How do you take a seriously underwhelming blood cancer drug and turn it into a blockbuster? By developing it for multiple sclerosis, of course.
This seems to be the strategy hit on by Novartis, which today revealed more details about its quiet plan to reformulate Arzerra for what analysts see as a far more lucrative indication. The Swiss group is not alone in following the lead of Roche’s Ocrevus, whose recent approval at last validated the CD20 hypothesis in multiple sclerosis (see table below).
This hypothesis suggests that CD20-positive B cells are involved in myelin and axonal damage, and thus play a role in multiple sclerosis (MS) biology. An anti-CD20 MAb like Ocrevus could slow down this process (Roche prices Ocrevus for maximum disruption, March 29, 2017).
Novartis is one of two companies trying their luck at emulating this approach, the other being TG Therapeutics, whose own anti-CD20 MAb, ublituximab, is in phase II MS studies in addition to its more advanced setting in chronic lymphoblastic leukaemia (CLL). Preliminary data recently showed safety, but of course no actual efficacy against MS has yet been seen.
CLL is the indication for which Arzerra got its first approval back in 2009, but the drug has since disappointed, and it came to Novartis via the 2015 Glaxosmithkline asset swap. This year’s sales will not even reach $100m as the CLL space is overwhelmed by such successes as Abbvie’s Imbruvica and Abbvie/Roche’s Venclexta.
In fact some Arzerra sales come courtesy of other companies’ purchase of the drug for its use as a comparator agent in CLL clinical trials.
The MS plan could thus be an ingenious way of resurrecting this asset, and Novartis started making noises about this in January. Of course, it is not the Arzerra brand that is to be used in MS but rather its active ingredient, ofatumumab; for MS use Novartis refers to this asset under the lab code OMB157.
Unlike the IV Arzerra, OMB157 is formulated for subcutaneous delivery, something that could differentiate it from the injected Ocrevus. A further advantage is that this way Novartis might be able to achieve indication-based pricing – an especially handy move if MS requires vastly different dosing versus CLL.
Two similarly designed 900-subject phase III trials, Asclepios I and II, are under way, and Novartis today said it expected to report data and file in 2019. Sellside consensus compiled by EvaluatePharma shows 2022 revenue of $572m for OMB157 versus a still optimistic $267m for Arzerra, and Leerink reckons ofatumumab’s MS incarnation could be generating blockbuster sales by 2026.
Novartis has speculated that OMB157 could cover some 75% of the MS market, from relapsing/remitting to secondary progressive disease. However, only relapsing MS is being studied; in contrast, Ocrevus’s stunning clinical success gave it a broad label in relapsing as well as the highly intractable primary progressive type of MS.
Still, while Ocrevus was the first anti-CD20 agent to show strong efficacy, it was not the first studied. That distinction belongs to Rituxan, which in the Olympus trial failed to show an effect on disease progression.
Given Rituxan’s limited patent life its failure might have been a godsend to the Ocrevus franchise, though Rituxan is being used off label for MS and is in several academic-sponsored studies in MS.
It is not obvious why Ocrevus worked where Rituxan had failed – this could have been down to antibody design, as new generations of MAbs have attempted to improve binding and reduce immunogenicity by modifying several characteristics, for instance by humanising the antibody. But the patient numbers in the Rituxan studies were small, and luck might have played a part.
If is also not entirely clear why, if Ocrevus showed the way, only some CD20-focused competitors are following. This could change soon, though an entrenched Ocrevus will pose a tough barrier – to novel agents and OMB157 alike.
|Selected anti-CD20 antibody attributes|
|Anti-CD20 MAb||Company||MAb structure||Killing mechanism||Status in MS||Trial ID|
|Ocrevus||Roche||Type I, humanised||Strong ADCC, reduced CDC||Approved for relapsing or PP MS||NCT01194570|
|OMB157||Novartis/ Genmab||Type I, fully human||ADCC & strong CDC||Phase III in relapsing MS||NCT02792231|
|Ublituximab||TG Therapeutics||Type I, chimaeric, glycoengineered||Strong ADCC||Phase II in relapsing MS||NCT02738775|
|Rituxan||Roche||Type I, chimaeric||ADCC & CDC||Failed Olympus trial in PP MS||NCT00087529|
|Gazyva||Roche||Type II, humanised, glycoengineered||Strong ADCC, v little impact on CDC||Not studied for MS||NA|
|Veltuzumab||Immunomedics||Type I, humanised||Strong CDC||Not studied for MS||NA|
|Ocaratuzumab||Mentrik Biotech||Type I, humanised||Strong ADCC||Not studied for MS||NA|
|Source: scientific papers; ADCC=antibody-dependent cellular cytotoxicity; CDC=complement-dependent cytotoxicity; PP=primary progressive.|