Roche’s boast on Monday to have in ocrelizumab the first project to show efficacy in a large phase III trial for primary progressive multiple sclerosis is quite a claim, and draws attention to this relatively rare but tricky form of the neurodegenerative disease.
The group might well celebrate: while the relapsing-remitting MS space is crowded, ocrelizumab is one of just a handful of projects in development for the primary progressive form (see table below). However, if Roche has stumbled on a new mechanistic insight this also raises questions that academics and biotechs alike will ask about competing CD20-targeting projects.
For now nothing has been disclosed beyond Roche’s statement that ocrelizumab had reduced disability progression versus placebo at 12 weeks, according to the EDSS scale. Topline data from the 732-patient phase III trial, Oratorio, are being presented at a late-breaker at the ECTRIMS meeting next week.
However, Roche made a point of stressing the involvement of CD20-positive B cells in myelin and axonal damage, thus implying their role in disease biology. And if ocrelizumab, an anti-CD20 MAb, works in this disease then why not other anti-CD20 agents?
These include two available haematological cancer drugs, Rituxan and Arzerra - while ublituximab and veltuzumab are in development by TG Therapeutics and Immunomedics respectively, and preclinical CD20 MAbs are in research at Biocon, Caliber, ImmunGene, Vaccinex and Valor Biotherapeutics.
Indeed, Rituxan is in a small trial in primary progressive MS patients sponsored by Johns Hopkins University. It and ocrelizumab are two of just 13 agents in active development for this MS subtype, an analysis of Clinicaltrials.gov reveals.
|Primary progressive multiple sclerosis (PPMS) trials|
|Gilenya||S1P receptor modulator||Novartis||969-pt phase III Informs study||NCT00731692||Trial failed; marketed for RRMS|
|700-pt single-arm extension||NCT01779934|
|Ocrelizumab||Anti-CD20 MAb||Roche||741-pt pase hIII Oratorio study||NCT01194570|
|Masitinib||c-kit TK & PDGFr inhibitor||AB Science||450-pt phase II/III||NCT01433497||Filed for pancreatic cancer & GIST|
|85-pt phase I/II||NCT01854359|
|Laquinimod||Immunomodulator*||Teva||375-pt phase II, 2-dose study||NCT02284568||EU filing for RRMS rejected|
|Ibudilast (MN-166)||Glial activation inhibitor||Medicinova||250-pt safety & tolerability study||NCT01982942||Marketed in Japan as Pinatos for asthma|
|MD 1003||Vitamin H||MedDay||144-pt phase II||NCT02220933||Includes PPMS & SPMS patients|
|Fampridine (BIIB041)||Potassium channel blocker||Biogen||Phase III in 101 Japanese pts||NCT01917019||Marketed as Fampyra for MS walking disability|
|H.P Acthar Gel||ACTH||Mallinckrodt||100-pt phase II||NCT01950234||Marketed for various uses|
|Idebenone||Coenzyme Q10||NIH||85-pt phase I/II||NCT00950248||Filed for LHON|
|IB-MS||Andrographolide||Innobioscience||68-pt phase I/II safety study||NCT02273635|
|MIS416||TLR 9 & NOD-2 agonist||Innate Immunotherapeutics||34-pt phase I/II||NCT01191996||Trial completed|
|Tysabri||Anti-VLA-4 MAb||Rigshospitalet, Denmark||24-pt ph II NAPMS study||NCT01077466||Trial completed; marketed for RRMS|
|Rituxan||Anti-CD20 MAb||Johns Hopkins||12-pt phase I||NCT02253264||Roche Olympus study (NCT00087529) failed|
|*Possible downregulator of VLA-4-mediated adhesiveness|
However, in Olympus, an earlier trial sponsored by Roche, Rituxan failed to improve disease progression. Thus, if Roche can argue that there is something more specific in the way ocrelizumab acts, it might fend off future competition.
Agents that do not target CD20 include Gilenya and Tysabri, which are already approved for the more common relapsing-remitting form of MS. This accounts for some 85% of MS diagnoses, where patients have clearly defined attacks followed by recovery; in primary progressive disease patients have MS worsening from the start, without remission.
Meanwhile, around 65% of relapsing remitting patients go on to what is termed secondary progressive MS. Some guidelines have proposed the grouping of primary and secondary progressive MS into one entity – notwithstanding the clear differences between them – and some studies include both types of progressive MS patients.
This is the case, for instance, with MedDay Pharmaceuticals’ MD 1003 and Medicinova’s MN-166. Tysabri, meanwhile, is separately being tested in Ascend, a large trial in 889 secondary progressive patients.
MD 1003 this year showed a statistically significant effect on disease progression and other measures in a small phase III trial, though MedDay, a private French biotech, did not split out the benefit in primary progressives.
But this project is basically a food additive, meaning that the bar to competitor entry might be low, while it is not clear how the mechanisms of action of some of the other projects might make them suitable for treating primary progressive MS.
As such Roche would appear to have built up a strong case with ocrelizumab – in this as well as relapsing-remitting MS – and this could help it make up for lost time (Roche arrives late to the multiple sclerosis party, June 30, 2015). The ECTRIMS data will be closely watched.