Transplant anti-host disease (GVHD) new drug development strategy.

Transplant anti-host disease (GVHD) is a serious complication after hematopoietic stem cell transplantation (HCT), and 10%-50% of HCT patients have an immune response due to the recipient being attacked by the donor immune system, leading to inflammation formation, tissue damage and organ failure.
changes in the onset of acute and chronic GVHD were bounded by the onset of HCT 100 days after the onset of the disease, less than 100 days of onset of acute GVHD, and later than 100 days of onset of chronic GVHD.
acute GVHD mainly consists of Th1 cytokines, including IL-1 beta, IL-6 and IFN-cyto, which mainly cause adverse reactions such as skin, gastrointestinal and liver damage.
And chronic GVHD incidence in addition to involves mainly Th2 and Th17 inflammatory factors, macrophages and B cells also play a role, macrophages produced by the conversion growth factor beta (TGF-beta) levels will damage T-reg function, so that the inflammatory response increased.
At the same time, the steady state and tolerance mechanism of the supply B cells is disturbed so that memory function is reduced, and the B cells expand rapidly after being activated by the host antigen, causing more infections such as the lungs and eyes than the skin, gastrointestinal tract and liver.
Incyte two JAK inhibitors of the two outcome JAK inhibitors in a variety of autoimmune diseases, including rheumatoid arthritis, baldness, specific dermatitis and other diseases, but incyte / Novartis co-development of JAK1/2 inhibitors reed cortinib has come out of a different way.
after being approved by the FDA in 2011 and 2014 for bone marrow fibrosis and true erythrocytosis, it was approved in 2019 as the first JAK inhibitor to treat acute GVHD in children and adults 12 years of age and older with steroids.
From a mechanism point of view, JAK1/2 plays an important role in signal conduction of the main inflammatory factors of GVHD disease, such as IL-1 beta, IL-6 and IFN-terpene, so JAK inhibitors may be ideal for GVHD treatment, as evidenced by the approval of reeds.
in the one-arm REACH1 trial, 49 patients were evaluated for 57% ORR on the 28th day and CR up to 31%.
in the REACH2 study, the Jakavi treatment group achieved a significant increase in ORR (62% vs.39%, p.001) on the 28th day compared to the BAT treatment group, reaching the main endpoint of the study.
, reedin is also actively expanding the adaptation of chronic GVHD, and in July this year it was announced that the single-drug phase III trial Reach3 of the BAT treatment group had reached its main endpoint.
is expected to continue to expand.
's commercial interests outside the U.S. are currently owned by Novart, but Incyte still has $1,685 million in sales in 2019, or 78 percent of Incyte's global revenue, compared with its current commercial interest outside the U.S.
While Incyte is home to three hot JAK inhibitors from the product line, it has only received royalties since it abandoned co-development with Lilly in 2019.
Incyte's share of product sales from 2015 to 2019, as it strives to expand reedcotinib adaptation, Incyte is also trying to get rid of betting on a product in the hope of JAK1 inhibitor Itatinib, but in the first-line treatment of the key Phase III GRAVITAS-301 In the study, the overall 28-day remission rate of Itacitinib combined corticosteroid first-line treatment of type II-IV acute GVHD did not achieve a significant difference (66.4% vs. 74%) compared to the single agent of corticosteroids, and did not achieve a 16% improvement in the experimental hypothesis.
, however, an ex post facto analysis found that patients in the Itacitnib group received significantly higher CR rates than those in the placebo group, and a lower rate of patients who discontinued the trial because they were insatiable or should not answer.
Itatinib is continuing to conduct first-line studies on the treatment of chronic GVHD, and trials with calcium-adjusted neurophosphatase inhibitors as preventive treatments for GVHD.
December 2018, Cyda acquired clinical development and commercialization rights for three drugs, includingChinese mainland Itacitnib, from Incyte, as well as in Hong Kong, Macau and Taiwan, and is currently conducting Phase I/II clinical trials in China.
The pathogenesis of chronic GVHD in the treatment of B-cells and T-cell pathogenesis is more complex than that of acute GVHD, and is usually divided into three stages: acute inflammation, chronic inflammatory immune disorders, and abnormal tissue repair that continue to lead to fibrosis.
currently being developed for chronic GVHD therapy focuses on inhibiting stage 2, including inhibiting iso-reactive T cells, restoring Treg function, inhibiting B cells or their signaling paths, etc.
after transplantation, the recipient's body B cells continue to lack period, at this time the survival and proliferation of normal B cells need B cell activator (B cell activefactor, BAFF) levels will continue to rise until B cells return to normal, but the occurrence of cGVHD patients after transplantation BAFF levels continue to rise but B cell levels rise, so that B cells in the body to achieve super-activated state.
In addition to BAFF, the antigen-specific B-cell acceptor (BCR) of B cells is activated by antigens, the phosphateization of B-cell joints BLNK and spleen tyrosine kinase (SYK) increases, and the NF-B and ERK signaling paths are activated to regulate abnormal amplification of B cells.
so any signaling process is thought to inhibit the B-cell signaling path.
Ibtinib inhibits BTK and T cellular ligands associated with leucocyte interleulin 2 induced kinase (ITK), based on a one-arm Phase II trial Study 1129 approved by the FDA in August 2017, becoming the only second-line and later chronic GVHD treatment.
Acalabrutinib is currently conducting clinical trials of chronic GVHD.
other promising new drug in the field of chronic GVHD is the KD025 (belumosudil) that inhibits the T-cell signaling path.
KD025 is an oral selective Rho-related curly helix protein kinase 2 (ROCK2) inhibitor that reduces the release of T-cytokines IL-21 and IL-17 by inhibiting signal conduction of STAT3, IRF4, and ROR-t, while also increasing the expression of STAT5 activity to increase the expression of Foxp3-Treg cells, resulting in a reduction in the number of effect T cells and T-regulated cell level reconstruction.
although T-cell-mediated inflammation is a major feature of aGVHD, fibrosis is often the end result of chronic GVHD, and ROCK kinase systems are critical as a common and end pathway to fibrosis.
the effectiveness of Ibdinib and KD025 on chronic GVHD compared to the results of the Ibdini trial, the Phase II trial of KD025 included people who had received more line therapy in the past and were older This includes 30 per cent of subjects with Ibtinib and/or ruxolitinib, who still have a higher response rate than Ibdinib and are currently rolling through the Real-Time Oncology Review (RTOR) Pilot Program for rolling submission to the NDA.
KD025 is currently in phase II trials of systemic sclerosis.
Pharmaceuticals won the development rights of KD025 in China and is currently in the IND stage.
exploed GVHD sub-population currently although there are many drugs in the field of GVHD treatment progress, but due to the recurrence of the cause and usually difficult to effectively intervene in the early stages of the disease, many listed immuno-related drugs are also exploring the relative segment of GVHD population.
gastrointestinal tract is the most common affected organ in GVHD patients, and Takeda Pharmaceuticals' Vedolizumab regulates the migration of lymphocytes to the intestines by binding the integrative alpha4 beta7, which in turn can exhibit intestinal-specific anti-inflammatory effects.
F-652 is an IL-22-Fc fusion protein that is currently used in GVHD patients with gastrointestinal reactions due to targeted organ targeting.
, a collective supply of enemas containing a variety of microbial species, is currently being developed by MaaT Pharma of France.
The main GVHD subdivision population clinical research project for children with acute GVHD patients, only 30%-50% of the first-line corticosteroid treatment response, second-line treatment is currently not the best recommended option, ElsaLys biopharmaceutical innolimomab is currently used in the development of SR-aGvHD, including pediatric patients.
single anti-drug targeting IL-2R, blocking the proliferation of IL-2 by blocking the surface of the overactive T cells of the supply.
if acute GVHD occurs, the risk of chronic GVHD will increase, so preventing GVHD is also an important development strategy.
CSL developed CSL964 is alpha-anti-trypsin (AAT), which has been marketed in Denmark for alpha1-anti-trypsin deficiency, primarily by inhibiting GVHD by reducing inflammation and increasing the ratio of regulatory T-cells to effect T-cells.
is currently developing two adaptive disorders: acute GVHD, which relapses after the treatment of steroids.
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Immune is a targeted immune checkpoint that reduces the activity of NF-B by inhibiting Siglec-10 and inhibits the expression of inflammatory cytokines such as TNF-alpha, IL-6 and IL-1.
Ocugen specializes in ophthalmology GVHD, an eye GVHD is a common complication that occurs in 40% of patients with allogeneic bone marrow transplants, which can lead to damage to the eye watch and tear glands, redness, inflammation and burning sensations, traditional eye drops can not be alleviated, and over time, visual impairment can greatly reduce quality of life and limit daily activities.
OCUS300 (Brommonidine 0.18% nano emulsion) mainly works in two ways: first, the preservative-free formula can prevent corneal damage, and second, the use of ophthalmology nano-emulsion technology (OcuNanoE™), the drug will stay on the surface of the patient's eyes for longer, and improve the absorption of target tissue, thereby improving its effectiveness.
GVHD incidence increases with the use of HCT in a variety of blood diseases, the incidence rate in the United States is about 1-9 per 100,000 people, still belongs to the category of rare diseases, the FDA orphan drug qualification and related incentives, so that more new drugs willing to enter the GVHD sub-groups for development.
April Chen Source: Medical Rubik's Cube !-- end of content display -- !-- to determine whether login is over.