The preliminary results from the DIPAK 1 study were presented at the ERA-EDTA Copenhagen Congress in May 2018 by Prof Ron Gansevoort, lead investigator. I was in the audience, eagerly anticipating the results. This was a large, investigator-driven, well-conducted trial across 4 centres in the Netherlands investigating the efficacy of the somatostatin analogue lanreotide on the rate of kidney function loss in ADPKD patients. The trial was funded by the Dutch Kidney Foundation, the Dutch Ministry of Economic Affairs, and an unrestricted grant from Ipsen Pharmaceutical. Lanreotide is licensed for the treatment of tumours. In 2015, the European Medicines Agency granted orphan designation to lanreotide for the treatment of ADPKD (Disclosure: I represented patients in the EMA submission).
Animal studies and small clinical trials had shown that somatostatin analogues reduced the growth rate of polycystic kidneys by suppressing cAMP which slowed cyst formation and growth. cAMP is known to play an important, even key role in the signaling pathways in the kidney cells of ADPKD patients. The hypothesis is that reducing cyst and total kidney volume (TKV) growth can result in reduced kidney function decline - as witnessed in the tolvaptan trials which also reduces cAMP and TKV. To our huge disappointment, DIPAK 1 did not show the hoped-for efficacy. Lanreotide did not preserve kidney function and its use in treating later-stage ADPKD is not supported by these findings. The full results were published in JAMA in October 2018.
DIPAK 1 was an open-label, randomised trial with blinded endpoint assessment that was run over 2.5 years. 377 patients were screened and 309 were randomized. In the lanreotide group, 153 patients with later-stage ADPKD began the study; all their data was included in the primary efficacy analysis. There were 153 patients in the control group. The two groups were well matched demographically at baseline, with mean age of 48.4 years, 53.4% women, and mean eGFR of 50 ml/min/1.73m^2. In the lanreotide group, 118 completed the study. In the control group, 143 completed the study.
Lanreotide was injected subcutaneously every 4 weeks; the starting dose was 120mg and the mean dose at the end was 112mg. Both groups received equivalent standard care at their renal units.
The primary outcome was annual change in the eGFR slope of decline. After 2.5 years, annual eGFR loss was -3.53 in the lanreotide group vs -3.46 in the control group - no statistically significant difference between the groups. There was also no difference in the secondary outcome of pre- and post-treatment eGFR change. However, lanreotide did slow TKV - 4.15% vs 5.56%, a significant difference of -1.33% a year.
Interestingly, there were no significant differences in quality of life - as measured by the validated ADPKD Impact Score - despite the expected adverse drug administration and GI events, plus a high number of unexpected liver cyst incidents.
“Whilst extremely disappointing for the investigators and patients, we are grateful that this trial was conducted. So often, studies are conducted on small patient numbers in single centres - with the predictable conclusion that ‘larger trials are needed’.”
The DIPAK 1 team are to be congratulated for raising the funds for this large trial - no pharmaceutical firm was willing to commit. As a community, we can learn from failure as much as from success.
Is this the end of somatostatin analogue trials in ADPKD therefore? Curiously, in August 2018, the Italian Medicines Agency approved the reimbursement of octreotide (another somatostatin analogue) to slow progression of ADPKD in adults with CKD stage 4 and increased risk of rapid progression to dialysis. This decision is presumably on the basis of the results of the Italian ALADIN studies which showed some efficacy in reducing eGFR decline rate after 3 years of treatment. Yet, DIPAK 1 included later-stage CKD patients and they had less favourable results than earlier stage. We await the real-world evidence from the prescribing of octreotide in Italy. Could there be a difference between lanreotide and octreotide? Or should DIPAK 1 have run longer than 2.5 years? These questions will await a deep pocketed investigator to run a long and large study.
There is one other hope for ADPKD patients from these types of drugs. Most of the earlier studies showed that they significantly reduce polycystic liver volume as well as TKV. A number of ADPKD patients around the world already receive these drugs off-label to mitigate the hugely debilitating impact of massive livers. Changes in liver volume in those patients in DIPAK 1 with livers over 2000 ml will be analyzed. If there is a significant decline, there may still be potential for commercialising somatostatin analogues for the treatment of severe polycystic liver disease (PLD). The numbers of patients with severe PLD are less than the ADPKD population but there are no treatments other than risky surgery for this group, and it is a painful, burdensome, life-threatening complication. Unfortunately, given the high number of liver cyst incidents in the treatment arm of DIPAK 1 group, this may exclude lanreotide from consideration.
Commentary by Tess Harris
Tess Harris is a patient with ADPKD, who is currently on the transplant list. She has other family members with ADPKD as well. She is the President of PKD International and CEO of the PKD Charity UK. In addition she also chairs the ADPKD Clinical Study Group for the UK Kidney Research Consortium, and is a SONG (Standardised Outcomes in Nephrology) Executive Committee member and on the International Advisory Board of the Can-SOLVE CKD. Watch an interview she has given on living with ADPKD. She tweets as @Elektra, and also runs @PKD_Int, @PKDCharity and @CiliaAlliance. The opinions expressed in this commentary are personal and do not represent any of the organizations above.