Novartis’s Gilenya quietly seized third place among the world’s best-selling multiple sclerosis therapies last year, but the fun is about to end as it faces US patent expiry in 2019.
As of today, however, the Swiss group can boast a new pillar for its Gilenya follow-on plan: siponimod, a similarly acting project, has posted an unexpected phase III success. Still, these molecules’ pharmacology represents a crowded area, and Novartis has to spin the clinical success into a therapeutic advantage (see table below).
Indeed, until full data are revealed at the Ectrims meeting next month the main advantage siponimod boasts is that it has shown a benefit in secondary progressive MS. This is the form of the disease that develops with time in about 65% of relapsing MS patients as their disease worsens.
Novartis today said the phase III Expand trial showed siponimod cut the risk of three-month disability progression versus placebo, the primary endpoint.
At this point this suggests a strong but theoretical advantage, since currently secondary progressive patients continue to be given the same types of drugs that they have received for their initial relapsing disease, and no drug is approved specifically for secondary progressive MS.
Novartis will therefore have to carve out siponimod’s benefit into a specific label claim – problematic if one disease is simply seen as a severe form of the other – as well as possibly arguing that this could also translate into a strong benefit in relapsing MS, backing premium pricing after Gilenya’s patent expiry.
The idea was not dreamed up overnight; Novartis specifically designed Expand to target secondary progressive disease. Expand started four years ago and recruited 1,652 patients.
Remarkably, while secondary progressive patients have participated in many MS studies, Expand was one of very few to focus on it specifically. Many of the others featured old drugs, including domperidone and simvastatin, and several have been withdrawn or terminated, including the Ascend trial of Biogen’s Tysabri.
Those still ongoing include a 180-patient study of Tcelna, an autologous T-cell therapy in development by Opexa Therapeutics.
Given how unique the Expand data could make siponimod, it is strange how low-key a profile the asset had. At Novartis’s second-quarter financials presentation it was merely listed among many phase III projects expected to be filed in 2019, and the Expand readout was not even highlighted as an important imminent event.
Until now Novartis’s Gilenya genericisation survival strategy has focused on the marketed anti-CD20 MAb Arzerra, whose pivotal relapsing MS trial reads out in 2019 (16 months on, Novartis sees Arzerra’s multiple sclerosis value, August 24, 2015). This follows in the footsteps of Biogen, whose CD20-targeting agent ofatumumab scored an important hit in primary progressive MS.
Primary progressive MS accounts for just 15% of initial diagnoses, but is important because of its severity and lack of treatments, and is thought to represent a clearly defined, separate disease. That said, some guidelines propose grouping primary and secondary progressive MS into one entity, which could be significant for Novartis and siponimod.
A further consideration, however, is the proliferation in competitor assets piggybacking on Gilenya’s mechanism of sphingosine-1-phosphate (S1P) receptor modulation. Most important is ozanimod, for whose originator, Receptos, Celgene shelled out $7.2bn last year.
A phase III MS study of ozanimod, which targets the same S1P receptor subtypes as siponimod, reads out next year, but recruited patients with the relapsing form of the disease, as did the rest of the projects targeting this mechanism.
Should any of them score a clinical hit over the coming years it would be down to Novartis to play its secondary progressive advantage to the full.
|S1P targeting projects|
|Company||Project||Pharmacology class||Trial ID||Note|
|Novartis||Gilenya||S1P receptor modulator||–||US patent expires 2019|
|Novartis||Siponimod||S1P 1 & 5 receptor modulator||NCT01665144||Secondary progressive MS|
|Celgene||Ozanimod||S1P 1 & 5 receptor modulator||NCT02576717||Data in 2017; Celgene bought Receptos for $7.2bn|
|Actelion||Ponesimod||S1P 1 receptor agonist||NCT02425644||Data in late 2018|
|Biogen/Mitsubishi Tanabe||Amiselimod||S1P 1 receptor antagonist||NCT01890655||Study completed Mar 2016|
|Suzhou Connect Biopharmaceuticals||CBP-307||S1P 1 receptor modulator||NCT02280434||Enrolment completed Jan 2016|
|Arena Pharmaceuticals||Etrasimod||S1P 1 receptor modulator||–||MS is not the lead indication|
|Lexicon Pharmaceuticals||LX2931||S1P lyase inhibitor||–||Phase II for RA; preclinical MS potential had been discussed|
|Novartis/Kyorin||KRP-203||S1P 1, 4 & 5 agonist prodrug||–||Phase II for lupus & organ rejection|
|Actelion||Cenerimod||S1P receptor modulator||–||Phase II for lupus; might have been studied in phase I for MS|
|Akaal Pharma||AKP-11||S1P 1 receptor agonist||–||Phase II for psoriasis; preclinically compared vs Gilenya in MS|
|Ono Pharmaceutical||ONO-1266||S1P 1 receptor antagonist||–||Phase I in portal hypertension; Ono's ceralifimod failed in phase II MS trial|
|RedHill Biopharma||Yeliva||S1P 2 kinase inhibitor||–||Oncology indications – note distinct mechanism|