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Articles
Safety in Lactation: Protein kinase inhibitors
23 September 2020Protein kinase inhibitors, whether used as monotherapy or in combination with other antineoplastics, are contra-indicated in breastfeeding because of their effects on dividing cells and…
Lactation Safety Information
No published evidence of safety
Serious adverse effects reported in adults
22 September 2020
New Medicines
Jakavi (EU), Jakafi (US) Acute graft versus host disease (GvHD) in patients aged 12 years and older
Information
Jakavi (EU), Jakafi (US)
Licence extension / variation
Novartis
Incyte
Development and Regulatory status
Launched
Launched
Launched
Yes
May 22Approved in EU for the treatment of patients aged 12 years and older with acute or chronic GVHD who have inadequate response to corticosteroids or other systemic therapies [21].
Mar 22Licence extension approved in the UK. The new indication is ´Jakavi is indicated for the treatment of patients aged 12 years and older with acute graft versus host disease who have inadequate response to corticosteroids´ [20].
Mar 22Recommended for EU approval by CHMP “treatment of patients aged 12 years and older with acute graft versus host disease or chronic graft versus host disease who have inadequate response to corticosteroids or other systemic therapies.” [19].
Jul 21Has orphan drug status in US for treatment of steroid-refractory acute GVHD in adult and pediatric patients 12 years and older [18].
Apr 21Novartis has filed in the EU during Q1 2021 for acute and chronic GvHD [17].
Mar 20EU filing planned for 2021 [14].
May 19US FDA announced approval of ruxolitinib for treatment of steroid-refractory acute GVHD in pts aged 12 years and older.[12]
Dec 18Planned filing date (presumably EU) is 2020 [11].
Oct 18US FDA grants Priority Review for ruxolitinib as a treatment for patients with acute GVHD who have had an inadequate response to corticosteroids. The submission is based on data from the REACH1 study [10].
Jun 18Following positive data from REACH 1, Incyte announced plans to file a sNDA for the approval of ruxolitinib to treat steroid-refractory acute GVHD with the US FDA during Q3 2018.[8]
Dec 17Filings now expected 2020 [7].
Mar 17Novartis plans to file in 2019 [6].
Jun 16Incyte announce that the FDA has granted Breakthrough Therapy designation for ruxolitinib for treatment of patients with acute graft versus host disease (GVHD) [1].
Category
JAK1 and JAK2 inhibitor
Incidence of acute GVHD after bone marrow and stem cell transplant varies widely, between 10% and 80% depending on risk factors. It is a prominent cause of death in recipients of such transplants [3].
Acute graft versus host disease (GvHD) in patients aged 12 years and older
Oral
Further information
Yes
Trial or other data
Nov 20Acute GVHD is a major cause of morbidity and mortality after bone marrow or stem-cell transplantation. There are a number of accepted treatments, including systemic corticosteroids, calcineurin inhibitors, and extracorporeal photopheresis, however there are few reported randomised controlled trials and evidence for many of the treatments used is limited [4, 5]. This first-in-class JAK1/JAK2 inhibitor is the first FDA-approved treatment for this indication [12].
Jul 20Incyte announces PIII REACH3 study meets primary endpoint [16].
Apr 20The REACH2 RCT (n=309) found that ruxolitinib therapy led to significant improvements in overall response at day 28 compared to control group (62% vs. 39%; OR 2.64; 95% CI, 1.65 to 4.22; p<0.001) with a higher incidence of thrombocytopenia, the most frequent toxic effect [15].
Oct 19PIII REACH2 trial meets primary endpoint of improved overall response rate (ORR) at day 28 with ruxolitinib vs best available therapy [13].
Jun 18Data for pivotal PIII studies in steroid-refractory acute GVHD (REACH2) and steroid-refractory chronic GVHD (REACH3) are expected in 2019.[8]
Jun 18The REACH 1 trial, evaluating ruxolitinib (Jakafi®) + corticosteroids for treatment of steroid-refractory acute GVHD met its primary endpoint. REACH 1 is a single-cohort, pivotal PII study (NCT02953678) which demonstrated an overall response rate (ORR) of 55% (n=39/71) at Day 28 and the best overall response rate (BORR), i.e. the no of pts achieving a response at any time point during the study, was 73% (n=52/71). The most common treatment-emergent adverse events of any grade were anemia (61%), thrombocytopenia (61%) and neutropenia (56%).[8]
Feb 17PIII REACH2 study to evaluate the safety and efficacy of ruxolitinib compared to Best Available Therapy in patients with corticosteroid-refractory acute graft vs. host disease after allogeneic stem cell transplantation (NCT02913261). 308 patients aged 12 years and older will be recruited from Europe (including UK) and other countries around the world, except the US. Primary outcome is overall response rate; collection of these data due to complete June 19 [9].
Jun 16 Incyte intend to initiate a pivotal PIII study during the second half of 2016 [2].
Evidence based evaluations
Jakavi (EU), Jakafi (US) Chronic graft versus host disease (GvHD) in patients aged 12 years and older
Information
Jakavi (EU), Jakafi (US)
Licence extension / variation
Novartis
Incyte
Development and Regulatory status
Launched
Launched
Launched
May 22Approved in EU for the treatment of patients aged 12 years and older with acute or chronic GVHD who have inadequate response to corticosteroids or other systemic therapies [18].
Mar 22Licence extension approved in the UK. The new indication is ´Jakavi is indicated for the treatment of patients aged 12 years and older with chronic graft versus host disease who have inadequate response to corticosteroids´ [17].
Mar 22Recommended for EU approval by CHMP “treatment of patients aged 12 years and older with acute graft versus host disease or chronic graft versus host disease who have inadequate response to corticosteroids or other systemic therapies.” [16].
Sep 21Company announces FDA has approved ruxolitinib to treat chronic graft-versus-host disease based on positive results from PIII REACH3 trial [16]
Jun 21To allow time for review of additional data, the FDA has extended the review period for ruxolitinib (Jakavi) by 3 months. The new PDUFA target action date is September 22, 2021 [12].
Apr 21Novartis has filed in the EU during Q1 2021 for acute and chronic GvHD [13].
Feb 21Filed in the US with priority review status for the treatment of steroid-refractory chronic graft-versus-host disease (GVHD) in adult and paediatric patients 12 years and older. PDUFA date set for 22 July 2021 [11].
Jan 21Filings for chronic (and acute) GvHD in EU and Japan planned for H1 21 [10].
Mar 20Filings planned for 2021 [8].
Dec 18Filings remain on course for 2020 [5].
Dec 17Filings planned for 2020 [3].
Category
JAK1 and JAK2 inhibitor
This is an important entity and a major cause of late non-relapse death after haematopoietic cell transplantation. It is recommended that all patients be scored initially at three months post-transplant and every three months thereafter if they are diagnosed with GvHD. There are two aspects to the scoring, resulting in a classification of mild, moderate and severe chronic GvHD [1]. Incidence rates range from 6 to 80%, depending upon presence of risk factors and diagnostic criteria used [2].
Chronic graft versus host disease (GvHD) in patients aged 12 years and older
Oral
Further information
Yes
Trial or other data
Jul 21REACH3 RCT (n=329) found overall response at week 24 was greater in the ruxolitinib group than in the control group (49.7% vs. 25.6%; OR 2.99; p<0.001) but incidence of thrombocytopenia and anaemia was greater with ruxolitinib [14].
Jul 20Topline data from PIII REACH3 trial show ruxolitinib has superior overall response rate (ORR) at week 24 in patients with moderate or severe steroid-refractory or steroid dependent chronic graft versus host disease (GVHD), compared to best available treatment. This was the primary efficacy endpoint. Two key secondary endpoints, failure-free survival and patient reported symptoms based on a modified Lee chronic GVHD symptom scale, were superior for ruxolitinib compared to best available treatment [9].
Dec 19Estimated primary completion date for NCT03112603 has moved back to March 2020, but filings remain on course for 2020 [6,7].
Jun 17PIII REACH-3 study assessing the efficacy of ruxolitinib against best available therapy in steroid refractory chronic Graft versus host disease in patients 12 years and older starts (NCT03112603). 324 patients will be recruited globally including in the US & EU (plus UK). Primary outcome is overall response rate; collection of these data is due to complete Jul 19 [4].
Evidence based evaluations
OpzeluraShort-term treatment of mild to moderate atopic dermatitis (AD) - topical formulation
Information
Opzelura
New formulation
Incyte
Incyte
Development and Regulatory status
Phase III Clinical Trials
Phase III Clinical Trials
Launched
Oct 21Launched in the US [18]
Sep 21US FDA approves ruxolitinib cream the short-term and non-continuous chronic treatment of mild to moderate AD in non-immunocompromised pts aged ≥ 12 years whose disease is not adequately controlled with topical therapies or when those therapies are not recommended. [17]
Jul 21Despite recent safety concerns for JAK inhibitors as a class, the FDA review panel has voted 12-1 in favour of approval of topical ruxolitinib for atopic dermatitis, with final decision expected Sep 21 [16].
Jul 21Incyte has yet to decide on its plans for filing in the UK [15].
Jun 21To allow time for review of additional data, the FDA has put off its decision for ruxolitinib cream in atopic dermatitis by three months, making the drug´s new decision date Sep 2021 [14].
Feb 21the FDA has accepted for Priority Review the New Drug Application (NDA) for ruxolitinib cream as a treatment for atopic dermatitis [12].
Apr 20The 2019 Incyte Annual Report states that they plan to file an NDA seeking approval of ruxolitinib cream with the FDA before the end of 2020. Plans for Europe are not stated [9].
Nov 19till listed as PIII in Incyte pipline [6].
Jun 18Preparations are underway for a global, pivotal PIII program [3].
Category
JAK inhibitor
In adults, population studies report an overall prevalence of 2-18%, in children around 20% [2].
Short-term treatment of mild to moderate atopic dermatitis (AD) - topical formulation
Topical
Trial or other data
Sep 21FDA approval was based on data from the TRuE-AD1 and TRuE-AD2 studies (n >1,200). Ruxolitinib demonstrated significantly clearer skin and itch vs. placebo (non medicated vehicle cream). In TRuE-AD1 and TRuE-AD2, 53.8% and 51.3% hit the Investigator’s Global Assessment (IGA) Treatment Success (IGA-TS, primary endpoint) vs. 15.1% and 7.6% with plaecbo respectively. The most common drug related side effects due to ruxolitinib were nasopharyngitis, diarrhea, bronchitis, ear infection, increased eosinophil count, urticaria, folliculitis, tonsilitis and rhinorrhea.[17]
Apr 21Incyte have announced findings from three pooled analyses of TRuE-AD1 and TRuE-AD2, presented as part of the American Academy of Dermatology Virtual Meeting Experience 2021. Across all analyses, the overall safety profile of ruxolitinib cream was consistent with previously reported data and no safety signals were observed [13].
Nov 20The 44-week long-term safety and efficacy portion of both the TRuEAD1 and TRuE-AD2 trials are ongoing [11].
Oct 20Pooled data from TRuE-AD1 and TRuE-AD2 will be presented as part of the 29th European Academy of Dermatology and Venereology; the data reinforce that treatment with ruxolitinib cream resulted in a rapid, substantial and sustained reduction in itch; and improved the extent and severity of AD as measured by the Eczema Area Severity Index (EASI) and Scoring Atopic Dermatitis (SCORAD) assessment tools [10].
Apr 20both PIII studies TRuE-AD1 and TRuE-AD2 met the primary endpoint. Significantly more patients treated with ruxolitinib cream 0.75% BID [50.0% and 39.0% respectively] and 1.5% BID [ 53.8% and 51.3%] achieved IGA-TS compared to vehicle [non-medicated cream [15.1% and 7.6%]; P < 0.0001. Additionally, a significant proportion of patients treated with ruxolitinib cream 0.75% BID [56.0% and 51.5%] and 1.5% BID [62.1% and 61.8% respectively] achieved EASI75 at Week 8 compared to vehicle [24.6% and 14.4%], P < 0.0001. Significantly more patients treated with ruxolitinib cream experienced a clinically meaningful reduction in itch (NRS4) than patients given vehicle at Week 8, compared to patients given vehicle (P < 0.001 and P < 0.0001 respectively) [8].
Jan 20Incyte announce results from PIII TRuE-AD2 trial show ruxolitinib is superior to placebo by at least 2 points in the Investigator’s Global Assessment Treatment Success score [7].
Nov 19Primary completion date for PIII TRuE-AD1 is December 2019; primary completion date for PIII TRuE-AD2 is November 2019 [5].
Dec 18first patient treated in the Phase 3 TRuE-AD clinical trial program (NCT03745638 and NCT03745651) [4].
Sep 18PIIb dose-ranging, vehicle- and active-controlled study evaluated ruxolitinib cream in patients with atopic dermatitis found that ruxolitinib cream 1.5% BD significantly improved Eczema Area and Severity Index (EASI) scores from baseline versus vehicle control at Week 4 [1].
OpzeluraNon-segmental vitiligo that does not exceed 10% body surface area (BSA), in patients aged 12 years and older
Information
Opzelura
New formulation
Incyte
Incyte
Development and Regulatory status
None
Pre-registration (Filed)
Launched
Jul 22Available in the US, with a $1,950 list price for a 60-g tube [11].
Jul 22Company announces FDA has approved ruxolitinib 1.5% cream for the topical treatment of the nonsegmental vitiligo in adults and children 12 years of age and older. The drug is approved for continuous topical use twice a day to affected areas of up to 10% of body surface area. Treatment may require more than 24 weeks for a satisfactory response [10]
Mar 22In the US, the FDA has extended the review period for the sNDA for ruxolitinib cream for treatment of vitiligo by 3 months to Jul 18, 2022. The extension is to allow time to review additional data from the ongoing PIII studies submitted by Incyte in response to the FDA’s information request [8].
Dec 21Incyte announces that the FDA has accepted for Priority Review the the supplemental New Drug Application (sNDA) for ruxolitinib cream as a potential treatment for adolescents and adults (age ≥12 years) with vitiligo. The Prescription Drug User Fee Act (PDUFA) target action date is April 18, 2022 [7]
Oct 21Filed in the EU treatment for treatment of adolescents and adults (age >12 years) with non-segmental vitiligo with facial involvement [6].
May 21Filings for approval in US and EU are planned for the second half of 2021[4].
Category
JAK inhibitor, applied twice daily.
It occurs in about 0.5-2% of the population. It is more obvious - and therefore reported more in dark-skinned races - but no more prevalent. It is also diagnosed more frequently in women, although sex distribution is in fact equal. It affects all age groups but in more than half of cases, onset is before the age of 20 [1].
Non-segmental vitiligo that does not exceed 10% body surface area (BSA), in patients aged 12 years and older
Topical
Further information
Yes
Trial or other data
Mar 22Incyte announce new 52-week results from PIII TRuE-V trials. At Week 52, approximately 50% of patients achieved ≥75% improvement in the facial Vitiligo Area Scoring Index (F-VASI75) compared to the F-VASI75 improvement from baseline reported for these patients at Week 24 (the primary endpoint of the study) which was approximately 30%. At Week 52, approximately 75% of patients achieved ≥50% improvement in F-VASI (F-VASI50), and nearly one-third (approximately 30%) achieved ≥90% improvement in F-VASI (F-VASI90) compared to the Week 24 response rates for F-VASI50 and F-VASI90 which were approximately 51% and 15%, respectively [9]
Oct 21In PIII TRuE-V1 and TRuE-V2 PIII studies (n=300), 29.9% of patients applying 1.5% ruxolitinib cream twice daily achieved primary endpoint at week 24 [5].
May 21Incyte announces PIII trials of ruxolitinib cream have met their primary endpoints. In TRuE-V1 and TRuE-V2 facial vitiligo improved by 75% or more at week 24 in patients treated with ruxolitinib [4].
Nov 20PIII long-term efficacy and safety trial is recruiting; it started in Sep 20 (NCT04530344;INCB 18424-308). This double-blind, vehicle-controlled, randomised trial will recruit 500 patients in the US. The purpose of this study is to evaluate the duration of response following withdrawal of ruxolitinib cream (Cohort A vehicle group), safety and maintenance of response with continued use of ruxolitinib cream in participants who have completed either Study NCT04052425 or NCT04057573 (parent studies) in which the participants will have been using ruxolitinib cream BID for the previous 28 to 52 weeks depending on their initial randomization in the parent study. Due to complete collection of primary outcome data in Jan 24 [2].
Nov 20Enrolment completes in the TruE-V1 and TRuE-V2 trials [2].
Sep 19PIII TRuE-V2 trial to evaluate safety and efficacy of ruxolitinib cream followed by an extension period in children, adolescents and adult patients with vitiligo starts (NCT04057573; INCB 18424-307). 344 patients will be recruited in Bulgaria, Canada, France, Germany, Italy, the Netherlands, Poland, Spain and the US. Primary outcome is ≥ 75% improvement from baseline in Face Vitiligo Area Scoring Index (F-VASI) score; collection of these data is due to complete Apr 21 [2].
Sep 19Incyte Corporation initiates the PIII TRuE-V1 trial to evaluate safety and efficacy of ruxolitinib cream followed by an extension period in patients with vitiligo (NCT04052425; INCB 18424-306). The randomised, double-blind trial will enrol 330 patients aged 12 years and older in the US, Canada and Europe (not UK). Primary outcome is ≥ 75% improvement from baseline in Face Vitiligo Area Scoring Index (F-VASI) score; collection of these data is due to complete Apr 21 [2].
Evidence based evaluations
Alopecia areata, moderate-to-severe
Information
New formulation - repurposed medicine
Concert Pharmaceuticals
Concert Pharmaceuticals
Development and Regulatory status
None
None
Phase III Clinical Trials
Category
Selective inhibitor of Janus kinase 1 and Janus kinase-2 inhibitors (JAK 1 and 2). Deuterated formulation of ruxolitinib alters its human pharmacokinetics which may enhance its use as a treatment for alopecia areata.
In the UK, alopecia areata is estimated to affect about 15 in 10,000 people. [1]
Alopecia areata, moderate-to-severe
Topical