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Insight

Treating rejection in organ transplants

Read time: 10 mins
Published:10th Aug 2020
Source: Medthority
Over 139,000 transplants are estimated to take place every year, but what treatments are available if these organs are rejected? Discover the range of therapies currently available and in clinical trials for the treatment of transplant rejection in liver, kidney, heart and lung transplants.

The World Health Organization (WHO) and the Global Observatory on Donation and Transplantation (GODT) estimate that over 32,000 liver, 90,000 kidney, 7,500 heart and 6,000 lung transplants are carried out every year around the world1.

A variety of common diseases can cause end-stage organ failure and require treatment with liver, kidney, heart or lung transplantation. Liver transplantation has become an established and well-accepted therapeutic pathway for patients with acute and chronic liver failure. Common indications for liver transplant can include hepatitis, alcoholic liver disease, cirrhosis, metabolic diseases and drug induced acute liver failure2.

The limited number of donor hearts and lungs available restricts transplantation to a small fraction of patients. Common indications for heart transplants include non-ischemic cardiomyopathy, ischemic cardiomyopathy, coronary heart disease and valvular heart disease3. The most common indications for lung transplants is chronic obstructive pulmonary disease (COPD) with other common indications being interstitial lung disease (ILD) and cystic fibrosis4.

There are also around three million people in the UK who have chronic kidney disease, the most common cause of kidney failure5. Following kidney failure, dialysis or transplant is essential to prevent a build-up of harmful waste.

With transplantation growing increasingly common, effective treatments for transplant organ rejection are becoming ever more important.

Treating rejection in liver transplants

Drugs approved for liver transplants include Advagraf/Astagraf XL (tacrolimus prolonged release) and Zortress/Certican (everolimus) from Novartis, which was approved in the US in February 2013 to treat both liver and kidney transplantation and shows superior graft survival to tacrolimus immediate release over five years. Sales of everolimus in 2018 were 274 million Euros, around half the sales of tacrolimus. However, the patent on this drug has expired.

Finally, Campath-1H (alemtuzumab) from Genzyme/Sanofi is a humanized, rat monoclonal IgG1 antibody which is used off-label for treating solid organ rejection. It is approved for CLL but has been used as induction therapy and as an anti-rejection agent in kidney transplants6. Campath was withdrawn from the market by Sanofi in Multiple Sclerosis to make way for Lemtrada.

On the horizon – kidney transplants

There are several drugs in late phase clinical trials. Idefirix (imilifidase) from Hansa BioPharma AB was filed with the EMA in March 2019 with PRIME designation for the treatment of highly sensitised patients to enable more effective kidney transplantation.  Hansa has submitted responses to the CHMP which is expected to report sometime in 2020. In addition, Hansa met with the FDA in November 2019 and agreed a new trial to support registration in the context of US Kidney Allocation System and plans to file in 2023.

ALD 518 (clazakizumab) is a monoclonal antibody against interleukin-6 from Vitaeris/CSL. It is also in a Phase III trial to treat “chronic activated antibody mediated rejection in patients with Kidney Transplantation rejection”. In phase II trials patients treated with clazakizumab showed stabilization of renal function.

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MDR 101 from Medeor is a cellular therapy consisting of kidney donor-derived CD34+ HSCs and CD3+ T-cells. It is currently in Phase III to treat kidney transplant patients for functional donor specific immune tolerance at the completion of anti-rejection therapy (to avoid continued needs of immunosuppressive drugs). Funding has been raised and the completion date for Phase III trial is expected to be January 2022.

Luveniq (voclosporin) from Vifor Fresenius Medical Care Renal Pharma is an analog of cyclosporin that has enhanced action against calcineurin and greater metabolic stability. It is currently in Phase III for kidney transplant treatment. It is designed to minimise the safety and side-effect issues including headache, nausea, diarrhoea, high blood pressure, tremors and kidney toxicity associated with both cyclosporin and the more potent tacrolimus. The PROMISE study in 2012 had shown voclosporin non-inferior to tacrolimus with a reduction in new onset diabetes after transplantation, a common side effect.

CFZ 533 (iscalimab) from Novartis showed in a Phase II trial that it may be possible to prolong the durability of transplanted kidneys and allow patients to avoid dialysis or require a second kidney transplant. CFZ 533 demonstrated lower chronic allograft damage index scores (CAD) compared to tacrolimus. Lower CAD scores have been associated with improved long-term outcomes. This was a small trial and the findings have yet to be confirmed.

Heart and Lung transplants

Annually there are around 7500 heart transplants globally1. Drugs used to treat rejection include generic Zortress/Certican, Grafalon, Thymoglobulin from Genzyme/Sanofi and cyclosporin. In terms of maintenance immunosuppressive protocols, a three-drug regimen is used consisting of a calcineurin inhibitor (CNI, cyclosporine or tacrolimus), an antimetabolite agent (mycophenolate mofetil [MMF] or less commonly azathioprine), and glucocorticoids7.

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For lung transplants, the most advanced new treatment is L-CsA-i (liposomal cyclosporine A) from Breath Therapeutics/Zambon. This treatment is a formulation of liposomal cyclosporine A for inhalation delivered by an optimized high-performance nebulizer. It aims to improve the pharmacological profile and highly variable bioavailability along with the severe side effects of oral cyclosporine A. Zambon recently received Fast Track status from the FDA and the company is processing the BOSTON programme (BOSTON 1 (phase III),2 (phase III),3 (phase II), and 4 (phase II trials).

References

  1. Global Observatory on Donation and Transplant (GODT), The World Health Organisation (WHO). Organ Donation and Transplantation Activities Executive summary. 2017 http://www.transplant-observatory.org/. Accessed 2 July 2020.
  2. Graziadei I, Zoller H, Fickert P, Schneeberger S, Finkenstedt A, Peck-Radosavljevic M, et al. Indications for liver transplantation in adults. Wien Klin Wochenschr. 2016;128(19–20):679–690.
  3. Alraies MC, Eckman P. Adult heart transplant: Indications and outcomes. J Thorac Dis. 2014;6(8):1120–1128.
  4. Weill D. Lung transplantation: Indications and contraindications. J Thorac Dis. 2018;10(7):4574–4587.
  5. Kidney Care UK. Facts and Stats. https://www.kidneycareuk.org/news-and-campaigns/facts-and-stats/. Accessed 2 July 2020.
  6. van der Zwan M, Baan CC, van Gelder T, Hesselink DA. Review of the Clinical Pharmacokinetics and Pharmacodynamics of Alemtuzumab and Its Use in Kidney Transplantation. Clin Pharmacokinet. 2018;57(2):191–207.
  7. Kim IC, Youn JC, Kobashigawa JA. The past, present and future of heart transplantation. Korean Circ J. 2018;48(7):565–589.

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