Since the launch of Prolia in 2010, only three drugs for the treatment of osteoporosis have come through the drug development pipeline from promising preclinical hits to regulatory registrations; odanacatib (Merck), romosozumab (Amgen/UCB), and abaloparatide (Radius Health); three drugs with excellent data in reducing fracture risk and strong physician enthusiasm. Yet the development of odanacatib ceased in 2016 due to safety concerns, and romosozumab is in regulatory limbo due to a cardiovascular safety signal; only abaloparatide has managed to make it to market thus far. Key opinion leaders interviewed by DRG were asked to give their views on the current state of osteoporosis drug development. An over-riding theme from these interviews was physician’s concern regarding the paucity of drugs in the pipeline.
"Other than romosozumab and abaloparatide, I don’t see that this field has a big pipeline, and that’s a problem. All of the companies that I know have pulled out of this market. I think it’s because they think that there are already good therapies. They probably see the approval process as being a steep and costly investment. It’s drying up the pipeline.”
— Physician, United States
So, what’s causing this paucity of candidates?
The cost of clinical trials is somewhat to blame, in part due to the high barriers to approval in terms of efficacy and safety. The relative infrequent occurrence of fractures in the lower risk patient population typically used in clinical trials demands large cohort sizes, pushing up R&D costs substantially. This is coupled with the high number of drugs that fail to gain approval on safety grounds, highlighting the narrow margins of safety that are expected for regulatory approval. The dominance of the low-cost, highly efficacious bisphosphonates has likely led most large pharmaceutical companies to conclude that the substantial development costs, and significant risk of failing to reach the market, doesn’t outweigh the potential rewards. However, as Eli Lilly’s Forteo and Amgen’s Prolia have demonstrated, there are rich rewards for companies whose drugs demonstrate substantial clinical benefit. Both drugs have become blockbusters, with Radius Health’s Tymlos (abaloparatide), and, if approved, Amgen/UCB’s Evenity (romosozumab), expected to join their ranks.
Where might the next generation of osteoporosis blockbuster drugs come from?
Apart from abaloparatide and romosozumab, there are no drugs in the late-stage osteoporosis pipeline, and that isn’t set to change in the next 5 years. However, several recent discoveries are beginning to create a buzz in the osteoporosis field, which interviewed experts hope could lead to the next generation of therapies.
- Anti-follicle stimulating hormone (FSH) therapy: High levels of FSH during the late perimenopause have been linked to bone loss. By blocking FSH, scientists at the Icahn School of Medicine at Mount Sinai have demonstrated an increase in bone mass, as well as reduction in fat cells (Liu P, 2017).
- Targeting senescent cells (cells that have stopped dividing) using “senolytic” compounds: Researchers at the Mayo Clinic found this resulted in improved bone mass and strength, and better bone microarchitecture due to lower bone resorption. Senescent cells have also been shown to be involved in a number of other age-related comorbidities, including insulin sensitivity, frailty, and cardiovascular function; therefore, senolytic compounds could have wide utility (Farr JN, 2017).
- Recent genetic studies that have identified genes hitherto not associated with bone formation: Undertaking a genome-wide association study, scientists identified 203 loci significantly associated with low bone mineral density, 153 of which were previously unreported. It seems very likely that pharmaceutical companies will be pouring of these data searching for promising candidate drug targets (Kemp JP, 2017).
So, has the osteoporosis pipeline burst? No, but it will likely be 10-20 years before the next wave of therapies flow from the promising to the profitable. Such a dearth of competition from new entrants into the osteoporosis field represents a significant opportunity. But can abaloparatide and romosozumab capitalize on it to boost uptake and sales? Radius Health and Amgen/UCB will certainly be hoping so.
For more information on the Osteoporosis market, click here.
Farr JN, et al. Targeting cellular senescence prevents age-related bone loss in mice. Nat Med. 2017 Sep;23(9):1072-1079.
Kemp JP, et al. Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis. Nat Genet. 2017 Oct;49(10):1468-1475.
Liu P, et al. Blocking FSH induces thermogenic adipose tissue and reduces body fat. Nature. 2017 Jun 1;546(7656):107-112.