A pipeline of new drugs for giant cell arteritis is creating a more optimistic outlook.
The ongoing shortage of the monoclonal antibody tocilizumab, as a result of global demand for its use as a therapy for severe covid, has drawn into sharp focus the lack of treatment options for patients with giant cell arteritis (GCA).
But with several clinical trials under way, the outlook for this vasculitis, which affects about 1,000 Australians each year, is looking more promising.
Tocilizumab has become a really important therapy for giant cell arteritis patients, says Professor Philip Robinson from the University of Queensland, who is a senior rheumatology specialist at the Royal Brisbane and Women’s Hospital.
“Prior to tocilizumab, there was little alternative for giant cell arteritis patients apart from glucocorticoids, occasionally with methotrexate,” he said, adding that not only did this treatment have high relapse rates, it could also be difficult to manage in elderly patients who often had a range of other conditions including diabetes and cardiovascular disease.
“But tocilizumab is an effective therapy for GCA, and the issue for GCA patients is that without effective treatment, they go blind, and they can’t get that eyesight back.”
Combination tocilizumab and glucocorticoid treatment schedules over 52 weeks were associated with a sixfold reduction in GCA relapse.
Professor Robinson says that GCA is the most common vasculitis that most rheumatologists will treat, and he sees new cases each week of this autoimmune inflammation affecting arterial blood vessels.
“Without access to tocilizumab, we need to treat GCA patients with more glucocorticoids, which have more adverse events,” he said.
High-dose glucocorticoid use is also risky during the current pandemic, as it might raise the rate of severe covid to around 20%.
Filling the gaps as more tocilizumab supply comes on board
Dr Claire Barrett, who is vice-president of the Australian Rheumatology Association (ARA), nominated two upcoming therapies of interest in the near future for GCA patients.
These are mavrilimumab, a GM-CSF inhibitor, and ustekinumab, an IL12/23 inhibitor and a treatment that Australian rheumatologists are very familiar with in treating psoriatic arthritis.
But for current GCA patients, low supply is a right-now issue – she says the ARA has been promised adequate supply for patients with juvenile idiopathic arthritis (JIA) and GCA and is working with the TGA and tocilizumab supplier Roche to make that happen.
“From 25 October until 5 November the supply of the tocilizumab pre-filled syringe will be extremely low and hence ARA, TGA and Roche have established a process where interruptions of access to PBS-funded treatment will be managed with the offer of sample packs of the subcutaneous doses of tocilizumab to ensure continuity of treatment for existing patients,” said Dr Barrett.
“All rheumatologists have been made aware that the supply of sample packs is to be conserved for patients who are in immediate need of their next treatment dose. Supply will also be prioritised for patients with GCA and JIA, where no or very few alternative treatments are available.”
Dr Barrett says that Roche has indicated that tocilizumab supplies will improve after the first week of November.
Clinical trials an option for some GCA patients
“A GCA diagnosis is typically an emergency, because patients are at risk of blindness or stroke,” said ARA President Professor Catherine Hill.
Since the TGA approved tocilizumab for use in GCA in 2017, the standard treatment for GCA involves a high-dose glucocorticoid such as prednisolone to suppress inflammation, with tocilizumab introduced within the first six weeks, allowing more rapid tapering.
Professor Hill pointed out that while PBS-funded support for tocilizumab expires after 52 weeks, more than half of GCA patients remain in symptom remission after the treatment regime.
“For those that have a relapse after that year, it can be difficult to get more tocilizumab without patients self-funding unless we ask the company for compassionate supply,” she confirmed.
A sub-group of GCA patients can be well maintained on alternate weekly doses of tocilizumab, which can also help clinicians conserve tight supplies until shortages are addressed, she says.
Professor Hill noted that Australian rheumatologists might not realise that their GCA patients are well served with access to tocilizumab compared with the UK – where tocilizumab is approved only for GCA patients who relapse and involves attending a committee meeting to request access – and New Zealand, where there’s no current access to tocilizumab.
For patients that relapse, or experience known adverse events from tocilizumab use – including abnormal liver function, rising cholesterol and even bowel perforation – there are few options. There has therefore been a great deal of interest in new treatments under investigation.
Professor Hill has offered her GCA patients the option of participating in an international clinical trial of upadacitinib that is running across 24 countries, including six Australian sites.
Four in five patients on the trial receive the clinical trial drug over the placebo, she adds, making this a viable option for some patients.
New biologic mavrilimumab avoids inflammation masking in blood tests
Professor Ian Wicks, head of the Clinical Translation Inflammation division at the Walter and Eliza Hall Institute of Medical Research, is involved in an international phase 2 trial of the monoclonal antibody mavrilimumab.
The research investigated the utility of mavrilimumab in enabling clinicians to assess GCA disease activity through monitoring patient blood levels of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), both of which can be masked by tocilizumab use.
“We initially looked at mavrilimumab in the context of a treatment for rheumatoid arthritis, where it had promising results,” he said.
Market considerations led to a change in ownership for the drug, with the new company now targeting the far-less crowded market of GCA, where there is an unmet treatment need.
Professor Wicks says that there are some lingering concerns that because tocilizumab acts on the acute phase response to GCA by blocking the interleukin-6 pathway, the underlying disease might not always be switched off – but the only way to monitor remission status is through symptom return, because tocilizumab masks blood levels of ESR and CRP.
This is not the case with mavrilimumab, he says; patients who relapsed also showed increased blood levels of ESR and CRP.
“The trial was designed with a treatment regime similar to the way tocilizumab is used, so that mavrilimumab is added in as steroids are tapered, and serves to stop symptoms from flaring,” he said.
“GCA patients are in an age cohort where reducing cumulative steroid exposure is necessary, as comorbidities are common and can include diabetes, cardiovascular disease, osteoporosis, cataracts and so on – none of which are conducive to high steroid use.”
Professor Wicks says that mavrilimumab has also been looked at as a potential therapy in severe covid-19, suggesting that it acts on an inflammation pathway that might operate across a range of disorders.
“The study also showed that mavrilimumab is well tolerated; this is reassuring as there is collectively quite a lot of patient experience,” he added.
However, with clinical trials of mavrilimumab in GCA now complete, there is still an approvals process to go through – so it is safe to assume it could be a few years before clinicians are able to access the treatment for their patients.
In the pipeline: other biologics
A recent review by Dr Patricia Harkins and Dr Richard Conway, of St Vincent’s University Hospital in Dublin, explored upcoming GCA therapies. They cited 10 ongoing randomised controlled trials of potential GCA therapies expected to be completed between March 2021 and March 2026.
Of the 10, the authors cited mavrilimumab, ustekinumab (an IL-12/23 inhibitor) and abatacept (a T-cell modulator) as showing early promise in achieving GCA remission.
Ustekinumab is a monoclonal antibody that inhibits IL-12 and IL-23 mediated effects including Th1 and Th17 immune responses – both implicated as playing an important role in GCA.
While two ustekinumab trials – one comprising 25 refractory GCA patients, the other, 10 patients – reported contradictory results, the authors suggest a larger trial under way, completing in Jun 2021, will provide more clarity on appropriate patient cohorts.
Another promising therapy is abatacept, a small-molecule fusion protein that inhibits T cell activation and which is licensed in rheumatoid arthritis and juvenile idiopathic arthritis. A double-blind trial with 49 patients found that abatacept users showed longer remission times than those receiving the placebo.
And in presentations at the 2021 ACR Convergence, there were positive findings for small trials of secukinumab and baricitinib.
Reason for optimism
“At the moment, if GCA patient symptoms are not in remission after 52 weeks treatment, we get into a bit of difficulty,” said Professor Catherine Hill.
However, she says, the range of new drugs coming down the pipeline means that the outlook for managing GCA patients in the future is looking positive.
