Which is better for lupus nephritis?
Here is my answer!
Which is better for lupus nephritis? Benlysta or Lupkyinis? … and the winner is… (read below)
Updated 6/1/21: I included:
– The specifics on the complete renal responses Benlysta vs Lupkynis
– Included information on extra renal lupus
– Included information about the long term extension trial to 104 weeks with Lupkynis Background on lupus nephritis:– Systemic lupus erythematosus (SLE) is an autoimmune disease where the immune system attacks the person’s own body.
– Around 40% of the time, it will attack the kidneys. This is called lupus nephritis (LN).
– It causes no symptoms whatsoever until it is severe and permanent damage is already occurring. This is why we ask our SLE patients to give a urine sample every 3 months to look for increased protein in the urine (proteinuria) as a sign of nephritis.
– Up to recently, our treatments have not been very good, with around 15% of our patients going into kidney failure by 10 years after their diagnosis. Then they need dialysis or a kidney biopsy. This is one reason why we need better treatments. “Standard of care” with mycophenolate and cyclophosphamide are NOT good enough.
– Our goal in treating LN is to get it into remission.
– Numerous drugs have been studied this past decade, trying to find better treatments. In those studies, only 22% to 32% of patients go into remission on the usual treatments of mycophenolate or cyclophosphamide. Remission is so important because this is the best way to prevent kidney failure and death.
A normal nephron in the kidney. Also called a glomerulus. We have millions of these. They are the filters of the kidney. Photo = by OpenStax College from wikipedia.com glomerulus entry
Lupus class IV (diffuse proliferative nephritis). Photo by “nephron” at wikipedia.com diffuse proliferative glomerulonephritis entry
The role of the kidney biopsy:
– A kidney biopsy is essential to help figure out what to do. After numbing up the back under the ribcage, a tiny needle is inserted to grab a tiny piece of kidney. We then look at it under the microscope.
– Above are two examples of kidney biopsies as seen under the microscope.
– Note the normal kidney top right. The glomerulus (nephron) is one of millions of tiny filters in our kidneys. Note all the white spaces. These white spaces are essential for waste products to fill up and flow into the urine.
– Now look at the LN kidney on the bottom affected by the worst form called “class IV diffuse proliferative nephritis.” Note how there is hardly any of the large white spaces that you see in the normal glomerulus. This filter (glomerulus) is unable to filter out waste products. Without good treatment, this patient would absolutely go into complete kidney failure.
Food and Drug Administration (FDA) = responsible for evaluating the safety and effectiveness of new drugs. Photo from Wikipedia
Prior to 2020, there were no FDA-approved drugs to treat LNDecember 17, 2020: Benlysta (belimumab) was the 1st FDA-approved drug to treat adults with lupus nephritis (LN) when added on top of standard of care (high doses of steroids plus either mycophenolate or cyclophosphamide)
January 21, 2021: Lupkynis (voclosporin) was the first oral drug FDA-approved to treat adults with LN when added on top of standard of care (high dose steroids plus mycophenolate)
May 5, 2021: Benlysta is approved to treat adults with LN in the European Union!
So, which is better? Benlysta or Lupkynis?
I think that is best answered by looking at the pros and cons of both drugs:
Benlysta (belimumab)
Data below is from the phase III clinical trial (BLISS-LN) unless otherwise stated
PROS:
– Flexible options. Given both by IV (intravenous) by a nurse, or at home by self injection (SQ form).
– Has been around and used for a long time (since March 2011), so there is a lot of experience with its safety and effectiveness– Its safety in the lupus nephritis trials was similar to its safety in the phase III clinical trials for SLE.
– You don’t have to fail other drugs 1st before using it for LN
– Most patients studied had class III or class IV nephritis
– Steroids had to be tapered to 10 mg a day or less of prednisone by week 24
– Complete renal response (CRR, remission or close to remission) at 104 weeks was 30% on Benlysta plus mycophenolate (MMF) or cyclophosphamide + steroids versus only 20% on standard of care alone (MMF or cyclophosphamide + steroids). Cautionary note: the definition for CRR was stricter in the Benlysta trial than the Lupkynis trial, so you cannot assume that Lupkynis did better for CRR. The Benlysta trial required better kidney function results than the Lupkynis trial did. – The odds ratio for the CRR was 1.74 meaning that patients who received Benlysta plus standard of care had a 74% greater odds of achieving a CRR compared to patients treated with standard of care alone (ie placebo). Again, remember that the Benlysta trial had a stricter definition for CRR. You cannot compare the 1.74 for Benlysta to 2.7 for Lupkynis.
– Patients receiving Benlysta plus standard of care had a 58% increased likelihood at any time of achieving a CRR and remaining in a CRR until week 104. Note that this timing cannot be compared to Lupkynis’ timing for decreased proteinuria. These are two different measurements.
- Black patients were more likely to achieve a CRR at 104 weeks on Benlysta plus standard of care compared to standard of care alone. However, these results were not calculated in the research paper.
- Benlysta plus standard of care resulted in a 49% lower likelihood of a “renal-related event or death” up to week 104 compared to placebo plus standard of care treatment.
– Benlysta was studied combined with both mycophenolate and cyclophosphamide. Lupkynis was only studied along with mycophenolate.
– Excellent patient assistance program at www.benlysta.com.
– Both the IV form and the self-injectable SQ forms can be used to treat lupus nephritis.
– Much easier dosing than Lupkynis. IV form is the same as that for SLE. The SQ form is 2 injections (400 mg) weekly for 4 doses followed by 1 injection weekly after that.
– The package insert does not recommend use in pregnancy (was not studied). However, the pregnancy registry conducted for more than 10 years has thus far shown no signals for fetal problems. Some rheumatologists have used it safely during pregnancy.
– There was a question of possible increased suicides, suicidal thoughts, and worsened depression in previous IV Benlysta studies. However, in this lupus nephritis study, there were actually more of these problems in the placebo group. However, this was most likely not statistically significant.
– Proven in multiple phase III clinical trials that it is safe and effective for systemic lupus problems other than kidney inflammation. This especially is true for arthritis, cutaneous (skin) lupus, and patients with high anti-dsDNA and low C3 and low C4 levels. Though the FDA would not allow a fatigue mention (due to not having a validated fatigue measure for SLE), there was improvements in energy (and I note this in my own patients). Of note, it is even FDA-approved to treat children with SLE as young as 5 years old!
- Both were studied for 104 weeks
CONS:
– People who don’t like injections may not like it
– Only around 14% of the patients were black (under-recruitment of black patients is a continuing problem) – On the surface, the Lupkynis numbers are more impressive regarding how fast proteinuria is decreased and the number of patients who go into a complete renal response (CRR). However, definitions for these goals were different in the two studies, so direct comparisons cannot be made. From experience, we do know that other calcineurin inhibitors, such as tacrolimus, can have markedly fast and profound effects on proteinuria, so it would not be surprising if Lupkynis were to reduce proteinuria faster than Benlysta. SEE MY INDEPTH DISCUSSION ON THE CRR BELOW.
- It is expensive. But not as expensive as Lupkynis. The ICER (Institute for Clinical and Economic Review) estimates a yearly price of $43,000 for patients who stay on Benlysta.
Lupkynis (voclosporin)
Data below is from the phase III clinical trial (AURORA trial) unless otherwise stated
PROS:
– Oral capsule form. Not an injection.– It is brand new with no long term data. However, it is in a class of drugs called calcineurin inhibitors (CNI) which have been around for a long time.
– It is a new and improved 3rd generation CNI. It is more potent than cyclosporine (another CNI) and is less likely to cause cholesterol problems than cyclosporine. It is much less likely to cause diabetes compared to the CNI called tacrolimus. It results in such a stable, predictable drug level that blood drug levels are not needed.
- You don’t have to fail other drugs 1st before using it for LN
– Most patients studied had class IV nephritis (the type with the worst prognosis)
– Amazing steroid taper! Only 500 mg IV SoluMEDROL for 2 days (many docs use 1000 mg for 3 days) followed by 25 mg a day prednisone tapered to 5 mg a day by 2 months and 2.5 mg a day by 4 months. Many, to most docs, use 40 mg to 60 mg a day after the IV steroids. So, starting with just 25 mg is phenomenal!
– Complete renal response (CRR, remission or close to remission) at 52 weeks was 41% on Lupkynis plus mycophenolate (MMF) + steroids versus only 23% on standard of care alone (MMF + steroids).
- The odds ratio for the CRR was 2.7 meaning that patients who received Lupkynis plus standard of care had a 170% greater odds of achieving a CRR compared to patients treated with standard of care alone (ie placebo).
- Lupkynis plus standard of care resulted in low urine protein levels (urine protein to creatinine ratio of 0.5 mg/mg or less) twice as fast compared to standard of care. The median time to this goal was 172 days for Lupkynis and 372 days for standard of care! “Time is kidney,” we want our treatments to work as fast as possible, so this is amazing.
– 46% of black patients on Lupkynis had a CRR by 1 year compared to 16% on standard of care. In other words, three times as many black patients achieved a CRR on Lupkynis compared to standard of care! Our black patients are harder to treat and get their disease under control, so this is promising.
– Likewise, 39% of Hispanic patients on Lupkynis had a CRR at 1 year compared to 19% on standard of care (again, they typically are harder to treat, so this is promising).
– When looking at the type of LN, the worst type, class IV diffuse proliferative– 47% of patients had a CRR at 1 year on Lupkynis, while 25% of those did on standard of care.
– It has 2 modes of action. In addition to the immunosuppressive effects, it also stabilizes podocytes, which are essential kidney cells that ensure the kidney filters (nephrons, glomeruli) are working properly and not allowing large proteins to escape from the blood into the urine.
– Excellent patient assistance program, Aurinia Alliance. They will get medication in the patient’s hands within 5 days if there is any delay in getting it while they help work on the prior authorization process: support@AuriniaAlliance.com and 833-287-4642
– It is not FDA-approved to treat SLE problems other than lupus nephritis. However, in both the phase 2 and phase 3 clinical trials, there were some numerical improvements in a lupus disease measurement called the SELENA-SLEDAI score. The lupus nephritis trials were not designed to answers this question. I hope Aurinia pharmaceuticals considers doing an SLE study.
– Although the phase III clinical trial was only 52 weeks, a press release in May 2021 stated that low urine protein levels along with stabilization of kidney function was seen through week 104 in the long term extension trial.
CONS:
– Lots of pills to take daily. Most commonly 3 capsules twice daily
– Only around 9% of the patients were black (under-recruitment of black patients is a continuing problem)
– As expected for a calcineurin inhibitor, decreased kidney function and high blood pressure were the most common side effects
– However, at week 24 and week 52, there was no difference in blood pressure between patients on Lupkynis and those on placebo plus standard of care
– In those with decreased kidney function, the dose of Lupkynis was decreased as recommended in the package insert. Most patients rebounded well to normal or to their target kidney function goal. In the end, there was “no clinically meaningful differences in mean eGFR vs placebo plus standard of care.”
– The next most common side effects, as expected, were gastrointestinal issues, infections, and headaches.
– Long term side effects for infections and cancer is unknown.
– Lupkynis is more expensive. The ICER estimates a yearly price of $92,000 for patients who stay on it.
– Complicated dosing. The dose should be reduced if the kidney function decreases too much, or if there is cirrhosis of the liver, or if used with drugs that affect metabolism (CYP3A4 inducers, inhibitors, and P-gp substrates)
– Numerous potential drug interactions (such as listed above). It is important to use a drug interaction program such as UpToDate.
– Blood pressure and kidney function need checked before treatment, then every 2 weeks the first month. Kidney function should be checked monthly on treatment after month 1.
– Use during pregnancy and breastfeeding not recommended. – Benlysta was studied combined with both mycophenolate and cyclophosphamide. Lupkynis was only studied along with mycophenolate. – More difficult to prescribe than Benlysta. Only one specialty pharmacy handles it. Must contact Aurinia Alliance for assistance 1-833-287-4642
THE COMPLETE RENAL RESPONSE CRITERIA OF EACH RESEARCH STUDY
Why is a complete renal response (CRR) so important? Our goal in treating lupus nephritis is to get it into remission. Patients who reach remission are much less likely to go into kidney failure, have less organ damage, and live significantly longer than patients who have a partial response to therapy. CRR is not called “remission” because you truly do not know if the patient is in remission unless you do a kidney biopsy, but it is the closest we have without the biopsy.
First, what did they have in common? – Both did not allow any significant increase in steroids, change in doses of ACEi’s or ARBs (blood pressure medicines that lower urine protein), addition of an antimalarial if not on one already, and no addition of any other immunosuppressant drug.
The other is they both had a similar urine protein to creatinine ratio (UPCR) goal (with one slight, nonsignificant difference). Lupkynis patients had to reach a UPCR of 0.5 mg/mg or less; Benlysta patients had to be below 0.5 mg/mg.
The big difference for complete renal response was in the kidney function stabilization criteria:
Benlysta required a eGFR of 90 ml/min or higher (or within 10% of the baseline if less than 90).
Lupkynis patients could have a eGFR of 60 ml/min or more (or within 20% of the baseline if less than 60).
It is much more difficult to have an eGFR of 90 ml/min or higher when you have severe lupus nephritis. So, this was an impressive requirement.
However, this is balanced out by Lupkynis using the CRR as its primary endpoint, while Benlysta used it as a secondary endpoint. Having it as the primary endpoint is wonderful as that is truly our goal. We don’t just want a “renal response,” with a treatment, we want remission (CRR or close to a CRR).
INTERESTING FACT ABOUT LUPKYNIS AND PREGNANCY:
Other calcineurin inhibitors (such as tacrolimus) are safe to use in pregnancy.
Why is it recommended not to use Lupkynis in pregnancy? Each capsule of Lupkynis contains 21 mg of alcohol.
Putting it into perspective, 5 oz of red wine contains around 4000 mg of alcohol.
However, the Centers for Disease Control states, ” There is no known safe amount of alcohol use during pregnancy or while trying to get pregnant.”
And the answer is (Benlysta vs Lupkynis) …
Neither is definitely any better or worse than the other!
They are both game changers in the treatment for lupus nephritis, and they both have their place
What would I do if I had severe lupus nephritis?
Whenever I treat a patient, I always put myself in their shoes and ask myself, “what would I want if I were the patient, knowing everything that I know?” Or, what would I recommend to my family member if they were the patient.
The problem with the treatments for lupus nephritis prior to Benlysta and Lupkynis is that most patients do NOT go into remission.
Previous therapies (called “”standard of care” in the research studies) take too long to work. While we wait for them to work, permanent damage to the kidneys occurs. Once you lose each nephron (filter) due to lupus inflammation, it is gone forever.
We end up having to use too much steroids which cause side effects in everyone when used at high doses for lupus nephritis. These high doses of steroids also cause organ damage themselves. We always want to get away from treatments that also cause damage to our bodies!
So here we have two drugs that have proven themselves to increase remission, work faster, and decrease the need for steroids.
Plus, they had excellent safety in the studies. In my opinion, they are markedly safer than steroids.
If I had lupus nephritis, I would absolutely want Benlystaor Lupkynis plus mycophenolate plus hydroxychloroquine plus an angiotensin converting enzyme inhibitoror an angiotensin receptor blocker plus vitamin D plus religious sunscreen usage immediately as my treatment.
If my nephritis were severe, I’d only want 250 mg to 500 mg IV pulse SoluMEDROL for only 2 days followed by just 20 mg to 25 mg a day of prednisone daily with a rapid taper. I want as little of steroids as possible.
I would also see if my insurance would allow me to use both Benlysta plus Lupkynis at the same time! They work in 2 different directions and if they could get me into remission faster and get me off steroids faster, why not?
What should you do if you have lupus nephritis?
– Learn as much as you can. Knowledge is Power!
– Mentally accept the fact that you will need to take numerous medications to treat the nephritis. Take all the medicines religiously. When you get tired of taking your medicine, tell yourself, “I want to do everything possible to stay off dialysis and prevent needing a kidney transplant.” Each treatment has its reason behind using it. Your goal is to let the other meds (Hydroxychloroquine, vitamin D, sunscreen, mycophenolate or cyclophosphamide, Benlysta, Lupkynis, ACEi or ARB) do their magic so you can get under control faster and get down and off of those steroids! Just for example, I recently started taking care of this very nice gentleman with severe lupus nephritis who had numerous, painful, broken bones in his spine from steroids (his treatment did not include all the things I mention above). I wish I could have taken care of him from day #1. I’m confident I could have helped prevent that from happening. Don’t let that be you.
– If you want an easy to take medicine that has proven long term safety, and is less of a hassle to take, then Benlysta may be a good choice for you.
– If you think that Lupkynis may work faster and better (we do not know this 100%, however), then Lupkynis may be a good choice if you don’t mind taking 6 capsules daily and getting frequent blood pressure and blood work done.
– If you want to give it everything possible (like I would) ask your doctor about taking both.
For more in-depth information on lupus nephritis and its treatment:
Furie R, Rovin BH, Houssiau F, Malvar A, Teng YKO, Contreras G, Amoura Z, Yu X, Mok CC, Santiago MB, Saxena A, Green Y, Ji B, Kleoudis C, Burriss SW, Barnett C, Roth DA. Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis. N Engl J Med. 2020 Sep 17;383(12):1117-1128. doi: 10.1056/NEJMoa2001180. PMID: 32937045.
Kuglstatter A, Mueller F, Kusznir E, et al. Structural basis for the cyclophilin A binding affinity
and immunosuppressive potency of E‐ISA247 (voclosporin). Acta Crystallogr D Biol Crystallogr.
2011;67(pt 2):119‐123
Bîrsan T, Dambrin C, Freitag DG, et al. The novel calcineurin inhibitor ISA247: a more potent
immunosuppressant than cyclosporine in vitro. Transpl Int. 2005;17(12):767‐771.
Mayo PR, Huizinga RB, Ling SY, et al. Voclosporin food effect and single oral ascending dose
pharmacokinetic and pharmacodynamic studies in healthy human subjects. J Clin Pharmacol.
2013;53(8):819‐826.
Gibson K, Parikh S, Saxena A, et al; AURORA Study Group. AURORA phase 3 study
demonstrates voclosporin statistical superiority over standard of care in lupus nephritis.
Presented at: National Kidney Foundation virtual 2020 Spring Clinical Meetings; March 26‐29,
2020.
Arriens C, Polyakova S, Adzerikho I, et al; AURORA Study Group. AURORA phase 3 study
demonstrates voclosporin statistical superiority over standard of care in lupus nephritis.
Presented at: EULAR European E‐Congress of Rheumatology 2020; June 3‐Sept 1, 2020
Askanase A, Randhawa S, Lisk L, et al. Efficacy of voclosporin across lupus nephritis
biopsy classes: pooled data from the AURORA 1 and AURA‐LV trials. Presented at:
National Kidney Foundation virtual 2021 Spring Clinical Meetings; April 6‐10, 2021.
Abstract/ePoster 283
Rovin BH, Parikh SW, Huizinga RB, et al; AURORA Study Group. Management of lupus nephritis with voclosporin: an
update from a pooled analysis of 534 patients. Presented at: American Society of Nephrology Kidney Week 2020
Reimagined; Oct 19‐25, 2020
Caster DJ, Solomons N, Randhawa S, et al; AURORA Study Group. AURORA phase 3 study demonstrates voclosporin
statistical superiority over standard of care in lupus nephritis. Presented at: ERA‐EDTA Virtual Congress; June 6‐9, 2020
DISCLAIMER: I am on the Speaker’s Bureaus for both Benlysta and Lupkynis. I do this proudly as I believe strongly in how much these medications can improve the treatment of our lupus patients, helping them live longer, better lives. I hope you can agree that the information I presented above is unbiased, using the data from the research studies. However, the opinions expressed in what I would want for treatment and what I recommend for patients are my opinions, based upon the research results.
I have some cons to include/add to Benlysta (IV) at an infusion center…. it takes time to be infused. From start (vitals, questions, pre meds, iv placement, blood drawn for blood work, saline, pharmacy mixing meds) and the hour of actually being infused it is two hours on the short side. On a bad day it could be closer to four hours due to staff shortage, pharmacy back up, poor scheduling, over crowding at the center (beyond capacity due to closing for holidays, snow storms or any number of things like the Charlottesville riot).
Can you provide additional detail on the difference in criteria for a complete renal response between the two studies? Stricter, sure, but how much stricter?
Bo: Sorry for the delay in my response. I’ll include this information in the blog post as well.
First, what did they have in common? – Both did not allow any significant increase in steroids, change in doses of ACEi’s or ARBs, addition of an antimalarial if not on one already, and no addition of any other immunosuppressant drug.
The other is they both had a similar urine protein to creatinine ratio (UPCR) goal (with one slight, nonsignificant difference). Lupkynis patients had to reach a UPCR of 0.5 mg/mg or less; Benlysta patients had to be below 0.5 mg/mg.
The big difference was in the kidney function stabilization criteria. Benlysta required a eGFR of 90 ml/min or higher (or within 10% of the baseline if less than 90), while Lupkynis patients could have a eGFR of 60 ml/min or more (or within 20% of the baseline if less than 60). It is much more difficult to have an eGFR of 90 ml/min or higher when you have severe lupus nephritis. So, this was an impressive requirement.
However, this is balanced by Lupkynis using the CRR as its primary endpoint, while Benlysta used it as a secondary endpoint. Having it as the primary endpoint is wonderful as that is truly our goal. We don’t just want a “renal response,” with a treatment, we want remission (CRR or close to a CRR).
Thanks for this important question
Hello, 2 year data is now available for Lupkynis (See EULAR readout)… It was extremely well tolerated over the duration and had additional efficacy benefits. 3yr readout will be available some time next year, but for now Lupkynis is demonstrated to be tolerated well for the same duration as Benlysta.
Sam: Yes, I heard the same. Thus far, all we could say is that it is safe and effective for 52 weeks (the number of weeks in the phase 3 clinical trial). However, we usually use lupus nephritis therapies much longer than that. I cannot wait for the data to be published so I can review it.
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I would be very interested in your opinion as to whether or not you recommend adding Benlysta or Lupkynis for your patients who have a history of nephritis and are on mycophenolate, plaquenil, and an ACE or ARB but are currently stable or “in remission”.
Thank you
Ann: Once we find a combo that has someone in remission, we like to stay there. Many of us now recommend after 3 years of lupus nephritis remission… getting another kidney biopsy. If no inflammation… then see if we can slowly taper off the mycophenolate. REASON: Some patients look like they are in remission, but really are not. If mycophenolate is tapered without knowing this, they are the ones who are at high risk of flaring… then you are looking at more steroids and probably increased kidney damage. This comes form the work of Dr. Brad Rovin at OSU. Have a Merry Christmas! … Donald Thomas, MD
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