Mixed Data For Merck KGaA's Disease-Modifying OA Drug
German firm looking to partner sprifermin
Executive Summary
Sprifermin could be the first drug to affect the underlying disease process in osteoarthritis but data show no significant improvement in symptoms.
No drugs are currently approved to treat the underlying cause of osteoarthritis but Merck KGaA is hoping that sprifermin, which has shown promise in mid-stage trials, could be the first disease-modifying therapy for the disabling condition.
The German group's hopes are based on results from FORWARD, a five-year, Phase II study of sprifermin, a recombinant human fibroblast growth factor-18, in patients with symptomatic radiographic knee osteoarthritis (OA). The data, published in the Journal of the American Medical Association, show statistically significant, dose-dependent increases in joint cartilage thickness compared with placebo, Merck noted.
The study, led by researchers at the University of Maryland School of Medicine (UMSOM), involved 549 volunteers with knee OA who were randomly assigned to get injections of placebo or sprifermin 30 micrograms (μg) or 100μg once or twice a year. The researchers found that those who received a 100μg experienced a significant but slight gain in joint cartilage thickness after two years – 0.03 or 0.02mm – compared with the placebo group that lost 0.02mm of cartilage during the same period; those given smaller doses had smaller gains in cartilage which were not deemed to be significant.
While injections were stopped after 18 months, the analyses showed that the difference between the groups that received the higher dose of sprifermin and placebo persisted out to three years.
Describing the publication of the FORWARD data as "noteworthy,” Merck R&D chief Luciano Rossetti, noted that this represented an area of significant medical need, "as OA is a degenerative condition with no approved treatment options that directly target structural disease progression.”
No Improvement In Symptoms
FORWARD was not all positive, however. Patients treated with the higher dose of sprifermin did not experience any significant improvement in their arthritis symptoms – including pain, stiffness and physical dysfunction like walking difficulties – compared with those given the lower dose or placebo.
Lead investigator Marc Hochberg of UMSOM, pointed out that “while the increase in cartilage thickness is a positive sign, we do not know at this point whether it has any clinical significance. It is not known whether those who experience increased cartilage thickness over time will be able to avoid or delay knee replacement surgery.”
Sprifermin may prove more successful in higher-risk patients however. In a more recent post-hoc analysis of the data, the UMSOM researchers evaluated a subgroup of OA patients with severe pain and narrow joint space in their knee who were at higher risk of disease progression and found that those who received sprifermin 100µg every six months experienced significant improvements in their arthritis symptoms 18 months after their last injection compared with those on placebo.
Those results "support further investigation of sprifermin as a potential OA treatment for both structure modification and symptom relief for higher-risk patient populations,” Hochberg said.
Not A Core Asset
It seems doubtful that Merck will embark on those studies and certainly not on its own. The Darmstadt-based company noted that it was "evaluating external partnership opportunities for its OA portfolio, including sprifermin, with the goal of finding the right partner to advance the development of structurally-modifying treatments to change the course of OA."
At its capital markets day last month, Merck acknowledged that sprifermin was a top priority for externalization and it had received interest from venture capital firms as well as big pharma. Its focus is on growing sales of the multiple sclerosis drug Mavenclad (cladribine) and the Pfizer Inc.-partnered checkpoint inhibitor Bavencio (avelumab) and progressing the oral MET kinase inhibitor tepotinib, the bifunctional immunotherapy bintrafusp alfa and the Bruton’s tyrosine kinase (BTK) inhibitor evobrutinib through the pipeline. (Also see "Merck KGaA Says New Meds Will Add €2bn Sales" - Scrip, 13 Sep, 2019.)
Whichever partner takes on sprifermin could be getting hold of a potential game-changer for a big market. Merck estimates that there are 237 million people worldwide living with symptomatic and activity-limiting OA, "the third most rapidly rising condition associated with disability globally," and UMSOM said that more than 10% of Americans over age 60 experience knee pain related to OA.
As well as Merck, a number of companies are looking at drugs that could offer structural improvement. One of them is Medivir AB and the Swedish company's MIV-711, a cathepsin K inhibitor in development for cartilage repair, has been studied in two Phase II trials in patients with moderate knee OA. Other drugs in the space include OrthoTrophix's TPX-100, a 23-amino-acid peptide, and Samumed LLC's lorecivivint, an inhibitor of the Wnt pathway which has just started Phase III trials (see sidebar).