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13th December 2023
The recent UK approval of ruxolitinib for the blood cancer polycythaemia vera marks a significant milestone in tackling unmet need for an under-represented patient population. Here, consultant haematologist Professor Claire Harrison speaks to Rod Tucker about ongoing challenges for the condition’s management, how this latest approval will benefit patients and clinicians, and other key research in the pipeline.
Ruxolitinib is a Janus kinase 2 (JAK2) inhibitor with diverse indications covering conditions such as eczema, psoriasis, vitiligo and myelofibrosis.
Most recently, in the UK at least, it has been added to the treatment arsenal for the rare blood cancer polycythaemia vera (PV) after its recommendation in October 2023 by the National Institute for Health and Care Excellence (NICE).
Professor Claire Harrison, consultant haematologist, professor of myeloproliferative neoplasms at Guy’s and St. Thomas’ NHS Foundation Trust in London, UK, has dedicated much of the last decade to researching ruxolitinib for use in PV and was instrumental in securing NICE’s endorsement.
‘It’s [a good] example of following a scientific story from discovery of the mutation, development of the drug, testing it in a more severe but related condition (myelofibrosis) then putting it into second line for PV,’ she says.
Despite the approval, there’s still work to be done to achieve the next ambition of ruxolitinib being approved for first-line use in PV. And Professor Harrison is on hand to get the ball rolling.
Today, diagnosing PV is much easier than when Professor Harrison first started as a consultant in 2001.
Previously, the diagnosis was arrived at following a series of tests to exclude all other possible causes of a patient’s symptoms and abnormal blood count. But after the description of a JAK2 mutation which is present in 97–98% of patients with PV, the diagnosis can be arrived at much more quickly.
‘This particular mutation for which it’s very easy to test for. It’s a cheap test and, for the most part, if it’s present, the patient has either got PV or one of the family of conditions, or it has very low levels of mutations but is likely to change into that,’ Professor Harrison says.
In general, the lay perception of a cancer diagnosis is that it represents a death sentence, and it becomes difficult to assuage patients of this fear.
While PV is incurable and lowers life-expectancy, it is not usually life-threatening, although Professor Harrison says some patients do present with life-threatening blood clots.
‘It’s a cancer but some low-risk patients we just treat with aspirin and phlebotomy, so removing blood,’ she says. ‘So that’s quite tricky saying “you’ve got cancer, but all we’re going to give you is an aspirin and take a pint of blood off you”, and other patients we do give treatments to, but we have limited options.’
Moreover, while these treatments do provide a clinical benefit in some patients, they frequently fail to alleviate symptoms.
This has become abundantly clear from the findings of the ongoing prospective REVEAL study. This showed that patients with PV experience symptoms that affect their quality of life and lead to work productivity impairments with an overall negative impact on their lives.
‘So, 80% of patients will complain of fatigue,’ Professor Harrison says. ‘It’s PV, it’s not a nothing condition: 20% of patients have to give up work or reduce their working time, others do die of the condition and the average life-expectancy is probably 15 to 20 years.’
Professor Harrison also highlights poor awareness of PV. ‘What patients would say, probably, is that people don’t understand the condition, GPs don’t understand the condition and their employers don’t understand the condition. It takes up a lot of their time and it has a big burden on their quality of life.’
She hopes that greater awareness of the condition will make it easier for people to support and make adaptations for this patient group.
There haven’t been any new treatments for PV in around 20 years, with hydroxyurea and interferon alpha having long been the two options.
But that all changed with the description of the mutation. Professor Harrison says that after first helping with diagnosis, these learnings aided the development of drugs that could target the downstream effects of that mutation, principally JAK inhibitors.
‘These were first tested and used in more aggressive conditions in the family such as myelofibrosis. But with the advent of these drugs and their use in PV, we have been able to show that we can address some of the other unmet needs for patients,’ she says.
‘I could comment on how disappointing it is that the UK is five years behind the rest of Europe in the approval of ruxolitinib for PV, but I would prefer to celebrate that it’s a really important milestone for patients that they have an alternative therapy.’
This is particularly important as resistance or intolerance to treatments can develop in some patients, and there are other side effects and contraindications that mean traditional treatments may not be suitable.
‘An important side effect of hydroxyurea, which is also a side effect of ruxolitinib, is skin cancer,’ says Professor Harrison. ‘That’s something that we need to manage very carefully. If a patient has a skin cancer on hydroxyurea, we will sometimes change the therapy.
‘Interferon does cause quite serious mood disturbance – sometimes suicidal ideation – so it can’t really be used in patients who’ve got a significant history of anxiety or depression.
‘Similarly, [hydroxyurea] can’t be used for the 20% of patients below the age of 40 who might want to conceive a child. But we have the option to alternate between the first-line therapies.’
One of the key studies that led to the approval of ruxolitinib for PV in the UK was MAJIC-PV. This phase II trial, for which Professor Harrison was the lead author, randomised patients to either ruxolitinib or best available care in those intolerant or resistant to hydroxyurea, which is the current standard care therapy.
What was clear from MAJIC-PV was the superiority of ruxolitinib, with 43% of patients achieving a complete response based on several haematological criteria compared with only 26% of those receiving current best practice care.
While ruxolitinib does not cure PV, the MAJIC-PV trial provided reassurance that over five years no new longer-term safety issues emerged, Professor Harrison notes.
The trial also uncovered several additional biological actions of the drug. During the study, researchers measured the amount of abnormal JAK2 present in patients. This enabled clinicians to determine whether treatments had any effect on the aberrant mutations that were present.
Surprisingly, in those assigned ruxolitinib, there was a reduction in the level of this mutation.
As such, the MAJIC-PV study hinted at a mutation-specific effect of the drug which hadn’t previously been observed. Furthermore, this reduction in the level of abnormal JAK was associated with an increased life expectancy and a reduction in PV-related complications for patients.
‘Interestingly, when we were using the drug to treat patients with myelofibrosis, colleagues in Italy were reporting that their patients who had myelofibrosis but had the autoimmune condition alopecia, the hair was coming back,’ Professor Harrison adds. This hints at the wider benefits of ruxolitinib as an anti-inflammatory drug which is being harnessed in for example the treatment of eczema.
Delving deeper, Professor Harrison also describes how in research by colleague Adam Mead ruxolitinib appeared to modify PV at the stem cell level using research tools enaling the analysis of mutations at a single cell level.
Despite MAJIC-PV showing that ruxolitinib reduced levels of the abnormal JAK mutations, the current NICE approval recommends that the drug is used second-line for patients who either become resistant to or intolerant of hydroxyurea.
Notwithstanding this restriction, Professor Harrison still feels that it is important for patients to have access to ruxolitinib as another treatment option, either because of contra-indications or adverse effects from the currently available drugs.
Another consideration is the issue of drug resistance. ‘All of the available drugs are generally effective for the majority of patients, but over time, around 20–25% of patients will become resistant to that drug,’ she explains.
As a result, relying on a single drug isn’t the most effective way of controlling a patient’s blood count over time.
Encouraged by the findings from MAJIC-PV, a further phase III open-label trial, MITHRIDATE, for which Professor Harrison is the chief investigator, is starting to enrol patients.
It is designed to compare ruxolitinib with either hydroxyurea or interferon alpha as first-line therapy for high-risk PV patients.
Ruxolitinib also has a powerful effect on disease related symptoms for example patients with PV experience pruritus (itching) which can be extremely disabling, and the drug has a big impact on this troublesome symptom.
Although it is too early to draw any conclusions, Professor Harrison is hopeful that the MITHRIDATE trial will demonstrate the advantages of using ruxolitinib as a first-line treatment option and perhaps offer further insight into the drug’s disease-modifying properties.
While the introduction of JAK inhibitors such as ruxolitinib are a welcome addition to a clinician’s arsenal in the treatment of PV, Professor Harrison believes that future treatments need to focus on the off-target effects of these drugs such as immune suppression.
Although the development of JAK mutation-specific therapies in PV would be an advantage, Professor Harrison is of the opinion that it is just as important to improve understanding of how and when to use ruxolitinib in patients with PV.
Alongside the potential development of mutation-specific drugs, there is increasing interest in immune-mediated therapy.
‘I think we’ve had this massive step forward with description of molecular markers and therapies targeting JAK. We’ll probably go to treating PV earlier, and treating with a disease-modifying therapy,’ she concludes.
But focusing on the latest developments, Professor Harrison believes the introduction of innovations such as ruxolitinib would not have been possible without the support of various charities such as MPN Voice and Blood Cancer UK, as well as various academic centres and companies such as Novartis.
Working collaboratively, it has been possible to clearly demonstrate that ruxolitinib can go a long way towards helping to relieve the symptom burden of patients living with polycythaemia vera and improve quality of life for this under-represented patient population.
25th September 2023
The kinase inhibitor ruxolitinib (brand name Jakavi) has been recommended in draft guidance by the UK’s National Institute for Health and Care Excellence (NICE) for the treatment of patients with the blood cancer polycythaemia vera (PV), its manufacturer Novartis has announced.
The endorsement covers the approved oral indication of ruxolitinib for the treatment of PV in adults who are unable to tolerate the standard treatment of hydroxycarbamide, or when the condition is resistant to it.
Commenting on the approval, Dr Claire Harrison, consultant haematologist at Guy’s and St Thomas’ NHS Foundation Trust in London, said: ‘There is a significant unmet need for people with polycythaemia vera in England and Wales, who live with a large symptom burden as a result of their condition.
‘[This] decision is a step in the right direction for providing additional treatment options that reduce the burden of these symptoms and improve disease progression, in this under-represented patient population.‘
Jon Mathias, co-chair of MPN Voice – a charity that supports and advocates on behalf of PV patients – added: ‘We welcome this recommendation from NICE, as polycythaemia vera can be an extremely debilitating illness that has a significant impact on patients’ lives in terms of day-to-day symptoms.
‘It affects not only patients but also their families and carers and turns many everyday tasks into major hurdles. Ruxolitinib addresses a significant unmet need in patients who cannot tolerate or no longer respond to HC/HU.‘
In 2015, a phase 3 randomised trial showed that in patients with PV who had an inadequate response or unacceptable side effects from hydroxycarbamide, ruxolitinib was superior with respect to controlling the haematocrit, reducing the spleen volume and improving associated symptoms.
Moreover, ruxolitinib has also been shown to be efficacious and well tolerated in PV patients who were previously treated with interferon.
PV is rare blood cancer affecting the bone marrow. A myeloproliferative disorder, it involves uncontrolled red blood cell production resulting in an elevated red blood cell mass. The condition affects an estimated 1,130 people in the UK every year and the underlying cause of the disease is related to dysregulation of the JAK-STAT pathway. Typically, patients have an elevated haematocrit, leading to blood thickening, increasing the risk of blood clots, as well as higher white blood cell and platelet count.
Ruxolitinib is an inhibitor of the JAK 1 and JAK 2 tyrosine kinases and was recently approved in the UK in a topical form as a treatment for non-segmental vitiligo in adults and adolescents with facial involvement.
7th July 2023
Topical ruxolitinib has been approved by the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) for the treatment of non-segmental vitiligo in adults and adolescents with facial involvement.
The MHRA has granted marketing authorisation for ruxolitinib cream 15mg/g (brand name Opzelura) for treating patients from 12 years of age who have non-segmental vitiligo affecting facial areas.
The approval was based on the findings from two identical phase 3 trials TRuE-V1 and TRuE-V2, which evaluated the efficacy and safety of ruxolitinib cream compared to placebo in over 600 patients with non-segmental vitiligo.
Manufactured by Incyte, Opzelura is now the first and only approved treatment in the UK to offer eligible patients with non-segmental vitiligo support for repigmentation. The MHRA decision follows the European Commission approval in April 2023 and FDA approval in July 2022.
Dr Viktoria Eleftheriadou, consultant dermatologist and lead for vitiligo clinic and research, Walsall Healthcare NHS Trust and The Royal Wolverhampton NHS Trust, said: ‘The MHRA approval is welcome news for dermatologists and people with vitiligo seeking treatment who until now have had limited options. The data supporting this approval demonstrate the potential for ruxolitinib cream to make a difference in the lives of people living with this condition.’
Founder and chief executive officer of the charity Vitiligo Support UK Emma Rush added: ‘While more and more people are proud of their vitiligo, there are still so many people who don’t feel comfortable in their skin. This new treatment option provides a choice for those who wish to treat their condition.’
Voicing the manufacturer’s delight at the approval, Peter Williams, general manager at Incyte UK and Ireland, said: ‘We are now working in partnership with the NHS to ensure that eligible patients seeking to treat their vitiligo are able to access this innovative medicine.’
The combined results of the two randomised, double-blind, vehicle-controlled trials were published as a single paper in the New England Journal of Medicine in October 2022. Both included patients aged 12 years or older who had non-segmental vitiligo with depigmentation covering 10% or less of total body-surface area.
Patients were randomly assigned in a 2:1 ratio to apply 1.5% ruxolitinib cream or vehicle control twice daily for 24 weeks to all vitiligo areas on the face and body, after which all patients could apply 1.5% ruxolitinib cream through to week 52.
The primary end point was an improvement of at least 75% from baseline in the facial Vitiligo Area Scoring Index (F-VASI75), which ranges from 0 to 3, with higher scores reflecting a greater area of facial depigmentation.
A combined total of 674 patients, 330 in TRuE-V1 and 344 in TRuE-V2, were randomised to ruxolitinib. After 24 weeks of therapy, a F-VASI75 response occurred in 29.8% of those taking ruxolitinib in TRuE-V1 compared to 7.4% of those assigned the vehicle control (p < 0.001). Similarly, in TRuE-V2, 0.9% of those receiving ruxolitinib cream achieved a F-VASI75 response (p < 0.001) compared to 7.4% in the vehicle group.
Around one in 100 people in the UK develop vitiligo, with eight in 10 suffering from the non-segmental vitiligo, where both sides of the body are affected by symmetrical white patches. The treatment is approved for twice-daily topical use to the depigmented skin areas up to a maximum of 10% body surface area. Satisfactory re-pigmentation may require treatment with ruxolitinib cream for more than 24 weeks.
31st October 2022
Topical ruxolitinib produces significantly greater re-pigmentation over 52 weeks compared to placebo in patients with non-segmental vitiligo according to the combined results of two randomised, double-blind, placebo-controlled trials by researchers from the TRuE-V study Group.
Vitiligo describes an autoimmune disease in which there is progressive destruction of melanocytes in the skin leading to patchy depigmentation and the condition has an estimated prevalence of 0.5% in the general population.
Due to the visible nature of vitiligo, not surprisingly, patients experience a reduction in many aspects of quality of life including feelings of stigmatisation, adjustment disorders, sleep disturbance, relationship difficulties and avoidance or restriction behaviour.
Studies suggest that active vitiligo peri-lesional skin is characterised by prominent type 1 and 2 associated immune responses and induces melanocyte dysfunction and an epidermal inflammatory response through Janus Kinase signalling.
In fact, in a phase 2 trial, use of topical ruxolitinib was associated with substantial re-pigmentation of vitiligo lesions up to 52 weeks of treatment. Based on these early positive data, in the current study, researchers undertook two identical, randomised, double-blind, placebo-controlled trials, Topical Ruxolitinib Evaluation in Vitiligo Study 1 (TRuE-V1 and 2 (TRuE-V2), using a formulation containing 1.5% ruxolitinib.
Individuals 12 years of age and older with non-segmental vitiligo (i.e. where symptoms are bilateral) and depigmentation covering 10% or less of their body surface area and at least 0.5% of the body surface area of the face, were enrolled and randomised, 2:1 to topical ruxolitinib 1.5% or a matching placebo. Treatments were applied twice daily for 24 weeks to all affected areas and after this point, all of the patients were eligible to apply the active treatment up until week 52.
The study primary endpoint was a 75% reduction (i.e., improvement) from baseline in the facial vitiligo area scoring index (F-VASI), which ranges from 0 to 3 and where higher scores are indicative of greater facial depigmentation. The primary outcome was assessed at week 24 and secondary endpoints included a F-VASI50 and F-VASI90.
Topical ruxolitinib and improvement of vitiligo
A total of 330 patients with a mean age of 40.2 years (56.4% female) were enrolled in TRuE-V1, of whom, 221 received ruxolitinib. There were 343 participants randomised in TRuE-V2 with a slightly lower mean age (38.9 years, 50.1% female). The baseline mean F-VASI score was 0.95 in TRuE-V1 and 0.88 in TRuE-V2.
In TRuE-V1 the primary outcome was achieved by 29.8% of those receiving ruxolitinib and 7.4% of those using placebo (relative risk, RR = 4, 95% CI 1.9 – 8.4, p < 0.001). Similarly, in TRuE-V2, there was a significant difference between the active and placebo arms (RR = 2.7, 95% CI 1.5 – 4.9, p < 0.001).
For the secondary outcomes, in TRuE-V1, 15.3% of those assigned to ruxolitinib achieved a F-VASI90 (i.e., 90% improvement in score from baseline) compared to only 2.2% of placebo patients.
In terms of safety, mild or moderate adverse events occurred in a similar proportion of ruxolitinib patients in both trials when assessed up to 52 weeks (54.8% and 62.3%). The most common adverse events in ruxolitinib patients were application site acne (6.3%) and application site pruritus (5.4%).
The authors concluded that topical ruxolitinib was superior to placebo for re-pigmentation in vitiligo, adding that longer trials were needed to determine the effect and risks of ruxolitinib in vitiligo.
Citation
Rosemarin D et al. Two Phase 3, Randomized, Controlled Trials of Ruxolitinib Cream for Vitiligo N Eng J Med 2022.
28th July 2022
Ruxolitinib cream has been approved by the US Food and Drug Administration for the treatment of non-segmental vitiligo, the manufacturer Incyte has announced.
Ruxolitinib is a Janus kinase inhibitor and the cream has already shown anti-inflammatory and prompt antipruritic effects in the management of patients with atopic eczema.
The FDA decision to approve ruxolitinib (brand name Opzelura) was based on the findings of two clinical trials, TRuE-V1 and TRuE-V2. Both were similar in design and evaluated the efficacy and safety of ruxolitinib cream in adolescent (12 years and older) and adult participants with non-segmental vitiligo for whom the vitiligo involved area (facial and non-facial) did not exceed 10% of their body surface area (BSA).
In each of the trials, participants were randomised received ruxolitinib cream 1.5% or vehicle for 24 weeks which was applied twice daily. Following on from the initial 24 week period, participants were offered the opportunity to continue in the treatment extension arm for up to 52 weeks.
The primary endpoint for both trials was the facial Vitiligo Area Scoring Index (F-VASI75) and a 75% improvement from baseline in the F-VASI (F-VASI75) has been identified as within-patient clinically meaningful thresholds.
A dose ranging Phase II randomised trial did provide evidence for the effectiveness of the treatment. In the trial, 157 patients (mean age, 48·3 years, 46% male), with depigmentation of 0·5% or more of their facial body surface area (BSA) and 3% or more of their non-facial BSA, were randomised 1:1:1:1 to receive ruxolitinib cream (1·5% twice daily, 1·5% once daily, 0·5% once daily, or 0·15% once daily) or vehicle twice daily.
The primary endpoint was a F-VASI50 after 24 weeks and this was achieved after 24 weeks by 45% of patients using the 1.5% cream twice daily and 50% of those using the same strength once daily compared to only 3% receiving placebo.
Although the results of TRuE-V1 and V2 are not yet published, the manufacturer reports that after 24 weeks, approximately 30% of patients using ruxolitinib cream achieved the primary endpoint compared with approximately 8% of those using the vehicle in TRuE-V1 and 13% in TRuE-V2.
Additionally, after 24 weeks, more than 15% of those receiving ruxolitinib cream achieved a F-VASI90 (i.e., 90% improvement from baseline), compared to approximately 2% of patients treated with vehicle. At week 52, approximately 50% of ruxolitinib cream patients achieved the primary endpoint and 30% had achieved a F-VASI90.
Vitiligo has two main types, non-segmental and segmental with the former being symmetrical, whereas the latter is more localised. Non-segmental vitiligo is the more common form and accounts for 85–90% of cases.
Ruxolitinib cream has yet to be approved by the European Medicines Agency, but it is currently under review by the organisation.
26th October 2021
Biopharmaceutical company Incyte has been granted approval by the FDA for Opzelura™ (ruxolitinib) cream, the first, topical janus kinase (JAK) inhibitor used in the treatment of mild to moderate atopic dermatitis (AD). More specifically, Opzelura™ can be used for the short-term and non-continuous, chronic treatment of AD in non-immunocompromised patients, 12 years of age and older whose disease is not adequately controlled with topical prescription therapies. The importance of inhibition of JAK is based on the fact that the janus kinase (JAK)-signal transducer and activator of transcription (STAT), or JAK-STAT pathway, has been shown to play an essential role in the dysregulation of immune responses in AD. Although there are four separate JAK-STAT pathways, ruxolitinib, is a selective inhibitor of only JAK1 and JAK2, effectively suppressing the cytokine signalling involved in AD pathogenesis.
Clinical efficacy
The efficacy of ruxolitinib was examined in a 2020 study among adult patients with mild to moderate AD. Participants were randomised for 8 weeks to three different strengths of ruxolitinib; 1.5% cream, applied twice daily or once daily, a 0.5% and 0.15% cream, vehicle or triamcinolone cream 0.1% applied twice daily for 4 weeks, then vehicle for 4 weeks.
The results showed that all concentrations of ruxolitinib were more effective after 4 weeks than placebo, the greatest improvement occurred with the 1.5% strength, based on an improvement in the Eczema Area and Severity Index (71.6% vs 15.5%; ruxolitinib vs placebo, p < .0001). Interestingly, the authors of the study reported that use of ruxolitinib 1.5% both once a twice daily produced a numerically greater improvements compared with triamcinolone after 4 weeks but that the difference was not statistically significant.
Based on these early finding, the company conducted two phase 3, randomised, placebo-controlled trials comparing topical ruxolitinib 0.75% and 1.5% in patients 12 years and over with mild to moderate AD. The primary outcome was Investigator’s Global Assessment treatment success at week 8 (i.e., an investigator’s Global Assessment score of 0/1 and ≥2-grade improvement from baseline). The results were published in May 2021 and showed that significantly more patients achieved the primary outcome at week 8 with 0.75% ruxolitinib (50.0% vs 15.1%, ruxolitinib vs placebo) and 1.5% ruxolitinib (53.8% and 7.6%), both with p < 0.001.
The company have now released data on the trial’s secondary outcomes which included the proportion of participants with at least a 4-point improvement in the itch Numerical Rating Scale (NRS), and the proportion of participants with at least a 6-point improvement in the Patient-Reported Outcomes Measurement Information System (PROMIS) Short Form. The latest data release show that 20.9% and 23.8% of patients using 0.75% and 1.5% topical ruxolitinib achieved a greater than 6-point improvement in sleep scores. Similarly, 41.5% and 51.5% using the 0.75% and 1.5% creams had at least a 4-point improvement in NRS.
Now that ruxolitinib has been approved by the FDA, the company intends to seek EMA approval.
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