Considering that lupus represents something of a black hole for the pharmaceutical sector, the mid-stage pipeline of novel therapies is relatively full. Unfortunately for those hoping for new medicines to emerge soon, confirmatory data on this next swathe of hopefuls are unlikely to start emerging until next year (see tables below).
Notably in next year’s calendar are pivotal results from probably the most advanced asset, Astrazeneca’s anifrolumab. The antibody targets the interferon alpha receptor, the first of its kind to do so, raising hopes that it will work where other similar attempts have failed. Other closely watched assets include Celgene’s CC-022 and Biogen’s BIIB059, though confirmation of their potential is even further away.
According to EvaluatePharma, anifrolumab is one of only three novel agents in phase III testing. The analysis below excludes validated immune suppressing agents being studied in lupus patients, for example Bristol-Myers’ T cell inhibitor Orencia or anti-TNF agents.
A number of novel RA therapies and psoriasis drugs including the new Jak inhibitors and Johnson & Johnson’s Stelara have also been excluded for brevity, although they could generate practice-changing results. Perhaps most notable of this group is Ablynx’s vobarilizumab – phase II results next year in lupus will determine whether anything can be salvaged from a former Abbvie option deal over the asset.
|Novel lupus pipeline – ones to watch|
|Product||Company||Pharmacological Class||Trial ID (recruitment)||Data due|
|Anifrolumab||Astrazeneca||Anti-interferon type I MAb||NCT02446899 (360)||Nov-18|
|Lupuzor||Immupharma||CD4 T cell modulator||NCT02504645 (200)||Q1 2018|
|Voclosporin||Aurinia||Calcineurin inhibitor||NCT03021499 (324; Aurora)||Dec-19|
|RSLV-132||Resolve Therapeutics/Takeda||Interferon alpha pathway inhibitor||NCT02660944 (50)||Jun-17|
|BMS-931699 (lulizumab)||Bristol-Myers Squibb||Anti-CD28 domain antibody||NCT02265744 (350)||Jul-17|
|XmAb5871||Xencor||Anti-CD19 MAb||NCT02725515 (90)||Jan-18|
|Adcetris||Seattle Genetics||Anti-CD30 MMAE conjugate||NCT02533570 (40)||Nov-18|
|Dapirolizumab||Biogen/UCB||Anti-CD40L MAb||NCT02804763 (160)||H2 2018|
|IFNα-Kinoid||Neovacs||Anti-interferon alpha vaccine||NCT02665364 (178)||H2 2018|
|BIIB059||Biogen||Anti-BDCA2 MAb||NCT02847598 (290; Lilac)||Mar-19|
|RG7845||Roche||BTK inhibitor||NCT02908100 (241)||Jun-19|
|CC-220 (iberdomide)||Celgene||Immunomodulator||NCT02185040 (42)||Mar-18|
|BI 655064||Boehringer Ingelheim/Abbvie||Anti-CD40 MAb||NCT02770170 (120)||Aug-19|
|M2951||Merck KGaA||BTK inhibitor||NCT02975336 (432)||Dec-19|
|Cenerimod||Actelion||S1P 1 immunomodulator||NCT02472795 (64)||has results|
|NCT03161483 (280)||Not yet recruiting|
All these agents are attempting to control the autoimmune disease through immune suppression, although they are employing very different mechanisms to do so.
With anifrolumab, for example, Astra is targeting interferon alpha; by blocking the interferon alpha receptor rather than the ligand, it is hoped that signalling can be shut down more completely. The pivotal Tulip programme will report sometime next year – it is thought that the trials are close to being fully recruited.
Aurinia recently started dosing patients in Aurora, a phase III trial of voclosporin, a failed agent for immune suppression in organ transplant patients. Mixed phase II results mean hopes are muted (Aurinia suffers a headache with Aura, 15 August 2016).
Similarly, caution is warranted with the other late-stage agent, Lupuzor. Developer Immupharma said earlier this month that 200 patients had been successfully recruited, with results due early next year. However the project has a long and chequered development history – Teva handed back rights in 2011 and a new partner has never materialised.
Coming behind these agents are several promising new mechanisms. Like Astra, some are targeting highly inflammatory interferons, for example Biogen with BIIB059 – by engaging the BDCA2 receptor, the company hopes to show inhibition of the production of interferons and other inflammatory proteins. And Neovacs recently expanded its phase IIb trial of IFNα Kinoid to include US centres, after securing an IND from the FDA.
Elsewhere, Celgene’s CC-220 has received considerable attention and the company presented data from a small trial at EULAR this week, confirming the agent’s safety profile. The study was not powered to establish efficacy though the company touted “trends” towards improvements on multiple disease activity scores.
The agent works by inducing degradation of transcription factors called Aiolos and Ikaros, which are over-expressed in lupus patients. These transcription factors play a critical role at specific stages of B cell differentiation – lupus is thought to be largely mediated by autoreactive B cells, which cause long-term chronic inflammation.
The BTK inhibitors being developed by Roche and Merck KGaA are also acting directly on B cells – BTK is important for B cell development.
Alongside this focus specifically on B cells, several projects targeting T cells remain active. For example Boehringer started a phase II trial of BI 655064 last month – the antibody blocks CD40, a T cell target. And Bristol-Myers’ lulizumab targets the T cell-specific surface glycoprotein CD28. Results on this should emerge in the coming months though the company has said little about the project.
Meanwhile, the phase II pipeline could soon have another entrant in the shape of cenerimod, one of the assets to be developed by the Actelion spin out Idorsia. The company is about to start a large trial of the S1P1 immunomodulator, which works by reducing the availability of circulatory effector T and B cells.
Substantial unmet need in lupus means that an effective agent will be widely welcomed, whatever mechanism it uses. Unfortunately, history tells us that the success rate among these projects is likely to be low.