What is Graft Versus Host Disease?

Graft-versus-host disease (GvHD) is an immune condition that occurs when immune cells (T cells) after transplant procedures from the donor (known as the graft or graft cells) attack the recipient patient host’s tissues (healthy cells); the disease is a side effect that is common after an allogeneic bone marrow transplant (stem Cell Transplantation).

The two main types of GvHD are acute GvHD and chronic GvHD. Other than this, GvHD is classified into other types, namely: classic acute GvHD, persistent, recurrent, late-onset acute GvHD, classic chronic GvHD, and overlap syndrome and de novo chronic GvHD. Patients who get acute GvHD have a 50% chance of developing chronic GvHD.

Acute GvHD (aGvHD) might occur once the donor’s cells have engrafted in the transplant recipient and have been observed to affect skin, liver, or gastrointestinal tract. Symptoms might appear within 3 months after the transplant. Symptoms of acute GvHD include skin rash or reddened areas on the skin, jaundice, and abnormal blood test results and nausea, vomiting, diarrhea, or abdominal cramping.

Chronic GvHD (cGvHD) usually develops later than 100 days after the transplant, and it might occur in the skin, liver, mouth, lungs, gastrointestinal tract, neuromuscular system, or genitourinary tract. Its diagnosis is based on manifestations and not timing.

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Symptoms of chronic GvHD might include any of the following: rash, raised or discolored areas, skin thickening or tightening, jaundice, abdominal swelling, dry eyes or vision changes, dry mouth, white patches inside the mouth, pain or sensitivity to spicy foods, shortness of breath, difficulty swallowing, pain with swallowing, or weight loss, fatigue, muscle weakness, vaginal dryness or pain with intercourse, tightness in joints, etc.

The diagnosis of aGvHD is based wholly on clinical criteria that can be established by biopsy of one of the three target organs. Additionally, laboratory data and/or imaging studies are also useful tests in the diagnostic approach to GvHD.

Treatment is grounded on drugs that reduce the body’s immune response and reduce T cells' number. The current hallmark of treatment for GvHD is Immunosuppressant medications. These include both corticosteroid drugs and more advanced medications and techniques that decrease the immune response.

Commonly used medications that are given in the management of GvHD include steroids (prednisolone; Methylprednisolone), Calcineurin inhibitors (Cyclosporine; Tacrolimus), Cyclophosphamide (Cytoxan), Antithymocyte globulins (Thymoglobuline; ATG-Grafalon), Monoclonal antibodies (Alemtuzumab; Infliximab; Rituximab; Basiliximab), Mechanistic target of Rapamycin (mTOR) inhibitor (Sirolimus; Everolimus), Tyrosine kinase inhibitors (Imatinib), Tumor necrosis factor (Etanercept), Thalidomide, Inosine monophosphate dehydrogenase (IMDH) inhibitor (mycophenolate mofetil), chemotherapy drugs (Pentostatin; Methotrexate), Janus kinase (JAK) inhibitor (Ruxolitinib; Itacitinib) and Bruton’s tyrosine kinase (BTK) inhibitor (Ibrutinib).

Advanced hematologic malignancies and some nonmalignant disorders can be treated with allogeneic hematopoietic cell transplantation. The GvHD epidemiology projection methodology is based on an analysis of country-specific HSCT performed in the 7MM. Allogeneic cases are taken forward to extrapolate aGvHD and cGvHD patients, thereby total GvHD cases in the 7MM.

Corticosteroids (steroids), either alone or in conjunction with other agents, have long been the mainstay of first-line treatment. Enhanced immunosuppression in the form of corticosteroids (medicines such as prednisone, methylprednisolone, dexamethasone, beclomethasone and budesonide) is effective across many patients who experience aGvHD. Patients experiencing mild skin-only aGvHD would normally keep their current drugs, such as cyclosporine or tacrolimus, and add a topical steroid cream to the treatment regimen. Patients with systemic or "whole-system" symptoms and/or more serious aGvHD are normally treated by continuing immunosuppressive therapy and adding a corticosteroid like methylprednisolone or prednisone to their regimen. As said earlier, in the event of GvHD, corticosteroids are the first line of treatment; however, secondary data demonstrate that up to 40%-60% of all patients will be refractory to steroids. This is one of the major challenge in treating GvHD patients. Patients with more serious symptoms or cGvHD that affects several organs usually need “systemic” medication, which passes through the bloodstream and enters cells all over the body. For cGvHD, prednisone is the preferred first-line treatment.

In 2017, the USFDA gave a green signal to Imbruvica [Ibrutinib, Pharmacyclics (acquired by Abbvie)], for the treatment of adult patients suffering with cGvHD after failure of one or more lines of systemic therapy. It was the first ever approved treatment targeting this specific patient pool.

Another approved drug is Jakafi (Ruxolitinib, Incyte) which was approved by the FDA in May 2019 for the treatment of steroid-refractory aGvHD in adult and pediatric patients 12 years and older. The single-arm, multicenter phase II REACH1 trial was conducted to justify the approval of ruxolitinib. Before the REACH1 trial, a series of anecdotal publications demonstrating effective ruxolitinib treatment propelled momentum and fueled clinicians' desire to recruit patients and lobby for the trial.

Looking at the scarcity of approved and legalized treatment options, many key companies across the world are developing a novel therapy that would help in combating the complications caused by GvHD, in addition to this, the developers are also trying to come up with the salvage therapy or curative therapy.

“The market size of GvHD in the 7MM is expected to grow at a CAGR of 15.9% for the study period (2018–2030). According to the estimates, the United States had the highest market size in GvHD in 2018, owing to the higher patient pool and higher treatment cost”

The dynamics of the Graft versus Host Disease market is anticipated to change in the coming years owing to the improvement in the rise in number of healthcare spending across the world. Key players, Companies like CSL Behring [CSL 964 Alpha-1 antitrypsin (AAT)], Medac [Obnitix (MC0518)], Takeda [Entyvio (Vedolizumab; MLN0002)], MaaT Pharma [MaaT013], OncoImmune/Merck (MSD) [MK-7110 (CD24Fc)], ElsaLys Biotech/Mediolanum Farmaceutici Spa [Leukotac (Inolimomab)], Xenikos [T-Guard], Mesoblast/Osiris Therapeutics [Ryoncil (Remestemcel-L; Prochymal)] and others are involved in the development of phase III drugs. Apart from this, phase II drugs are being developed by Syndax Pharmaceutical [Axatilimab (SNDX-6532)], Kadmon Corporation [KD025 (Belumosudil)], Regimmune Corporation (RGI-2001 and several others.

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