Biotech Values

[dewophile]

This letter to the editor was unfortunately pretty prescient wrt the cv risks of the drug:

Cosman et al. found that romosozumab, which binds sclerostin, significantly reduces the risk of vertebral fractures in patients with osteoporosis as compared with placebo (1.8% vs. 0.5%). Sclerostin inhibits bone formation; its deficiency leads to high bone mass. When implementing antisclerostin therapy, one should remember that bone formation is not restricted to bone.
Medial arterial calcification is a prevalent process involving bone formation in the tunica media of the arterial wall that leads to arterial stiffening and subsequently to chronic cardiovascular diseases such as heart failure, cerebral small-vessel disease, and peripheral artery disease.1 In medial arterial calcification, sclerostin is up-regulated in vascular smooth-muscle cells,2 and serum sclerostin levels have been reported to be inversely related to arterial calcifications. Therefore, the inhibition of sclerostin might result in increased medial arterial calcification.3
Bisphosphonates, the current standard of care in osteoporosis treatment, might reduce medial arterial calcification and cardiovascular mortality.4 Since the long-term cardiovascular effects of romosozumab are as yet unknown, we suggest careful monitoring for medial arterial calcification and chronic cardiovascular events in future trials.
Guido Kranenburg, M.D.
Jonas W. Bartstra, M.Sc.
Pim A. de Jong, M.D., Ph.D.
University Medical Center Utrecht, Utrecht, the Netherlands

Concerns regarding the target and CV related risks were raised even a couple years prior to this in 2014 in yet another NEJM letter:

McClung and colleagues (Jan. 30 issue)1 report increases in bone mineral density in postmenopausal women after treatment with romosozumab, a humanized monoclonal anti-sclerostin antibody. The incidence of severe adverse events in the placebo group was 14%, as compared with 10% in the group receiving the highest dose of romosozumab. The authors point out that the risk of extraskeletal effects with the use of romosozumab is low, since the expression of the gene encoding sclerostin (SOST) “is limited to skeletal tissue.” We dissent from this bone-focused view, since Wnt signaling is increasingly recognized to be involved in vascular pathophysiology.2 Both experimental3 and clinical4 data confirm the expression of SOST protein in calcifying vascular tissues. We acknowledge that it remains to be shown whether sclerostin in the vasculature exerts paracrine antimineralization effects similar to those observed in bone. Recent clinical data showing an inverse association between circulating sclerostin levels and mortality among patients undergoing dialysis further fuel concerns with regard to the cardiovascular safety of drugs targeting sclerostin.5 We therefore consider it mandatory to carefully evaluate the effect of prolonged romosozumab treatment on cardiovascular health, especially in high-risk populations