Medivir this week joined a short list of four drug developers hoping to advance a project that promises to change the course of osteoarthritis. That few venture here is understandable – arresting or reversing the course of progressive joint damage would be no small feat – and none have made it close to making such a claim (see table below).
The Swedish company thinks it has a chance, and is looking for a partner to push MIV-711 into later-stage studies, but this will be a hard sell. Big companies have shown a notable lack of interest in this space, the phase IIa study that Medivir presented as a win failed on its primary endpoint, and its compound belongs to a class with a long list of failures.
None of this deterred investors, however, who sent Medivir stock up 33% yesterday on the news. After a series of disappointments in hepatitis C that have caused its valuation to halve over the last three years, shareholders are perhaps keen to focus on the positives.
These could only be found among secondary analyses of the 244-patient, phase IIa study that used change on a patient-reported knee pain score over six months as primary endpoint. No difference was seen between the active and placebo arms, a reading that the company defended as expected in a short-term study. MIV-711 is not an analgesic, it pointed out, and an impact on pain should be felt over the longer term, as join degeneration is slowed or stopped.
Whether MIV-711 is capable of changing the course of osteoarthritis remains to be proven, though Medivir claimed that successful secondary endpoints demonstrated its disease-modifying benefits. Joint bone area progression as measured by MRI was significantly reduced in MIV-711 patients, while a benefit on cartilage degradation was seen, although presumably this missed statistical difference.
Still, it will take a bold partner to make a bit bet on this asset. MIV-711 inhibits cathepsin K, which is involved in the breakdown of collagen in bone and cartilage, and belongs to the same class as Merck & Co’s odanacatib. This was shelved as an osteoporosis project last year after being linked to stroke, joining a fairly extensive list of other abandoned cathepsin K inhibitors (Odanacatib’s 15 minutes of fame, 5 September 2016).
|Disease-modifying approaches in osteoarthritis|
|Project||Pharma class||Company||Notes||Trial ID|
|Invossa||TGF beta 1 cell therapy||Tissuegene||Phase III to begin in 2018; data due 2021||NCT03203330; NCT03291470|
|MIV-711||Cathepsin K inhibitor*||Medivir||Phase II toplined Sep 2017||NCT02705625|
|SM04690||Wnt/beta-catenin signalling pathway modulator||Samumed||Phase II interim data presented Aug 2017; more data due in 2018||NCT02536833; NCT03122860|
|TPX-100||Anti-rheumatic||Orthotrophix||Phase II reported Dec 2016||NCT03125499|
|*Only oral agent in clinical development.|
Of the other assets in development, Tissuegene has probably the most advanced one, having listed two large 500-patient phase III trials on Clinicaltrials.gov, slated to begin early next year.
Called Invossa, the allogeneic cell therapy comprises human chondrocytes that have been developed to induce cartilage regeneration. The product was launched in South Korea earlier this year via a licensee, and is similar to autologous chondrocyte therapies developed by Tigenix and Vericel, which won approval for cartilage repair.
These are hardly a good proxy, however; both pulled their products in Europe after failing to establish a market, although Vericel is now trying to launch a next-generation therapy, Maci, in the US. Presumably Tissuegene sees greater commercial viability in an off-the-shelf offering.
Elsewhere, Samumed is in the midst of revealing data from its large US-based phase II programme of SMO4690. The project inhibits Wnt signalling, which is involved in a number of cellular pathways; the private California company believes that its relevance in osteoarthritis relates to a role in the regulation of self-renewal and differentiation of adult stem cells, as well as involvement in increased bone formation and cartilage breakdown.
Interim results from the first study, which was not powered for statistical analysis, yielded some encouraging signals earlier this year; the second should generate data early next year.
Looking less certain to progress is Orthotrophix with TPX-100, after reporting mixed results from a phase II study late last year. Its project is described as a peptide derived from matrix extracellular phosphoglycoprotein, a protein that is involved in bone and cartilage formation; TPX-100 is thought to work by stimulating the production of new hard tissue matrix.
The trial recruited patients with bilateral osteoarthritis – disease in both knees – who were injected with the active ingredient in one knee and placebo in the other. MRI measures failed to detect any difference in cartilage thickness or volume after one year, but various patient-reported measures such as knee daily function demonstrated statistically significant improvements in TPX-100-treated knees.
Subjective measures such as pain and function are notoriously unreliable, particularly when they come from small studies. These developers will have to generate much more convincing long-term evidence of both pain alleviation and joint preservation to achieve a label claim of disease modification – the big win that all are striving for.
They have a long way to go, and all are going to need further funds to get there. But it is hard to see big partners paying big bucks for these projects as they stand today.