTRACTIntroductionHemophilia comprises a group of X-linked hemorrhagic disorders that result from a deficiency of coagulation factors. The disorder affects mainly males and leads to chronic pain, joint deformity, reduced mobility, and increased mortality. Current therapies require frequent administration of replacement clotting factors, but the emergence of alloantibodies (inhibitors) diminishes their efficacy. New therapies are being developed to produce the deficient clotting factors and prevent the emergence of inhibitors.Areas CoveredThis article provides an update on the characteristics and disease pathophysiology of hemophilia A, as well as current treatments, with a special focus on ongoing clinical trials related to gene replacement therapies.Expert OpinionGene replacement therapies provide safe, durable, and stable transgene expression while avoiding the challenges of clotting factor replacement therapies in patients with hemophilia. Improving the specificity of the viral construct and decreasing the therapeutic dose are critical toward minimizing cellular stress, induction of the unfolded protein response, and the resulting loss of protein production in liver cells. Next-generation gene therapies incorporating chimeric DNA sequences in the transgene can increase clotting factor synthesis and secretion, and advance the efficacy, safety, and durability of gene replacement therapy for hemophilia A as well as other blood clotting disorders.

ABSTRACTIntroductionCurrently, a few in vivogene replacement therapies are commercially available, with many in clinical development for the treatment of some inherited monogenic diseases. These disorders arise from mutations in genes encoding essential proteins with a well understood biological function. Wide adoption of gene replacement therapies requires solid safety and efficacy profiles with demonstrable long-term durability and cost-benefit advantages vs standard therapies.Areas coveredThis expert review outlines the challenges and opportunities in treating hemophilia, including the progression from in vivogene therapies toward in vivogene editing, focusing on pre-clinical and emerging clinical data for gene editing and addressing the need for sustained and durable gene expression during hepatocyte proliferation when the liver is unable to maintain steady gene expression and protein production.Expert opinionIn vivogene editing in liver tissues may be able to rescue patients younger than 18 years who are not eligible for gene replacement therapies, with hemophilia as a prime example.

Responsive assessment of disease activity in patients who have rheumatoid arthritis (RA) is necessary to evaluate therapeutic efficacy and guide treatment. We compared the utility of the multibiomarker disease activity (MBDA) score in the assessment of RA disease activity with that of the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28‐ESR) score and the Clinical Disease Activity Index (CDAI) in a multicenter, randomized, placebo‐controlled trial of repository corticotropin injection (RCI) in patients with persistently active RA. Patients received 80 units of RCI twice weekly during a 12‐week open‐label period; those who experienced low disease activity at week 12 were randomly assigned to receive either 80 units of RCI or placebo twice weekly during a 12‐week double‐blind period. Changes in disease activity (measured by DAS28‐ESR, CDAI, and MBDA scores) and correlations between MBDA scores and both DAS28‐ESR and CDAI scores were assessed. Changes from baseline in DAS28‐ESR and CDAI scores suggested that RCI therapy led to clinically meaningful improvements in disease activity, but improvements from baseline in MBDA scores were below the minimally important difference threshold. For the DAS28‐ESR and CDAI, correlations with total MBDA and individual component scores were generally low (r ≤ 0.3) and occasionally moderate (r > 0.3 but r < 0.5). The results of the present study suggest overall MBDA scores are not sufficiently responsive for assessing RA disease activity after RCI therapy. These findings are consistent with those seen with other RA drugs and, although they are from a clinical trial, suggest the MBDA should not be a preferred disease activity measure in clinical practice.

OBJECTIVE: To estimate the comparative lifetime cost-effectiveness of sequenced therapy with tumor necrosis factor (TNF) antagonists as the initial therapeutic intervention for patients with early rheumatoid arthritis (RA). METHODS: Because patients with RA switch regimens many times throughout the course of disease, sequenced therapeutic interventions were modeled, continuing until the last effective agent failed or death occurred. The model used published clinical outcomes from short-term, randomized controlled trials. Direct treatment costs and costs of lost productivity were modeled for each of 5 alternative treatment sequences. Incremental cost-effectiveness ratios are expressed as quality-adjusted lifeyears (QALY) gained. RESULTS: Treatment sequences that included TNF antagonists produced a greater number of QALY than conventional disease modifying antirheumatic drug regimens alone. The cost-effectiveness of sequenced therapy initiated with adalimumab plus methotrexate (MTX) extendedly dominated both infliximab-plus-MTX-initiated and etanercept sequences. The cost of adalimumab plus MTX per QALY was US $47,157 excluding productivity losses, and $19,663 including productivity losses. A supplementary sequence that incorporated adalimumab-plus-MTX-initiated first-line therapy followed by another TNF antagonist as second-line therapy was modeled; this sequence resulted in additional QALY gained and extendedly dominated all single-TNF strategies. CONCLUSION: Of the 3 single-TNF antagonist sequences, the adalimumab-plus-MTX-initiated sequence was cost-effective in producing the greatest number of QALY. Multiple TNF strategies, such as the supplementary sequence modeled in this analysis, may be cost-effective in producing even greater health gain.