ACTIVExtend Supports Value of Abaloparatide, Then Alendronate

Pam Harrison

February 08, 2017

New data from the extension study of the original Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) trial support earlier suggestions that treatment with an osteoanabolic agent followed by maintenance treatment with an antiresorptive (eg, a bisphosphonate) continues to protect postmenopausal women with osteoporosis against vertebral and nonvertebral fracture for a further 6 months.

These latest results come from a preplanned interim analysis of the ACTIVExtend trial, published in the February issue of the Mayo Clinic Proceedings.

"Osteoanabolic treatment is most appropriate for patients who have already experienced osteoporosis-related fractures or who have very low bone-mineral density [BMD] or other risk factors," say Felicia Cosman, MD, Columbia University, New York, and colleagues in their paper.

"[And we found that] the sequence of [subcutaneous abaloparatide, Radius Health] ABL-SC followed by 6 months of [alendronate] ALN improved BMD and reduced fracture risk throughout the skeleton and is likely to be a highly effective treatment option for postmenopausal women at risk for osteoporosis-related fractures," they note.

Abaloparatide is an investigational agent, awaiting approval in the United States, with a decision from the Food and Drug Administration expected by March 30.

Asked by Medscape Medical News to comment on these latest results, Benjamin Leder, MD, associate professor of medicine, Harvard Medical School, Boston, Massachusetts, and chair of the professional practice committee of the American Society of Bone Mineral Research (ASBMR), said these latest results don't really show anything new; they simply replicate the findings of ACTIVE.

And the fact that women at high risk of fracture at baseline were assigned to placebo in this trial is something he doesn't think would be likely to happen in a trial starting now.

In addition, he believes the evidence supporting the benefit of using an anabolic agent first, followed by an antiresorptive — rather than the other way around — is still limited and is not yet based on hard end points such as reduced fracture risk.

ACTIVE Trial Details

As previously reported by Medscape Medical News, findings from the 18-month, randomized, double-blind placebo-controlled ACTIVE trial involving over 2400 women were initially presented at ENDO 2015, the annual meeting of the Endocrine Society in 2015.

At the end of the 18-month trial, subcutaneous abaloparatide was associated with an 86% reduction in the incidence of vertebral fracture, the primary end point of the trial, compared with placebo, and the results were later published in the Journal of the American Medical Association (JAMA. 2016;316:722-733).

Participants in both the placebo and the ABL-SC arms were then invited to continue with active treatment in the form of the bisphosphonate alendronate so as to assess the long-term safety of ABL-SC. (In the ACTIVE trial, a third group of women were randomized to open-label teriparatide [Forteo, Lilly], another osteoanabolic agent, for 18 months, but the primary end point of ACTIVE compared the effect of ABL-SC on vertebral fracture incidence vs placebo, and teriparatide was not included in the primary end-point calculation).

All participants who entered into the extension trial received alendronate 70 mg orally once a week for 24 months. A total of 1139 women who were enrolled in the original ACTIVE trial continued on to the extension study.

As noted by the investigators, women 65 years of age or younger with prior radiographic evidence of a vertebral fracture or who had experienced a nonvertebral fracture in the previous 5 years and who also met specific BMD criteria were invited to participate in the ACTIVE trial, as were women who were over the age of 65 who again met specific BMD criteria for the older age group.

At baseline, 22% of ACTIVE participants had a prevalent vertebral fracture while almost half had a history of a nonvertebral fracture. The mean age at baseline for ACTIVE participants was 68.6 years.

ACTIVExtend Results

At the preplanned 6-month interim analysis, investigators documented no new vertebral fractures among women who had transitioned from daily ABL-SC to alendronate (ABL-SC/ALN) in the extension study vs seven new vertebral fractures in placebo patients who also received alendronate (PBO/ALN) in ACTIVExtend.

Calculated over a 25-month interval, Kaplan-Meier estimates suggest that daily treatment with ABL-SC for 18 months followed by alendronate reduced the incidence of new vertebral fractures to 0.55% compared with 4.4% for placebo patients, for an 87% relative risk reduction over the 25-month interval (< .001) during which ACTIVExtend is planned.

Similarly, three new nonvertebral fractures were documented during the first 6 months of the ACTIVExtend trial among women originally treated with ABL-SC compared with seven fractures in those who received placebo. Again, the Kaplan-Meier estimate at 25 months dropped from 5.6% in the original placebo group to 2.7% in the original ABL-SC group for a 52% relative risk reduction in the incidence of nonvertebral fractures in favor of the original ABL-SC group (P = .02).

Based on the same Kaplan-Meier 25-month estimates, rates of major osteoporotic fractures also dropped to 2% in the ABL-SC/ALN group vs 4.7% of PBO/ALN patients, for a 58% reduction in risk for the group receiving ABL-SC in the original trial (P = .01).

"There was also a prolonged time to first clinical fracture in the ABL-SC/ALN group vs the PBO/ALN group through the first 25 months, with a 45% reduction in risk (P = .02)," the investigators add.

Improvements in BMD were also significantly greater in women who received ABL-SC in the ACTIVE study compared with their placebo counterparts. Specifically, over 25 months, investigators calculated that there was an average gain of 12.8% in BMD at the lumbar spine in the original ABL-SC group compared with an average gain of 3.5% in the original placebo group.

Over the same time interval, comparable average gains in BMD at the total hip were 5.5% vs 1.4%, while an average gain of 4.5% vs 0.5% in femoral neck BMD was also calculated for the two groups, respectively (P < .001 for all differences for each site).

There were no differences in adverse events between the two groups during the transition phase to ACTIVExtend.

Placebo-Controlled Arm Not Likely to Be Used Going Forward

Dr Leder feels that the ACTIVExtend investigators are again just demonstrating the 0- to 18-month efficacy data shown in the original ACTIVE trial.

"In this extension trial, investigators are just focusing on the 6-month extension, and teriparatide was not included in the extension trial — it was not blinded in ACTIVE — which is why they don't discuss it at all in this new study," he explained.

And perhaps a more important point, he says, is the fact that ACTIVE investigators randomized what were high-risk women at baseline into the original study to placebo or active therapy.

"I think that it's become less and less acceptable to do placebo-controlled trials in osteoporosis, and moving forward, in all likelihood the design of these studies is going to have to change," Dr Leder elaborated.

For example, patients randomized to a placebo arm in newly designed trials of osteoporosis will have to be at substantially lower risk for fracture than they were in the current ACTIVE trial or they will have to receive an active comparator to evaluate the experimental drug under study, he explains.

"When this study was initiated, it was probably one of the last ones where it was acceptable to do a placebo-controlled study," Dr Leder noted. "So I would be surprised to see if this kind of study will continue to be done."

Preserving Benefit: Does It Matter Which Way Around Drugs Are Given?

As Dr Cosman and colleagues explain in their paper, antiresorptive therapy following anabolic therapy in theory helps preserve the benefits accrued by initial osteoanabolic therapy.

"The observation that there were significantly fewer vertebral and nonvertebral fractures during 6 months of ALN treatment in the group that was originally randomized to receive ABL-SC suggests that there is a persistent effect of ABL-SC on improving bone strength," they observe.

"And the sequence of anabolic therapy followed by antiresorptive therapy may have the greatest chance of achieving increases in BMD and reaching the goal of preventing fractures," they add.

Dr Leder says ACTIVE and ACTIVExtend are not the first studies to have suggested that using an osteoanabolic agent first, followed by an antiresorptive agent, may be more effective at building bone mass and quality than using them in reverse.

"To say that this order is better for fracture efficacy, you would have had to have a group that got alendronate first, then ABL-SC, which the ACTIVE investigators didn't do," he observed.

"But there have been a variety of studies that have shown it's probably best to use an anabolic agent first followed by an antiresorptive agent, even though the primary end points of these studies still have been [only] BMD," he acknowledged.

ACTIVE study investigators hope to demonstrate that the benefits of early ABL-SC will be maintained with the use of alendronate through the full 24-month follow-up of ACTIVExtend, but whether patients achieve similar benefits from using an antiresorptive agent first followed by ABL-SC would need to be addressed in a separate study.

The study was funded by Radius Health. Dr Cosman has been a consultant, advisor and collaborator to Radius Health; a consultant, advisor, research grant recipient and speaker for Amgen and Eli Lilly, and an advisor for Merck, Tarsa and Semonix. Disclosures for the coauthors are listed in the paper. Dr Leder reports consulting for both Eli Lilly and Amgen.

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Mayo Clin Proc. 2017;92:200-210. Article

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