NVS - Ultragenyx And Mereo's Setrusumab For Osteogenesis Imperfecta: Criticisms And Concerns

Summary

• Mereo and Ultragenyx are collaborating to develop setrusumab, a sclerostin inhibitor, for treating patients with Osteogenesis Imperfecta.
• ASTEROID Phase 2 trial showed that setrusumab improved bone markers and density, and strength but not patient-reported outcomes or fracture reduction, despite baseline advantages.
• Setrusumab's failure to reduce fractures, despite increasing bone mineral density, may be due to its inability to improve the bone's microarchitecture, as suggested by HR-pQCT.
• Ultragenyx is currently enrolling patients for a pivotal phase 2/3 trial to determine whether setrusumab reduces fractures as the primary endpoint.
• While it is worthwhile to continue developing setrusumab for the severe condition of OI, it is unlikely to be successful. This is particularly concerning for Mereo, as they are more dependent on the drug's success than Ultragenyx.

Introduction

Mereo BioPharma ( MREO ) is a clinical-stage biopharmaceutical company that focuses on developing innovative therapies for patients with rare diseases. One of their experimental drugs is setrusumab, a fully humanized monoclonal antibody designed to inhibit sclerostin. This drug, co-developed by Ultragenyx ( RARE ), is being developed to treat Osteogenesis Imperfecta [OI], a rare genetic disorder that affects the body's ability to produce strong and healthy bones.

The following article will dive into phase 2 data and setrusumab's prospects for its pivotal trial and possible marketization.

Mereo/Ultragenyx Setrusumab Collaboration & Financials

Per a 2020 collaboration agreement , Ultragenyx will lead the global development of setrusumab for pediatric and adult patients, while Mereo has granted an exclusive license for its commercialization in the US and the rest of the world, except Europe. Both companies will handle post-marketing responsibilities in their respective territories. Ultragenyx will pay an initial $50 million to Mereo and cover global development costs until approval, with a potential payment of up to $254 million upon reaching clinical, regulatory, and commercial milestones. Royalties will be paid to both companies based on net sales, with Mereo also paying Novartis ( NVS ) a percentage of the proceeds from Ultragenyx, based on a prior 2017 agreement.

Ultragenyx reported their last financials for the quarter ending September 30, 2022. Summarized, as follows:

It appears both companies have no more than ~18 months of cash runway.

Understanding Osteogenesis Imperfecta and Its Management Strategies

Osteogenesis imperfecta [OI] is a genetic disorder that weakens bones and increases the risk of fractures due to mutations in collagen genes. In healthy bones, bone formation and resorption occur simultaneously, with new bone tissue helping to maintain strength and density, and old bone tissue releasing minerals into the bloodstream. However, in OI, this balance is disrupted, reducing bone mass and density. Patients with OI have lower baseline levels of sclerostin relative to healthy individuals, a protein that regulates bone resorption by inhibiting the formation of bone-resorbing cells. The lower levels of sclerostin in OI may be due to a negative feedback mechanism that down-regulates sclerostin to prevent further bone loss. However, sclerostin also stimulates RANKL secretion from osteocytes, which induces osteoclastogenesis and leads to increased bone resorption.

OI management is a multidisciplinary approach that includes physical therapy, surgery, and bone-targeted therapy to improve bone health, muscle strength, mobility, function, and quality of life. Bisphosphonates are commonly used for moderate-to-severe OI with a high risk of fractures. Treatment decisions should be made by specialists at experienced centers, and ongoing monitoring for extraskeletal features, such as hearing loss and cardiovascular abnormalities, is also important. Management aims to improve both skeletal and extraskeletal health in persons with OI.

Understanding Bone Mineral Density: Importance for OI Patients and Differentiating Cortical and Trabecular Bone

Bone mineral density [BMD] is a crucial measure of the amount of mineral in bone tissue, typically expressed in grams of mineral per area or volume of bone. For patients with OI, monitoring BMD is especially important. Various techniques, such as dual-energy X-ray absorptiometry (DXA), quantitative computed tomography (QCT), and peripheral quantitative computed tomography (pQCT), can be used to measure BMD.

Cortical and trabecular bones are two distinct types of bone tissue that serve different functions and have different microstructures. The outer layer of bone tissue that provides structural support and protects the inner bone tissue is known as cortical bone, while the inner layer, which is responsible for metabolic functions and bone remodeling, is called trabecular bone.

Although BMD measurements provide information on the overall density of bone tissue, they do not differentiate between cortical and trabecular bone. Other imaging techniques, such as QCT or pQCT, can provide separate measurements of cortical and trabecular bone density and microarchitecture.

Exploring Setrusumab & FDA-Approved Sclerostin/RANKL Inhibitors

Setrusumab is a monoclonal antibody that targets sclerostin and inhibits its activity, strengthening the already-present negative feedback loop in OI. In a phase 2a study, setrusumab demonstrated a significant effect on the markers of bone formation, with an increase in P1NP by 84%, P1CP by 53%, BSAP by 59%, and OC by 44%. However, setrusumab did not show a significant effect on the bone resorption marker, CTX-1a, which decreased by 44%, but the change was not statistically significant. These changes translated to improvements in BMD, discussed more below.

Another sclerostin inhibitor, romosozumab , has been FDA-approved to treat osteoporosis in postmenopausal women at high risk for fracture. However, romosozumab has a boxed warning for cardiovascular risk and is limited to 12-month use due to waning effectiveness. Another similar drug, denosumab , a RANKL inhibitor also approved for fracture prevention in at-risk groups, has been found to have a rebound phenomenon, where bone loss occurs after treatment is stopped, necessitating subsequent antiresorptive treatment after its use.

Assessing the Efficacy of Setrusumab in Osteogenesis Imperfecta: Insights from the ASTEROID Trial

In a phase 2b dose-finding study called ASTEROID , intravenous setrusumab was evaluated in 112 adults diagnosed with type I, III, or IV OI and a confirmed COL1A1/COL1A2 mutation who had fractured over the previous 5 years. The study evaluated three dose levels of setrusumab, 2 mg/kg (low), 8 mg/kg (medium), and 20 mg/kg (high). Due to a protocol amendment, patients originally receiving placebo switched to setrusumab 20 mg/kg after an average of 5 months. The primary endpoint of the study was the change over baseline in Tr.vBMD of the wrist at 12 months, followed by changes in bone strength measured by Finite Element Analysis (FEA) (hierarchical), assessed using HR-pQCT. While the primary endpoint was not met, UX143 did demonstrate a clear benefit in multiple pre-specified endpoint analyses, including improvements from baseline in bone strength (stiffness) at the wrist and tibia, and areal BMD at the lumbar spine, as measured by DXA.

One possible explanation for why the drug failed to show bone improvement in HR-pQCT but did show improvement in DXA is that the two tests examine different aspects of bone structure. DXA measures areal BMD, which is a two-dimensional measurement of the mineral content of bone in a specific region of interest. HR-pQCT, on the other hand, measures three-dimensional microarchitecture of bone at the radius or tibia, which includes trabecular and cortical bone microstructure. It is possible that setrusumab may have had a more prominent effect on the mineral content of bone, as measured by DXA, than on the microarchitecture of bone, as measured by HR-pQCT. This could be due to differences in the way the two techniques assess bone structure or to differences in the sensitivity of the two techniques to changes in bone structure. Additionally, it is also possible that the drug's effect on bone may be more prominent in certain regions of the body, such as the lumbar spine or hip, which are not assessed by HR-pQCT.

It is noteworthy that patients receiving setrusumab did not report superior patient-reported outcomes compared to those who received the placebo.

Imbalance in Gender Distribution Raises Questions about Generalizability of Results

During the initial 5 months of the trial, the incidence of fractures categorized as Serious Adverse Events (SAE) in the placebo group (2/20, 10.00%) was lower compared to the other groups. However, it's worth noting* that the placebo group transitioned to open-label treatment after the initial 5 months, making a direct comparison between the placebo group and the other groups difficult. The trial protocol was modified by the company to have placebo patients switch to open-label setrusumab. It would have been more informative to keep the patients on placebo since this further complicates the data, which is already limited by a small sample size.

Explanation of How Increased BMD May Not Necessarily Improve Overall Bone Health

While increasing bone mineral density [BMD] can improve bone strength in terms of failure load and bone stiffness, as seen in ASTEROID data, it can still lead to an increased risk of fractures. This is because BMD is an important factor, but not the only factor, that affects bone strength in OI patients. Other factors such as bone microarchitecture, bone turnover rate, and collagen cross-linking also play a crucial role in determining bone strength in OI patients. A medication that increases BMD may increase bone mass but not necessarily improve bone microarchitecture, which is a critical determinant of bone strength in OI patients. In some cases, an increase in bone mass without a corresponding improvement in bone quality can result in bones that are more brittle and prone to fracture in OI patients.

The study on setrusumab used DXA and HR-pQCT , two different tests used to measure bone health. DXA measures the mineral content of bone in a two-dimensional area, while HR-pQCT measures the three-dimensional structure of both trabecular and cortical bone. The results of the study showed that setrusumab improved bone mineral density as measured by DXA but did not significantly improve the microarchitecture of bone as measured by HR-pQCT in OI patients.

The reason for this discrepancy is not entirely clear, but it may be because DXA and HR-pQCT measure different aspects of bone health or because the tests are more or less sensitive to changes in bone structure in different parts of the body. So, while setrusumab may have improved bone mineral density as measured by DXA, it did not improve the microarchitecture of bone as measured by HR-pQCT, which could explain why OI patients randomized to setrusumab experienced more fractures relative to placebo despite documented improvements in bone mineralization.

Ultragenyx and Mereo's ORBIT Study: Evaluating Setrusumab for Osteogenesis Imperfecta with a Primary Focus on Fracture Reduction

Ultragenyx and Mereo are conducting the pivotal ORBIT phase 2/3 study , which includes four arms: a low-dose setrusumab arm, a high-dose setrusumab arm, a setrusumab selected dose arm, and a placebo comparator arm. All participants will receive daily calcium and vitamin D supplementation, as well as a monthly intravenous infusion of setrusumab or placebo. The trial has two phases, and the primary outcome measures are the percent change in serum amino-terminal propeptide of type 1 procollagen (P1NP) at month 1 and the annualized rate of all radiographically-confirmed fractures during the double-blind treatment period (phase 3).

The ASTEROID data showed that the presence of fractures didn't seem to benefit setrusumab, although this might have been a chance occurrence due to the limited number of participants. However, this is not a positive sign for setrusumab as it approaches pivotal data. It's worth noting that if the treatment groups had shown a decrease in fractures compared to the placebo group, the company would have probably emphasized this in their presentations and press releases, as they did with the non-significant, underpowered, and supposedly dose-dependent reductions observed within the treatment groups.

The mechanism of action of setrusumab also raises concerns. Setrusumab is in the same drug class as romosozumab, which could result in a boxed warning for cardiovascular risk if approved, even if there are no signals in the ASTEROID and ORBIT data. Though the risk is reduced with limited (12-month) use of romosozumab, it is noteworthy for setrusumab's market prospects. If setrusumab is approved, it will likely be used for no more than 12 consecutive months. Given the complexity of OI and the variations in severity, it will be difficult to determine when setrusumab should be used. Once setrusumab treatment is discontinued, any increase in bone mineral density is likely to decline quickly, similar to the pattern seen with romosozumab. Additionally, there is a possibility of a rebound effect, as shown with denosumab after cessation, though this may be less significant in OI patients due to their lower baseline levels of sclerostin.

Outlook for Setrusumab as a Treatment for Osteogenesis Imperfecta Appears Grim Despite Potential Benefits

The analysis of data from the ASTEROID trial suggests that setrusumab may not be an effective treatment for osteogenesis imperfecta. Although it led to significant improvements in bone mineral density, it did not reduce fractures or improve patient-reported outcomes compared to placebo. Setrusumab's failure to reduce fractures, despite increasing bone mineral density, may be due to its inability to improve the bone's microarchitecture, as suggested by HR-pQCT. Furthermore, the drug's use may be limited to no more than 12 consecutive months, which may complicate treatment given the complexity and variability of OI. There is also the possibility of waning effectiveness and a rebound effect, which could limit its long-term effectiveness.

Despite these limitations, the development of setrusumab continues due to the severity of OI and the lack of effective treatments. Although the chances of success appear slim, the demand for effective treatments and the potential benefits to patients make the continued development of setrusumab a justifiable risk/reward for Ultragenyx. As for Mereo, which is far more dependent on the success of setrusumab, investors should practice caution ahead of pivotal data.

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