BiotechTracker: Poor Results for Preos Plus Alendronate Combination Therapy

BiotechTracker: Poor Results for Preos Plus Alendronate Combination Therapy

September 23, 2003 Three New England Journal of Medicine articles – two clinical trial manuscripts and an editorial – published online Saturday affect the developmental outlook for NPS’s (NASDAQ: NPSP) Preos. Preos is a full-length recombinant parathyrioid hormone construct that will compete with Eli Lilly’s (NYSE: LLY) Forteo, a truncated version of the same protein. The data, out of the ongoing PaTH (PTH/alendronate) study, significantly reduce the probability that NPS will be able to rely on synergistic Preos combinations in competitive attempts to offset the lead-time advantage enjoyed by Forteo in the recombinant parathyroid hormone market.

Although the data generate an array of complex clinical questions that remain unresolved, the outlook for Preos use in combination with Merck’s (NYSE: MRK) Fosamax (alendronate) and other bisphosphonates has taken a significant turn for the worse. Although it had long been thought that parathyroid formulations’ ability to stimulate bone formation would augment the ability of Fosamax and other antiresorptive drugs to reduce bone resorption to a clinically significant degree, multiple findings now suggest that this is not generally true.

Osteoporosis drug-naïve, postmenopausal women did not benefit from a Preos/alendronate combination:
- no significant difference between the therapeutic effects exerted by Preos alone and Preos plus alendronate
- Preos monotherapy remains a viable candidate for management of spinal bone mineral reinforcement
- the protocol studied is extremely unlikely to provide fracture risk reduction.
- Men adding Preos to alendronate did not benefit from a Preos/alendronate combination:
- alendronate impaired Preos’s ability to increase bone mineral density at the lumbar spine and the femoral neck
- continued study of Preos-based combination therapy remains appropriate with administration schedules of greater than 12 months duration.

Results of both investigations suggest that the notion that parathyroid hormone is bone-building and bisphosphonates are anti-resorptive is an oversimplification:
- alendronate impairs anabolic Preos activity
for spine bone mineral density management, Preos monotherapy > combo therapy > alendronate monotherapy
- known aspects of the complex biology likely accounts for the disappointing findings
- alendronate’s inhibition of overall bone turnover most likely a key aspect
- alendronate’s inhibition of bone resorption, per se, most likely not a key aspect
variation on some aspects of study design may yield niche applications for Preos/bisphosphonate management.
- Preos plus Alendronate in Women

A randomized, double-blind, clinical trial of Preos and alendronate assigned 238 postmenopausal women (not using bisphosphonates) with low bone mineral density at the hip or spine to receive daily Preos (100 µg; n=119), alendronate (10 mg; n=60), or both (n=59). The study subjects were followed for 12 months.

No evidence of clinical synergy was observed for the Preos/alendronate combination in this sample population. Moreover, the combination’s clinical failure was reinforced by multiple biochemical and imaging findings suggesting that alendronate impairs the bone-building effects of parathyroid hormone (or at least of Preos). Preos monotherapy appeared to remain a viable candidate for management of spinal bone mineral reinforcement.

Although bone mineral density at the spine increased in all treatment groups, there was not a significant difference between the therapeutic effects exerted by Preos alone compared to Preos plus alendronate. Although trabecular bone density at the spine increased substantially in all groups, the increase in the Preos monotherapy group was approximately twice that found in either of the other groups. Bone formation benefit was clinically significant in the Preos monotherapy group, but not in the combination therapy group. Bone resorption, as expected, decreased in the combination drug group and the alendronate group.

In all, this investigation showed little evidence that a Preos/alendronate combination will outperform either drug alone. The ultimate question of the benefit of parathyroid hormone–based combination therapy for reduction of fracture risk may actually require too many resources to merit continuation of trials in this area. Abandoning such trials, though, may prove conceptually difficult given that pharmacological precedent exists for observation of certain ultimate clinical benefits in the absence of surrogate marker benefits. In this study, Preos recipients experienced a clinically significant magnitude of benefit when one looks at markers of bone formation, but this was tied in with a delayed but concerning pro-resorption profile. The overall efficacy profile continued to challenge the hypothesis that combination therapy would maintain the increased bone formation while minimizing increased mineral resorption. The pace at which these findings were established suggest that finding a benefit for an endpoint of fracture is unlikely, probably not worth additional investigation with this same study design.

However, this study examined Preos-based combination therapy only in women not already taking medication for osteoporosis. Thus, investigation with regard to antiresorptive therapy (especially bisphosphonates) initiated before or after the initiation of Preos remains an avenue to be explored. Preos monotherapy remains a viable alternative to Forteo, but more mature data are still required to solidify Preos as a real-world Forteo competitor.

The generalizability of the current data set to a Forteo-based combination regimen given in the same manner remains uncertain. However, the results do not support the concurrent initiation of alendronate with recombinant parathyroid hormone treatment in the population and manner studied.

Preos plus Alendronate in Men

A randomized, double-blind clinical trial assigned 83 men, ages 46 to 85, with low bone density to receive alendronate (10 mg daily; n=28), Preos (40 µg subcutaneously daily; n=27), or both (n=28). Alendronate was administered for 30 months, and Preos was initiated at month 6.

This investigation clearly demonstrated that alendronate impaired Preos’s ability to increase bone mineral density at the lumbar spine and the femoral neck in men when the drugs are administered in this fashion. Biochemical evidence suggests that the failure is due to an alendronate-induced attenuation of Preos effect in terms of bone formation.

Femoral neck bone mineral density increased significantly more in the Preos group than in the alendronate group (p<0.001) or the combination therapy group (p=0.01). Lumbar spine bone mineral density increased significantly more in the Preos monotherapy group (p<0.001 for both comparisons). Interestingly, lumbar spine bone mineral density increased significantly more in the combination therapy group than in the alendronate group (p<0.001).

The benefits observed in femoral neck bone mineral density peaked between 12 and 24 months after Preos initiation, suggesting that continued study of Preos, even Preos-based combination therapy, remains appropriate with administration schedules of greater than 12 months duration.

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