Treatment with disease-modifying lorecivivint resulted in positive patient-reported outcomes (PROs) in patients with knee osteoarthritis (OA), according to results of a post hoc analysis, presented at the 2019 American College of Rheumatology/Association of Rheumatology Professionals (ACR/ARP) Annual Meeting, held November 8 to 13, 2019, in Atlanta, Georgia.1
Yusuf Yazici, MD, lead author of the paper, rheumatologist at New York University and Chief Medical Officer of Samumed, LLC, in San Diego, California, spoke with Rheumatology Advisor at ACR 2019 to further discuss the results of this study.
Rheumatology Advisor: Dr Yazici, please tell us about your recent paper on OA presented at ACR 2019.
Yusuf Yazici, MD: We are developing lorecivivint, a small-molecule inhibitor of the Wnt pathway, for the treatment of OA. Lorecivivint is a potential disease-modifying drug, which is a huge unmet need in OA because we have always had [medications] — nonsteroidal anti-inflammatory drugs and steroid injections — to treat the signs and symptoms of OA. However, repeated steroid injections potentially harm the joints in the long-term. There are no disease-modifying agents in OA as there are for rheumatoid arthritis (RA).
The Wnt pathway plays a key role in maintaining the health of the joints as indicated by data. So far, we have finished 3 studies (one phase 1 [ClinicalTrials.gov Identifier: NCT02095548] and two phase 2 trials [ClinicalTrials.gov Identifiers: NCT02536833 and NCT03122860]), where we evaluated the safety and efficacy of the compound; results indicated that [lorecivivint] was well-tolerated and safe in that there was no real difference between rates of adverse events and serious adverse events between the placebo and patient group.
In a 1-year trial among patients with unilateral OA, compared with placebo, lorecivivint was effectively able to treat pain and function, which was the primary PRO of the study. We also showed structural benefits with slowing down and/or increasing joint space; resulting data were consistent with previous animal models as a disease-modifying component. We then conducted a 6-month trial where we assessed pain and function in OA. The 0.07-mg dose, the dose we were using in our pivotal trials, helped with both pain and function in a safe manner.2
After this, we started 2 trials, similar to our 1-year phase 2 trials, where pain and function are being assessed at 12 weeks and radiographic benefit at 12 months. This trial is [scheduled] for January 2020, and we are hoping that it will be completed by the end of 2020 or the early part of 2021. If the results from these studies are as good as what they were in the phase 2 trials, we’re hoping to submit and market the first potential disease-modifying drug for OA, which is a big unmet need.
Rheumatology Advisor: How can the safety and efficacy of intra-articular injections compare with gene transfer methods in OA?
Dr Yazici: There are several groups working on gene transfer, not just in OA, but also other conditions. So far, they are in very early stages of development. As far as I know, [gene transfer therapy] is a promising methodology in theory, but it has not really been proven to help yet.
On the other hand, we are now in phase 3 trials with [intra-articular injections], and so far have been able to show that both our safety and efficacy targets are very much involved in defining the disease. In OA, Wnt mutations are higher, weight and trauma [increase] the expression, which leads to excess bone and the risk of losing coverage. By bringing the bone part down to where it is supposed to be — homeostatic range — at least in animals, we have shown to increase the chondrocyte numbers, build more cartilage, and so on. That is the true potential of disease modification, and we want to be able to demonstrate that.
Rheumatology Advisor: How can clinicians address the unmet needs in OA?
Dr Yazici: We published a paper that I presented at ACR last year where we compared [data on] patients with OA with patients with RA.3 Results of this study showed that patients with OA and RA had similar levels of pain and functional improvement; both groups of patients were also indicated to be unhappy with [treatment for the] active disease. Since there are disease-modifying drugs for RA, our focus should now be on getting disease-modifying [drugs] for OA.
The PROs in OA, including Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the pain scales, are not being used commonly in routine care; however, those numbers are improving. Having treatment options that can really make patients feel better will be an impetus to get these drugs implemented and document how patients are doing. If they’re not doing as well as they should be, maybe additional therapies can be considered.
Rheumatology Advisor: How beneficial is PRO-based research to clinicians, and how often are data and results from such studies considered while making clinical decisions?
Dr Yazici: We do not have a lot of data on this, except in RA. Studies have shown that when physicians collect these data, they are trying to reach a certain threshold, such as low disease activity, and change treatments according to patients’ response to it.
Patients do much better over the long-term — more patients are in remission, more patients experience low disease activity, and less damage may be present — when that target is used. Therefore, it is an objective way of quantifying disease activity and trying to achieve the target. We need more of that in rheumatology, not just in RA, but in OA, lupus, and other conditions.
Rheumatology Advisor: How can PRO studies in other rheumatologic disease states, including RA, compare with that in OA?
Dr Yazici: The advantage [in RA and lupus] is because a lot of drugs are in development, it becomes important to document to PROs. Osteoarthritis has not really had that yet, but new drug development will be the impetus to gain interest in this area.
The Osteoarthritis Research Society International (OARSI) has been working towards this cause for some time; they developed the OARSI response tool as a threshold. [This tool needs to be used by physicians more] to document the benefits that patients are experiencing or the lack of benefits so the treatment can be changed accordingly.
Rheumatology Advisor: What’s your stance on the use of opioids for pain management?
Dr Yazici: [Opioids] do work for pain, especially among patients with [a predisposition to developing addictions]. However, we do not have a real way of identifying these individuals, but there are certain risk factors that could help physicians. There are certain conditions where the pain can only be controlled with opioids, and we should really reserve them after every other option has been tried. In addition, [physicians must consider administering] the lowest dose in the shortest amount of time, while also considering that pain is something we should treat. With opioids, although there is a risk [for] addiction and side effects, pain is not good for patients, especially if there is a known cause, its short-term, and can be managed.
We have to be very careful about [prescribing opioids], even though there is a role for them [in pain management]. With risky medications like opioids, it is even more important to individualize treatment for patients.
Disclosure: Dr Yazici declared an affiliation with Samumed, LLC.
1. Yazici Y, Kennedy S, Swearingen C, Tambiah J. The novel, intra-articular CLK/DYRK1A inhibitor lorecivivint (LOR; SM04690), which modulates the Wnt pathway, improved responder outcomes in subjects with knee osteoarthritis: a post hoc analysis from a phase 2b trial. Presented at: 2019 ACR/ARP Annual Meeting; November 8-11, 2019; Atlanta, GA. Abstract 1327.
2. Yazici Y, McAlindon TE, Gibofsky A. Results from a 52-week randomized, double-blind, placebo-controlled, phase 2 study of a novel, intra-articular wnt pathway inhibitor (SM04690) for the treatment of knee osteoarthritis. Osteoarthr Cartil. 2018;26(1):293-294.
3. Pincus T, Castrejon I, Yazici Y, Gibson K, Bergman M, Block J. Osteoarthritis is as severe as rheumatoid arthritis: evidence over 40 years according to the same measure in each disease. Clin Exp Rheumatol. 2019;37(120):7-17.