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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…
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Lactation Safety Information

No
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)

Information

Jakavi (EU), Jakafi (US)
Licence extension / variation
Novartis
Incyte

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Launched
Yes
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)
Oral

Further information

Yes
Suspended

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)

Information

Jakavi (EU), Jakafi (US)
Licence extension / variation
Novartis
Incyte

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Phase III Clinical Trials

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)
Oral

Further information

Yes
Suspended

Evidence based evaluations

Non-segmental vitiligo that does not exceed 10% body surface area (BSA), in patients aged 12 years and older

Information

New formulation
Incyte
Incyte

Development and Regulatory status

None
Phase III Clinical Trials
Phase III Clinical Trials

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

Atopic dermatitis

Information

New formulation
Incyte
Incyte

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Pre-registration (Filed)
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].
Atopic dermatitis
Topical

Trial or other data

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].

Alopecia areata, moderate-to-severe

Information

New formulation
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