NICE Recommends First Ever Drug - Tolvaptan (JINARC®) - to Treat ADPKD
LONDON, 4 September 2015: Hope for families in England and Wales that a treatment option for this incurable condition will be available in the NHS by early 2016.
The Polycystic Kidney Disease (PKD) Charity is delighted that the National Institute for Health and Care Excellence (NICE) has recommended tolvaptan (brand name: JINARC®) to treat the world’s most common inherited kidney disease - autosomal dominant polycystic kidney disease or ADPKD.
Treatment with tolvaptan is recommended for adults with ADPKD who have chronic kidney disease (CKD) stage 2 or 3 at the start of treatment and evidence of rapidly progressing disease. (See below for explanation of CKD stages). Tolvaptan is expected to slow the progression of ADPKD and the rate at which kidney failure may develop, thereby improving the quality and increasing the longevity of the lives of those affected.
First observed in the 16th century, ADPKD is incurable. It occurs in males and females equally, across all ethnic groups, and affects millions worldwide.
ADPKD is a complex, progressive, systemic genetic condition characterised by an increase in the number and size of fluid-filled cysts in the kidney. The cysts develop throughout the approximately one million nephrons in the kidney that perform the constant, essential daily filtering of blood.
Over time, the cysts profoundly enlarge the size, weight and volume of the kidneys, and replace healthy tissue. A normal kidney weighs approximately 150 g; an ADPKD kidney can grow over 50 times as big. In one extreme case, two ADPKD kidneys together weighed 22 kg or approximately one fifth of the patient’s body weight. Individual cysts themselves can expand to 9 or 10 cm in length – which is the size of an average, normal human kidney.
The photo above shows an ADPKD polycystic kidney compared to a normal kidney. [Courtesy: PKD Foundation]
For many patients with ADPKD, life with these large cystic kidneys is debilitating and painful. Kidney cysts can burst and bleed, causing severe pain, infections and sometimes hospitalisation. Surgical interventions may be needed, such as cyst aspiration or even removal of one or both kidneys, especially in the years prior to kidney failure.
Kidney failure or end-stage renal disease (ESRD) occurs in most ADPKD patients on average before the age of 60 years. Not all patients will reach ESRD, but when that occurs, dialysis and/or transplantation are the only life-saving treatments.
The photo above shows the extent of abdominal expansion caused by massive kidney cyst growth. This man is 40 years old and has given permission for his photo to be shown.
In the MRI photo above, this man’s kidneys fill the entire abdominal cavity. Most of his intestinal tract has been pushed right down into the pelvic region. Lungs are slightly compressed. His heart is lying on its side. Stomach, spleen and pancreas are pushed up under the liver.
Tolvaptan received European marketing authorisation in May 2015, based on the findings of the TEMPO 3:4 trial – the largest clinical study conducted in ADPKD to date. In this three-year, randomised, double-blind and placebo-controlled study, tolvaptan reduced significantly the rate of increase in total kidney volume (TKV) by approximately 50 per cent compared with a placebo: 2.80% per year vs. 5.51% per year. Furthermore, tolvaptan showed a statistically significant reduction in the risk of worsening kidney function and other events such as pain and infections.
NICE expects the NHS in England and Wales to make tolvaptan available to patients within 3 months of publication of its final guidance (scheduled for October). See the NICE website for more details about the tolvaptan appraisal and relevant documents http://www.nice.org.uk/guidance/indevelopment/gid-tag447/documents
The Scottish Medicines Consortium (SMC) will appraise tolvaptan in November 2015 for patients in Scotland.
Tess Harris, CEO of the Polycystic Kidney Disease (PKD) Charity, herself affected by ADPKD, said: “We hugely welcome NICE’s decision to recommend tolvaptan, the first ever therapy to target the underlying disease and not just the management of symptoms and complications. Tolvaptan is acknowledged by NICE as an innovative treatment and the first shown to specifically impact on ADPKD progression. Until now, there was no specific therapy to treat ADPKD and doctors have focused on treating the signs and symptoms of ADPKD, such as hypertension, chronic and acute pain, infections and brain aneurysms.
We are deeply grateful to the thousands of patients who have taken part in tolvaptan studies and trials over the past 10 years, particularly those who live in the UK. Many of these patients have continued to participate in on-going tolvaptan studies. We thank their families who supported them, the doctors and nurses who cared for them, the researchers and Otsuka Pharmaceutical Ltd who funded the development and trials of tolvaptan.”
Margaret Pope, trustee of the PKD Charity, said: “At the age of 15, I became aware that I may have inherited PKD. At 42 the diagnosis was confirmed. I am now 70. A lifetime of wondering, of worrying what the future may hold for myself, my children and others affected by PKD. Tolvaptan has given us all hope of a brighter future as the rate of progression will be much reduced.”
Professor Pat Wilson, UCL Centre for Nephrology, Royal Free Hospital and Chair of the PKD Charity Research Advisory Board, said: "This is an important landmark decision by NICE for several reasons. Not only for PKD patients who will be the recipients of the first therapy aimed directly at slowing down the underlying processes leading to cystic kidney enlargement, but also for individual researchers and companies to provide stimulus and incentive to discover and develop complementary therapeutic compounds."
Professor Albert Ong, Professor of Renal Medicine, Kidney Genetics Group, University of Sheffield, said: “The recommendation of Tolvaptan by NICE represents the culmination of over four decades of sustained research into the genetics and biology of ADPKD by doctors, scientists and patients. It will give hope to thousands of patients and their families in the UK and stimulate further drug discovery for this common kidney disease”.
Dr Richard Sandford, a consultant in Renal Genetics in Cambridge, said: “For the first time we can now discuss with individuals and their families who are affected with ADPKD or who are risk of developing it, that there is a treatment that has been shown to improve the long term outlook. Whilst it may not be suitable for everyone with ADPKD, the path to developing tolvaptan as a treatment has told us how we may best monitor disease progression over the long term and identify those that will benefit from treatment the most. It will also help some families to decide when to consider screening for this condition, often a difficult decision.”
Contact: Tess Harris, CEO
Polycystic Kidney Disease Charity
020 7387 0543 | 07793 819868
About ADPKD – Autosomal Dominant Polycystic Kidney Disease
- ADPKD was famously first observed in the autopsy of Polish King Stefan Bathory in 1586. The kidneys of the king, who killed Ivan the Terrible, were described as “like those of an ox, with an irregular and bumpy surface”.
- Described pathologically in 1841, the genes responsible – PKD1 and PKD2 - were identified in the 1990s.
- ADPKD also occurs in cats; about 1 in 3 Persians has ADPKD.
- Global prevalence rates in humans range from 1 in 500 to 1 in 40001, with a large number of individuals being undiagnosed during life. ADPKD can, however, be diagnosed at any time, in adulthood or in children (sometimes in utero).
- Data from the UK Renal Registry in England and Wales, for the period 1 January 2000 and 31 December 2011, showed that the median age of those with ADPKD starting renal replacement therapy (RRT) for dialysis or transplantation was 55 years. This compared with 62 and 66 years in those with diabetes or other kidney disease. This young age of starting RRT had not changed within the ADPKD group over the 10-year period2.
- Cysts can also develop in other organs, notably the liver which can grow massively, endangering life and occasionally resulting in liver transplantation.
- In the PKD Charity’s survey of UK Patients’ and Carers’ Experiences of ADPKD3, nearly half of all patients (250 individuals) reported suffering acute severe pain at least once a month, 1 in 10 on a daily basis. Most said that pain interfered with normal daily life ‘extremely’. Over 4 in 10 reported inadequate pain relief.
- In the PKD Charity survey, people reported loss of personal and family earnings of between £10,000 and £100,000. Costs fall on carers as well as patients: 1 in 5 carers in the PKD survey said they had left their employment to take care of affected family members (spouses and children). Most people diagnosed with ADPKD will experience increased travel insurance premiums and the majority will be denied life and health insurance. Many will need welfare benefits.
- Being diagnosed with ADPKD can have significant consequences on parenthood decisions. In the PKD Charity survey, some respondents said they had chosen not to have children to avoid the risk of passing on ADPKD.
About Chronic Kidney Disease (CKD)
- CKD is a long-term condition where the kidneys lose function over time and do not work effectively.
- There are five stages of CKD; people with stage 1 have normal kidney function whilst those at stage 5 have ESRD or end stage renal disease.
- CKD stages are based on estimated or measured GFR or glomerular filtration rate (eGFR or mGFR).
- ADPKD patients at stages 2 to 3 have eGFR between 89 and 30, which is approximately 90-30% kidney function.
- More information on CKD and eGFR visit http://www.renal.org/information-resources/the-uk-eckd-guide/ckd-stages#sthash.ute7YXv7.dpbs
About the Polycystic Kidney Disease (PKD) Charity
- The PKD Charity was established in 2000 by Dr Anand Saggar (St George’s Hospital, London) and a patient.
- Our mission is to improve the lives of everyone affected by polycystic kidney disease.
- We support individual patients, their families and carers. We provide information, understanding, practical and emotional support.
- With money raised by supporters, we are building a research fund to enable us to support top-quality PKD research.
- We take every opportunity to bring PKD to the attention of the media, healthcare professionals, policy makers and the government.
- We collaborate nationally and internationally with health and social care professionals, other kidney and related genetic charities, scientists and industry to bring the latest knowledge to those affected and promote research and integrated care.
About Tolvaptan and its Mechanism of Action
- Tolvaptan was developed by Otsuka Pharmaceutical Co Ltd and is marketed under the brand name JINARC®.
- Tolvaptan works by suppressing the effects of vasopressin, a known 'antidiuretic hormone' that regulates water and sodium in the kidneys.
- Vasopressin is a key driver in kidney cyst formation and growth, and fluid secretion; it is increased in ADPKD and contributes to the massive enlargement of polycystic kidneys.
- Tolvaptan binds to the vasopressin V2 receptor at collecting tubule-derived cell membranes.
- The inhibition of kidney cyst development by a vasopressin V2 receptor antagonist was first described in 20034 and 20045.
- Preclinical studies in 1998 on tolvaptan had justified studying its effects in humans6; it was approved for use in treating volume overload in heart failure in Japan.
- The TEMPO 3:4 trial reported in 20127.
1 Ong et al. Lancet 2015; 385: 1993-2002
2 Shaw C, et al. Nephrol Dial Transplant 2014;29:1910–8
3 During November and December 2014, the PKD Charity ran a specially designed survey amongst UK adults with ADPKD, plus their relatives and carers, on the impact of the condition on overall health, wellbeing and quality of life. A total of 651 individuals responded, of whom 513 were ADPKD patients, and 138 relatives/carers.
4 Gattone VH, Wang X, Harris PC, Torres VE. Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. Nat Med 2003;9:1323-6.
5 Torres VE, Wang X, Qian Q, Somlo S, Harris PC, Gattone VH II. Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease. Nat Med 2004;10:363-4.
6 Yamamura Y, Nakamura S, Itoh S, et al. OPC-41061, a highly potent human vasopressin V2-receptor antagonist: pharmacological profile and aquaretic effect by single and multiple oral dosing in rats. J Pharmacol Exp Ther 1998;287:860-7.
7 Torres VE, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2012;367:2407–18