This month, FDA is expected to make a qualification decision for total hip bone mineral density (BMD) as an approvable surrogate endpoint for future osteoporosis drug approvals. If “approved,” BMD will be the first surrogate endpoint to be qualified under FDA’s Biomarker Qualification Program, enacted as part of the 21st Century Cures Act of 2016. Entera Bio (Nasdaq: ENTX) is the company most leveraged to FDA’s BMD decision. EB613, Entera’s oral parathyroid hormone (PTH 1-34), is a Phase 3 ready asset. Assuming FDA qualifies BMD, EB613 will almost certainly be the first drug to enter a pivotal osteoporosis study using BMD as its primary endpoint. If clinically successful, EB613 would become the first new osteoporosis drug approved since 2019 and the first-ever approved oral anabolic agent. However, the first step is to get BMD qualified by FDA.
BMD Paving The Way
The Biomarker Qualification Program is likely an unfamiliar pathway for most investors. That’s because the groups championing these qualification submissions are usually public-private partnerships, with industry taking a more passive role. In the case of BMD, the process has been championed by the Foundation for the National Institutes of Health (FNIH) and the American Society for Bone and Mineral Research (ASBMR), but with prominent industry support from Amgen, Eli Lilly, and Merck, among others. In November, another public-private consortium, this time focused on a surrogate endpoint for kidney transplant studies, announced they were proceeding to the final step of FDA’s biomarker qualification program. There are earlier-stage submissions for novel endpoints in frontotemporal dementia and primary sclerosing cholangitis, among many others seeking FDA qualification.
Although the qualification process may be foreign to investors today, we suspect it will become more topical, especially after FDA’s impending first qualification decision on BMD. As the ASBMR stated in their March 2024 press release about the impending FDA qualification decision, “If BMD is qualified by the FDA as a surrogate endpoint, it will be the first such biomarker accepted by the FDA for a surrogate endpoint under the 21st Century Cures Act and could also pave the way for the qualification of biomarkers in other disease areas.”
Ten Years (Plus) In The Making…
In 2013, FNIH began studying BMD as a potential surrogate endpoint for osteoporosis drug approvals through its Bone Quality Project (now called the SABRE project). Novel drug development for osteoporosis had markedly declined, largely due to the time and cost of running studies with fracture as the primary endpoint. FNIH believed that a validated surrogate endpoint for fracture would incentivize research and development in osteoporosis. “FDA qualification of the change in BMD as a surrogate endpoint for fractures would promote innovation in drug development for osteoporosis by reducing the costs and time to bring new treatments to patients,” stated Dennis Black, Principal Investigator on the SABRE project.
FDA was one of the founding public-sector partners in the SABRE project. In the press release announcing the launch of the project in 2013, FDA’s Director of the Center for Drug Evaluation and Research, Janet Woodcock, was quoted as saying, “There is an imperative need for continued development of new osteoporosis drugs and for determining rational clinical strategies for their use…we applaud the FNIH for spearheading this important work.”
FDA supported FNIH’s SABRE project launch in 2013. In 2016, FNIH submitted its Letter of Intent to FDA to qualify BMD as a surrogate endpoint for fracture, kicking off the qualification process. Since then, there have been numerous interactions between FDA and the FNIH (SABRE), culminating in a qualification package with data from over 170,000 patients from 50 randomized controlled fracture studies. SABRE’s findings have been extensively published in journals such as The Lancet, Lancet Diabetes & Endocrinology, and as recently as December 2024 in the Journal of Bone Mineral Research, where the authors concluded, “These data support the very strong relationship between hip BMD and fracture risk and provide supporting rationale for change in TH (total hip) BMD as a surrogate for fracture risk reduction in future RCTs.”
In March 2024, ASBMR announced that FDA had communicated to the SABRE project team that it would make its qualification decision within ten months. As recently as September’s ASBMR 2024 annual meeting, FDA’s Director of Endocrinology, Theresa Kehoe, presented during a session titled “Update on the Strategy to Advance BMD as a Regulatory Endpoint (SABRE) for Clinical Trials.”
FDA commended the FNIH when it launched its BMD project in 2013. FDA has regularly interacted with the FNIH/SABRE team during the multi-year qualification process. FDA shared a podium with the principal investigator of the SABRE project as recently as three months ago. FDA has directly or indirectly been encouraging this project since its inception. Either FDA has been toying with FNIH/SABRE for the past eleven years, or BMD is getting qualified.
Why Should Investors Care?
In the near term, amongst publicly traded companies, Entera has the most to gain or lose from the impending FDA qualification decision. We have previously written about Entera’s EB613 oral PTH as the most advanced, Phase 3-ready osteoporosis asset in development. In 2022, Entera announced that it had FDA alignment on a single Phase 3 registrational study design for EB613 in osteoporosis that included BMD as the primary endpoint. However, Entera would have to run this study at risk without assurances from FDA that an improvement in BMD would be sufficient for approval. With the BMD qualification process ongoing, the company, after discussing the idea of funding an at-risk study with investors, opted to wait for FDA’s qualification decision before funding and launching its Phase 3 study.
If FDA qualifies BMD as an approvable surrogate endpoint, Entera should have options for funding its Phase 3 study. Given the quality of the existing EB613 data, the familiarity with osteoanabolics, specifically Forteo (daily injectible PTH 1-34), and the size of the osteoporosis opportunity, the company should have plenty of interest from investors and strategics. The company has had a few years to flirt with both groups as it awaits the qualification decision, and assuming FDA meets its timelines, it should be able to fund and launch its Phase 3 program in 2025.
Speaking of meeting timelines, if there is a risk around the FDA decision, it is more of a delay than a rejection risk, in our opinion. The qualification decision is expected shortly before an administration change, and the outgoing FDA leadership could push this decision onto the new leadership. Then again, having the first FDA-qualified surrogate endpoint under the 21st Century Cures Act might be a symbolic decision that this outgoing leadership wants for its legacy.
Qualify, reject, or delay….investors should know FDA’s decision on BMD shortly.