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Insight

Challenges in transplant organ rejection

Read time: 5 mins
Published:10th Aug 2020
Since the first successful organ transplant procedures in the 1950s, immunosuppressive agents have played a key role by reducing grafted organ rejection and improving patient survival. In this series of articles, we’ll give updates on the various existing treatments as well as on the horizon for transplant organ rejection.

Clinically, immunosuppression takes place in three stages: induction or short-term post-transplant treatment, long-term maintenance, and anti-rejection treatment for acute rejection episodes, with different drugs often called on for each phase1.

Prior to about 2010, the most commonly used treatments to tackle organ rejection were Cell Cept (mycophenolate mofetil) from Chugai/Roche, Rapamune (sirolimus) from Pfizer, and cyclosporine, as Neoral / Sandimmune / Gengraf. All these drugs are now generic. At the same time, a number of therapies had to be shelved due to low demand or limited efficacy. But by around 2010 a number of new therapies began to appear.

In 2011, a treatment called Nulojix (belatacept), a T cell co-stimulation blocker, from BMS, was approved in the EU and US for prophylaxis in kidney transplantation. Nulojix was a modified version of the fusion protein found in Orencia (abatacept) the rheumatoid arthritis treatment. Though Nulojix treatment often led to an improvement in long-term graft survival, this drug is now rarely used due to cost, availability issues and limited safety data.  More commonly used are drugs such as Prograf (tacrolimus), also generic, which is now the primary agent in use for maintenance stage treatment2.

Though there is a clear need for better drugs, the pharma industry faces a market that is complex, involving heart, kidney, liver, lung and pancreatic transplant rejection along with specific challenges such as hematopoietic stem cell transplantation and thrombotic microangiopathies. At the same time, there has been a lack of head-to-head trials, while approved therapies have been bedevilled by side-effects and toxicities3.

Calcineurin inhibitors

Currently the calcineurin inhibitors – principally Prograf and Neoral/Sandimmune - are expected to dominate the global market for immunosuppressants through the next 5 years. These remain effective drugs, have been used in renal transplant recipients for more than 20 years, and have well characterised toxicity profiles. Meanwhile the interleukin-2 (IL-2) receptor antagonist Simulect (basiliximab) from Novartis, approved in EU and US in 1990s, dominates induction phase and anti-rejection treatments, with more than 80% of induction therapy recipients in the US since 2004 receiving IL-2 receptor antagonists4.

Despite a global shortage of organs for transplantation, analysts estimate that the global organ transplant immunosuppressant drugs market size will reach more than $10 billion by 2023, growing at a CAGR (compound annual growth rate) of up to 10% for the period spanning 2019-2023. At the same time India and China are merging as low-cost transplant destinations, so there is keen interest in new formulations to tackle organ rejection.

Kidney and Liver Transplant Treatments

Kidney transplants make up some 70% of transplant operations. Drugs approved for this procedure includes generics Nulojix, Rapamune, Zortress/Certican (everolimus) from Novartis and Simulect, along with non-generic Grafalon (anti-thymocyte globulin) from Fresenius Medical/Neovii Biotech. Grafalon was EU approved in 2013 via the decentralized national procedures, and is indicated for prevention and treatment of acute rejection in organ transplantation.

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In phase III trial data, Grafalon did not meet its primary endpoint, although the company reported that the trial did show “a statistically significant reduction in acute Graft versus Host Disease (GvHD) II-IV as well as moderate and severe GvHD. (see below)” Recent studies in India suggest induction with Grafalon was associated with a high rate of acute rejection. It is not currently approved in the US.    

In addition, calcineurin-inhibitor Advagraf (tacrolimus extended release) from Astellas was approved in the EU and US in 2012/2013 and is indicated for kidney and liver transplants, the latter making up around a fifth of the total annual organ transplantations. Though it has similar immunosuppressive properties to cyclosporin, Advagraf is much more potent: immunosuppression with tacrolimus has been associated with a significantly lower rate of acute rejection compared with cyclosporin-based immunosuppression:  30.7% vs 46.4% in one study.

Envarsus XR (tacrolimus once daily) from Veloxis/Ashai and Chiesi was first approved in July 2014. Supplementary approval in the US was also given in December 2018 for de novo kidney transplants and immunosuppressants. The drug is used in about 90% of US kidney transplant centres.

References

  1. Claeys E, Vermeire K, Leuven KU. Immunosuppressive drugs in organ transplantation to prevent allograft rejection: Mode of action and side effects. J Immunol Sci. 2019;3(4):14–21.
  2. Daniel Abramowicz, Oberbauer R, Heemann U, Viklicky O, Peruzzi L, Mariat C, et al. Recent advances in kidney transplantation: a viewpoint from the Descartes advisory board. Nephrol Dial Transpl. 2018;33(10):1699–1707.
  3. Saldanha IJ, Akinyede O, Robinson KA. Immunosuppressive drug therapy for preventing rejection following lung transplantation in cystic fibrosis. Cochrane Database Syst Rev. 2018;6(6). doi:10.1002/14651858.CD009421.pub4.
  4. Benvenuto LJ, Anderson MR, Arcasoy SM. New frontiers in immunosuppression. J Thorac Dis. 2018;10(5):3141–3155.

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